UPDATE: Antiretroviral Therapy
Updates to sections of this guideline are date stamped. As of June 2016, “Selecting an Initial ART Regimen” is under revision. Please refer to the April 2015 update of the DHHS guideline for the most current information on ART for adults.
June 24, 2016: New York State Department of Health Policy defines eligibility for HIV care and treatment based on infection status, thus making any person with a diagnosis of HIV eligible for care. Read policy announcement.
September 2015: The recommendation for initiation of treatment was updated to initiate treatment at the time of diagnosis. This recommendation is based on 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 (see Section III: When to Initiate ART).
Public health guidance currently recommends that all patients living with HIV be treated with 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.
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). See all commercially available antiretroviral drugs that are FDA-approved for the treatment of HIV/AIDS.
II. GOALS, BENEFITS, AND RISKS OF ART
Updated March 2006; reviewed April 2015
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)
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).
III. WHEN TO INITIATE ART
Updated June 2016
Evaluation and preparation for ART initiation includes each of the following essential components:
- Discussion with the patient about risks and benefits of ART (AIII) (see Section A: Counseling and Education Before Initiating ART)
- Assessment of patient readiness (AIII)
- Identification and amelioration of factors that might interfere with successful adherence to treatment, including inadequate access to medication, inadequate supportive services, psychosocial factors, active substance use, or mental health disorders (AII)
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. (AIII)
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. (AIII)
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. (AII)
Preliminary results from the START trial1 and increasingly strong cohort data show that untreated HIV infection leads to increased morbidity and mortality from both HIV-related and 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 all adequately prepared patients, including patients diagnosed with acute HIV infection (for more discussion see Diagnosis and Management of Acute Infection). Patients in care who are documented long-term nonprogressors or elite controllers are a group that may warrant special consideration (see Section B: Deferring ART). 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.
In START, a randomized trial initiating ART in treatment-naïve patients with CD4 counts >500 cells/mm3 versus waiting for a decrease to ≤350 cells/mm3 before initiation showed a 53% reduction in serious illness and death in the early ART group.1 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.2 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 3, as well as in the cohort who initiated ART in the 350-500 cells/mm3 range compared with those deferring to 3.2 Although other cohort studies demonstrated only a minimal survival advantage3 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/mm3.4-6 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.7 A randomized study of early versus deferred therapy in patients with CD4 counts in the 350-550 cells/mm3 range showed no mortality benefit8; 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,7,9-12 neurocognitive dysfunction,13-16 and some non-HIV-related malignancies.17-20 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.21 The poor immunologic recovery seen in older patients is associated with higher morbidity and mortality, particularly cardiovascular events.22 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.23
Studies have shown that, for HIV-infected pregnant women, the administration of ART during pregnancy and/or intrapartum significantly reduces the risk of mother-to-child transmission (MTCT) of HIV.24,25 In addition, a large study showed a 96% reduction in transmission between serodiscordant heterosexual couples when the positive partner was receiving ART,8 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. Although the majority of patients both in New York and worldwide present later in the course of their HIV infection,26-28 ongoing efforts to offer universal HIV testing to all 13- to 64-year-old patients may begin to identify patients earlier in their disease who can benefit from immediate treatment.
For HIV therapy to be successful over time, the initiation of ART should involve both the selection of the most appropriate regimen and the acceptance of the regimen by the patient, bolstered by 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).
A. Counseling and Education Before Initiating ART
Counseling and education should include the following:
- Basic education about HIV, CD4 cells, viral load, and resistance (AIII)
- Available treatment options and potential risks and benefits of therapy (AIII) (see Table 4)
- The need for strict adherence to avoid the development of viral drug resistance (AII) (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 (AIII)
Clinicians should involve the patient in the decision-making process regarding initiation of ART. (AIII)
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 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.29 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.30 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 Programwhich 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: 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 (1-800-TRIALS-A, 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.
B. Deferring ART
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 NYSDOH Linkage, Retention, and Treatment Adherence Initiative). (AII)
Potential Barriers to Adherence
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 active alcohol or drug use; lack of insurance, transportation, or housing; depression; mistrust of medical providers; or a poor social support system. (AIII)
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 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.44 These patients should remain under particularly close observation for clinical and laboratory signs of disease progression.46 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 NYSDOH Linkage, Retention, and Treatment Adherence Initiative).
Long-Term Nonprogressors and Elite Controllers
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. (AIII)
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.48 Another study found higher rates of hospitalizations in elite controllers compared to treatment suppressed patients, particularly for cardiovascular and psychiatric conditions49; however, there were important limitations in this analysis and it does not provide definitive evidence in favor of treating this rare population based on current information.50 The clinician and patient should discuss the current data on 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.
C. Initiating ART Following Acute Opportunistic Infections
Clinicians should recommend that patients beginning treatment for acute opportunistic infections (OIs) initiate ART within 2 weeks of OI diagnosis (see next recommendation for exceptions). (AI)
Clinicians should not immediately initiate ART in patients with tuberculous meningitis or cryptococcal meningitis. (AI)
Consultation with a clinician with experience in management of ART in the setting of acute OIs is recommended.(AIII)
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 3: 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.51 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.52-54 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 counts3 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 adverse events and mortality in this setting.55-59 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).
IV. THE IMPORTANCE OF PATIENT ADHERENCE
Updated July 2004, currently under revision
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.
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.
- 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.
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.
- 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.
C. Educating the Patient About Adherence
- 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.
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.
- 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.
E. Substance Use and Adherence
- 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.
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.60 Customized patient medication packaging has been shown to increase adherence to complex therapeutic regimens such as those required for patients with HIV/AIDS.60 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.
- 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).
V. SELECTING AN INITIAL ANTIRETROVIRAL REGIMEN
This section is currently under revision. Please refer to the DHHS guideline What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient for the most current information on preferred initial ART regimens, alternative initial ART regimens, considerations for prescribing initial ART in the setting of specific clinical scenarios, and advantages and disadvantages of antiretroviral components recommended as initial ART.
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 June 2016
- Quarterly CD4 count monitoring is no longer recommended for non-pregnant patients receiving ART who have consistently undetectable HIV RNA levels and CD4 counts >200 cells/mm3 (see Table 5 for recommended intervals). (AII)
- Regular monitoring of HIV RNA levels remains the most accurate and meaningful measure of effective ART (see Table 5 for recommended intervals). (AI)
Clinicians should monitor HIV RNA levels and CD4 counts according to the recommended intervals in Table 5. Follow-up visits should be scheduled more frequently as clinically necessary to address non-HIV-related conditions, secondary prevention, and issues that may affect adherence to ART or retention in care, such as substance use, mental health disorders, unstable housing, or need for supportive services. (AIII)
Clinicians should assess response to ART using viral load assays. (AI)
CD4 cell counts should not be used for diagnosis of HIV infection. (AI)
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. Monitoring of HIV RNA levels to confirm appropriate response to treatment and durable viral suppression is the most accurate and meaningful measure of the effectiveness of ART.61
Very few studies address the appropriate frequency of viral load monitoring. A recent retrospective study noted that the strongest predictor of virologic failure at 12 months was a missed or cancelled appointment rather than the interval of follow-up.62 However, this and other similar studies63,64 have significant limitations, including their retrospective nature and short follow-up periods. Until more definitive data are available, the decision to lengthen monitoring intervals for HIV RNA level should be individualized. Patients who are monitored at longer intervals should be carefully selected based on length of viral suppression, CD4 count, and adherence to medical care, including visit attendance and retention in care.
Quarterly HIV RNA monitoring remains appropriate for patients with a recent history of non-adherence, mental health disorders, substance use, homelessness, poor social support system, or other major medical conditions. Semiannual monitoring may be appropriate for patients with persistently undetectable HIV RNA and none of the above characteristics.
Table 5 provides a guide for monitoring HIV RNA levels and CD4 counts.
Plasma HIV-1 RNA Level (Viral Load)
Plasma levels of viral RNA have been shown to correlate with clinical outcome, including overall mortality, and measurement of HIV RNA levels provides the most precise means of establishing whether a response to ART has occurred.67-71 HIV RNA levels should be obtained from all patients at baseline.72-77
For patients beginning ART, or those changing therapy as a result of virologic failure, HIV RNA should be measured at 4 weeks after initiation of therapy and should decrease by at least 1 log (10-fold) in the presence of effective therapy78 (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 a baseline HIV viral load >100,000 copies/mL can be expected to 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 resistance79,80 (see Section IV: The Importance of Patient Adherence and Section VIII: Failure to Achieve Goals of Initial ART).
Patients on previously suppressive ART with newly detectable HIV RNA levels of 50 to 500 copies/mL may be experiencing low-level transient viremia (“blip”) and not virologic failure. A blip by definition means that the viral load is again below the level of quantification on repeat testing performed promptly after a detectable result in someone previously suppressed. Persistent elevation, even at low levels, warrants further investigation. Acute concurrent illness and/or recent vaccination may cause this transient rise; however, studies have suggested that low-level transient viremia represents random biologic and statistical variation or false elevations of viral load resulting from laboratory processing.81,82 Blips are not known to be associated with the development of resistance mutations or virologic failure and do not require a change in ART.82 Retesting should be performed within 4 weeks to differentiate low-level transient viremia (a blip) from sustained viremia and possible virologic failure. The risk of virologic rebound (breakthrough) increases when values are >500 copies/mL.66 However, ART should not be changed based on a single viral load elevation.
Advances in molecular detection technology have led to the development of HIV nucleic acid tests (NATs) that are highly sensitive and more reliable than earlier versions. Real-time polymerase chain reaction (PCR) technology has been widely adopted for HIV-1 RNA quantification, but new technologies are continually emerging and being adapted to viral detection and quantification. The currently available HIV-1 viral load tests that use real-time PCR technology offer larger dynamic range of quantification than early-version viral load tests. The lower and upper limits of quantification of the currently available FDA-approved HIV-1 viral load tests are shown in Table 6. Several different HIV viral load tests have been developed, and four are currently approved for use in the United States.
All of the current FDA-approved viral load assays quantify the level of cell-free virus in an individual’s plasma and are approved for monitoring response to ART, tracking viral suppression, and detecting treatment failure. Successful ART should decrease viral load 1.5 to 2 logs (30- to 100-fold) within 6 weeks, with the viral load decreasing below the limit of detection within 6 months.83 Cohort studies strongly suggest that patients with viral loads <50 copies/mL have more sustained viral suppression than patients with viral loads between 50 and 400 copies/mL. Assays that can detect <50 copies/mL are recommended for determining prolonged viral suppression and for monitoring patients who are on ART.
Achieving and maintaining an undetectable viral load is always the goal of ART (see Appendix D and Appendix E).
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).84,85 Low CD4 cell counts can be seen in other disease processes and should therefore not be used for diagnosis of HIV. Although, historically, CD4 cell count was used to establish a threshold for initiating ART, current guidelines in New York State recommend ART for all HIV-infected patients 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.
Although CD4 counts should be obtained from patients at baseline,86-90 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 quantified 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 old91,92 and patients with low initial CD4 cell counts (<100 cells/mm3).86,93,94
Absolute CD4 cell counts are calculated values that may fluctuate widely. The calculation is made by multiplying the total white blood cell count (in thousands) by the percentage of total lymphocytes and then by the percentage of CD4 lymphocytes. Therefore, any change in one of these three parameters will cause the absolute CD4 count to vary. CD4 percentage is a direct measurement and more reliable than the calculated absolute CD4 value, especially over time. A stable CD4 percentage, even in the setting of fluctuations in the absolute CD4 cell count, can reassure both the patient and the clinician that immunologic stability is present.
Some factors that can cause these fluctuations include sex, age, race, drugs (zidovudine, cephalosporins, cancer chemotherapy, nicotine, interferon, and corticosteroids), anti-lymphocyte antibodies, and splenectomy. Differences in reagents and equipment both within a laboratory and between laboratories may further contribute to variations in CD4 cell counts. There is also interlaboratory variation of normal range.
B. HIV Resistance Assays
Updated June 2016
Clinicians should consult with an expert to interpret the results of resistance assays because such results are often complex (AIII) (the NYSDOH AIDS Institute’s Clinical Education Initiative line is available for phone consultation: 800-637-2342)
When determining the optimal regimen for achieving viral suppression, clinicians should:
- Perform genotypic resistance testing that includes the protease and reverse transcriptase genes:
- At baseline, regardless of whether ART is being initiated (AII)
- In ART-naïve patients before initiation of ARTa (AII)
- In patients experiencing treatment failureb or incomplete viral suppression; such testing should be performed while patients are still on therapy, but no longer than 4 weeks after stopping ART, given the rapid return of wild-type virus (AII)
a In the settings of pregnancy and acute infection, treatment should not be withheld while awaiting the results of resistance testing; adjustments may be made to the regimen once resistance results are available (see Diagnosis and Management of Acute HIV Infection and Use of Antiretroviral Therapy in HIV-Infected Pregnant Women).
b Virologic failure is defined as >200 copies/mL (see Antiretroviral Therapy, Section VI: Monitoring of Patients Receiving ART).
The interpretation of HIV resistance assays is one of the most challenging tasks clinicians encounter when caring for HIV-infected patients and crucial for tailoring an effective therapeutic ART regimen. The replicative mechanisms of HIV lack proof-reading capacity, making them error-prone and subject to cumulative mutations (i.e., changes in its genetic sequence). This lack of replicative fidelity, coupled with the selective pressure of sub-therapeutic drug levels, can lead to the development of clinically significant (i.e., resistance-bearing) mutations.
Resistance testing is recommended when patients are interrupting incompletely suppressive ART. Because of the rapid return of wild-type virus without selective pressure from ART,95 testing is preferred before cessation of treatment. In cases where the patient has already stopped therapy, testing should be performed as soon as practical and no more than 4 weeks after cessation, before the return of wild-type virus. Mutations detected in this setting may provide useful information, but the absence of mutations does not rule out their presence in minor variants.
The most commonly used ART drugs are targeted to inhibit the activity of three specific viral enzymes: the protease, reverse transcriptase (RT), and integrase. Mutations have been identified that interfere with the ability of one or more ART agents to inhibit viral protein activity, thus rendering the virus resistant to the drug(s). HIV resistance mutations and mechanisms for less commonly used ART drugs that target fusion and viral entry have also been identified.
New resistance mutations and the emerging clinical significance of these mutations frequently change. Several resources are available for more information on drug resistance mutations and resistance testing. These include:
- Stanford University HIV Drug Resistance Database
- IAS-USA 2014 Update of the Drug Resistance Mutations in HIV-1
- HIV Resistance Response Database Initiative
- Los Alamos National Laboratory HIV Databases
- HIV French Resistance Database
- HIV InSite Links: HIV Resistance and Resistance Testing
Two methods are used to determine drug resistance for HIV: genotyping, which detects treatment-resistant genetic mutations; and phenotyping, which assesses the viral response to ART agents. Genotyping is the preferred test in most clinical situations.
In New York State, third-party reimbursement programs, including Medicaid, the New York State AIDS Drug Assistance Program (ADAP), and private insurers, often limit the number of resistance tests per year (within 12 months following date of first use). Medicaid Managed Care Plans (MMCPs) and private insurers may require prior authorization for these services and may limit the number of resistance tests performed annually, such as three tests per year, regardless of whether genotyping, phenotyping, or a combination of testing is obtained.
Providers should refer to their patient’s specific plan regarding frequency, annual limits, and whether prior authorization is required for any genotypic and phenotypic HIV resistance tests. Detailed information regarding Medicaid managed care-covered benefits for resistance testing, including current procedural terminology (CPT), codes is available at www.health.ny.gov/health_care/medicaid/program/update/2014/2014-03.htm#exp.
Investigational technologies, such as “single-copy” assays or “deep sequencing,” are under development; however, because they are not currently in use in clinical settings, these tests are not addressed here.
Updated June 2016
Genotypic resistance assays detect mutations known to be associated with therapeutic failure by directly sequencing the genomic coding region of the protein inhibited by the ART drug. The genomic mutations, which may include substitutions, insertions, or deletions in the viral protein’s coding region, are then compared with the known mutation(s) associated with the ART agent(s) clinical resistance profile.
Direct sequencing-based methods have been approved by the FDA, but the ViroSeq HIV-1 Genotyping System (Abbott Laboratories) is the only FDA-approved assay currently available. In addition, laboratory-developed (“in-house”) genotyping assays are available through several commercial laboratories (e.g., GenoSure MG, Monogram/LabCorp). Advances in genotyping assays continue to evolve. Testing for resistance to integrase strand transfer inhibitors and fusion inhibitors is now available and should be considered when resistance to these classes of drugs is a concern, such as when transmission of resistant virus is suspected or when a patient fails a regimen that includes one of these drugs.
In the RNA-based genotyping assays, the HIV-1 RNA is isolated from a plasma specimen and reverse-transcribed to produce complementary DNA (cDNA). Specific regions of the HIV genome are amplified by PCR and sequenced. This sequence is then compared with that of a drug-sensitive (“wild-type”) strain of HIV, and differences (mutations) present in the specimen sequence are noted. Computer software is generally used to perform this comparison and to predict whether resistance to specific drugs is likely to result from the particular combination of mutations detected in the virus. For most genotypic assays, this prediction is based on a set of rules derived from clinical observations, laboratory studies, and the advice of experts in the field. The actual prediction of resistance may vary from laboratory to laboratory for some combinations of mutations, depending on the interpretation algorithm used to define the rules.
Currently available RNA genotypic assays require a minimum viral load in the range of 500 to 2,000 copies/mL, depending on the assay, and generally require 2 weeks or less for results. DNA-based genotypic assays96 are becoming commercially available, such as the GenoSure Archive (Monogram/LabCorp). These assays use next-generation sequencing technology and are designed to overcome the limitations that commonly used RNA genotypic assays encounter in the presence of low-level viremia. In traditional genotypic assays, identification of resistance mutations is often not possible when viral load levels are below the lower limit of detection of a given assay; the lower limit may range from 500 to 1,000 copies/mL across available assays.
In DNA-based genotypic assays, integrated proviral DNA is extracted from HIV-infected cells, rather than from the circulating HIV in the plasma. Once the proviral HIV cell-associated DNA is extracted, the DNA is PCR-amplified, sequenced, and analyzed in analogous fashion to the older genotype RNA methodologies. The coding sequences for reverse transcriptase-, protease-, and integrase-targeted inhibitors are matched, as with the RNA-resistance genotype assays, with known resistance-associated mutations. The results are usually reported as “sensitive,” “resistant,” or “resistance possible” for a given ART agent. Although the clinical efficacy of the DNA-based genotype assays has not been fully validated, this technology can provide information on “archived,” or noncirculating, viral resistance. It should not be assumed that all previous mutations will be detected. Although concordance across various studies using in-house, laboratory-developed tests was relatively high, the peripheral blood mononuclear cell (PBMC)-derived DNA assays often did not detect known previous mutations that had been documented with plasma-based RNA tests97-99; the results could vary by class, with the manufacturer’s own study showing lower concordance for protease mutations relative to those of reverse transcriptase in patients whose current viral load was undetectable.100 However, testing of archived proviral DNA may provide useful additional information when making decisions about switching ART regimens for those who are virologically suppressed or those with repeated low-level viremia, especially when historical data are unavailable.101 The commercial assay has not been validated for patients with viral loads >500 copies/mL, although some studies are investigating the assay’s performance at higher viral loads, when wild-type virus may have replaced drug-resistant variants typically detected by RNA-based assays.102 The results obtained from archived proviral DNA testing should be used to supplement all other available information regarding treatment and resistance history.
Neither the RNA- nor DNA-based resistance assays can detect mutations associated with currently available HIV entry inhibitors (see below).
An older, algorithmic resistance profile based on genomic sequencing “virtual phenotype” (VIRCO, vircoTYPE) ceased to be clinically available in the United States as of December 2013. It compared the results of a patient’s genotype and predicted potential drug sensitivities by comparing a patient’s genotypic mutational profile with a database of laboratory and genotypic (sequence) and phenotypic (drug sensitivity) data and samples.
Updated June 2016
Although still available, phenotypic assays generally do not add to the information provided by currently used genotypic assays. A phenotypic assay provides a direct measure of drug resistance and is analogous to antibiotic-susceptibility testing of bacteria. The currently available phenotypic assays use recombinant DNA methods to measure the ability of a patient’s virus to grow in the presence of a drug. Therefore, results from a phenotypic test include the net effect of any and all resistance mutations.
In the phenotypic assay, HIV RNA is isolated from plasma and converted into cDNA, and the relevant region is amplified by PCR. This amplified material is inserted into a recombinant virus system whereby the susceptibility to different drugs can be tested. The result from the phenotypic assay is a value that defines the concentration of the drug required to reduce growth of the virus by 50% (IC50). The IC50 of the patient’s virus is compared with the IC50 of a drug-sensitive (wild-type) reference virus, and the fold change is defined. If the IC50 of a person’s virus is greater than that of the reference virus for a particular drug, then the person’s virus has decreased sensitivity to the drug. The relative fold change helps determine whether the drug should still be included in the ART regimen or whether it should be removed entirely. Monogram Biosciences offers phenotypic resistance testing through clinical laboratories with the PhenoSense assay. Phenotypic assays have a minimum viral load requirement of 500 to 1,000 copies/mL and generally require 3 to 5 weeks for results. Phenotypic assays are more technically complex, labor-intensive, and expensive than genotypic assays.
3. Technical Limitations of Genotypic and Phenotypic Assays
Updated June 2016
In addition to the minimum viral load requirements needed for amplification (generally at least 500 to 1,000 copies/mL) in genotypic or phenotypic RNA-based resistance assays, all resistance assays, including the DNA-based genotype, are limited by sampling bias. Unlike acute infection, where infection is often established by a single progenitor virion103 (see Diagnosis and Management of Acute HIV Infection), in established HIV infection, HIV exists as a virus population comprising multiple genomic variants. Genotypic and phenotypic resistance assays are each more likely to detect the common viral variants and fail to identify the minor variants. Similarly, standard genotypic and phenotypic resistance testing performed on plasma specimens will not detect noncirculating, or archived, resistant virus (i.e., virus resistant to ART agents from previous regimens). If therapy is stopped altogether, the selective pressure from the ART agents suppressing the noncirculating virus is removed and a pan-sensitive or wild-type HIV population over time will begin to resurface and dominate the circulating virus population. When this occurs, the RNA-based genotypic and phenotypic resistance assays may fail to detect the ART-resistant virus, despite being present either as archived virus or at low levels. Although a DNA-based assay may have utility in these circumstances, clinical data are insufficient to recommend for or against its use in the patient care setting. For these reasons, all copies of the patient’s previous genotype and/or phenotype resistance testing, along with the ART medication history, should be retained, and the information should be combined and used in constructing a subsequent ART regimen. Once resistance develops, it can be expected to persist indefinitely to that specific drug in archived form.
Another, more subtle, limitation is related to the level at which a virus is sensitive to a given ART agent. This “cutoff” may vary across assays, even when the same viral sample is used. Consultation with an experienced provider for interpretation of results is crucial.
4. Co-Receptor Tropism Assay
Updated June 2016
Co-receptor tropism analysis determines which cellular co-receptor (CCR5 or CXCR4) is used by the HIV-infected individual’s dominant viral population to gain access to host cells. The majority of acutely or recently infected individuals, including perinatally infected children, have a CCR5-tropic virus.
Because CCR5-tropic virus predominates early in HIV infection, whereas CXCR4-tropic virus is often present in late-stage disease, the CCR5 variant may be preferentially transmitted compared with CXCR4 variants. In chronically HIV-infected individuals, a population of mixed CCR5- and CXCR4-tropic viruses, as well as dual-tropic viruses, may also be detected. The tropism of these viral populations is often referred to as dual/mixed or D/M HIV.
In the United States, most co-receptor tropism testing involves phenotypic assays. However, genotypic assays, which predict tropism based on algorithmic analysis of viral V3 sequencing binding site,104,105 are also available.
Although phenotypic testing can determine a viral population containing both tropisms, it is not sufficiently sensitive to differentiate between mixed and dual tropism. The Trofile (Monogram Biosciences) co-receptor tropism assay is an RNA-based test that permits phenotypic identification of CCR5, CXCR4 co-receptor, or dual/mixed-tropic (CXCR4/CCR5-utilizing) HIV-1 and should be used prior to the initiation of a receptor antagonist.
Another commercially available recombinant phenotypic assay for assessing HIV chemokine co-receptor tropism is the Phenoscript assay (Eurofins VIRalliance). In this assay, a 900-bp portion containing the patient’s V1-V3 envelope virus is amplified and inserted into a HIV-1 vector lacking the corresponding V1-V3 section. The fully complemented HIV-1 is then able to produce virus that can be used to infect cell lines with either CCR5 or CXCR4 on their surfaces with a colorimetric readout. The results are reported in a similar manner as the Trofile (i.e., CCR5-trophic, CXCR4-trophic, or dual/mixed tropic). This assay has not been validated in a clinical trial setting or against the Trofile assay.
Two DNA-based tropism assays are also available. The HIV-1 Coreceptor Tropism, Proviral DNA (Quest Diagnostics) uses population sequencing of the HIV envelope V3 loop to detect the presence of CXCR4-tropic HIV-1.106 The Trofile DNA (Monogram Biosciences) uses the complete gp160 coding region to distinguish whether the HIV-1 population uses CCR5, CXCR4, or both (i.e., dual/mixed tropism) to gain entry into the cell. Unlike HIV-1 RNA-based assays, both the Trofile DNA and HIV-1 Coreceptor Tropism can detect virus in the setting of undetectable HIV-1 viral load levels and should be used when HIV RNA is beneath the lower limit recommended for RNA-based tropism assays (<1,000 copies/mL).
Resistance to the class of CCR5 co-receptor antagonists develops by two unrelated mechanisms. First, the patient’s viral population shifts its co-receptor usage (i.e., uses CXCR4 exclusively or uses both CCR5 and CXCR4 receptors to gain entry into the cell). The current assays are not sufficiently sensitive to discriminate between mixed- or dual-tropic populations. The second method by which resistance to a CCR5 receptor antagonist may develop is by the virus mutating and binding to the CCR5 receptor with the drug antagonist still in place. This second method can be discerned by a flattening of the IC90 curves in a phenotypic assay or potentially by genotypic analysis. Analysis by phenotypic assay is the preferred method for this purpose because genotypic data are more complex.
5. Replicative Capacity
Replicative capacity information may be provided as an adjunct to phenotypic or combination genotypic-phenotypic resistance assays. The relative replicative capacity of the virus from the patient is calculated as the ratio of the patient-derived sequences to wild-type sequences. A ratio of less than 1 reflects a reduced replicative capacity as compared with that of the wild-type control. The full clinical value of this adjunctive information remains under investigation, and it has no clear clinical value at this time.
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. A table of common and/or severe adverse effects associated with ART is available in the Department of Health and Human Services guidelines, see Table 14: Antiretroviral Therapy-Associated Common and/or Severe Adverse Effects.
Bone Marrow Suppression
Updated March 2006
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.
Updated March 2006
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.
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.
Lactic Acidosis/Hepatic Steatosis
Updated March 2006
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.
Updated January 2007
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. 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.107 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 after the first 8 weeks of pregnancy if there are no other options and the benefits outweigh the risks. For additional information, see the DHHS Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.
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.
Updated September 2012
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.108,109 Renal impairment necessitates dose adjustment or discontinuation of many antiretroviral agents.
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:
- 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/
- 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/
- 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.109,110 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.
D. Monitoring for Allergic Reactions Associated with ART
Updated June 2010
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 8). (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)
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 8). 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.
Individuals with human leukocyte Ag (HLA)-B*5701, HLA-DR7, and HLA-DQ3 have a genetic predisposition to development of abacavir hypersensitivity. HLA-B*5701 testing is the most thoroughly documented method for assessing for abacavir hypersensitivity and should be determined prior to treatment with this agent.111,112 Unlike virus-specific tests (HIV genotype, phenotype, co-receptor tropism assays), HLA genotyping is necessary only once during an individual’s lifetime, because it will not change over time.
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.
VII. CHANGING A SUCCESSFUL INITIAL ART REGIMEN
Updated March 2006
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
VIII. FAILURE TO ACHIEVE GOALS OF INITIAL ART
Updated March 2006, currently under revision
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.113
IX. SECOND-LINE REGIMENS AND SALVAGE ART
Updated March 2006, currently under revision
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.
X. MANAGEMENT OF TREATMENT INTERRUPTION
Updated June 2006
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)
There 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/.
XI. REFERRING PATIENTS TO RESEARCH STUDIES
Updated March 2006
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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APPENDIX A: NEW YORK STATE DEPARTMENT OF HEALTH POLICY STATEMENT, JUNE 23, 2016
Posted June 23, 2016
APPENDIX B: EVIDENCE BASE FOR RECOMMENDATIONS TO INITIATE ART
Under Revision June 2015
APPENDIX D: RISK OF PROGRESSION TO AIDS-DEFINING ILLNESS IN A COHORT OF HOMOSEXUAL MEN PREDICTED BY BASELINE CD4 T CELL COUNT AND VIRAL LOAD
APPENDIX E: PROGNOSIS ACCORDING TO CD4 CELL COUNT AND VIRAL LOAD IN THE PRE-HAART AND HAART ERAS