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UPDATE: Antiretroviral Therapy

Updated January 2014

What’s New — January 2014 Update
Section VI. A: Virologic and Immunologic Monitoring
January 2013 Update
Section III: When to Initiate ART in Patients with Chronic Infection


I. INTRODUCTION

Antiretroviral therapy (ART) refers to the use of pharmacologic agents that have specific inhibitory effects on HIV replication. The use of less than three active agents is not recommended for initiating treatment. These agents belong to six distinct classes of drugs: the nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs, NtRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs), the protease inhibitors (PIs), the fusion inhibitors (FIs), the CCR5 co-receptor antagonists, and the integrase strand transfer inhibitors (INSTIs). The commercially available antiretroviral drugs that are approved by the Food and Drug Administration (FDA) for the treatment of HIV/AIDS are listed in Appendix A.

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II. GOALS, BENEFITS, AND RISKS OF ART

Updated March 2006; reviewed 2013

RECOMMENDATIONS:
Clinicians should prescribe an ART regimen that is best able to delay disease progression, prolong survival, and maintain quality of life through maximal viral suppression (see Table 1). (I)

The clinician should involve the patient in the decision-making process when determining whether to implement ART. The clinician should review the benefits and risks of treatment for each individual patient. (III)

Table 1: Goals of Antiretroviral Therapy
  • Maximal and durable suppression of viral replication (measured by viral load assays)
  • Restoration and/or preservation of immune function
  • Reduced HIV-related morbidity and mortality
  • Improved quality of life
  • Limitation of the likelihood of viral resistance to preserve future treatment option


In typical clinical practice, durable suppression of viral replication to undetectable levels may be achieved in approximately 80% of cases. The maximal suppression of viral replication is generally associated with gradual increases in the CD4 count and clinical stabilization or improvement of HIV-associated symptoms. When maximal suppression is not attainable due to the inability to construct an effective regimen for the patient, partial viral suppression (≥0.5 log reduction, or 3-fold, from baseline viral load value) and stable CD4 counts are reasonable alternative goals. However, incomplete suppression of viral replication may be associated with continued immunologic and clinical deterioration and the evolution of additional resistance mutations. Patients who are unable to adhere strictly to complex medication regimens are those most likely to develop HIV-drug resistance and to face limited future ART options (see Section IV: The Importance of Patient Adherence). The clinician needs to review the benefits and risks of treatment for each individual patient (see Table 2).

Table 2: Benefits and Risks of Antiretroviral Therapy
The benefits of ART include:

  • The preservation and/or restoration of immune function
  • Improvement of overall health and the prolongation of life
  • The suppression of viral replication
  • The possible decrease in risk of viral transmission to others (including fetal transmission)

The risks of ART include:

  • Adverse effects of the medications on quality of life
  • Known, and as yet unknown, long-term drug toxicities, including potential fetal toxicity
  • The development of HIV drug resistance to drugs currently available and possibly to those not yet available, which may limit future treatment options

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III. WHEN TO INITIATE ART IN PATIENTS WITH CHRONIC INFECTION

Posted January 2013

Preface

Public health guidance currently recommends that all patients living with HIV be treated with antiretroviral therapy (ART) to reduce transmission of HIV in a strategy commonly known as “treatment as prevention.” This Committee strongly supports the idea of treatment as prevention.

This clinical practice guideline governs how physicians interact with and treat patients to ensure that health is maximized for each individual patient. In keeping with recent evidence supporting earlier initiation of ART, New York State now recommends that all patients with established HIV infection, regardless of CD4 count, be evaluated for initiation of ART. This recommendation is based on increasing evidence that patients with established HIV infection benefit from ART at all stages of disease and on recent data that demonstrate a dramatic reduction of HIV transmission risk from ART-treated patients.

Table 3: Recommendations for Initiating ART
1. All patients with chronic HIV infection should be evaluated for initiation of ART, regardless of CD4 count. (AII)

2. Certain conditions increase the urgency for initiation of ART. Clinicians should strongly recommend initiation of ART in patients who meet any one of the following criteriaa:

  • AIDS-defining condition (AI)
  • pregnancyb (AI)
  • two successive measurements of CD4 counts <500 cells/mm3 (AII)
  • symptomatic from HIV (AI), regardless of CD4 count, including any of the following:
    • HIV-associated neurocognitive disorder (HAND)c (AII)
    • Severe thrombocytopenia (AII)
    • HIV-associated nephropathy (AII)
    • HIV-related malignancies (AII)
  • chronic hepatitis B or C infectiond,e (AII)
  • age 50 or older (AII)
  • rapidly declining CD4 counts (>100 cells/mm3 per year) (AIII)

3. Patients with seronegative partners should be counseled about the reduction of HIV transmission risk when effective ART is initiated; ART is strongly recommended in these patients. (AI)

a See Appendix C for evidence and ratings.
b For recommendations on initiating ART in HIV-infected pregnant women, refer to Use of Antiretroviral Therapy in HIV-Infected Pregnant Women.
c HAND is currently used to encompass a hierarchy of progressive patterns of central nervous system involvement ranging from asymptomatic neurocognitive impairment (ANI), to minor neurocognitive disorder (MND), to the more severe HIV-associated dementia (HAD) (see Cognitive Disorders and HIV/AIDS).
d Initial ART regimens for patients with chronic hepatitis B must include NRTIs that are active against hepatitis B (see Hepatitis B Virus guidelines).
e In co-infected patients with HCV genotype 1 and CD4 counts >500 cells/mm3, some clinicians would defer ART until HCV treatment is concluded due to significant interactions between some antiretroviral agents and NS3/4A protease inhibitors used as part of hepatitis C therapy (see Hepatitis C Virus guidelines).


RECOMMENDATIONS:
Evaluation and preparation for ART initiation includes each of the following essential components:

Clinicians should refer patients for supportive services as necessary to address modifiable barriers to adherence. An ongoing plan for coordination of care should be established.

Clinicians should involve patients in the decision-making process regarding initiation of ART. The patient should make the final decision of whether and when to initiate ART.

When the decision to initiate treatment is made, ART should be prescribed and monitored by, or in consultation with, clinicians who have experience in managing ART.

Increasingly strong cohort data suggest that untreated HIV infection may lead to increased morbidity and mortality from non-HIV-related conditions, even at high CD4 counts. Together with the dramatic reduction of transmission risk with effective treatment, these data support the initiation of ART regardless of CD4 count in adequately prepared patients. Randomized studies are still lacking to help define the treatment benefit in asymptomatic patients with CD4 counts >500 cells/mm3, although one protocol is in progress (the START trial is currently enrolling and will evaluate initiating treatment at CD4 counts >500 cells/mm3 compared with initiating at CD4 counts <350 cells/mm3). Patients in care who are documented long-term nonprogressors or elite controllers are another group for whom data are lacking and warrant special consideration (see Section B: Deferring ART). Insufficient data exist to categorically recommend for or against starting all patients with acute HIV infection on immediate therapy (for more discussion see Diagnosis and Management of Acute Infection). Patients with chronic infection and higher CD4 counts are at low risk for short-term adverse outcomes, allowing time for proper assessment, education, and engagement of the patient in the decision to treat.

Data from NA-ACCORD, a large observational cohort study, showed that both morbidity and mortality were improved by initiation of ART in patients with CD4 counts in the high or even normal range.1 A significantly decreased risk of death was observed in patients who initiated therapy at CD4 counts >500 cells/mm3 compared to those who deferred to <500 cells/mm3, as well as in the cohort who initiated ART in the 350-500 cells/mm3 range compared to those deferring to <350 cells/mm3.1 Although other cohort studies demonstrated only a minimal survival advantage2 or no survival advantage among those starting ART at the highest CD4 counts, they did confirm the benefits of initiating ART at levels <500 cells/mm3.3-5 Another showed an approximately 33% reduction in the risk of death from end-stage liver disease, non-AIDS infections, and non-AIDS-defining cancers with each 100 cells/mm3 increase in CD4 count.6 The only randomized study of early versus deferred therapy in patients with CD4 counts in the 350-550 cells/mm3 range showed no mortality benefit but a higher incidence of drug-related adverse effects7; however, this study has significant limitations, most notably a relatively brief follow-up period.

Accumulating evidence suggests that patients who initiate ART earlier or spend less cumulative time with detectable plasma viremia are less likely to suffer certain complications, such as cardiovascular disease,6,8-11 neurocognitive dysfunction,12-15 and some non-HIV-related malignancies.16-19 Cohort data also demonstrate that although older patients are likely to achieve virologic suppression, they are less likely to achieve an immunologic response, as measured by an increase of CD4 count by 100 cells/mm3, and that patients >55 years old may be at higher clinical risk even after starting therapy.20 The poor immunologic recovery seen in older patients is associated with higher morbidity and mortality, particularly cardiovascular events.21 In one study, men >50 years of age who initiated ART with CD4 counts in the 351-500 cells/mm3 range were able to achieve similar immunologic responses as younger men who initiated at lower CD4 counts.22

In addition, a recent study showed a 96% reduction in transmission between serodiscordant heterosexual couples when the positive partner was receiving ART,7 adding to the body of evidence that lower viral load reduces transmission risk. ART is now part of the established strategy aimed at reducing HIV transmission and is an essential component of prevention interventions along with risk-reduction counseling, safer-sex practices, and avoidance of needle-sharing (see Prevention With Positives: Integrating HIV Prevention into HIV Primary Care).

While newer data focus on those with higher CD4 counts, it should be recognized that this group is only a minority of those with known HIV infection. Most newly diagnosed and previously diagnosed patients with HIV infection have CD4 counts <500 cells/mm3, other signs of symptomatic HIV infection or AIDS, or other indications for initiation of ART (e.g., concurrent hepatitis B or hepatitis C, age over 50), and would therefore already have been strongly encouraged to initiate ART promptly according to the 2010 New York State recommendations. In New York City, 70% of newly diagnosed patients have CD4 counts <500 cells/mm3. NA-ACCORD data23 showed that the median CD4 count at presentation in 2007 was 317 cells/mm3, and a 2010 report from the US Centers for Disease Control and Prevention (CDC)24 documented that only 7% of newly diagnosed patients have a CD4 count over 500 cells/mm3. The CDC also reported that in 2008, 36% of people newly diagnosed with HIV progress to AIDS within 1 year.25 Ongoing efforts to offer universal HIV testing to all 13- to 64-year-old patients may begin to identify patients earlier in their disease.

Key Point:
To be successful over time, initiation of ART is a process that involves both the selection of the most appropriate regimen for the individual and its acceptance by the patient with education and adherence counseling. All are critical in achieving the goal of durable and complete viral suppression.

The CEI Line provides primary care providers in New York State the opportunity to consult with clinicians who have experience managing ART. The CEI Line can be reached at 1-866-637-2342 or 1-585-273-2793.

The AIDS Institute maintains a voluntary HIV Provider Directory to assist with identification of experienced providers in New York State. Experienced providers can also be identified through the American Academy of HIV Medicine (AAHIVM) and the HIV Medicine Association (HIVMA).


See Appendix B for a comparison of the recommendations from the New York State Department of Health AIDS Institute, the Department of Health and Human Services, and the International AIDS Society – USA Panel.

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A. Counseling and Education Before Initiating ART

RECOMMENDATIONS:
Counseling and education should include the following:

  • Basic education about HIV, CD4 cells, viral load, and resistance
  • Available treatment options and potential risks and benefits of therapy (see Table 4)
  • The need for strict adherence to avoid the development of viral drug resistance (see Section IV: The Importance of Patient Adherence)
  • Use of safer-sex practices and avoidance of needle-sharing activity, regardless of viral load, to prevent HIV transmission or superinfection

Clinicians should involve the patient in the decision-making process regarding initiation of ART.

Discussion of ART should occur at the start of care for all HIV-infected patients, regardless of CD4 count. The clinician and patient should discuss the risks and benefits of early ART (see Table 4) and individual factors that may affect the decision to initiate, such as patient readiness or reluctance and adherence barriers. Clinicians should involve the patient in the decision-making process regarding initiation of ART.26 When clinicians and patients engage in shared decision-making, patients are more likely to choose to initiate ART and to achieve an undetectable viral load.27 Misconceptions about treatment initiation should be addressed, including the implication that starting ART represents advanced HIV illness. Initiating ART before symptoms occur allows patients to stay healthier and live longer.

  • Patients who do not have health insurance may qualify for Medicaid or the NYSDOH HIV Uninsured Care Program which provides access to free health care (HIV Drugs, Primary Care, Home Care, and the ADAP Plus Insurance Continuation Program, or APIC) for residents who are HIV-infected but uninsured or underinsured. The program is open Monday – Friday, 8:00AM – 5:00PM and can be reached at: In State – 1-800-542-2437; Out of State – 1-518-459-1641; TDD – 1-518-459-0121.
  • If eligible, patients may also consider treatment options through enrollment in clinical trials. A resource that may help with this process is the AIDS Clinical Trials Information Service (phone: 1-800-TRIALS-A; website: http://www.actis.org).


Table 4 outlines the risks and benefits of early ART to discuss with patients when making the decision of whether and when to initiate ART.

Table 4: Benefits and Risks of Early ART in Asymptomatic HIV-Infected Patients
(early therapy = initiation at CD4 counts >500 cells/mm3)
Benefits of early therapy

  • Earlier treatment may reduce both HIV-related and non-HIV-related morbidity and mortality1,6,9,17,28-31
  • Delay or prevention of immune system compromise32
  • Possible lower risk of antiretroviral resistance33
  • Decreased risk of sexual transmission of HIV*7,34-36

Disadvantages of early therapy

  • Potential drug-related reduction in quality of life in otherwise asymptomatic individuals37-39
  • Possibility of greater cumulative side effects from ART40
  • Possibility for earlier development of drug resistance and limitation in future41 antiretroviral options if adherence and viral suppression are suboptimal
  • Possibility for earlier onset of treatment fatigue
  • Higher prescription drug costs for the individual
* The risk of viral transmission still exists even when the plasma viral load is undetectable; ART is not a substitute for primary HIV prevention measures (e.g., avoiding sharing needles, practicing safer sex).42

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B. Deferring ART

RECOMMENDATION:
Except in cases when initiation of treatment is urgent (see Section C: Initiating ART Following Acute Opportunistic Infections), clinicians should educate and prepare patients before initiating ART in those with potential barriers to adherence, including low health literacy; active alcohol or drug use; lack of insurance, transportation, or housing; depression; mistrust of medical providers; or a poor social support system.

In patients with advanced HIV (or AIDS), ART should be initiated even if barriers to adherence are present. In these cases, referrals to specialized adherence programs should be made for intensified adherence support (see Appendix D: New York State Adherence Services Contact List).

Decisions to initiate ART in long-term nonprogressors and elite controllers should be individualized. (AIII)

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Potential Barriers to Adherence

Although the current first-line regimens used for ART are much easier to tolerate with fewer side effects than earlier combinations, they are not free of side effects. Their use requires a lifelong commitment from the patient. Patients who prefer not to take medication, or who do not understand the significance of skipping doses are at high risk for poor adherence and subsequent viral resistance. Except when initiation of treatment is clinically urgent, more than one visit before initiating ART is advisable to ensure adequate understanding of the importance of adherence and to address potential barriers or impediments to therapy. These may include but are not limited to low health literacy; active alcohol or drug use; lack of insurance, transportation, or housing; depression; mistrust of medical providers; or a poor social support system. These barriers should not necessarily preclude initiation of ART; some may not be completely modifiable before starting therapy and will require ongoing attention and use of supportive services throughout the course of therapy.

Patients who are at high risk for poor adherence may benefit if initiation of ART is temporarily deferred while further patient education efforts are undertaken (see Section IV: The Importance of Patient Adherence). In these patients, the risk of viral resistance and eventual treatment failure may outweigh any clinical benefit from earlier treatment before strict adherence can be expected.41 These patients should remain under particularly close observation for clinical and laboratory signs of disease progression.43 ART should be initiated as soon as the patient seems prepared to adhere to a treatment regimen. In patients with advanced AIDS, it is appropriate to initiate ART even if some barriers to adherence are present. In these cases, referrals to specialized adherence programs should be made for intensified adherence support (see Appendix D: New York State Adherence Services Contact List).

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Long-Term Nonprogressors and Elite Controllers

RECOMMENDATION:
Clinicians should consult with a provider experienced in the management of ART when considering whether to initiate ART in long-term nonprogressors and elite controllers.

Long-term nonprogressors demonstrate a lack of disease progression, marked by no symptoms and low viral loads in the absence of therapy during long-term follow-up. Most published studies of long-term nonprogressors include 7-10 years of follow-up.

Elite controllers suppress HIV to low but detectable levels (<50-75 copies/mL) for many years.

See Ref. 44 for further definition of these groups and their characteristics.


The role of early ART initiation in long-term nonprogressors or elite controllers is unclear. At this time, there are not enough data to recommend for or against initiation of ART in long-term nonprogressors and elite controllers. Close monitoring of CD4 count and viral load level may be an acceptable approach. Declines in CD4 count should prompt consideration of initiation of ART. Elite controllers have demonstrated CD4 cell increases after initiation of ART.45 The clinician and patient should discuss the risks and benefits of early ART as well as individual factors that may affect the decision to initiate, such as patient readiness and reluctance, adherence barriers, CD4 cell count and viral load, comorbidities, age, and partner serodiscordance. If treatment is delayed, clinicians should counsel patients about the risk of HIV transmission to partners.

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C. Initiating ART Following Acute Opportunistic Infections

RECOMMENDATIONS:
Clinicians should recommend that patients beginning treatment for acute opportunistic infections (OIs) initiate ART within 2 weeks (see next recommendation for exceptions). (AI)

Clinicians should not immediately initiate ART in patients with tuberculous meningitis or cryptococcal meningitis. Consultation with a clinician with experience in management of ART in the setting of acute OIs is recommended.

For all other manifestations of tuberculosis (TB), clinicians should initiate ART in HIV-infected patients as follows:

  • For patients with CD4 counts ≥50 cells/mm3: as soon as they are tolerating anti-TB therapy and no later than 8-12 weeks after initiating anti-TB therapy (AI)
  • For patients with CD4 counts <50 cells/mm3: within 2 weeks of initiating anti-TB therapy (AI)

In a randomized study, patients who initiated ART at a median of 12 days from start of OI therapy had better outcomes, as measured by disease progression and death, without an increase in adverse events, compared to those who initiated ART at a median of 45 days from presentation.46 Although this study excluded patients with active TB, three randomized controlled trials in patients newly diagnosed with HIV and pulmonary TB have demonstrated a significant mortality benefit when ART was initiated during the first 2 months of starting anti-TB therapy and a further benefit when those who were severely immunocompromised initiated therapy in the first 2 weeks.47-49 Although antiretroviral agents and anti-TB medications can have overlapping toxicities, ART should be initiated within the first 8 to 12 weeks of starting anti-TB therapy. Patients with CD4 counts <50 cells/mm3 should receive ART within the first 2 weeks of initiating anti-TB therapy.

Tuberculous meningitis and cryptococcal meningitis are exceptions; there are data showing that early initiation of ART increases mortality in this setting.50,51 Close attention should be paid to possible drug-drug interactions between OI therapy and ART. In some cases, determining the optimal timing for initiating ART in patients with OIs can be complex and may require consultation with a clinician with experience in management of ART in this context.

After initiating ART, clinicians need to be alert to the possibility of immune reconstitution syndromes as CD4 cell counts are restored (see Immune Reconstitution Inflammatory Syndrome).

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IV. THE IMPORTANCE OF PATIENT ADHERENCE

Updated July 2004, currently under revision

RECOMMENDATIONS:
A team approach to achieving adherence should be used. Nurses, pharmacists, peer counselors, caseworkers, and others who work in outreach, evaluation, and support of adherence should be involved. (III)

The clinician should assess treatment readiness prior to initiation of treatment, adherence readiness for subsequent regimens, and adherence at every clinical visit. (III)

Interventions should be intensified in times of decreased adherence.

Information about patients’ beliefs and attitudes should be communicated with all members of the healthcare team so that each provider can consistently address treatment adherence issues within the context of the overall treatment plan. (II)

If the patient is not fully committed to adhering to therapy, treatment should be delayed, and the clinician should continue to work on abating the patient’s concerns. Appropriate referrals should be provided for support groups, mental health, and drug treatment. (III)

Potential barriers to adherence include:

  • Communication difficulties that arise when the patient’s attitude about disease and therapy is different from that of the provider’s. Without open and nonjudgmental communication from the healthcare team, patients may not trust or may misunderstand the prescribed regimen.
  • Language or literacy barriers.
  • Unstable living situations (including limited or absent social support).
  • Discomfort with disclosure of HIV status, which may become known when medications are taken.
  • Inability to set long-term goals.
  • Inadequate knowledge about disease and effectiveness of medications or healthy living, including a patient’s lack of belief in his/her ability to take medications regularly.
  • Difficulty accessing adequate health care.
  • Housing, food, lack of childcare, or other immediate life needs, which are viewed as more pressing than taking the medications regularly.

Strict adherence to ART is essential for maintaining treatment benefit and preventing the development of HIV resistance. Study results are clear on the importance of a high level of adherence for good virologic control. Adherence to >95% of PI doses has been correlated with sustained viral suppression in several studies. Good adherence frequently wanes over time, and patients may need significant support the longer the duration of therapy.

Evidence from several studies suggests that patients who are confident about the efficacy of their treatment are more likely to adhere to their medication regimen and their healthcare visits. Confidence contains two significant components: understanding and belief.

Helping the patient understand the importance of treatment may be accomplished through a wide range of patient education activities, and especially through participation in peer education programs (see Section C: Educating the Patient About Adherence).

Encouraging belief in the efficacy of the regimen may be more challenging for the clinician and entails asking the patient what they believe about the causes of their disease and how it may be treated. Similarly, their opinions about what has contributed to the success or failure of their adherence to treatment should be sought (see Section D: Patients’ Beliefs and Attitudes).

For further guidance on assessing and promoting adherence, refer to Promoting Adherence to HIV Antiretroviral Therapy: Best Practices from New York State.

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A. The Patient-Healthcare Team Relationship: Involving the Patient

The quality of the relationship between the patient and the clinician greatly influences adherence. A trusting, open, and nonjudgmental relationship will improve the likelihood of strict adherence.

Strategies:

  • The healthcare team should promote active patient involvement in decision-making about initiating and managing ART regimens. The patient’s opinion of successes and challenges in maintaining adherence should be sought at routine visits.
  • A treatment plan should be negotiated, and active patient participation in the development of the treatment plan should be encouraged. Patient concerns and questions regarding the regimen should be elicited, and an individualized schedule should be made based on the patient’s lifestyle. A plan should be made for changes in routine (e.g., weekends, holidays, travel).
  • Patient trust should be established and a strong working relationship should be developed.
  • Questions regarding adherence should be open-ended and should be asked in a nonjudgmental manner with an understanding of the difficulty patients will have in admitting to adherence problems.
  • Members of the healthcare team should be open and accessible. Ways for patients to reach medical team members 24 hours/day when questions or concerns arise should be made available.
  • Intensive support should be provided to patients beginning medication regimens. Team members should meet with the patients frequently (or speak by phone) to provide encouragement, assess tolerability, assess adherence, and answer questions.

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B. Barriers to and Predictors of Adherence

The factors involved in adherence are complex. Age, race, sex, education level, and socio-economic status are not independent predictors of adherence. Although active substance use may affect adherence, a past history of substance use does not correlate with poor adherence (see Section E: Substance Use and Adherence). There is also a poor correlation between medical clinicians’ prediction of adherence and actual levels of adherence.

Strategies:

  • The healthcare team should be familiar with predictors of poor adherence and should address these issues in a caring and nonjudgmental manner.
  • Possible psychosocial factors and barriers to adherence, such as inadequate housing, active substance use, depression, or other mental health issues, should be addressed. Identifying patient-specific barriers to adherence will help determine which interventions are most appropriate.

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C. Educating the Patient About Adherence

Strategies:

  • To foster understanding of the importance of adherence, the healthcare team should present information in language that is easily understood by the patient, consistent with the patient’s level of education, and free of medical jargon.
  • Sufficient time should be taken to fully educate the patient about the goals of treatment and the need for adherence, both before beginning treatment and frequently during therapy.
  • Literature should be provided and, if available, peer counselors should be enlisted to reinforce education efforts. Attention to language and use of culturally sensitive education materials are essential.
  • Adherence tools should be provided. Written schedules, pictures of medications, pillboxes, alarms, and pagers may help patients understand and remember medication schedules. The need for greater adherence support (e.g., support groups, home visits, day treatment programs) should be assessed.
  • Reviewing the viral load response to ART in graphic form with the patient assists in reinforcing the efficacy of therapy.
  • The clinician should advise the patient regarding events that may interrupt treatment and interfere with patient access to medications (e.g., travel, pharmacy delays in restocking medications, manufacturer shortages, loss of medication, or incarceration). The patient should be counseled to notify his/her clinician for discussion of alternative options as soon as the patient foresees the occurrence of an interruption. Patients should be cautioned that if one (or more) drug in their ART regimen is not available for more than several days, all antiretroviral agents should be stopped until the entire ART regimen is again available to avoid the emergence of resistance while using a less suppressive regimen. This issue is of greatest concern when the antiretroviral agent in question is one to which a single point mutation confers a great degree of resistance (e.g., lamivudine and NNRTIs), which appears rapidly in the absence of a fully suppressive regimen.

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D. Patients’ Beliefs and Attitudes

When patients indicate that they do not believe that their medications will treat their infection, they are less likely to adhere to their regimens and need further preparation and guidance to successfully adhere to treatment.

Strategies:

  • If patients express beliefs that their medications work but also that diet, exercise, or prayer are particularly important in helping them fight their illness, then all of these modalities should be supported and integrated into the overall treatment plan, provided that they pose no harm to the patient.
  • Information about patients’ beliefs and attitudes should be communicated with all members of the healthcare team so that each provider can consistently address treatment issues within the context of the overall treatment plan.

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E. Substance Use and Adherence

Strategies:

  • Clinicians should help active substance users plan to decrease or stabilize their use in preparation for initiating ART.
  • The healthcare team should discuss with their patients how patterns of substance use may affect adherence and should work with other providers who possess experience with treating this group to encourage reduction in substance use. The link between reducing drug use and engaging in successful HIV treatment should be encouraged.

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F. How the Regimen Affects Adherence

Studies demonstrate the difficulty of maintaining strict adherence to complex ART regimens and show significant levels of poor adherence in the “real world” of HIV care. The largest obstacle in achieving strict adherence is the dosing schedule. There is a significant difference in adherence between regimens that are truly BID compared with TID or QID. Improved pharmacokinetics has produced ART regimens that simplify dosing; however, it is still important that clinicians devote sufficient time at each patient visit to assess the degree of adherence to prescribed therapies. Concern about potential side effects prompts some patients to diminish adherence, often without confiding in the healthcare team.

In November 2011, New York State adopted customized patient medication packaging, sometimes referred to as “comingling” of medications, which is a process whereby several different drugs are packaged together to be taken at the same time.52 Customized patient medication packaging has been shown to increase adherence to complex therapeutic regimens such as those required for patients with HIV/AIDS.52,/sup> In addition, customized patient medication packaging, simplifies dosing and may reduce reliance on daily “pill-minders” that patients often package themselves, which has a potential for error that would be avoided with use of customized patient packaging.

Strategies:

  • The entire medication list should be reviewed at every clinical visit to limit the concomitant use of unnecessary, ineffective, or contraindicated medications.
  • Patients should be educated about the risks and benefits of ART and preservation of future treatment options to allow them to develop realistic long-term expectations.
  • The side effects and toxicities associated with ART should be anticipated and explained. The patient should be informed that many side effects abate after the first weeks of treatment. Efforts should be made to plan for and to manage side effects at times when a new drug or regimen is being started.
  • The regimen should be simplified to the furthest extent possible. Attention should be paid to the pill count, frequency of dosing, meal requirements, potential side effects, and drug interactions when planning a regimen.
  • The regimen should be individualized. Each regimen should be planned on the basis of a given patient’s unique circumstances (e.g., difficulty swallowing pills; complex work schedule; irregular meals; need for privacy; preexisting symptoms, such as diarrhea, neuropathy, depression).

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V. SELECTING AN INITIAL ANTIRETROVIRAL REGIMEN

Updated September 2011

RECOMMENDATIONS:
Clinicians should obtain genotypic resistance testing at baseline and should consider repeating the test prior to initiating treatment in ART-naïve patients. (AIII)

Clinicians should involve their patients when deciding which antiretroviral regimen is most likely to result in patient adherence. (AIII)

For ART-naïve patients, the initial preferred antiretroviral regimen should include a combination of two nucleoside/nucleotide RTIs plus either a ritonavir-boosted PI, an NNRTI, or an INSTI. (AI)

For women considering pregnancy or not using effective contraception, efavirenz or combination pills containing efavirenz should be avoided. If there are no alternatives for efavirenz in women of childbearing potential, clinicians should strongly advise the use of effective contraception and should obtain a pregnancy test before initiating treatment. (AI)

Selection of antiretroviral agents should be individualized to address each patient’s concurrent morbidities and medications, ability to adhere to complex regimens, and personal tolerance for adverse medication effects. (AIII)

Clinicians should follow up with patients by phone or visit within 2 weeks of initiating therapy to assess tolerance and adherence to the antiretroviral regimen. Adherence should be reinforced at regular intervals during the course of therapy. (AIII)

Key Point:
The goal of the initial antiretroviral regimen is to achieve durable and maximal viral suppression (i.e., undetectable plasma HIV RNA) with minimal adherence challenges and long-term tolerability.


ART should be designed to achieve the maximal viral suppression. Such suppression generally requires three or more active agents to which the virus is susceptible.

Preferred, alternative, and contraindicated combinations for initial treatment of HIV infection are listed in Tables 5A-C. Clinicians should consult with a provider who has experience with ART when a patient’s resistance profile indicates the need for a regimen not listed in Tables 5-A or -B.

These tables should be used in conjunction with Appendix A, which includes specific dosing recommendations, including dose adjustments due to renal or hepatic impairment, adverse events, drug-drug interactions, and FDA pregnancy categories for each antiretroviral agent. For detailed information regarding ART in pregnant women, see Management of HIV-Infected Pregnant Women Including Prevention of Perinatal HIV Transmission.

Preferred regimens are those with optimal efficacy, favorable tolerability and toxicity profile, and simplified dosing.

Table 5-A: Preferred Antiretroviral Regimens for Initial Treatment of HIV-1 Infection in Non-Pregnant Adults and Adolescents*
              Dual N(t)RTI

  • tenofovir plus
    emtricitabine
    (co-formulated
    as Truvada†)
  • tenofovir plus
    lamivudine




+
              NNRTI             or

  • efavirenza,b
              PI                           or

  • atazanavir plus
    ritonavir
  • darunavir plus
    ritonavir (once-
    daily dosing)
  • fosamprenavir
    plus ritonavir
    (once-daily
    dosing)‡
             INSTI

  • raltegravirc
* Options are listed alphabetically. For recommendations for ART use during pregnancy, see Management of HIV-Infected Pregnant Women Including Prevention of Perinatal HIV Transmission.
† Fixed-dose combinations should not be used in patients who need dose adjustment due to renal failure. When combination pills are used, patients should be educated about which drugs are combined in that pill.
‡ See Appendix A for dose adjustments with this antiretroviral combination.
a When efavirenz is used with tenofovir + emtricitabine, Atripla, a fixed-dose, three-drug combination pill, can be prescribed.
b For women considering pregnancy or likely to become pregnant, efavirenz, or combination pills containing efavirenz, should be avoided. If there are no alternatives for efavirenz in women of childbearing age, clinicians should strongly advise the use of effective contraception and should obtain a pregnancy test before initiation.
c Disadvantage to this regimen is twice-daily dosing; however, the benefit of increased tolerability may outweigh the limitation of twice-daily dosing. For more information regarding raltegravir, see New Antiretroviral Drugs


Alternative antiretroviral regimens are effective and tolerable but have potential disadvantages compared with the preferred regimens in Table 5-A. In some cases, an alternative regimen may be the preferred regimen based on the individual characteristics of the patient. Additional alternative agents that are not listed in Table 5-B may be effective but are unlikely to be necessary as components of initial regimens.

Table 5-B: Alternative Antiretroviral Agents for Initial Treatment of HIV-1 Infection in Non-Pregnant Treatment-Naïve Adults and Adolescents*
N(t)RTI backbone

  • Abacavira + emtricitabine
  • Abacavira/lamivudineb
    (co-formulated as Epzicom†)
  • Tenofovir + lamivudine‡
  • Zidovudine + emtricitabine
  • Zidovudine/lamivudine
    (co-formulated as Combivir†)
NNRTI                          or

  • Rilpivirinec
PI                                       or

  • Darunavir + ritonavir
    (twice-daily dosing)
  • Fosamprenavir + ritonavir
    (twice-daily dosing)‡
  • Lopinavir/ritonavir†
    (co-formulated as Kaletra)
  • Unboosted atazanavird
  • Unboosted fosamprenavir
CCR5 Inhibitor

  • Maraviroce
*Options are listed alphabetically.
† Fixed-dose combinations should not be used in patients who need dose adjustment due to renal failure. When combination pills are used, patients should be educated about which drugs are combined in that pill.
‡See Appendix A for dose adjustments with this antiretroviral combination.

a To avoid hypersensitivity reaction, HLA-B*5701 testing should be performed before initiating abacavir-based therapy. Abacavir should be promptly discontinued when a hypersensitivity reaction is suspected and should never be re-started. Re-challenge may result in an anaphylactic reaction with associated hypotension or death. Use of abacavir is not recommended in patients with a Child-Pugh Score of 7-12. Risk for myocardial infarction may be increased in patients receiving abacavir.
b Preliminary evidence suggests that abacavir/lamivudine-containing combinations may not be as effective in reducing viral load in patients with viral loads >100,000 copies/mL. However, at this time, changes in practice are not recommended until these data are confirmed.
c When rilpivirine is used with tenofovir plus emtricitabine, Complera, a fixed-dose, three-drug combination pill, can be prescribed when clinically indicated. Note: When prescribing Complera, clinicians should be aware that a vitamin preparation has a similar trade name (i.e., Complere); confirmation that the correct prescription is dispensed to patients should be ensured. For more information regarding rilpivirine, see New Antiretroviral Drugs.
d This option is acceptable but may be less favored than the other alternative choices. If tenofovir is used as part of the NRTI backbone, atazanavir + ritonavir must be used.
e For more information regarding maraviroc, see New Antiretroviral Drugs.



Table 5-C: Regimens Not Recommended or Contraindicated for Initial Treatment of HIV Infection
Therapies and Components Not Recommended for Initial Treatment Rationale
  • Abacavir + lamivudine + zidovudine (co-formulated as Trizivir)
  • All triple and quadruple NRTI therapies
Higher rates of virologic failure with triple NRTI therapies
  • Didanosine + stavudine
There is high incidence of toxicities (peripheral neuropathy, pancreatitis, hyperlactatemia) associated with this combination
  • Etravirine
At this time, there are insufficient data to support using this agent as initial therapy (see New Antiretroviral Drugs)
  • Indinavir
Inconvenient dosing and pill burden
  • Saquinavir (without ritonavir-boosting)
Inferior efficacy unless boosted with ritonavir
  • Stavudine
The toxicities associated with stavudine generally outweigh the benefits when used as initial therapy, particularly when used in combination with didanosine
  • Tenofovir + didanosine + NNRTI
High risk of early failure, possibly due to a lower barrier to development of resistance; it is unknown whether combining tenofovir + didanosine + a PI is more efficacious
Contraindicated Therapies and Components for Initial Treatment (Do Not Use) Rationale
Emtricitabine + lamivudine These agents are interchangeable – do not use in combination
Fosamprenavir + lopinavir/ritonavir (co-formulated as Kaletra) The use of fosamprenavir with lopinavir/ritonavir causes a bi-directional drug interaction that results in lower drug levels
Ritonavir + nelfinavir Not easily tolerated and no additional boosting effect on nelfinavir
Stavudine + zidovudine Pharmacologic antagonism between stavudine and zidovudine
Two-drug therapy Insufficient data to recommend
Monotherapy Inferior efficacy

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Ritonavir Boosting

Therapeutic doses of ritonavir are poorly tolerated when used as the only PI in a regimen. However, when used at lower and better tolerated doses in combination with selected PIs, ritonavir may enhance the bioavailability and prolong the elimination half-life of these medications, thus improving therapeutic thresholds while reducing overall pill burden. This is often referred to as “boosting.” Initial ART regimens containing fosamprenavir and atazanavir are often given with ritonavir as a booster; however, darunavir and lopinavir must be given with ritonavir to be effective (lopinavir is co-formulated with ritonavir; therefore, a separate dose is not necessary).

Because all PIs, especially ritonavir, can greatly alter the levels of non-antiretroviral medications, clinicians should evaluate potential interactions with all concurrent prescription and over-the-counter medications.

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Rationale for Class-Sparing Regimens

Rational sequencing of antiretroviral agents may help to maximize the effect of each regimen and preserve future treatment options. Regimens can be designed to “spare” a particular class or classes of antiretroviral agents to simplify dosing regimens, delay certain side effects or drug interactions, and preserve the spared medications for later use in the event of failure of the initial regimen. Sequencing strategies should be individualized to address each patient’s concurrent morbidities and medications, ability to adhere to complex regimens, and personal tolerance for adverse medication effects. A table of advantages and disadvantages of ARV components is available in the Department of Health and Human Services guidelines, see Table 6.

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VI. MONITORING OF PATIENTS RECEIVING ART

Periodic laboratory tests are necessary to evaluate the response to ART and its potential related side effects. In the setting of ART failure, viral resistance assays should be used.

A. Virologic and Immunologic Monitoring

Updated January 2014

January 2014

  • Routine quarterly monitoring of CD4 count is no longer recommended for non-pregnant patients receiving antiretroviral therapy (ART) who have consistently undetectable HIV RNA levels and CD4 counts >200 cells/mm3 (see Table 6 for recommended intervals). (AIII)
  • Regular monitoring of HIV RNA levels remains the most meaningful measure of effective ART. (AI)


RECOMMENDATIONS:
Clinicians should monitor HIV RNA levels and CD4 counts according to the recommended intervals in Table 6.

In addition to recommended intervals for assessment of HIV RNA levels (see Table 6), clinicians should continue to schedule visits in accordance with clinical necessity to address any issues that may have an impact on adherence to ART or retention in care, such as substance use, mental health, unstable housing, lack of transportation, or social support, as well as non-HIV-related medical conditions. This may necessitate more frequent follow-up between monitoring visits. (AIII)

Regular monitoring of CD4 counts in patients with consistently undetectable HIV viral loads and CD4 counts >200 cells/mm3 offers little utility in clinical practice today. Clinicians rarely use this information to guide decision-making for clinically stable, virologically suppressed patients. Measurement of HIV RNA levels to confirm appropriate response to treatment and durable viral suppression is a more meaningful measure of the effectiveness of ART.

A retrospective study of 1820 patients with 25,463 paired measurements of HIV RNA level and CD4 count followed over 13 years showed a 97.1% probability that patients with HIV RNA levels <200 copies/mL and CD4 counts >300 cells/mm3 would maintain CD4 levels >200 cells/mm3 over a 4-year period. This probability increased to 99.2% over 5 years when non-HIV causes for decline, such as interferon therapy or chemotherapy, were excluded.53

Very few studies address the appropriate frequency of viral load monitoring. Although standard practice has been to monitor viral load on a quarterly schedule, a recent retrospective study showed that when suppressed at entry, failure rates at 12 months were similar in patients scheduled for 3-, 4-, or 6-month follow-up appointments. It should be noted that far fewer were scheduled for the longer follow-up interval, with only 8% at 6 months versus 66% and 26% in the 3- and 4-month groups, respectively.54 This study also noted that the single strongest predictor of virologic failure at 12 months was a missed or cancelled appointment, highlighting the importance of retention in care. This and other similar studies55,56 have important limitations, including their retrospective nature and short follow-up periods.

Until more definitive data are available, patients who are given longer monitoring intervals for HIV RNA level should be carefully selected based on length of suppression, CD4 count, and general adherence to medical care, including visit attendance. Quarterly monitoring may remain appropriate for some patients, especially those with a history of non-adherence, mental health disorders, substance use, homelessness, poor social support system, or other major medical conditions.

Key Point:
Table 6 provides a guide for monitoring HIV RNA levels and CD4 counts. Patients with a history of non-adherence, mental health disorders, substance use, homelessness, poor social support system, or other major medical conditions may need to be monitored more closely or may require more frequent visits.


Table 6: Virologic and Immunologic Monitoring*
HIV RNA Levels
(copies/mL)
CD4 Lymphocyte Count
(cells/mm3)
Baseline Yes (AI) Yes (AI)
Following initiation of ART or change of ART regimen • Within 4 weeks of initiation of ART or change in regimen (BIII)
• At least every 8 weeks until complete suppressiona is documented (BIII)
• At 12 weeks, then every 4 months until CD4 is >200 cells/mm3 (AI) on two measurements obtained at least 4 months apart
Treatment Monitoring
• Patients on ART who achieve complete suppression • At least every 3 months for one year after complete suppression (BIII)
• May extend intervals to at least every 6 months in selected stable patients with CD4 count >200 cells/mm3 after 1 year of complete suppression54 (BIII)
• At least every 6 months for patients with CD4 <300 cells/mm3 (BIII)
• At least every 12 months for patients with CD4 >300 cells/mm3 (BIII)
• Patients on previously suppressive ART with new HIV RNAb above the upper limit of a sensitive assay Repeat viral load test within 4 weeks to differentiate low level transient viremia (“blip”) from virologic failure.c If viral load remains detectable on repeat test:
• Assess adherence (AIII)
• Assess for drug-drug interactions (AIII)
• Obtain resistance testing (AI)
• Obtain CD4 count if not done within previous 6 months (BIII)
Patients not on ART
(According to NYSDOH recommendations, all HIV-infected patients should be evaluated for initiation of ART.d)
• At least every 4 months in patients with CD4 counts <500 cells/mm3 (BIII)
• At least every 6 months in patients with CD4 counts >500 cells/mm3 (BIII)
• Continue to discuss ART initiation (AIII)
• At least every 4 months for patients with CD4 <500 cells/mm3 (BIII)
• At least every 6 months for patients with CD4 counts >500 cells/mm3 (BIII)
• Continue to discuss ART initiation (AIII)
* For HIV-infected pregnant women, CD4 count and HIV RNA level should be monitored at baseline, within 4 weeks after initiating or changing ART, and every 3 months during pregnancy (at least once in each trimester). HIV RNA level should be obtained between 33 and 36 weeks’ gestation to evaluate the need for elective cesarean delivery if HIV RNA level is elevated (>1,000 copies/mL) and to allow time to change the ART regimen, if indicated, before delivery.
a Complete suppression is generally considered below the level of quantitation of a highly sensitive assay (< 20 to < 50 copies/mL).
b Patients with repeated intermittent low level viremia < 200 copies/mL over a period of years without demonstrated failure may continue routine testing intervals.
c ART should not be changed based on a single viral load elevation. The risk of virologic rebound (breakthrough) increases when values are > 500 copies/mL.57
d See Section III: When to Initiate ART in Patients with Chronic Infection.



Key Point:
For HIV-infected pregnant women, CD4 count and HIV RNA level should be monitored at baseline, within 4 weeks after initiating or changing ART, and every 3 months during pregnancy (at least once in each trimester). HIV RNA level should be obtained between 33 and 36 weeks’ gestation to evaluate the need for elective cesarean delivery if HIV RNA level is elevated (>1,000 copies/mL) and to allow time to change the ART regimen, if indicated, before delivery.


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Plasma HIV-1 RNA Level (Viral Load)

Measurement of HIV RNA levels provides the most precise means of establishing whether a response to ART has occurred. Because absolute CD4 cell counts are calculated values that fluctuate widely, they are a less precise indicator of antiretroviral response than HIV RNA level.

For patients beginning ART, or those changing therapy as a result of virologic failure, HIV RNA measured at 4 weeks after initiation of therapy should decrease by at least 1 log (10-fold) in the presence of effective therapy58 (see Table 7). For patients who do not have background antiretroviral resistance, an undetectable viral load (<50 copies/mL) is usually achieved within 3 months. Patients with resistance or a baseline HIV viral load >100,000 copies/mL typically achieve an undetectable viral load within 6 months of effective treatment. An absent or incomplete response of viral load to ART should raise concerns about poor adherence to therapy and/or viral resistance59 (see Section IV: The Importance of Patient Adherence and Section VIII: Failure to Achieve Goals of Initial ART).

Plasma levels of viral RNA have been shown to correlate closely with clinical outcome. More than a dozen clinical trials involving thousands of patients have demonstrated this correlation at various stages of disease and with a wide variety of previous experience with ART (see Appendix E and Appendix F).

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Lymphocyte Subsets (CD4 Cell Count)

CD4 lymphocyte count is used to evaluate immunologic staging, predict the risk of clinical progression, and make decisions regarding prophylaxis of opportunistic infections (see Opportunistic Infection Prophylaxis). Historically, CD4 cell count has been used to establish a threshold for initiating ART. However, current guidelines in New York State recommend that all HIV-infected patients be evaluated for ART, regardless of CD4 cell count. For patients who may not be ready to initiate ART, CD4 cell count can be used to guide discussions between patient and provider regarding the urgency of initiating ART.

Clinicians are unlikely to use CD4 counts to guide clinical decision-making in practice for virologically suppressed patients once their CD4 count remains above 200 cells/mm3. However, for persons infected with HIV-2 or HIV-1 variants that cannot be accurately quantitated using viral load assays, CD4 count remains the most effective monitoring tool for progression of disease. See Human Immunodeficiency Virus Type-2.

Although a significant CD4 count increase often occurs among patients treated with effective ART, the absence of such an increase should not be interpreted as treatment failure if the viral load declines appropriately. ART regimens are generally not changed in patients with undetectable viral loads who experience immunologic failure, although patients should remain on appropriate prophylaxis for opportunistic infections based on CD4 count. See Opportunistic Infection Prophylaxis. Lack of correlation between viral load and CD4 cell response is particularly common among patients > 50 years old60,61 and patients with low initial CD4 cell counts (<100 cells/mm3).62-64

Table 7: Interpretation of Viral Load
HIV-1 RNA Copy Number
Copies/mm3

1,000,000
100,000
10,000
1,000
100

Log10

6.0
5.0
4.0
3.0
2.0

Reduction with Antiretroviral Therapy if Patient Has 100,000 copies/mm3
Log Change Percent Decrease Fold Reduction Resultant Copy Number
0.5 66.00 3 33,000
1.0 90.00 10 10,000
2.0 99.00 100 1,000
3.0 99.90 1000 100>

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B. HIV Resistance Assays

Updated October 2006

RECOMMENDATIONS:
Clinicians should perform resistance testing under the following circumstances:

  • At baseline, regardless of whether ART is being initiated (genotypic testing)
  • In ART-naïve patients before initiation of ART (genotypic testing) (III)
  • In patients experiencing treatment failure or incomplete viral suppression while receiving ART (genotypic and/or phenotypic testing) (I)

When resistance testing is indicated, it optimally should be performed while patients are either receiving therapy or have been off therapy for less than 1 year. (III)

Clinicians should consult with an expert to interpret the results of resistance assays because the results of resistance assays are often complex (see Clinical Education Initiative sites available for phone consultation). (I)

In vitro testing for resistance to antiretroviral agents is an essential means of rationally directing therapy in treatment-experienced patients with virologic failure. Several cohort studies have demonstrated that up to 10% of recently infected ART-naïve patients harbor drug-resistant HIV. A recently reported resistance survey completed in New York State used genotypic testing to examine the prevalence of drug resistance in treatment-naïve persons and treatment-experienced persons off therapy for ≥6 months. This study found several important findings. First, 8.8% of ART-naïve patients harbored significant drug-resistance mutations. Resistance mutations were seen in 4.8% of those infected prior to 1999 compared with 11% of those infected in 2000-2001. The second important finding was that 28.6% of patients off therapy for ≥6 months had significant drug-resistance mutations. The prevalence of drug-resistance mutations was greater in patients with more extensive antiretroviral experience. Based on this, genotypic resistance testing of all patients before the initiation of ART is recommended. However, current techniques of assessing resistance have limitations, and treatment failure has been documented in the absence of resistance. In many cases, such failure may be attributable to either poor patient adherence or inadequate drug levels. The role of resistance testing has been best established in treatment-experienced patients in whom viral resistance often correlates closely with subsequent response to ART (see Table 8). Currently available resistance assays have been tested and are considered reliable only for clade B strains of HIV-1.

Key Point:
Resistance testing more reliably indicates drugs that are not likely to be effective rather than identifying those drugs that may suppress viral replication.


Table 8: Recommendations for the Use of Drug Resistance Assays
Clinical Setting/Recommendation Rationale
Prior to initiating treatment in ART-naïve patients, including in the setting of acute HIV infection

Virologic failure during ART

Suboptimal suppression of viral load after initiation of ARTa

Determine if drug-resistant virus was acquired so that an appropriate regimen may be chosen.

Determine the role of resistance in drug failure, and maximize the number of active drugs in the new regimen.

Determine the role of resistance, and maximize the number of active drugs in the new regimen if indicated.

Not generally recommended
More than 1 year after discontinuation of drugs


Plasma viral load <500 to 1000 HIV RNA copies/mLb

Drug-resistance mutations may become minority species in the absence of selective drug pressure and may not be detectable. Current assays may not detect minority drug-resistant species.

Resistance assays cannot be reliably performed because of the low copy number of HIV RNA.

Adapted from the DHHS Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents (2006).
a In pregnant women initiating therapy, the clinician may not have as much time to monitor for suboptimal suppression.
b The cutoff will vary according to the manufacturer of the kit.


Third-party reimbursement programs provide reimbursement for three assays (either genotype or phenotype) per year (within 12 months following date of first use).

All resistance assays are limited because 1) they only detect the most prevalent viral populations (i.e., HIV strains that represent >20% of the total viral population); 2) they require that patients have a viral load of 500 to 1000 copies/mL or greater; and 3) testing yields best results when performed in patients receiving ART. Resistance testing performed in antiretroviral-experienced patients who are not receiving ART may not display all of the resistance mutations given lack of selective pressure; however, some mutations might persist for an indefinite period. Demonstration of resistance mutations known to confer decreased susceptibility by genotypic testing or evidence of reduced susceptibility by phenotypic testing should be considered accurate. The absence of resistance by either genotypic or phenotypic testing may indicate poor adherence in the setting of virologic failure; the absence of resistance should not be interpreted to mean that all viral populations in an individual patient are sensitive or lack resistance mutations.

A particularly important concept in the interpretation of drug-resistance assay results is that less prevalent (minority) resistant strains tend to decrease to below the threshold of detection, whereas sensitive (wild-type) virus emerges after a sustained period of treatment interruption. This occurrence may follow interruptions as short as 2 weeks or as long as 1 year. This may lead clinicians to incorrectly assume that drug-resistance mutations are not present. Neither genotypic nor phenotypic resistance testing will detect these less prevalent strains, which, nevertheless, may become dominant when selective pressure is again applied with the introduction of ART. Thus, interpretation of resistance becomes complicated in patients who have failed multiple antiretroviral regimens and/or who have the test(s) performed after ART has been discontinued. Because the rules for interpretation of results may change as understanding of resistance increases, clinicians should consult with an expert when interpreting complicated results. Current information on relevant mutations by antiretroviral class can be found at the International AIDS Society-USA’s website: https://www.iasusa.org/

New resistance mutations and the emerging clinical significance of these mutations frequently change. Several resources are available for more information on drug resistance and resistance testing. These include:

The two types of resistance assays are described in the following sections. Each assay has advantages and disadvantages.

Genotypic Assays

Genotypic assays detect mutations in the genes of the reverse transcriptase and protease enzymes, as well as the gp41 domain for the currently available fusion inhibitors, that confer resistance to various antiretroviral drugs. The resistance mutation profile permits a prediction about the probability of resistance. Genotypic assays are less expensive, have a shorter reporting time (4-21 days) and have been more extensively studied. Disadvantages of the genotypic assays are that they may fail to identify important mutational changes that are not yet known to be associated with resistance, may be difficult to interpret, and may fail to detect interactions among mutations (e.g., M184V and zidovudine susceptibility).

One method of genotypic testing (“virtual phenotype type”) establishes a patient’s genotype and then predicts susceptibility by comparing a patient’s viral genotype to those in a large data set of viral isolates with correlated genotypic and phenotypic data. Viruses with similar genotypes to that of the patient’s virus are identified by searching the database, which then allows for the probable phenotype of the patient’s virus to be estimated. The advantages of this type of virtual phenotype testing are that the results are available quicker and the interpretation is similar to that of a conventional phenotype assay. A disadvantage is that the actual viral phenotype may be different as a result of limitations of the database.

For more information, refer to Diagnostic, Monitoring, and Resistance Laboratory Tests for HIV.

Phenotypic Assays

Phenotypic assays directly measure susceptibility of the patient’s HIV strain to specific individual drugs compared to sensitive HIV. The advantages of the phenotypic assays are that their results are easier to interpret than those of genotypic assays, they may also measure the effect of multiple mutations, and they may identify resistance as a result of mutations that may not yet be known. Disadvantages of phenotypic assays are that they are substantially more expensive, usually have a longer reporting time (21 to 28 days), and have thresholds for susceptibility that are undefined for some antiretroviral agents.

Of note, replicative capacity (RC) measurements may appear with the phenotypic testing results; however, there are no data regarding the utility of this measurement in therapeutic decision-making.

For more information, refer to Diagnostic, Monitoring, and Resistance Laboratory Tests for HIV.

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C. Laboratory Monitoring of ART Side Effects

This section describes monitoring of the following ART side effects: bone marrow suppression, pancreatitis, lactic acidosis/hepatic steatosis, hepatotoxicity, and renal toxicity. Recommendations concerning long-term metabolic and musculoskeletal complications, including glucose metabolism, dyslipidemia, body fat changes, osteopenia, osteoporosis, and avascular necrosis, are included in Long-Term Complications of Antiretroviral Therapy. A table of common and/or severe adverse affects associated with ART is available in the Department of Health and Human Services guidelines, see Table 13.

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Bone Marrow Suppression

Updated March 2006

RECOMMENDATIONS:
Complete blood counts should be measured before initiation of ART therapy and at least every 4 months thereafter. For patients at high risk for bone marrow toxicity (e.g., those with advanced HIV infection, those with pre-treatment cytopenias, or those who are receiving zidovudine), blood counts may have to be monitored more frequently because significant cytopenias may occur. (III)

Bone marrow suppression is most often associated with zidovudine therapy. Significant drug-induced cytopenias become more common in the later stages of symptomatic HIV infection but occasionally develop abruptly in patients at earlier stages.

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Pancreatitis

Updated March 2006

RECOMMENDATIONS:
When patients receiving ART present with signs or symptoms suggestive of pancreatitis, clinicians should obtain serum amylase and lipase levels. (III)

If signs or symptoms of pancreatitis occur in patients taking antiretroviral medications, the clinician should temporarily suspend the entire ART regimen. A new ART regimen may be initiated when enzymes are normalized but should not include antiretroviral medications that are most likely linked to pancreatitis, such as didanosine or stavudine.

An elevated serum amylase level should be confirmed with a serum lipase level. (III)

Clinicians should not prescribe didanosine for patients who have a history of pancreatitis. (III)

The incidence of pancreatitis is higher in patients infected with HIV and may be associated with opportunistic infections as well as ART. Didanosine has been the agent most often associated with this complication; however, cases of pancreatitis also have been reported with other antiretroviral agents since the advent of triple combination therapy. Tenofovir increases the levels of didanosine, thereby increasing the theoretical risk of pancreatitis. Thus, when these antiretroviral medications are used in combination, the dose of didanosine should be reduced (see Appendix A).

Pancreatitis should be considered in any patient receiving ART who presents with signs or symptoms of pancreatitis (e.g., abdominal pain, persistent nausea, and vomiting), and serum amylase and lipase should be obtained in this setting. Significant hypertriglyceridemia (>500 mg/dL) is associated with an increased risk of pancreatitis, particularly in patients with other risk factors for pancreatitis (e.g., alcohol or didanosine use). Other causes linked to pancreatitis in the general population should be included in the differential diagnosis.

Hyperamylasemia of non-pancreatic (e.g., parotid) origin may occur in HIV-infected patients. Serum lipase levels should be obtained to delineate the source of the increased amylase. Asymptomatic patients with modest elevations in amylase and lipase levels (<3-fold) may be monitored closely without change in therapy.

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Lactic Acidosis/Hepatic Steatosis

Updated March 2006

RECOMMENDATIONS:
When patients develop symptoms consistent with lactic acidosis syndrome in conjunction with an elevated lactate level (>2 mmol/L) and decreased serum bicarbonate (<20 mmol/L), the clinician should temporarily discontinue the entire ART regimen while an evaluation is conducted. (II)

Routine monitoring of serum lactate levels is not indicated in asymptomatic patients. (I)

Patients who are asymptomatic and have an unexplained decrease in serum bicarbonate level (<20 mmol/L) should be promptly re-evaluated with a repeat test and a venous or arterial lactate. (II) If a venous lactate is mildly elevated (2.1 to 5.0 mmol/L), an arterial lactate should be obtained, and re-assessment for the presence of symptoms associated with lactic acidosis should be performed. (I) If the lactate is persistently elevated, the arterial pH is abnormal, or the patient has become symptomatic, ART should be discontinued. (III)

The syndrome of lactic acidosis/hepatic steatosis is rare but associated with a high mortality rate and has been most often associated with the use of NRTIs. Groups at higher risk for this complication include African Americans, obese patients, female patients, and patients with chronic hepatitis C virus (HCV). The syndrome is marked by constitutional complaints, such as abdominal pain, anorexia, nausea/vomiting, hyperventilation, and/or myalgias associated with elevations in serum lactate levels and decreased serum bicarbonate levels. Blood sampling for venous lactate levels should avoid the use of prolonged tourniquetting, and samples should be transported on ice and processed promptly. Lactic acidosis is believed to manifest only at lactate levels >5 mmol/L with an accompanying decreased bicarbonate level.

Patients taking NRTIs who present with constitutional symptoms should be evaluated for lactic acidosis, including lactate (arterial or venous) and bicarbonate level, arterial blood gas determination, serum amylase and lipase, and serum liver enzymes. In conjunction with the evaluation, ART should be discontinued. If the evaluation does not support the diagnosis of lactic acidosis, ART may be restarted.

Patients with mildly elevated lactate levels (2.1 to 5.0 mmol/L) and a normal bicarbonate level are usually asymptomatic. The clinical significance of mildly elevated lactate levels is still unknown. In the absence of decreased bicarbonate levels, lactic acidosis is uncommon.

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Hepatotoxicity

Updated January 2007

RECOMMENDATIONS:
Clinicians should obtain serum liver enzyme levels at baseline and every 3 to 4 months thereafter in patients receiving ART. (III)

Clinicians should screen for alcohol use in patients with abnormal serum liver enzyme levels. (III)

Use of Nevirapine
Clinicians should not use nevirapine as part of the initial regimen in women with CD4 counts >250 cells/mm3 or men with CD4 counts >400 cells/mm3 because of an increased incidence of hepatotoxicity. (I)

When initiating an ART regimen that includes nevirapine, clinicians should obtain serum liver enzymes at baseline, at the time of dose escalation (14 days), and 2 weeks after dose escalation. (III)

Clinicians should counsel patients to seek medical evaluation when signs and symptoms of hepatitis, severe skin reactions, or hypersensitivity reactions related to nevirapine occur. Serum liver enzymes should be obtained whenever patients develop a rash during nevirapine therapy, particularly during the first 18 weeks of therapy. (II)

In the setting of hepatotoxicity related to nevirapine, patients should not be re-challenged with nevirapine. (I)

All antiretroviral agents have the potential to cause abnormalities in liver function, especially in patients with preexisting liver disease. Serum liver enzyme levels should be obtained at baseline and every 3 to 4 months in patients receiving ART. More frequent monitoring may be necessary for patients with preexisting liver disease or serum liver enzyme abnormalities. The use of full-dose ritonavir (600 mg twice daily) has been associated with worsening transaminases in patients with preexisting liver disease and should be avoided. Patients who develop serum liver enzyme abnormalities greater than five times the upper limit of normal should be promptly assessed. Any potentially hepatotoxic medication, including all antiretroviral agents, should be discontinued (see Section X: Management of Treatment Interruption).

A higher incidence of significant hepatotoxicity associated with nevirapine therapy has recently been reported, especially in women with CD4 counts >250 cells/mm3, men with CD4 counts >400 cells/mm3, and in the setting of HCV coinfection. The greatest risk of severe and potentially fatal hepatotoxicity occurs in the first 6 weeks of treatment; however, the FDA and the manufacturer strongly recommend intensive monitoring during the first 18 weeks of nevirapine therapy, with discontinuation of the drug if moderate or severe abnormalities occur. In the absence of definitive clinical evidence, monitoring serum liver enzymes every 2 weeks for the first month of nevirapine therapy, then monthly for the first 12 weeks, and every 1 to 3 months thereafter is a reasonable approach, given the potential severity of adverse events. It is essential that the 14-day lead-in period be strictly followed (see Appendix A for guidance on step-up dosing for nevirapine). In some cases, the hepatic injury progresses even after discontinuation of nevirapine. In the setting of hepatotoxicity related to nevirapine, the patient should not be re-challenged with nevirapine.

Some clinicians would avoid using efavirenz after severe nevirapine-related hepatotoxicity (LFTs >5x ULN) with or without Grade 4 rash (Stevens-Johnson syndrome); however, there is no clear evidence to support an association between nevirapine-related hepatotoxicity and efavirenz-related hepatotoxicity.65 For mild to moderate nevirapine-related hepatotoxicity (LFTs >3-5 x ULN), switching to efavirenz after complete resolution of hepatotoxicity is an option if there are no other contraindications to efavirenz. Contraindications to efavirenz include known adverse reactions to efavirenz, first-trimester pregnancy, or strong likelihood of becoming pregnant.

For pregnant women with nevirapine-related hepatotoxicity, the clinician should switch the regimen to 2 NRTIs + PI. Efavirenz should only be considered for women in the second or third trimester if there are no other options and the benefits outweigh the risks. See Management of HIV-Infected Pregnant Women Including Prevention of HIV Perinatal Transmission for more details.

In the setting of severe nevirapine-related hepatotoxicity, all antiretroviral agents and any other possible offending agents should be discontinued. The risk of severe hepatotoxicity outweighs the risk of possible emergence of resistance. See Section X: Management of Treatment Interruption.

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Renal Toxicity

Updated September 2012

RECOMMENDATIONS:
For all HIV-infected patients receiving ART:
Clinicians should routinely assess kidney function in all HIV-infected patients. A renal assessment should include:

  • Glomerular filtration rate estimated from serum creatinine (baseline and at least every 6 months) (AII)
  • Blood urea nitrogen (baseline and at least every 6 months) (AIII)
  • Urinalysis (baseline and at least annually) (AIII)
  • For patients with diabetes and no known proteinuria: calculation of urine albumin-to-creatinine ratio to detect microalbuminuria (baseline and at least annually) (AI)

For patients receiving tenofovir:
For patients initiating a tenofovir-containing regimen, clinicians should calculate glomerular filtration rates at initiation of therapy, 1 month after initiation of therapy, and then at least every 4 months thereafter.

Clinicians should adjust tenofovir dosing when glomerular filtration rate approaches 50 mL/min or discontinue tenofovir according to clinical status. (AII)

For patients receiving indinavir:
Clinicians should counsel patients receiving indinavir to drink at least 48 ounces of fluid per day.

HIV infection has been associated with several renal complications that may lead to renal insufficiency or failure.66,67 Renal impairment necessitates dose adjustment or discontinuation of many antiretroviral agents (see Appendix A).

Clinicians should routinely obtain urinalysis and serum creatinine levels as well as calculate glomerular filtration rates (GFR) to assess renal function. When calculating GFR, the clinician should consistently use the same method. GFR can be calculated by using one of the following equations:

  1. Chronic Kidney Disease Epidemiology Consortium (CKD-EPI): Estimates GFR based on age, race, and serum creatinine. A CKD-EPI calculator can be found at http://mdrd.com/
  2. Modification of diet in renal disease (MDRD): Estimates GFR based on age, sex, height, serum creatinine, serum albumin, and serum blood urea nitrogen (BUN). An MDRD calculator can be accessed at http://mdrd.com/
  3. Cockroft-Gault: Calculates creatinine clearance based on serum creatinine, age, weight, and sex. A Cockroft-Gault calculator can be accessed at http://nephron.com/cgi-bin/CGSI.cgi

Tenofovir is excreted by glomerular filtration and tubular secretion. Renal impairment has been reported in patients receiving tenofovir.67,68 The extent of this toxicity is unclear. Additional risk factors include low body weight, older age, use of boosted regimens, hypertension, diabetes, and use of other nephrotoxic drugs. Hypophosphatemia may be an early indicator of renal failure. Clinicians may want to use a lower threshold for dose adjustment in patients receiving tenofovir. Clinicians should discontinue tenofovir when patients present with symptoms suggestive of Fanconi syndrome, such as declining renal function with associated metabolic acidosis, hypophosphatemia, hypokalemia, glycosuria, and uricosuria. The decision to rechallenge with tenofovir should be made on a case-by-case basis.

Indinavir (especially when used with ritonavir) and agents used to prevent and/or treat opportunistic infections may cause hematuria, pyuria, or crystalluria. Patients receiving indinavir should be counseled to drink at least 48 ounces of fluid per day. Clinicians should consider urinalysis every 3 to 4 months for patients receiving indinavir-containing regimens.

For additional information regarding renal assessment and management of kidney disease in HIV-infected patients, see Kidney Disease in HIV-Infected Patients.

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D. Monitoring for Allergic Reactions Associated with ART

Updated June 2010

RECOMMENDATIONS:
When patients receive any new antiretroviral drugs, clinicians should educate them about the possibility of ART-associated allergic reactions, including a hypersensitivity reaction, and the range of possible symptoms (see Table 9). (III)

Clinicians should discontinue offending drugs when there is a moderate to severe skin reaction, mucous membrane involvement, systemic toxicity, or fever. (I)

Clinicians should perform HLA-B*5701 testing before initiating abacavir-based therapy.

Clinicians should avoid re-challenging patients with a medication that has been associated with a hypersensitivity reaction, especially in the setting of abacavir reactions and severe NNRTI reactions. (I)

In patients who develop mild rash in response to nevirapine, clinicians should avoid escalating the nevirapine dose to twice daily until after the rash has resolved. For patients with moderate to severe cutaneous toxicity, nevirapine should be discontinued and should not be re-challenged. Use of an alternate NNRTI should be avoided. (III)

Table 9: Antiretroviral Drugs Typically Associated with Allergic Reactions
Antiretroviral Drug
(usual timing of symptoms)
Most Frequent Symptoms Action
Abacavir*
(First 4-6 weeks after initiation)
Hypersensitivity reaction: Fever, headache, gastrointestinal symptoms, malaise, arthralgias, myalgias, and respiratory problems. Skin involvement, with rash and pruritus may be mild or absent. • Prompt discontinuation of abacavir

• Do not re-challenge

Delavirdine
(First 4 weeks after initiation)
Mild to moderate cutaneous allergy • Consider systemic antihistamines while continuing delavirdine for mild rashes

• Discontinue when there is a moderate to severe skin reaction, mucous membrane involvement, systemic toxicity, or fever

Efavirenz
(First 4 weeks after initiation)
Mild to moderate cutaneous allergy • Consider systemic antihistamines while continuing efavirenz for mild rashes

• Discontinue when there is a moderate to severe skin reaction, mucous membrane involvement, systemic toxicity, or fever

Enfuvirtide In the phase 3 trials of enfuvirtide, three cases of probable hypersensitivity were identified. These included, either individually or in combination, rash, fever, nausea and vomiting, chills, rigors, hypotension, and elevated LFTs.
Etravirine
(generally occurs in the 2nd week of treatment and is infrequent after week 4)
Severe reaction: cutaneous reaction involving the mucocutaneous surfaces (Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme)







Mild reaction: mild skin rash
Severe reaction:
▪ Discontinue etravirine promptly
Discontinue if rash accompanied by fever, hepatitis, and other systemic symptoms.
▪ Obtain serum liver enzyme levels

Grade 3 and 4 rashes reported in 1.3% of patients

Rash more common in women

Mild reaction:
▪ Manage with antihistamines and close monitoring

Fosamprenavir, tipranavir, and darunavir Mild to moderate cutaneous allergy • Patients with sulfa allergy may be at increased risk of developing an allergic reaction

• For mild rashes, consider using systemic antihistamines while continuing protease inhibitors with sulfa moiety

• Discontinue when there is a moderate to severe skin reaction, mucous membrane involvement, systemic toxicity, or fever

Nevirapine
(First 2 to 18 weeks after initiation)
Severe reaction: cutaneous reaction involving the mucocutaneous surfaces (Stevens-Johnson syndrome), often accompanied by fever and severe hepatitis




Mild reaction: mild skin rash

Severe reaction:
▪ Discontinue nevirapine promptly
▪ Obtain serum liver enzyme levels
▪ Do not re-challenge
▪ Do not use alternate NNRTI (however, patients with NNRTI rash did not have a higher incidence of rash when given etravirine)

Mild reaction:
▪ Close monitoring recommended, but most clinicians would switch to an alternative antiretroviral
▪ Obtain serum liver enzyme levels
▪ Do not escalate dose to twice daily until the rash has resolved

Raltegravir Rashes, including severe skin rashes and cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported • Discontinue if rash is accompanied by constitutional symptoms (i.e., fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema)
* HLA-B*5701 is a pharmacogenetic test (HLA-B*5701) used to identify patients who are predisposed to abacavir hypersensitivity. Clinicians should perform HLA-B*5701 testing before initiating abacavir-based therapy.


Many medications pose the risk of causing various types of allergic reactions, typically presenting as maculopapular rash, with or without fever. Occasionally, a more severe hypersensitivity reaction occurs, consisting of rash and fever, with a combination of other symptoms, such as headache, arthralgias, hepatitis, eosinophilia, and GI or respiratory symptoms. The hypersensitivity reaction usually occurs within 2 to 6 weeks after the drug is started.

Although trimethoprim/sulfamethoxazole is the drug most frequently implicated in common allergic reactions in HIV-infected patients, abacavir, darunavir, tipranavir, fosamprenavir, all of the NNRTIs (nevirapine, delavirdine, efavirenz, etravirine), and enfuvirtide (less commonly) have been associated with a hypersensitivity reaction or syndrome (see Table 9). These reactions are for the most part idiosyncratic and unanticipated. The reactions to darunavir, fosamprenavir, tipranavir (all have a sulfa moiety), delavirdine, and efavirenz are generally mild to moderate cutaneous allergy (drug rash). Patients may rarely develop severe mucous membrane involvement with systemic toxicity. Occasionally, patients will only have a fever. Clinicians should discuss the possibility of these reactions with patients initiating ART because they are most commonly seen in the first 4 weeks of treatment; clinicians should educate patients about the symptoms of hypersensitivity.

Systemic antihistamines may be useful in treating mild cases while patients continue to receive the offending drug. The offending drug should be discontinued when there is a moderate to severe skin reaction, mucous membrane involvement, systemic toxicity, or fever.

Hypersensitivity to abacavir occurred in as many as 5% of patients before routine HLA-B*5701 testing was recommended. The reaction usually occurs within the first 10 to 14 days of therapy and rarely occurs after the first 6 weeks. Fever, headache, GI symptoms, malaise, arthralgias, myalgias, and respiratory problems are the most frequent manifestations of the abacavir hypersensitivity reaction. Skin involvement, with rash and pruritus, may be mild or absent. HLA-B*5701 is a pharmacogenetic test (HLA-B*5701) used to identify patients who are predisposed to abacavir hypersensitivity. Clinicians should perform HLA-B*5701 testing before initiating abacavir-based therapy.

Prompt discontinuation of abacavir when a hypersensitivity reaction is suspected is necessary because symptoms will worsen over time. Once abacavir has been discontinued because of a possible or definite hypersensitivity reaction, abacavir should never be administered again. Re-challenge may result in an anaphylactic reaction with associated hypotension or death.

Nevirapine, an NNRTI, has been associated with severe hypersensitivity reactions in the first 2 to 12 weeks of use. Graduated dosing of nevirapine at initiation with 200 mg daily for the first 2 weeks followed by 200 mg twice daily thereafter has reduced the incidence of hypersensitivity reactions. Systemic antihistamines or corticosteroids given at the time of nevirapine initiation have not been proven useful. Such reactions manifest as severe cutaneous reaction involving the mucocutaneous surfaces (Stevens-Johnson syndrome), often with accompanying fever and severe hepatitis. Deaths associated with these reactions have been reported. Patients who develop mild rashes without systemic toxicity may be managed with antihistamines and close monitoring. The nevirapine dose should not be escalated to twice daily until the rash has resolved. However, those with moderate to severe cutaneous toxicity should discontinue nevirapine promptly and should not be re-challenged with this drug. Because of potential cross-reactivity, use of an alternate NNRTI should be avoided in patients who have a severe reaction to nevirapine; however, the incidence of etravirine rash is not high in patients with a history of NNRTI rash.

Etravirine, an NNRTI, has been associated with hypersensitivity reaction. Up to 10% of patients in clinical trials reported rashes. Most reported mild to moderate rashes. Grade 3 and 4 rashes reported in 1.3% of patients, and up to 2.2% of patients required etravirine discontinuation. Rashes generally occur in the second week of treatment and are infrequent after week 4. Etravirine should be discontinued for severe rash or if rash is accompanied by fever, hepatitis, and other systemic symptoms.

In the phase 3 trials of enfuvirtide, three cases of probable hypersensitivity to the drug were identified. These have included, either individually or in combination, rash, fever, nausea and vomiting, chills, rigors, hypotension, and elevated serum liver enzymes.

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VII. CHANGING A SUCCESSFUL INITIAL ART REGIMEN

Updated March 2006

RECOMMENDATIONS:
Clinicians should change a successful initial ART regimen when the patient’s adherence will be compromised by continuing the current regimen. (III)

When considering a change in the ART regimen due to drug toxicity, the clinician should confirm that the viral load is maximally suppressed. (III) If maximal viral suppression has been achieved, the clinician should substitute the offending drug. (I)

The clinician should review results from previous resistance testing before changing a successful regimen. (III)

Even when the goals of ART are achieved in a patient, clinicians may be faced with the challenge of making a change to a successful regimen. The reasons most often encountered are drug toxicity, quality-of-life issues, and/or fear of long-term adverse drug reactions. Changing therapy for quality-of-life issues or for fear of potential toxicity is appropriate if the patient’s concerns will lead to reduction in adherence or discontinuation of therapy. Many patients adhere less successfully to their ART regimen if they associate side effects with one or more of the drug components. It is important to fully discuss the issues of drug toxicity with the patient so that his/her expectations remain realistic.

Many side effects will abate after the first weeks of treatment. For patients who experience persistent mild to moderate side effects that cannot be managed and that would be expected to improve by a change in the ART regimen, it is good practice to consider changing the regimen when there are viable options. Following are examples of side effects that may be resolved by substituting the offending drug:

  • Peripheral neuropathy from stavudine or didanosine
  • Gastrointestinal intolerance from PIs
  • Insomnia, neuro-irritability, headaches, abnormal dreams from efavirenz or zidovudine
  • Changes in the skin/appendages (recurrent paronychia, xerosis, pruritus, jaundice) from indinavir, atazanavir, or zidovudine, emtricitabine (discoloration of palms/soles)
  • Renal lithiasis, renal colic from indinavir
  • Lipoatrophy or fat redistribution syndrome
  • Dyslipidemia, glucose intolerance from PIs
  • Rash from NNRTIs
  • Hypersensitivity from abacavir or nevirapine
  • Hepatitis from nevirapine or PIs

If adherence is compromised and the offending agent can be identified with a reasonable degree of certainty, a substitution for that one agent is appropriate as long as the viral load is maximally suppressed. Before changing therapy, however, results from previous resistance testing should be reviewed to identify drugs that are not likely to be effective.

In some situations, such as intractable diarrhea, one PI may be substituted for another. In other situations, a drug from one class may be replaced with a drug from another class. Studies have demonstrated that substituting an NNRTI for a PI in the setting of maximal suppression is generally safe and effective in the majority of patients. Although hypertriglyceridemia, hypercholesterolemia, or glucose intolerance would be expected to improve promptly by replacing a PI with an NNRTI, fat redistribution may change slowly after replacement of stavudine.

The risks of altering therapy are as follows:

  • The patient may experience toxicity with the new regimen
  • The exposure of HIV to multiple antiretroviral agents may increase the risk of drug resistance and reduce the number of available treatment options in the future
  • Maximal viral suppression may not be maintained
  • Changing regimens may have an emotional impact on the patient

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VIII. FAILURE TO ACHIEVE GOALS OF INITIAL ART

Updated March 2006, currently under revision

RECOMMENDATIONS:
Clinicians should address adherence, obtain resistance assays, and consult with a provider with experience in HIV treatment before changing ART regimens that have failed.

Clinicians should not change an ART regimen when there is incomplete but significant viral suppression (≥0.5 log reduction, or 3-fold, from baseline viral load value) compared with baseline and a more effective ART regimen cannot be constructed as a result of drug resistance or intolerance.

The goal of ART is to use a regimen that is well tolerated and that will promote maximal viral suppression and immune reconstitution. Failure to demonstrate a >1.5-log drop in viral load within 3 months of treatment and, more importantly, failure to achieve a viral load <50 copies/mL within 6 months (depending on baseline viral load) indicates unsuccessful ART. The initial ART regimen affords the best opportunity to attain maximal viral suppression. Currently, in clinic practice, only 60% to 70% of patients receiving initial ART will achieve sustained viral loads below the limits of detection by ultrasensitive assays. The reasons for this are complex. Low levels of detectable viremia should not be the sole determinant of treatment failure.

Treatment failure is best defined by any one of the following:

  • Failure of viral load to decrease from baseline
  • Progressive increase in viral load after initial suppression
  • Progressive decline of CD4 cell counts
  • Progression of HIV disease

Failure of decline (1.5- to 2.5-log drop) in HIV RT-PCR levels 3 months after initiating ART is a poor prognostic sign and usually indicates that continuation of that particular regimen will fail. Possible reasons for failure are poor patient adherence, primary HIV resistance to the chosen drug regimen, pharmacokinetic issues, and drug-drug interactions. In such cases, it is advisable to obtain appropriate resistance testing to determine the best treatment options (see Section VI: Monitoring of Patients Receiving ART). Early discontinuation of the failing regimen is important to reduce the likelihood of the development of resistance mutations. A significant increase in viral load after an initial good response has a similar implication and should be handled in the same manner.

In contrast to the above situations, some patients will demonstrate a major reduction in HIV RT-PCR levels within several months of initiation of ART, but their viral loads will fail to become undetectable. Many of these patients will have had viral set points of >500,000 copies/mL prior to ART. In these cases, the nadir of viral load may not decrease to less than 5,000 to 10,000 copies/mL with the initial three-drug regimen. Over time, such patients have a higher risk of treatment failure because of the selection of resistance mutations. In these cases, some clinicians may enhance drug levels through the use of pharmacologic boosting (e.g., adding ritonavir) or may add a single agent for intensification. Although treatment intensification may produce good results in selected patients with relatively low viral loads, many clinicians view this as a suboptimal option or sequential monotherapy; therefore, the potential benefits of this strategy should be carefully weighed against the risk of introducing a single agent to a failing regimen that invariably would lead to resistance. A genotypic assay should be obtained to exclude the existence of primary drug resistance before intensifying the regimen.

Despite even maximal HIV suppression, CD4 cell counts may increase very slowly or not at all, especially for patients with baseline CD4 counts <100 cells/mm3 at the time of initiation of ART. Such patients have been shown to benefit from ART (i.e., reduction in likelihood of clinical disease progression), and therapy should not be altered. However, a small percentage of patients with excellent viral suppression will continue to demonstrate decreasing CD4 cell counts. This discordant response has been reported in a number of studies, although the mechanism is poorly understood. Some experts suggest empirically changing regimens in this setting.

Patients with drug-resistant HIV infection may maintain increased CD4 counts, most likely from the decreased replicative capacity of the resistant virus. Ideally, resistance testing should be obtained to determine if a new ART regimen can be constructed using available antiretroviral agents to attempt to achieve maximal viral suppression. However, when this is not possible, maintenance of the current regimen is acceptable.69

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IX. SECOND-LINE REGIMENS AND SALVAGE ART

Updated March 2006, currently under revision

RECOMMENDATIONS:
Clinicians should consult with a provider with experience in HIV treatment when constructing a second-line regimen and salvage therapy regimens.

Clinicians should review individual antiretroviral history and results from HIV drug resistance testing when constructing salvage therapy regimens. Clinicians should consult with an expert to interpret the results of resistance assays. (I)

Clinicians should use a drug from a class that was not used in the first regimen when constructing a second-line regimen. (I)

When treating patients with high levels of HIV drug resistance, clinicians should consider using agents in novel antiretroviral classes or with unique resistance profiles, such as the entry inhibitors or drugs available through clinical trials or expanded access.

Although the best chance for success is with the initial ART regimen, the expectations are still good for second-line regimens, especially with the availability of new antiretroviral drugs. Salvage therapy refers to antiretroviral regimens prescribed for patients who have failed serial ART regimens. Use of the term “salvage therapy” originates from the clinical observation that fewer than 40% to 50% of patients will respond optimally to new ART regimens after first and second ART regimens have failed.

Because of cross-resistance within antiretroviral classes, the clinician cannot assume that the patient’s HIV strain(s) will be sensitive to a novel drug in the same class. Several studies examining the utility of HIV resistance testing in ART-experienced patients have shown that these tests are valuable when choosing subsequent successful ART regimens. However, when multiple regimens have failed in a patient, resistance testing is of limited value. In some cases, when multiple resistance mutations are found on genotypic resistance analysis, phenotypic resistance testing may be helpful in constructing an effective regimen. Expert interpretation of the resistance results in conjunction with a detailed antiretroviral history, including any previous resistance testing, is essential.

For a second-line regimen, drugs from a class that was not used in the first regimen should be used. Agents in new drug classes (e.g., an entry inhibitor) or with novel resistance profiles may lead to an improved antiviral response for patients with multi-drug resistant HIV. Clinical trials and “expanded access” therapies should be considered in this setting. Combinations of five or more antiretroviral drugs, colloquially referred to as “mega-ART” or “multi-drug rescue therapy,” may be attempted in patients who have a high level of drug resistance in all available antiretroviral classes. There are limited data on such an approach, with an unclear benefit in the context of the high pill burdens and significantly increased toxicity of such complex regimens.

When maximal suppression is not achievable due to inability to construct a fully effective regimen, partial viral suppression (<0.5 log or 3-fold reduction from baseline viral load value) and stable CD4 counts are reasonable alternative goals. When CD4 counts are decreased, prophylaxis for opportunistic infections should be initiated.

Several investigators have shown that individuals infected with HIV may become superinfected with a different strain of HIV in the setting of high-risk behavior. In some cases, superinfecting HIV strains may carry drug-resistance mutations. Therefore, sudden regimen failure in a patient who was virologically controlled should raise suspicion that HIV superinfection may be present. Resistance testing and safer-sex counseling are appropriate in these settings.

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X. MANAGEMENT OF TREATMENT INTERRUPTION

Updated June 2006

RECOMMENDATIONS:
Patients should be discouraged from stopping ART without first consulting with their clinician. (III)

When ART is interrupted, clinicians should inform patients of the potential increased risk of transmitting HIV. Risk-reduction counseling and prevention interventions should be intensified at this time.

Before interrupting ART in patients receiving antiretroviral medications with prolonged half-lives, such as NNRTIs, clinicians should consult with a provider with experience in HIV treatment for guidance on how to avoid the emergence of resistance.

Clinicians should not interrupt lamivudine, emtricitabine, or tenofovir (or combination pills containing these drugs) in patients who are co-infected with chronic hepatitis B without implementing another HBV treatment option.

Strategic treatment interruption (STI) is not recommended in the management of the HIV-infected patient. (I)

here are several reasons why it may be necessary to interrupt ART. Following are some scenarios that may result in an interruption in treatment:

  • Serious adverse drug reactions (e.g., rashes, neuropathy, severe lipoatrophy or fat redistribution, severe nephrolithiasis)
  • Lack of access to drugs due to poverty, incarceration, or lack of medical benefits
  • Medical/surgical conditions requiring patients to avoid eating or drinking for a specified time period (e.g., pancreatitis, appendicitis)
  • Poor adherence—in some cases, lack of adherence may be sufficient cause for the clinician to stop treatment while further interventions and education attempts are undertaken
  • Minor drug side effects that mimic disease progression, making it necessary to temporarily interrupt therapy for clinical evaluation of signs and symptoms
  • Patient choice—patients may decide to stop therapy due to treatment fatigue, fear of toxicities (e.g., fat redistribution, cardiac disease), traveling overseas for an extended period, perceived ineffectiveness of medications, or pregnancy and fear of teratogenicity.

Discontinuation of ART by patient’s choice is a complex issue regardless of whether viral suppression had been obtained with the regimen. In some instances, patients lack understanding of the benefits of the medications and fail to adhere to the prescribed regimen. The reasons for non-adherence are multiple (see Section IV: The Importance of Patient Adherence).

Treatment interruption, especially in established (>6 months) HIV infection, can be potentially dangerous. It could lead to dramatic increases in HIV viral load, which may exceed baseline viral load levels, and precipitous declines in CD4 cell counts, which may reach pre-treatment levels, with the risk of clinical events. The Strategies for Management of Antiretroviral Therapy (SMART) trial compared patients receiving continuous ART with patients who were given intermittent ART. The patients in the intermittent therapy group received ART whenever CD4 counts decreased to <250 cells/mm3 then discontinued treatment when CD4 counts increased again to >350 cells/mm3. Patients in the intermittent treatment group had more than twice the risk of progression to AIDS or death compared with the continuous therapy group.

During a treatment interruption, patients may present as if they have acute HIV syndrome or the initial HIV-related symptoms may return. Rebound in HIV-1 RNA plasma level may enhance horizontal and vertical transmission of HIV-1, which is of particular importance during pregnancy when a rebound in viral load may favor transplacental, peripartum, and breastfeeding-related transmission. CD4 cell counts may take longer to decrease after the discontinuation of ART; therefore, clinicians should inform patients that a stable CD4 count after discontinuation of therapy does not predict long-term immunologic stability.

Treatment interruption also may result in selection of resistance mutations. The increasing use of antiretroviral medications with prolonged half-lives and low resistance thresholds complicates discontinuation of treatment. Low plasma levels of antiretroviral medications with prolonged half-lives, such as nevirapine and efavirenz, can be detected many days after discontinuation of the medication. These low levels, although insufficient to suppress viral replication, may select for resistance mutations. Reports have documented the association between discontinuation of an NNRTI, lingering low plasma levels, and emergence of resistance mutations. The duration of these low detectable levels may vary widely from patient to patient. There is no consensus regarding how best to manage treatment discontinuation. Some experts would suggest replacing the NNRTI with a PI and continuing the two NRTIs and PI for approximately 1 week before interrupting therapy. Others would discontinue the NNRTI first and continue the NRTIs for several days (referred to as an “NRTI tail”). Resistant virus usually recedes and wild-type, susceptible virus predominates once treatment is interrupted; however, once antiretroviral medications are re-started, if resistance develops, selective pressure is again established and resistant virus again emerges. These complex considerations coupled with the rapid changes in knowledge and treatment regimens make it advisable to consult with a provider who has experience with management of ART when considering discontinuation of ART.

Structured or strategic treatment interruption is a theoretical approach aimed at reducing long-term toxicity and enhancing HIV-specific immune response while maintaining treatment options. To date, strategic treatment interruptions in patients receiving ART with an undetectable viral load have failed to consistently stimulate HIV-specific T-helper and cytotoxic T-lymphocyte responses. Ongoing clinical trials are trying to elucidate predictors of response. Several treatment interruption studies are basing re-initiation of treatment on CD4 threshold. Preliminary data from some of these trials indicate increased morbidity and mortality among patients in the treatment-interruption arm. At this time, structured treatment interruption cannot be recommended, and it should only be considered in the context of a clinical trial. To locate a clinical trial, refer to the AIDS Community Research Initiative of America clinical trials directory at: http://ziptrials.us/study/aids-community-research-initiative-of-america-hiv-study/.

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XI. REFERRING PATIENTS TO RESEARCH STUDIES

Updated March 2006

RECOMMENDATIONS:
Referral of patients to research protocols should be 1) to provide treatment or diagnostic options that may be otherwise unavailable and that may enhance treatment outcome, and 2) to attempt to answer a relevant research question. (III)

Patients should be fully informed of any financial benefit their referral to a research study might have for the referring clinician. (III)

Patients should be informed that research studies often require major commitments of time and effort in addition to potential unforeseeable risk. (III)

The clinician should provide assistance to patients who want to participate in research studies. (III)

The first priority in the care of any patient is to maximize the therapeutic benefit of treatment and to support the individual. Sometimes patients ask if they can help with any new research studies, and clinicians often realize that the patient might benefit from a therapy that is currently under study. In addition, many standard therapies are still being scrutinized in terms of timing and appropriateness. Because there are so many clinical uncertainties (e.g., when to initiate ART, what is the optimal initial therapy, whether there are occasions for interruption of therapy), the clinician should keep in mind that if a patient is willing to join a trial that will help to resolve these issues, then ultimately there may be a benefit to many others.

In considering referral to a clinical study, the clinician should review with the patient the risks and benefits of participating:

  • If the agent is new, what toxicities have been shown in preliminary trials?
  • What is the patient’s current clinical status and what would be the risks of not using the new agent(s) (i.e., the natural history of the patient’s current condition)?
  • If the trial compares randomization to 1 of 2 standard therapies, are the current data insufficient to recommend one or the other to the patient?
  • If the clinical trial is being held in a center other than the institution where the patient is receiving primary care, how much time and travel will the trial involve? Will the patient get any help with time/travel issues?
  • Is the patient willing and able to meet the rigors that may be imposed on study participants?
  • Is there a stipend for participation?

If the clinician is also an investigator on the study, it is important that he/she is scrupulous in avoiding any real or perceived conflict of interest in the referral. The informed consent that the patient signs should disclose any financial benefit to the clinician if the patient enrolls. Clinicians should be sensitive to some communities’ continued distrust derived from a history of research that was tainted by racism or other prejudice, such as the Tuskegee study. Discussions about research studies should be culturally sensitive, and the voluntary nature of all enrollments must be made very clear.

Clinicians providing care to patients with HIV/AIDS have an obligation to keep abreast of trials that are available in their geographic area and in the field of HIV/AIDS in general. A resource that may help with this process is the AIDS Clinical Trials Information Service (phone: 1-800-TRIALS-A; website: http://www.actis.org/). Other resources are listed at AIDS Community Research Initiative of America (http://ziptrials.us/study/aids-community-research-initiative-of-america-hiv-study/). Establishing a referral network with accessible study centers can be helpful. Centers involved in research should make an effort to be aware of HIV clinicians in their area and vice versa.

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REFERENCES

1. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009;360:1897-1899. [PubMed] Initiating ART at CD4 counts <500 cells/mm3 and older age were independently associated with increased mortality.

2. Wright ST, Carr A, Woolley I, et al. CD4 cell responses to combination antiretroviral therapy in patients starting therapy at high CD4 cell counts. J Acquir Immune Defic Syndr 2011;58:72-79. [PubMed] Minimal reduction in risk of AIDS incidence and/or death shown in patients who initiate ART with CD4 count >500 cells/mm3 vs those who initiate with CD4 counts 351-500 cells/mm3.

3. Writing Committee for the CASCADE Collaboration. Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters. Arch Intern Med 2011;171:1560-1569. [PubMed]

4. Cain LE, Logan R, Robins JM, et al, and the HIV-CAUSAL Collaboration. When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: An observational study. Ann Intern Med 2011;154:509-515. [PubMed] Initiation of ART at a CD4 threshold of 500 cells/mm3 increased AIDS-free survival compared with initiation at <350 cells/mm3.

5. The Opportunistic Infections Project Team of the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE) in EuroCoord. CD4 cell count and the risk of AIDS or death in HIV-infected adults on combination antiretroviral therapy with a suppressed viral load: A longitudinal cohort study from COHERE. PLoS Med 2012;9:e1001194. [PubMed] Although new AIDS-defining events and death are uncommon among patients whose viral load is suppressed by ART, the risk of a new AIDS-defining event or death follows a CD4 cell count gradient with the patients with the highest CD4 cell counts having the lowest risk of a new AIDS-defining event or death.

6. Marin B, Thiébaut R, Bucher HC, et al. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy. AIDS 2009;23:1743-1753. [PubMed]

7. Cohen MS, Chen YQ, McCauley M, et al., HPTN 052 Study Team Prevention of HIV-infection with early antiretroviral therapy. N Engl J Med 2011;365:493-505. [PubMed] Early initiation of ART reduced rates of sexual HIV transmission and clinical events, indicating both personal and public health benefits from early initiation.

8. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, Neaton JH, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355:2283-2296. [PubMed] In addition to showing that continuous use of ART is better than episodic use, this study also found a higher rate of cardiovascular disease in the group who did not receive continuous ART.

9. Ho JE, Deeks SG, Hecht FM, et al. Initiation of antiretroviral therapy at higher nadir CD4+ T-cell counts is associated with reduced arterial stiffness in HIV-infected individuals. AIDS 2010;24:1897-1905. [PubMed] Data suggest that cardiovascular risk among HIV-infected individuals could be reduced when ART is initiated at higher nadir CD4 counts.

10. Ho JE, Scherzer R, Hecht FM, et al. The association of CD4+ T-cell count on cardiovascular risk in treated HIV disease. AIDS 2012;26:1115-1120. Epub ahead of print. [PubMed] Data suggest that delayed therapy results in sustained harm to endothelial function.

11. Lichtenstein KA, Armon C, Buchacz K, et al. Low CD4+ T cell count is a risk factor for cardiovascular disease events in the HIV Outpatient Study. Clin Infect Dis 2010;51:435-447. [PubMed] CD4 count <500 cells/mm3 was an independent risk factor for incident cardiovascular disease in the HIV Outpatient Study cohort.

12. Tozzi V, Balestra P, Bellagamba R, et al. Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: Prevalence and risk factors. J Acquir Immune Defic Syndr 2007;45:174-182. [PubMed] The severity of neurocognitive impairment at the time of ART initiation seems to be the strongest predictor of persistent neuropsychologic deficits despite long-term ART. These data indicate that ART should be initiated as soon as neurocognitive impairment is diagnosed to avoid potentially irreversible neurologic damage.

13. Garvey L, Surendrakumar V, Winston A. Low rates of neurocognitive impairment are observed in neuro-asymptomatic HIV-infected subjects on effective antiretroviral therapy. HIV Clin Trials 2011;12:333-338. [PubMed] Rates of neurocognitive impairment were low in patients receiving ART.

14. Winston A, Puls R, Kerr SJ, et al. Dynamics of cognitive change in HIV-infected individuals commencing three different initial antiretroviral regimens: A randomized, controlled study. HIV Med 2012;13:245-251. [PubMed] Neurocognitive function improves over the first year of initiating ART in neuro-asymptomatic patients.

15. Ellis RJ, Badiee J, Vaida F, et al. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS 2011;25:1747-1751. [PubMed] Initiation of ART as early as possible may reduce the risk of developing HAND.

16. Silverberg MJ, Chun C, Leyden W, et al. HIV infection, immunodeficiency, viral replication, and the risk of cancer. Cancer Epidemiol Biomarkers Prev 2011;20:2551-2559. [PubMed] Immunodeficiency was positively associated with the following non-HIV-related malignancies: lung cancer, colorectal cancer, and melanoma compared with HIV-uninfected individuals. Earlier ART initiation to maintain high CD4 levels might reduce the risk of cancer.

17. Bruyand M, Thiébaut R, Lawson-Ayayi S, et al. Role of uncontrolled HIV RNA level and immunodeficiency in the occurrence of malignancy in HIV-infected patients during the combination antiretroviral therapy era: Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort. Clin Infect Dis 2009;49:1109-1116. [PubMed] CD4 counts maintained at >500 cells/mm3 helps to prevent the occurrence of malignancy.

18. Guiget M, Boue F, Cadranel J, et al. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): A prospective cohort study. Lancet Oncol 2009;10:1152-1159. [PubMed] Risk for malignancies is decreased when CD4 counts are maintained above 500 cells/mm3.

19. Sigel K, Wisnivesky J, Gordon K, et al. HIV as an independent risk factor for incident lung cancer. AIDS 2012;26:1017-1025. [PubMed] HIV infection was an independent risk factor for lung cancer after controlling for other factors, such as smoking.

20. Sabin CA, Smith CJ, d’Arminio Monforte A, et al., Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group. Response to combination antiretroviral therapy: Variation by age. AIDS 2008;22:1463-1473. [PubMed] Better virologic response but lower immunologic response in individuals 55 and older.

21. van Lelyveld SFL, Gras L, Kesselring A, et al., on behalf of the ATHENA national observational cohort study. Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort. AIDS 2012;26:465-474. [PubMed] Poor immunological recovery despite virological successful ART is associated with a higher risk for overall morbidity and mortality, underscoring the importance of starting ART at higher CD4 cell counts, particularly in older patients.

22. Li X, Margolick JB, Jamieson BD, et al. CD4 T-cell counts and plasma HIV-1 RNA levels beyond 5 years of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2011;57:421-428. [PubMed] Men >50 years of age who start ART with CD4 counts between 351-500 cells/mm3 could achieve the same immunologic response as younger men who started with lower CD4 counts.

23. Althoff KN, Gange SJ, Klein MB, et al. Late presentation for human immunodeficiency virus care in the United States and Canada. Clin Infect Dis 2010;50:1512-1520. [PubMed]

24. Centers for Disease Control and Prevention. Reported CD4+ T-lymphocyte results for adults and adolescents with HIV infection—37 atates, 2005–2007. HIV Surveillance Supplemental Report 2010;16(No. 1). Available at: http://www.cdc.gov/hiv/topics/surveillance/resources/reports/index.htm#supplemental Published March 2011.

25. Centers for Disease Control and Prevention. Diagnoses of HIV infection and AIDS in the United States and dependent areas, 2008. Vol. 20. Atlanta, Ga: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2010. Available at: http://www.cdc.gov/hiv/topics/surveillance/resources/reports/index.htm#supplemental. Published June 2010.

26. Salzburg Statement on Shared Decision Making. Salzburg Global Seminar, February 7, 2011. Available at: http://e-patients.net/u/2011/03/Salzburg-Statement.pdf

27. Beach MC, Duggan PS, Moore RD. Is patients’ preferred involvment in health decisions related to outcomes for patients with HIV? Gen Intern Med 2007;22:1119-1124. [PubMed]

28. When to Start Consortium. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: A collaborative analysis of 18 HIV cohort studies. Lancet 2009;373:1352-1363. [PubMed] Deferring ART until a CD4 count of 251-350 cells/mm3 was associated with higher rates of AIDS and death than starting treatment in the range of 351-450 cells/mm3.

29. HIV-Causal Collaboration. The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS 2010;24:123-37. [PubMed] Combination antiretroviral therapy halved the average mortality rate in HIV-infected individuals.

30. Phillips AN, Gazzard B, Gilson R, et al. Rate of AIDS diseases or death in HIV-infected antiretroviral therapy-naïve individuals with high CD4 cell count. AIDS 2007;21:1717-1721. [PubMed] The rate of AIDS or death in persons with most recent CD4 cell count 350-499, 500-649, and >650 cells/mm3 was 2.49, 1.54, and 0.96 per 100 person-years, respectively. The trend of decreasing rate of AIDS and death with higher CD4 cell count continues throughout the CD4 cell count >350 cells/mm3 range in ART-naive people.

31. Lewden C, Bouteloup V, De Wit S, et al, The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord. All-cause mortality in treated HIV-infected adults with CD4 >500 cells mm3 compared with the general population: Evidence from a large European observational cohort collaboration. Int J Epidemiol 2012;41:433-445. [PubMed] Mortality patterns in HIV-infected individuals with high CD4 counts who were receiving ART were similar to those in the general population.

32. Lewden C, Chene G, Morlat P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr 2007;46:72-77. [PubMed] During the 5,402 person-years spent with a CD4 count >500 cells/mm3, mortality rate reached the level of the general population after the sixth year after combination ART initiation.

33. Uy J, Armon C, Buchacz K, et al. Initiation of HAART at higher CD4 cell counts is associated with a lower frequency of antiretroviral drug resistance mutations at virologic failure. J Acquir Immune Defic Syndr 2009;51:450-453. [PubMed] Patients failing ART who initiated at <350 cells/mm3 were more likely to develop resistance mutations than failing patients who initiated ART at CD4 counts >350 cells/mm3.

34. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000;342:921-929. [PubMed] Heterosexual transmission was rare among persons with HIV viral load levels <1500 copies/mL.

35. Castilla J, del Romero J, Hernando V, et al. Effectiveness of highly active antiretroviral therapy in reducing heterosexual transmission of HIV. J Acquir Immune Defic Syndr 2005;40:96-101. [PubMed]When compared with the pre-HAART era, a reduction of approximately 80% in heterosexual transmission of HIV was observed after ART became widely available.

36. Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: A prospective cohort analysis. Lancet 2010;375:2092-2098. [PubMed] Use of antiretroviral therapy was accompanied by a 92% reduction in HIV-1 transmission to the uninfected partner.

37. Erikkson LE, Bratt GA, Sandrström E, et al. The two-year impact of first generation protease inhibitor based antiretroviral therapy (PI-ART) on health-related quality of life. Health Qual Life Outcomes 2005;3:32. [PubMed]

38. Guaraldi G, Murri R, Orlando G, et al. Severity of lipodystrophy is associated with decreased health-related quality of life. AIDS Patient Care STDs 2008;22:577-578. [PubMed] Health-related quality of life was strongly correlated with patient perception of the severity of lipodystrophy.

39. Burgoyne RW, Tan DH. Prolongation and quality of life for HIV-infected adults treated with highly active antiretroviral therapy (HAART): A balancing act. J Antimicrob Chemother 2008;61:469-473. [PubMed]

40. Volberding PA, Deeks SG. Antiretroviral therapy and management of HIV infection. Lancet 2010;376:49-62. [PubMed]

41. Barth RE, Aitken SC, Tempelman H, et al. Accumulation of drug resistance and loss of therapeutic options precede commonly used criteria for treatment failure in HIV-1 subtype-C-infected patients. Antivir Ther 2012;17:377-386. [PubMed] Rapid accumulation of drug resistance occurred when ART was continued despite virological failure. Treatment options were lost, even when failure criteria were not met.

42. Politch JA, Mayer KH, Welles SL, et al. Highly active antiretroviral therapy does not completely suppress HIV in semen of sexually active HIV-infected men who have sex with men. AIDS 2012;26:1535-1543. Epub ahead of print. [PubMed]

43. Wallis CL, Papathanasopolous MA, Fox M, et al. Low rates of nucleoside reverse transcriptase inhibitor resistance in a well-monitored cohort in South Africa on antiretroviral therapy. Antivir Ther 2012;17:313-320. [PubMed] Frequent viral load monitoring limits the level and complexity of resistance in HIV-1 subtype C, preserving susceptibility to second-line options.

44. Casado C, Colombo S, Rauch A, et al. Host and viral genetic correlates of clinical definitions of HIV-1 disease progression. PLoS One 2010;5:e11079. [PubMed]

45. Okulicz JF, Grandits GA, Weintrob, et al. CD4 T cell count reconstitution in HIV controllers after highly active antiretroviral therapy. Clin Infect Dis 2010;50:1187-1191. [PubMed]

46. Zolopa A, Anderson J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: A multicenter randomized strategy trial. PLoS ONE 2009;4:e5575. [PubMed] Initiation of early ART in patients with acute AIDS-related opportunistic infections resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART.

47. Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011;365:1471-1481. [PubMed]

48. Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med 2011;365:1482-1491. [PubMed]

49. Abdool Karim S, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 2011;365:1492-1501. [PubMed]

50. Lawn SD, Torok ME, Wood R. Optimum time to start antiretroviral therapy during HIV-associated opportunistic infections. Curr Opin Infect Dis 2011;24:34-42. [PubMed]

51. National Institute of Allergy and Infectious Diseases. Bulletin: HIV treatment study in patients with cryptococcal meningitis ends enrollment early: Higher mortality rate found with early antiretroviral therapy. May 30, 2012. [Bulletin]

52. New York State Education Department. Office of the Professions. Rules of the Board of Regents. Section 29.7. Customized patient packaging of medications for patients on complex medication regimens. Amended, effective November 9, 2011. Available at: http://www.regents.nysed.gov/meetings/2011Meetings/October2011/1011ppca1.pdf

53. Gale HB, Giettermann SR, Hoffman HJ, et al. Is frequent CD4+ T-lymphocyte count monitoring necessary for persons with counts >300 cells/mm3 and HIV-1 suppression? Clin Infect Dis 2013;56:1340-1343. [PubMed]

54. Buscher A, Mugavero M, Westfall AO, et al. The association of clinical follow-up intervals in HIV-infected persons with viral suppression on subsequent viral suppression. AIDS Patient Care STDs 2013;27:459-466. [PubMed]

55. Reekie J, Mocroft A, Sambatakou H, et al. Does less frequent routine monitoring of patients on a stable, fully suppressed cART regimen lead to an increased risk of treatment failure? AIDS 2008; 22:2381–2390. [PubMed]

56. Romih V, Zidovec Lepej S, Gedike K, et al. Frequency of HIV-1 viral load monitoring of patients initially successfully treated with combination antiretroviral therapy. PLoS One 2010; 5:e15051. [PubMed]

57. Grennan JT, Loutfy MR, Su D, et al. Magnitude of virologic blips is associated with a higher risk for virologic rebound in HIV-infected individuals: A recurrent events analysis. J Infect Dis 2012;205:1230-1238. [PubMed]

58. Haubrich RH, Riddler SA, Ribaudo H, et al. Initial viral decay to assess the relative antiretroviral potency of protease inhibitor-sparing, nonnucleoside reverse transcriptase inhibitor-sparing, and nucleoside reverse transcriptase inhibitor-sparing regimens for first-line therapy of HIV infection. AIDS 2011;25:2269-2278. [PubMed]

59. Townsend D, Troya J, Maida I, et al. First HAART in HIV-infected patients with high viral load: Value of HIV RNA levels at 12 weeks to predict virologic outcome. J Int Assoc Physicians AIDS Care (Chic) 2009;8:314-317. [PubMed]

60. Gras L, Kesselring AM, Griffin JT, et al. CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater. J Acquir Immune Defic Syndr 2007;45:183-192. [PubMed]

61. Sabin CA, Smith CJ, d’Arminio Monforte A, et al., Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group. Response to combination antiretroviral therapy: Variation by age. AIDS 2008;22:1463-1473. [PubMed]

62. Kelley CF, Kitchen CM, Hunt PW, et al. Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis 2009;48:787-794. [PubMed]

63. Garcia F, de Lazzari E, Plana M, et al. Long-term CD4+ T-cell response to highly active antiretroviral therapy according to baseline CD4+ T-cell count. J Acquir Immune Defic Syndr 2004;36:702-713.[PubMed]

64. Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis 2007;44:441-446. [PubMed]

65. Sulkowski MS, Thomas DL, Mehta SH, et al. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: Role of hepatitis C and B infections. Hepatology 2002;35;182-189. [PubMed] The greatest risk of NNRTI-associated severe hepatotoxicity was observed in patients taking NVP, those with hepatitis B or C co-infection, and those co-administered PIs.

66. Miro JM, Cofan F, Trullas JC, et al. Renal dysfunction in the setting of HIV/AIDS. Curr HIV/AIDS Rep 2012;9:187-199. [PubMed] HIV-infected individuals commonly experience renal complications and have a high prevalence of risk factors, including HIV infection itself, that contribute to the development of kidney disease.

67. Zaidan M, Lescure FX, Brochériou I, et al. Tubulointerstitial nephropathies in HIV-infected patients over the past 15 years: A clinico-pathological study. Clin J Am Soc Nephrol 2013;8:930-938. [PubMed] Drug toxicity, infection, and syndromes associated with immunosuppression in the setting of HIV demonstrate the importance of monitoring kidney function HIV-infected patients.

68. Laprise C, Baril JG, Dufresne S, et al. Association between tenofovir exposure and reduced kidney function in a cohort of HIV-positive patients: Results from 10 years of follow-up. Clin Infect Dis 2013;56:567-575. [PubMed] Tenofovir exposure significantly increased the risk of kidney dysfunction, but the loss in estimated glomerular filtration rate due to TDF was relatively mild over the long term.

69. Deeks SG, Hoh R, Neilands TB, et al. Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection. J Infect Dis 2005;192:1537-1544. [PubMed] Nucleoside analogues often exert continued antiviral activity in the setting of drug-resistance mutations and both nucleoside analogues and PIs can select for drug-resistance mutations that reduce viral fitness.

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APPENDIX A: CHARACTERISTICS OF ANTIRETROVIRAL DRUGS

FDA Pregnancy Categories

A Adequate and well-controlled studies of pregnant women fail to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of risk during later trimesters).

B Animal reproduction studies fail to demonstrate a risk to the fetus and adequate and well-controlled studies of pregnant women have not been conducted.

C Safety in human pregnancy has not been determined, animal studies are either positive for fetal risk or have not been conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the fetus.

D Positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.

X Studies in animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit.

Classification of Antiretroviral Drugs

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Nucleotide Reverse Transcriptase Inhibitor (NtRTI)

Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Protease Inhibitors (PIs)

Fusion Inhibitor

CCR5 Co-receptor Antagonist

Integrase Strand Transfer Inhibitors (INSTIs)

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APPENDIX B: WHEN TO INITIATE ART: COMPARISON OF NYSDOH, DHHS, IAS-USA RECOMMENDATIONS

Updated February 2013

NYSDOH AI Recommendations (2013)* DHHS Recommendations (2013) IAS-USA Recommendations (2012)
1. Evaluation for initiation of ART is recommended for all patients with chronic HIV infection, regardless of CD4 count. (AII)

2. The highest risk patients, in whom timely ART initiation is most important, continues to include those who:

  • have an AIDS-defining condition (AI)
  • are pregnant (AI)
  • are symptomatic from HIV (AI), regardless of CD4 count, including any of the following:
    • HIV-associated neurocognitive disorder (HAND) (AII)
    • Severe thrombocytopenia (AII)
    • HIV-associated nephropathy (AII)
    • HIV-related malignancies (AII)
  • have chronic hepatitis B or C infection (AII)
  • have two successive measurements of CD4 counts <500 cells/mm3 (AII)
  • are age 50 or older (AII)
  • have rapidly declining CD4 counts (>100 cells/mm3 per year) (AIII)

3. Patients with seronegative partners should be counseled about the reduction of HIV transmission risk when effective ART is initiated; ART is strongly recommended in these patients. (AI)

1. ART is recommended for all HIV-infected individuals. The strength and evidence for this recommendation varies on the basis of pretreatment CD4 cell count:

  • CD4 count <350 cells/mm3 (AI)
  • CD4 count 350 to 500 cells/mm3 (AII)
  • CD4 count >500 cells/mm3 (BIII)

2. ART is recommended for HIV-infected individuals for the prevention of transmission of HIV. The strength and evidence for this recommendation vary by transmission risk:

  • perinatal transmission (AI)
  • heterosexual transmission (AI)
  • other transmission groups (AIII)

3. Patients starting ART should be willing and able to commit to treatment and understand the benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.

ART is recommended and should be offered regardless of CD4 count. The strength of the recommendation increases as CD4 count decreases and in the presence of the following conditions:

  • Pregnant women
  • Chronic hepatitis B virus co-infection
  • Hepatitis C virus co-infection
  • Age >60 years
  • HIV-associated nephropathy
  • Acute phase of primary HIV infection, regardless of symptoms
* See Table 3.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. February 12, 2013. Available at: www.aidsinfo.nih.gov
Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International AIDS Society–USA Panel. JAMA 2012;308:387-402.

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APPENDIX C: Evidence Base for Recommendations to Initiate ART

Posted February 2013

Appendix C: Evidence Base for Recommendations to Initiate ART
Evaluation of all chronically infected patients for initiation of ART (AII)
Refs 1-6
Patients who are symptomatic (AI)
Refs 5-7
Patients who are pregnant (AI)
Ref 8
Patients with CD4 count <500 cells/mm3 (AII)
Refs 1, 4-6,9,10
Patients with HIV-related conditions
  • HIV-associated neurocognitive disorder
(AII)
Ref 11-14
  • Severe thrombocytopenia
(AII)
Refs 15-17
  • HIV-associated nephropathy
(AII)
Refs 5-7,18-20
  • HIV-related malignancies
(AII)
Refs 21-25
Patients with chronic HBV (AII)
Refs 5,6,9,26,27
Patients with chronic HCV (AII)
Refs 6,7,26,28,29
Patients 50 years of age or older (AII)
Refs 1,9,30-33
Patients with rapid decline in CD4 count, defined as >100 cells/mm3 per year (AIII)
Ref 5
Partner serodiscordance (AI)
Refs 34-37

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APPENDIX C REFERENCES

1. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009;360:1897-1899. [PubMed] Initiating ART at CD4 counts <500 cells/mm3 and older age were independently associated with increased mortality.

2. Writing Committee for the CASCADE Collaboration. Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters. Arch Intern Med 2011;171:1560-1569. [PubMed]

3. Marin B, Thiébaut R, Bucher HC, et al. Non-AIDS-defining deaths and immunodeficiency in the era of combination antiretroviral therapy. AIDS 2009;23:1743-1753. [PubMed]

4. Lewden C, Chene G, Morlat P, et al. HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr 2007;46:72-77. [PubMed] During the 5,402 person-years spent with a CD4 count >500 cells/mm3, mortality rate reached the level of the general population after the sixth year after combination ART initiation.

5. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. February 12, 2013. Available at: www.aidsinfo.nih.gov. Recommends treatment for all HIV-infected patients to reduce disease progression with strength and evidence varying by pretreatment CD4 count. ART also recommended to prevent transmission of HIV.

6. Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International AIDS Society — USA Panel. JAMA 2012;308:387-402. [PubMed] ART is recommended and should be offered regardless of CD4 count. Strength of the recommendation increases as CD4 cell count decreases and in the setting of pregnancy, chronic HBV or HCV co-infection, age >60 years, HIV-associated nephropathy, acute phase of primary HIV infection.

7. European AIDS Clinical Society (EACS). Guidelines for the clinical management and treatment of HIV-infected adults in Europe, version 6. October 2011. Available at: http://www.europeanaidsclinicalsociety.org/. Recommends treatment for patients with any of the following: symptomatic HIV disease, HIV-associated kidney disease, HIV-associated neurocognitive impairment, Hodgkin’s lymphoma, HPV-associated cancers, HBV requiring treatment, active HCV co-infection with CD4 <500 cells/mm3.

8. Centers for Disease Control and Prevention. Achievements in public health. Reduction in perinatal transmission of HIV infection–United States, 1985-2005. MMWR Morb Mortal Wkly Rep 2006;55:592-597. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5521a3.htm

9. Monforte A, Abrams D, Pradier C, et al., Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Group. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS 2008;22:2143-2153. [PubMed] Initiating ART at CD4 counts <500 cells/mm3, active hepatitis B, and older age were independently associated with higher risk of death due to AIDS-defining and non-AIDS-defining malignancies.

10. When to Start Consortium. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: A collaborative analysis of 18 HIV cohort studies. Lancet 2009;373:1352-1363. [PubMed] Deferring ART until a CD4 count of 251-350 cells/mm3 was associated with higher rates of AIDS and death than starting treatment in the range of 351-450 cells/mm3.

11. Tozzi V, Balestra P, Bellagamba R, et al. Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment: Prevalence and risk factors. J Acquir Immune Defic Syndr 2007;45:174-182. [PubMed] The severity of neurocognitive impairment at the time of ART initiation seems to be the strongest predictor of persistent neuropsychologic deficits despite long-term ART. These data indicate that ART should be initiated as soon as neurocognitive impairment is diagnosed to avoid potentially irreversible neurologic damage.

12. Ellis RJ, Badiee J, Vaida F, et al. CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS 2011;25:1747-1751. [PubMed] Initiation of ART as early as possible may reduce the risk of developing HAND.

13. Borjabad A, Morgello S, Chao W, et al. Significant effects of antiretroviral therapy on global gene expression in brain tissues of patients with HIV-1-associated neurocognitive disorders. PLoS Pathog 2011;7:e1002213. [PubMed] ART can be broadly effective in reducing pathophysiological changes in the brain associated with HAND.

14. Heaton RK, Franklin DR, Ellis RJ, et al. HIV-associated neurocognitive disorders before and after the era of combination antiretroviral therapy: Differences in rates, nature, and predictors. J Neurovirol 2011;17:3-16. [PubMed] Consistent association of neurocognitive impairment with nadir CD4 count in both the pre- and post-ART era suggests that earlier treatment may help to prevent HAND.

15. Arranz Caso JA, Sanchez Mingo C, Garcia Tena J. Effect of highly active antiretroviral therapy on thrombocytopenia in patients with HIV infection. N Engl J Med 1999;341:1239-1240. [PubMed] Significant increase in platelets in patients with moderate to severe thrombocytopenia after 3 months of ART.

16. Aboulafia DM, Bundow D, Waide S, et al. Initial observations on the efficacy of highly active antiretroviral therapy in the treatment of HIV-associated autoimmune thrombocytopenia. Am J Med Sci 2000;320:117-123. [PubMed] Increase in platelet count in patients with severe thrombocytopenia after 6 months of ART.

17. Carbonara S, Fiorentino G, Serio G, et al. Response of severe HIV-associated thrombocytopenia to highly active antiretroviral therapy including protease inhibitors. J Infect 2001;42:251-256. [PubMed] ART induced a sustained PLT response in HIV-associated severe thrombocytopenia. Authors conclude that an undetectable viral load is necessary for thrombocytopenia recovery.

18. Wearne N, Swanepoel CR, Boulle A, et al. The spectrum of renal histologies seen in HIV with outcomes, prognostic indicators and clinical correlations. Nephrol Dial Transplant 2012;27:4109-4118. Epub ahead of print. [PubMed] ART reduced mortality in patients with HIVAN. Patients with HIVAN alone were followed for 2 years on ART and showed stable GFR and a trend toward decreased proteinuria.

19. Lescure F-X, Flateau C, Pacanowski J, et al. HIV-associated kidney glomerular diseases: Changes with time and HAART. Nephrol Dial Transplant 2012;27:2349-2355. Epub ahead of print. [PubMed] Marked reduction in HIVAN in recent years as more patients are receiving ART.

20. Wyatt CM, Meliambro K, Klotman PE. Recent progress in HIV-associated nephropathy. Annu Rev Med 2012;63:147-159. [PubMed] Review investigating the role of HIV in HIVAN pathogenesis. Establishes HIVAN as a direct result of HIV infection and as indication for ART.

21. Silverberg MJ, Chun C, Leyden W, et al. HIV infection, immunodeficiency, viral replication, and the risk of cancer. Cancer Epidemiol Biomarkers Prev 2011;20:2551-2559. [PubMed] Immunodeficiency was positively associated with the following non-HIV-related malignancies: lung cancer, colorectal cancer, and melanoma compared with HIV-uninfected individuals. Earlier ART initiation to maintain high CD4 levels might reduce the risk of cancer.

22. Dezube BJ, Pantanowitz L, Aboulafia DM. Management of AIDS-related Kaposi sarcoma: Advances in target discovery and treatment. AIDS Read 2004;14:236-238, 243-244, 251-253. [PubMed] Review of literature concluding that patients with Kaposi’s sarcoma should be advised to initiate ART.

23. Hentrich M, Maretta L, Chow KU, et al. Highly active antiretroviral therapy (HAART) improves survival in HIV-associated Hodgkin’s disease: Results of a multicenter study. Ann Oncol 2006;17:914-919. [PubMed] Use of ART significantly improved the overall survival of patients with HIV-associated Hodgkin’s disease.

24. Weiss R, Mitrou P, Arasteh K, et al. Acquired immunodeficiency syndrome-related lymphoma: Simultaneous treatment with combined cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy and highly active antiretroviral therapy is safe and improves survival. Results of the German Multicenter Trial. Cancer 2006;106:1560-1568. [PubMed] Study concluded that patients with AIDS-related lymphoma should receive ART and CHOP concurrently as firstline therapy.

25. Guiget M, Boue F, Cadranel J, et al. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): A prospective cohort study. Lancet Oncol 2009;10:1152-1159. [PubMed] Risk for malignancies is decreased when CD4 counts are maintained above 500 cells/mm3.

26. Tedaldi E, Peters L, Neuhaus J, et al. For the SMART Study Group and INSIGHT. Opportunistic disease and mortality in patients coinfected with hepatitis B or C virus in the Strategic Management of Antiretroviral Therapy (SMART) study. Clin Infect Dis 2008;47:1468-1475. [PubMed] Both HBV and HCV co-infected patients not receiving ART had increased rates of opportunistic diseases and death compared to patients treated with ART.

27. Matthews GV, Avihingsanon A, Lewin SR, et al. A randomized trial of combination hepatitis B therapy in HIV/HBV coinfected antiretroviral naïve individuals in Thailand. Hepatology 2008;48:1062-1069. [PubMed]

28. Bani-Sadr F, Bedossa P, Rosenthal E, et al. Does early antiretroviral treatment prevent liver fibrosis in HIV/HCV-coinfected patients? J Acquir Immune Defic Syndr 2009;50:234-236. [PubMed] Increased risk of fibrosis (OR 1.084 per year) with longer interval between HIV diagnosis and ART initiation.

29. Shafran SD. Early initiation of antiretroviral therapy: The current best way to reduce liver-related deaths in HIV/HCV-coinfected patients. J Acquir Immune Defic Syndr 2007;44:551-556. [PubMed] Review of eleven cohort studies that have shown that ART is associated with a reduced rate of progression of HCV liver disease, and 4 of these studies demonstrated a reduction in liver-related mortality.

30. Sabin CA, Smith CJ, d’Arminio Monforte A, et al., Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group. Response to combination antiretroviral therapy: Variation by age. AIDS 2008;22:1463-1473. [PubMed] Better virologic response but lower immunologic response in individuals 55 and older.

31. van Lelyveld SF, Gras L, Kesselring A, et al., on behalf of the ATHENA national observational cohort study. Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort. AIDS 2012;26:465-474. [PubMed] Poor immunological recovery despite virological successful ART is associated with a higher risk for overall morbidity and mortality, underscoring the importance of starting ART at higher CD4 cell counts, particularly in older patients.

32. Gras L, Kesselring AM, Griffin JT, et al. CD4 cell counts of 800 cells/mm3 or greater after 7 years of highly active antiretroviral therapy are feasible in most patients starting with 350 cells/mm3 or greater. J Acquir Immune Defic Syndr 2007;45:183-192. [PubMed] CD4 counts >800 cells/mm3 can be achieved within 7 years of initiation of ART in most HIV-infected patients starting therapy with >350 cells/mm3 and achieving sufficient suppression of viral replication. The CD4 counts of patients who were >50 years of age at initiation of ART reached a plateau at a less than normal range after 5 years of therapy.

33. Li X, Margolick JB, Jamieson BD, et al. CD4 T-cell counts and plasma HIV-1 RNA levels beyond 5 years of highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2011;57:421-428. [PubMed] Men >50 years of age who start ART with CD4 counts between 351-500 cells/mm3 could achieve the same immunologic response as younger men who started with lower CD4 counts.

34. Cohen MS, Chen YQ, McCauley M, et al., HPTN 052 Study Team Prevention of HIV-infection with early antiretroviral therapy. N Engl J Med 2011;365:493-505. [PubMed]

35. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000;342:921-929. [PubMed] Heterosexual transmission was rare among persons with HIV viral load levels <1500 copies/mL.

36. Castilla J, del Romero J, Hernando V, et al. Effectiveness of highly active antiretroviral therapy in reducing heterosexual transmission of HIV. J Acquir Immune Defic Syndr 2005;40:96-101. [PubMed] When compared with the pre-HAART era, a reduction of approximately 80% in heterosexual transmission of HIV was observed after ART became widely available.

37. Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: A prospective cohort analysis. Lancet 2010;375:2092-2098. [PubMed] Use of antiretroviral therapy was accompanied by a 92% reduction in HIV-1 transmission to the uninfected partner.

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APPENDIX D: NEW YORK STATE ADHERENCE SERVICES CONTACT LIST

Updated January 2010

Click here to view the New York State Adherence Services Contact List.

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APPENDIX E: RISK OF PROGRESSION TO AIDS-DEFINING ILLNESS IN A COHORT OF HOMOSEXUAL MEN PREDICTED BY BASELINE CD4 T CELL COUNT AND VIRAL LOAD

Table 1: Risk of Progression to AIDS-Defining Illness in a Cohort of Homosexual Men
Predicted By Baseline CD4 T Cell Count and Viral Loada
CD4 ≤200
Plasma Viral Load (copies/mL)
b
% AIDS
(AIDS-Defining Complication)
c
bDNA RT-PCR n 3 years 6 years 9 years
≤ 500 ≤ 1,500
501 – 3,000 1,501 – 7,000
3,001 – 10,000 7,001 – 20,000
10,001 – 30,000 20,001 – 55,000
> 30,000 > 55,000
0d
3d
7
20
70
-
-
14.3
50.0
85.5
-
-
28.6
75
97.9
-
-
64.3
90.0
100.0
CD4 201–350e
Plasma Viral Load (copies/mL)
% AIDS
(AIDS-Defining Complication)
c
bDNA RT-PCR n 3 years 6 years 9 years
≤ 500 ≤ 1,500
501 – 3,000 1,501 – 7,000
3,001 – 10,000 7,001 – 20,000
10,001 – 30,000 20,001 – 55,000
> 30,000 > 55,000
3d
27
44
53
104
-
0
6.9
36.4
64.4
-
20.0
44.4
72.2
89.3
-
32.2
66.2
84.5
92.9
CD4 >350
Plasma Viral Load (copies/mL)
% AIDS
(AIDS-Defining Complication)
c
bDNA RT-PCR n 3 years 6 years 9 years
≤ 500 ≤ 1,500
501 – 3,000 1,501 – 7,000
3,001 – 10,000 7,001 – 20,000
10,001 – 30,000 20,001 – 55,000
> 30,000 > 55,000
119
227
342
323
262
1.7
2.2
6.8
14.8
39.6
5.5
16.4
30.1
51.2
71.8
12.7
30.3
53.5
73.5
85.0
Adapted from the DHHS Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents (2006).
a Data from the Multi-Center AIDS Cohort Study (MACS).
b MACS numbers reflect plasma HIV RNA values obtained by version 2.0 bDNA testing. RT-PCR values are consistently 2- to 2.5-fold higher than bDNA values, as indicated. It should be noted that the current generation bDNA assay (3.0) gives similar HIV-1 RNA values as RT-PCR except at the lower end of the linear range (<1,500 copies/mL).
c In this study, AIDS was defined according to the 1987 CDC definition and does not include asymptomatic individuals with CD4 T cell counts <200 mm3.
d Too few subjects were in the category to provide a reliable estimate of AIDS risk.
e A recent evaluation of data from the MACS cohort of 231 individuals with CD4 T cell counts >200 and <350 cells/mm3 demonstrated that of 40 (17%) individuals with plasma HIV RNA <10,000 copies/mL, none progressed to AIDS by 3 years (Alvaro Munoz, personal communication). Of 28 individuals (29%) with plasma viremia of 10,000-20,000 copies/mL, 4% and 11% progressed to AIDS at 2 and 3 years, respectively. Plasma HIV RNA was calculated as RT-PCR values from measured bDNA values.

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APPENDIX F: PROGNOSIS ACCORDING TO CD4 CELL COUNT AND VIRAL LOAD IN THE PRE-HAART AND HAART ERAS

Table 1: Prognosis According to CD4 Cell Count and Viral Load in the Pre-HAART and HAART Eras
Reprinted with permission from Elsevier (The Lancet, 2002, Vol 360, 19-29).




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