Updated August 2010

I. INTRODUCTION

Antiretroviral (ARV) therapy refers to the use of pharmacologic agents that have specific inhibitory effects on HIV replication. The commercially available ARV drugs that are approved by the Food and Drug Administration (FDA) for the treatment of HIV/AIDS are listed in Appendix A. The use of less than three active agents is not recommended for initiating treatment in non-pregnant adults.

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 CCR-5 co-receptor antagonists, and the integrase inhibitors. The current standard for formulating a highly active antiretroviral therapy (HAART) regimen recommends the use of either a PI or an NNRTI in combination with two NRTIs. The combination of three NRTIs or two NRTIs and an NtRTI is not as potent as the recommended combinations and should not be used for initiation of ARV therapy.

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II. GOALS, BENEFITS, AND RISKS OF HAART

March 2006

Recommendations:

Clinicians should prescribe a HAART 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 ARV therapy. 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 ARV therapy options (see Section IV: The Importance of Patient Adherence). Most patients will benefit from ARV therapy, provided that they are able to take the medications reliably. It is the clinician’s responsibility to involve the patient in the decision-making process when deciding whether to implement ARV therapy. The clinician needs to review the benefits and risks of treatment for each individual patient (see Table 2).

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III. DECIDING WHEN TO INITIATE ARV THERAPY

June 2009 – currently under revision

Evidence is accumulating to show that initiating antiretroviral therapy in patients with CD4 counts >350 cells/mm³ may result in reduced morbidity and mortality. After review of the available data, however, this Committee does not believe that a definitive recommendation to initiate therapy in all patients with CD4 counts >350 cells/mm³ can be made at this time. Rather, clinicians should evaluate patients with CD4 counts >350 cells/mm³ for comorbidities or coexisting conditions that may influence the decision to treat and should favor treating earlier when appropriate. Consultation with a clinician with extensive experience with ARV treatment and management is recommended. Therapy is also recommended for asymptomatic patients whose CD4 count is approaching 350 cells/mm³ rather than waiting until it decreases to <350 cells/mm³. Given the current data, there is no upper CD4 limit for initiating therapy in patients who wish to receive it. The decision to initiate therapy depends on many individual factors for each patient and requires both a careful review by the clinician and involvement of the patient.

The New York State Department of Health AIDS Institute follows the Centers for Disease Control and Prevention (CDC) definition of HIV/AIDS and list of AIDS-defining conditions.

See Appendix B for a comparison of the New York State Department of Health AIDS Institute recommendations and the Department of Health and Human Services recommendations.

General Recommendations:

The decision to begin ARV therapy should be individualized and should incorporate an assessment of the following factors:

• The patient’s risk of progression to illness or death if left untreated
• The patient’s readiness and willingness to adhere to the therapy prescribed and potential barriers to adherence
• Comorbidities and coexisting conditions
• The risk of long-term toxicity and drug-drug interactions

Clinicians should involve patients when planning their treatment regimens. In conjunction with their clinicians, patients should make the final decision of when to initiate ARV therapy.

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A. Benefits and Risks of Initiating ARV Therapy

Table 4 outlines the benefits and risks to consider when deciding when to initiate ARV therapy.

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B. Potential Barriers to Adherence

Recommendation:

Except when initiation of treatment is clinically urgent, clinicians should use more than one visit for education and counseling before committing a patient to a specific therapy. Counseling and education should include the following:

• Available treatment options and potential benefits and risks of therapy (see Table 4)
• The need for strict adherence and the risk of viral drug resistance when adherence is suboptimal (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
• Counseling regarding specific issues relevant to the patient’s individual clinical situation

Except when initiation of treatment is clinically urgent, more than one visit before initiating ARV therapy is advisable to ensure adequate education and understanding of the importance of adherence and to evaluate and address potential barriers to therapy. These barriers may include active alcohol or drug use, medication side effects, lack of insurance or transportation, depression, low literacy, or a poor social support system.

Patients who meet clinical criteria for initiation of ARV therapy but who are at high risk for poor adherence may benefit if long-term ARV therapy 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. These patients should remain under particularly close observation for clinical and laboratory signs of disease progression. ARV therapy should be initiated as soon as the patient seems prepared to strictly adhere to a treatment regimen. In patients with advanced AIDS, it may be appropriate to initiate ARV therapy even if barriers to adherence are present. In these cases, referrals to specialized adherence programs should be made for intensified adherence support (see Appendix C: New York State Adherence Services Contact List).

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C. Initiating ARV Therapy Following Acute Opportunistic Infections

Recommendation:

Clinicians should strongly recommend that patients recovering from acute opportunistic infections initiate ARV therapy as soon as it has been established that the patient can tolerate ARV therapy and the potential for drug-drug interactions has been minimized.

Clinicians should strongly recommend that patients recovering from acute opportunistic infections initiate ARV therapy as soon as it is safe based on patient tolerability and drug-drug interactions.³⁹ In some cases, determining the optimal timing for initiating therapy in these patients is complex and may require consultation from a clinician with extensive experience with ARV treatment and management. After initiating ARV therapy, clinicians need to be alert to the possibility of immune reconstitution syndromes as CD4 cell counts are restored (see Immune Reconstitution Inflammatory Syndrome [IRIS] in HIV-Infected Patients).

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IV. THE IMPORTANCE OF PATIENT ADHERENCE

July 2004

Recommendations:

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

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

Interventions should be intensified in times of decreased adherence.

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

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

Potential barriers to adherence include:

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

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

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

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

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

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

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

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

Strategies:

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

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B. Barriers to and Predictors of Adherence

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

Strategies:

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

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C. Educating the Patient About Adherence

Strategies:

• To foster understanding of the importance of adherence, the healthcare team should present information in language that is easily understood by the patient, consistent with the patient’s level of education, and free of medical jargon.
• Sufficient time should be taken to fully educate the patient about the goals of treatment and the need for adherence, both before beginning treatment and frequently during therapy.
• Literature should be provided and, if available, peer counselors should be enlisted to reinforce education efforts. Attention to language and use of culturally sensitive education materials are essential.
• Adherence tools should be provided. Written schedules, pictures of medications, pillboxes, alarms, and pagers may help patients understand and remember medication schedules. The need for greater adherence support (e.g., support groups, home visits, day treatment programs) should be assessed.
• Reviewing the viral load response to HAART 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 combination ARV regimen is not available for more than several days, all ARV agents should be stopped until the entire ARV regimen is again available to avoid the emergence of resistance while using a less suppressive regimen. This issue is of greatest concern when the ARV agent in question is one to which a single point mutation confers a great degree of resistance (e.g., lamivudine and NNRTIs), which appears rapidly in the absence of a fully suppressive regimen.

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D. Patients’ Beliefs and Attitudes

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

Strategies:

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

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E. Substance Use and Adherence

Strategies:

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

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F. How the Regimen Affects Adherence

Studies demonstrate the difficulty of maintaining strict adherence to complex ARV regimens and show significant levels of poor adherence in the "real world" of HIV care. Improved pharmacokinetics may produce HAART regimens that simplify dosing and that may be more forgiving of missed dosages; however, until then, it is imperative that the clinician devotes sufficient time at each patient visit to assess the degree of adherence to prescribed therapies.

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. The relationship of dosing with or without meals can add more complexity to the schedule. The concern about potential side effects prompts some patients to diminish adherence, often without confiding in the healthcare team.

Strategies:

• The entire medication list should be reviewed at every clinical visit to limit the concomitant use of unnecessary, ineffective, or contraindicated medications.
• Patients should be educated about the risks and benefits of HAART and preservation of future treatment options to allow them to develop realistic long-term expectations.
• The side effects and toxicities associated with HAART 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).
• Regimens can be designed to "spare" a particular class or classes of ARV drugs (see Table 5).

Class-sparing regimens may simplify dosing, delay certain side effects or drug interactions, and preserve the spared medications for later use in the event of failure of the initial regimen. Sequencing strategies should be individualized to address each patient’s concurrent morbidities and medications, ability to adhere to complex regimens, and personal tolerance for adverse medication effects.

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V. SELECTING AN INITIAL ANTIRETROVIRAL REGIMEN

August 2010

Recommendations:

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

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

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

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

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

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

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

Preferred, alternative, and contraindicated combinations for initial treatment of HIV infection are listed in Tables 6A-C. Clinicians should consult a provider with extensive experience with ART when a patient’s resistance profile indicates the need for a regimen not listed in Tables 6-A or -B.

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

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

Alternative antiretroviral regimens are effective and tolerable but have potential disadvantages compared with the preferred regimens in Table 6-A. In some cases, an alternative regimen may be the preferred regimen based on the individual characteristics of the patient. Additional alternative agents that are not listed in Table 6-B may be effective but are unlikely to be necessary as components of initial regimens.

Ritonavir Boosting

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

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

Rationale for Class-Sparing Regimens

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

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VI. MONITORING OF PATIENTS RECEIVING ARV THERAPY

The measurement of plasma viral load and of CD4 lymphocyte counts along with clinical assessment can provide an accurate picture of disease activity and response to ARV therapy. Periodic monitoring of viral load, CD4 counts, and other laboratory tests are necessary to evaluate the response to ARV therapy and its potential related side effects (see Figure 1). In the setting of HAART failure, viral resistance assays should be used. Appendix D lists drugs with overlapping toxicities to guide frequency of monitoring.

Figure 1: Monitoring Antiretroviral Therapy

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A. Monitoring Markers of HIV Infection

1. Viral Load

March 2006

Recommendations:

In ARV treatment-naïve patients or patients who are on a successful regimen, plasma viral load should be measured at baseline and every 3 to 4 months thereafter. Patients with CD4 counts >500 cells/mm³ may only require viral load monitoring every 6 months. (III)

Viral load should be measured immediately before initiation or change of ARV therapy and every 2 to 4 weeks after initiation or change until maximal suppression is documented. Once maximal suppression is attained, monitoring of viral load should occur every 3 to 4 months. (III)

If there is a significant increase (3-fold increase or more) in viral load without clear explanation, measurement should be repeated to confirm virologic failure. (III)

Virologic failure should prompt the clinician to assess the patient’s adherence and to check for the presence of viral resistance. (I)

Plasma levels of viral RNA have been shown to correlate closely with clinical outcome. More than a dozen clinical trials involving thousands of patients have demonstrated this correlation at various stages of disease and with a wide variety of previous experience with ARV treatment (see Appendix E and Appendix F). In addition, the level of viral RNA measured in this way provides the most precise means of establishing whether a response to ARV therapy has occurred. Typically, in patients beginning therapy or in those changing therapy as a result of virologic failure, viral load measured 2 to 4 weeks after therapy initiation decreases by at least 1 log (10-fold) in the presence of effective therapy (see Table 7). For patients who do not have background antiretroviral resistance, an undetectable viral load (<50 copies/mL) is usually achieved within a few months. Patients with resistance or a baseline viral load of >1 x 10^5-6 copies/mL typically achieve an undetectable viral load after 6 months of effective treatment. An absent or incomplete response of the viral load to ARV therapy should raise concerns about poor patient adherence to therapy and/or viral resistance (see Section IV: The Importance of Patient Adherence and Section VIII: Failure to Achieve Goals of Initial HAART).

Viral genetic diversity is characteristic of HIV-1. Furthermore, subtypes (clades) of the virus from various regions of the world are genetically distinct. Current polymerase chain reaction (PCR) viral load assays were developed primarily for clade B, which is the strain prevalent in Europe and North America. Non-clade B infections are present in approximately 2% of HIV-infected persons in the United States. Infection with a non-clade B strain should be suspected in the presence of 1) a low viral load and a low CD4 cell count in a patient not yet receiving HAART, or 2) a decreasing CD4 count despite a low or undetectable viral load. Occasionally, patients may be infected with other undetermined subtypes of HIV-1 or HIV-2. Currently, viral load assays are not available that quantify these subtypes; therefore, response to treatment should be monitored by CD4 counts and clinical parameters.

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2. Lymphocyte Subsets

March 2006

Recommendations:

Clinicians should measure CD4 cell counts at the time of diagnosis of HIV infection and every 3 to 4 months thereafter. (III)

The absence of a significant CD4 cell count increase should not be interpreted as treatment failure if the viral load declines appropriately. (III)

CD4 lymphocyte count, expressed as cells/mm³ of blood, is a less precise indicator of ARV response than viral RNA but is an essential measure to evaluate immunologic staging, to predict the risk of clinical progression, and to make decisions regarding prophylaxis of opportunistic infections. CD4 percentages are useful for comparison to absolute numbers, particularly in settings in which unexpected increases or decreases in absolute counts are observed. A significant change in CD4 cell percentage is a difference of >3%.

The CD4 response to ARV therapy, however, can be unpredictable. Although a significant increase often occurs among patients treated with effective ARV therapy, the absence of such an increase should not be taken to mean treatment failure if the viral load declines appropriately. Such a lack of correlation between viral load and CD4 cell response is particularly common among patients with extremely low initial CD4 cell counts (<50 cells/mm³). In addition, some patients have stable or increasing CD4 counts, although their viral loads are not well suppressed. Patients with these discordant responses who are clinically stable need close monitoring but may not need to change therapy immediately if an effective alternative HAART regimen cannot be constructed based on the results of resistance testing. Appendix E illustrates that both parameters in interaction are predictive of disease progression.

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3. HIV Resistance Assays

October 2006

Recommendations:

Clinicians should perform resistance testing under the following circumstances:

• At baseline in the setting of acute HIV infection, regardless of whether ARV therapy is being initiated (genotypic testing)
• In ARV therapy-naïve patients before initiation of ARV therapy (genotypic testing) (III)
• In patients experiencing treatment failure or incomplete viral suppression while receiving ARV therapy (genotypic and/or phenotypic testing) (I)

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

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

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

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

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

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

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

• HIVresistanceWeb (www.hivresistanceweb.com)
• Stanford University HIV Drug Resistance Database (hivdb.stanford.edu)
• HIV Sequence Database (www.hiv.lanl.gov/content/hiv-db/mainpage.html)

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

Genotypic Assays

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

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

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

Phenotypic Assays

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

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

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

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4. Antiretroviral Serum Levels (Therapeutic Drug Monitoring)

March 2006

Recommendation:

Monitoring blood levels of ARV drugs is not currently recommended. (III)

Monitoring of plasma drug levels, particularly the PIs, has been valuable in clinical research protocols to assess patient adherence and drug absorption, correlate ARV drug levels to virologic response, and evaluate drug-drug interactions. However, reliable drug level monitoring has not been conclusively proven to enhance patient management. At the current time, monitoring of ARV drug levels is not recommended outside clinical trials.

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B. Laboratory Monitoring of Antiretroviral Therapy Side Effects

This section describes monitoring of the following ARV therapy side effects: bone marrow suppression, pancreatitis, lactic acidosis/hepatic steatosis, hepatotoxicity, and renal toxicity. Recommendations concerning long-term metabolic and musculoskeletal complications, including glucose metabolism, dyslipidemia, body fat changes, osteopenia, osteoporosis, and avascular necrosis, are included in Long-Term Complications of Antiretroviral Therapy.

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1. Bone Marrow Suppression

March 2006

Recommendation:

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

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

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2. Pancreatitis

March 2006

Recommendations:

When patients receiving ARV therapy 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 ARV medications, the clinician should temporarily suspend the entire ARV regimen. A new ARV regimen may be initiated when enzymes are normalized but should not include ARV 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 HAART. Didanosine has been the agent most often associated with this complication; however, cases of pancreatitis also have been reported with other ARV agents since the advent of triple combination therapy. Tenofovir increases the levels of didanosine, thereby increasing the theoretical risk of pancreatitis. Thus, when these ARV medications are used in combination, the dose of didanosine should be reduced (see Appendix A).

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

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

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3. Lactic Acidosis/Hepatic Steatosis

March 2006

Recommendations:

When patients develop symptoms consistent with lactic acidosis syndrome in conjunction with an elevated lactate level (>2 mmol/L) and decreased serum bicarbonate (<20 mmol/L), the clinician should temporarily discontinue the entire ARV 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, ARV therapy 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, ARV therapy should be discontinued. If the evaluation does not support the diagnosis of lactic acidosis, ARV therapy may be restarted.

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

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4. Hepatotoxicity

January 2007

Recommendations:

Clinicians should obtain serum liver enzyme levels at baseline and every 3 to 4 months thereafter in patients receiving HAART. (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 ARV 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 ARV 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 HAART. 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 ARV agents, should be discontinued (see Section X: Management of Treatment Interruption).

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

Some clinicians would avoid using efavirenz after severe nevirapine-related hepatotoxicity (LFTs >5x ULN) with or without Grade 4 rash (Stevens-Johnson syndrome); however, there is no clear evidence to support an association between nevirapine-related hepatotoxicity and efavirenz-related hepatotoxicity.⁴⁰ For mild to moderate nevirapine-related hepatotoxicity (LFTs >3-5 x ULN), switching to efavirenz after complete resolution of hepatotoxicity is an option if there are no other contraindications to efavirenz. Contraindications to efavirenz include known adverse reactions to efavirenz, first-trimester pregnancy, or strong likelihood of becoming pregnant.

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

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

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5. Renal Toxicity

November 2006

Recommendations:

HIV infection has been associated with several renal complications that may lead to renal insufficiency or failure.⁴¹ Renal impairment necessitates dose adjustment or discontinuation of many ARV agents (see Appendix A).

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

1. Modification of diet in renal disease (MDRD): calculates creatinine clearance 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/
2. 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

Renal impairment has been reported in patients receiving tenofovir.^42,43 The extent of this toxicity is unclear. Tenofovir is excreted by glomerular filtration and tubular secretion, and a preliminary study suggests that persons with low estimated GFR are at a higher risk for tenofovir-associated renal toxicity even when baseline serum creatinine is normal. 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.

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6. Myopathy/Myositis

March 2006

Recommendation:

Measurement of serum creatinine phosphokinase (CPK) is not routinely indicated. If the patient becomes symptomatic (e.g., muscle pain or weakness), CPK should be measured. (II)

HIV infection may be associated with asymptomatic elevation of CPK. In this setting, serial monitoring is not indicated.

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C. Monitoring for Allergic Reactions Associated With ARV Therapy

June 2010

Recommendations:

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

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

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

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

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

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

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

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

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

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

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

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

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

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VII. CHANGING A SUCCESSFUL INITIAL HAART REGIMEN

March 2006

Recommendations:

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

When considering a change in the ARV 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 HAART 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 HAART 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 ARV 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 ARV agents may increase the risk of drug resistance and reduce the number of available treatment options in the future
• maximal viral suppression may not be maintained
• changing regimens may have an emotional impact on the patient

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VIII. FAILURE TO ACHIEVE GOALS OF INITIAL HAART

March 2006 – currently under revision

Recommendations:

Clinicians should address adherence, obtain resistance assays, and consult with an HIV Specialist before changing HAART regimens that have failed.

Clinicians should not change an ARV 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 HAART regimen cannot be constructed as a result of drug resistance or intolerance.

The goal of HAART 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 HAART. The initial HAART regimen affords the best opportunity to attain maximal viral suppression. Currently, in clinic practice, only 60% to 70% of patients receiving initial HAART 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 HAART 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 ARV Therapy). 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 HAART, 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 HAART. 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 HAART. Such patients have been shown to benefit from HAART (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 HAART regimen can be constructed using available ARV agents to attempt to achieve maximal viral suppression. However, when this is not possible, maintenance of the current regimen is acceptable.⁴⁴

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IX. SECOND-LINE REGIMENS AND SALVAGE HAART

March 2006 – currently under revision

Recommendations:

Clinicians should consult with an HIV Specialist when constructing a second-line regimen and salvage therapy regimens.

Clinicians should review individual ARV 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 ARV 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 HAART regimen, the expectations are still good for second-line regimens, especially with the availability of new ARV drugs. Salvage therapy refers to ARV regimens prescribed for patients who have failed serial HAART 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 HAART regimens after first and second HAART regimens have failed.

Because of cross-resistance within ARV 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 ARV-experienced patients have shown that these tests are valuable when choosing subsequent successful HAART 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 ARV 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 ARV drugs, colloquially referred to as “mega-HAART” or “multi-drug rescue therapy,” may be attempted in patients who have a high level of drug resistance in all available ARV classes. There are limited data on such an approach, with an unclear benefit in the context of the high pill burdens and significantly increased toxicity of such complex regimens.

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

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

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X. MANAGEMENT OF TREATMENT INTERRUPTION

June 2006

Recommendations:

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

When HAART 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 HAART in patients receiving ARV medications with prolonged half-lives, such as NNRTIs, clinicians should consult with an HIV Specialist 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 ARV therapy. 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 ARV therapy 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 ARV therapy with patients who were given intermittent ARV therapy. The patients in the intermittent therapy group received ARV therapy 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 HAART; 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 ARV medications with prolonged half-lives and low resistance thresholds complicates discontinuation of treatment. Low plasma levels of ARV 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 ARV 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 an HIV Specialist when considering discontinuation of ARV therapy.

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 HAART 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://trialsearch.org/clinical_trials/index.html.

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XI. REFERRING PATIENTS TO RESEARCH STUDIES

March 2006

Recommendations:

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

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

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

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

The first priority in the care of any patient is to maximize the therapeutic benefit of treatment and to support the individual. Sometimes patients ask if they can help with any new research studies, and clinicians often realize that the patient might benefit from a therapy that is currently under study. In addition, many standard therapies are still being scrutinized in terms of timing and appropriateness. Because there are so many clinical uncertainties (e.g., when to initiate ARV therapy, 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://trialsearch.org/clinical_trials/index.html), http://www.aidsinfonyc.org/ and the AIDS Treatment Data Network (http://www.atdn.org/).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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XII. ACCESS TO EXPANDED ACCESS OR COMPASSIONATE USE THERAPIES

March 2006

Obtaining drugs on compassionate use can be a time-consuming and cumbersome task, particularly for clinicians who are at institutions without any research support system, but it is often the patient with the fewest options who needs these drugs the most. Clinicians should consider making these expanded access or compassionate use therapies available if the need exists in their practice. If the infrastructure is not present to do so, referral to other sites should be made.

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XIII. FUTURE DIRECTIONS OF HAART

March 2006

Although HAART has been successful in suppressing viral replication, treatment failures are common and most available ARV agents have class-cross resistance problems. There are many new drugs in development in both existing and novel classes (e.g., entry inhibitors, integrase inhibitors) that may offer more solutions for these problems. As these agents are approved by the FDA, updates to these guidelines will be made available on the HIV Clinical Resource website at: http://www.hivguidelines.org.

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REFERENCES

1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3, 2008. Available at: http://www.aidsinfo.nih.gov. Recommends treatment for patients with any of the following: AIDS-defining illness, HIV-associated nephropathy, and HBV co-infection that requires treatment.

2. Hammer SM, Eron JJ Jr, Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society — USA Panel. JAMA 2008;300:555-570. [PubMed] Recommends treatment for patients with any of the following: symptomatic HIV disease, HIV-associated nephropathy, active HBV or HCV co-infection, plasma HIV viral load >100,000 copies/mL, rapidly declining CD4 count (>100 cells/mm³ per year).

3. European AIDS Clinical Society (EACS). Guidelines for the clinical management and treatment of HIV-infected adults in Europe, version 4. October 2008. Available at: www.eacs.eu. Recommends treatment for patients with any of the following: symptomatic HIV disease, active HCV co-infection, plasma HIV viral load >100,000 copies/mL, age >55 years.

4. May M, Sterne JA, Sabin C, et al. Prognosis of HIV-1–infected patients up to 5 years after initiation of HAART: Collaborative analysis of prospective studies. AIDS 2007;21:1185–1197. [PubMed] Significantly less risk for AIDS/death in patients who initiated therapy between 200-300 cells/mm³ than those who initiated at CD4 counts <200 cells/mm³.

5. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355:2283-2296. [PubMed] Patients with CD4 <350 cells/mm³ who were not receiving ARV therapy were at higher risk for both HIV-related and non-HIV-related mortality.

6. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naïve participants and in those not receiving ART at baseline in the SMART study. J Infect Dis 2008;197:1133-1144. [PubMed] Less opportunistic infections and serious non-AIDS-related events occurred in patients who initiated ARV therapy at CD4 counts >350 cells/mm³ rather than <250 cells/mm³.

7. When to Start Consortium, Sterne JA, May M, Costagliola D, et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: A collaborative analysis of 18 HIV cohort studies. Lancet 2009;373:1352-1363. [PubMed] Results suggest that 350 cells/mm³ should be the minimum threshold for initiation of ARV therapy.

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

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

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

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

12. Atta MG, Gallant JE, Rahman MH, et al. Antiretroviral therapy in the treatment of HIV-associated nephropathy. Nephrol Dial Transplant 2006;21:2809-2813. [PubMed] Patients with biopsy-proven HIVAN treated with ART had better renal survival compared with patients who did not receive ART.

13. Schwartz EJ, Szczech LA, Ross MJ, et al. Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal disease. J Am Soc Nephrol 2005;16:2412-2420. [PubMed] Data from a mathematical model concluded that prevention of progression to ESRD should focus on early antiretroviral treatment of HIV-infected patients who have evidence of HIV-associated nephropathy.

14. Wilkin TJ, Gulick RM. When to start antiretroviral therapy? Clin Infect Dis 2008;47:1580-1586. [PubMed] Recent review of data suggesting initiation of ARV treatment in patients with CD4 count >350 cells/mm³ and comorbidities, including HIV-associated nephropathy, active HBV or HCV co-infection.

15. Lucas GM, Eustace JA, Sozios S, et al. Highly active antiretroviral therapy and the incidence of HIV-1-associated nephropathy: A 12-year cohort study. AIDS 2004;18-541-546. [PubMed] HAART was associated with a substantial reduction in HIVAN incidence.

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

17. Ratner L, Lee J, Tang S, et al. Chemotherapy for human immunodeficiency virus-associated non-Hodgkin’s lymphoma in combination with highly active antiretroviral therapy. J Clin Oncol 2001;19:2171-2178. [PubMed] Patients with non-Hodgkin’s lymphoma who were receiving ARV therapy experienced a decrease in viral load and increase in CD4 count, despite concurrent chemotherapy. Improved immune function as a result of ARV therapy may result in improved bone marrow function.

18. Hoffman C, Chow KU, Wolf E, et al. Strong impact of highly active antiretroviral therapy on survival in patients with human immunodeficiency virus-associated Hodgkin’s disease. Br J Haematol 2004;125:455-462. [PubMed] Demonstrated significant improvement in survival for patients with HIV-associated Hodgkin’s disease who were receiving effective ARV therapy.

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

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

21. Medical Care Criteria Committee. Hepatitis B Virus. New York State Department of Health AIDS Institute; 2008. Available at: www.hivguidelines.org. Recommends treatment for patients with HBV co-infection that requires treatment.

22. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009;360:1815-1826. [PubMed] Initiating ARV therapy at CD4 counts <500 cells/mm³ and older age were independently associated with increased mortality.

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

24. Robbins GK, Spritzler JG, Chan ES, et al. Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trials Group Protocol 384. Clin Infect Dis 2009;48:350-361. [PubMed] Patients beginning ARV therapy with CD4 counts over 350 achieved greater normalization of CD4 counts and Cd4 subsets than patients starting with CD4 counts under 350.

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

26. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS 2008;22:841-848. [PubMed] Higher CD4+ counts on antiretroviral therapy are associated with lower rates of non-AIDS diseases and AIDS.

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

28. Egger M, May M, Chene G, et al. Prognosis of HIV-1–infected patients starting highly active antiretroviral therapy: A collaborative analysis of prospective studies. Lancet 2002;360:119-129. [PubMed] Baseline HIV-1 viral load was associated with a higher probability of progression when 100,000 copies/microL or above.

29. Wood E, Hogg RS, Yip B, et al. Higher baseline levels of plasma human immunodeficiency virus type 1 RNA are associated with increased mortality after initiation of triple-drug antiretroviral therapy. J Infect Dis 2003;188:1421-1425. [PubMed] Baseline levels of HIV RNA of >100,000 copies/mL are independently associated with mortality.

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

31. Marine-Barjoan E, Saint-Paul MC, Pradier C, et al. Impact of antiretroviral treatment on progression of hepatic fibrosis in HIV/hepatitis C virus co-infected patients. AIDS 2004;18:2163-2170. [PubMed] Patients with severe fibrosis had greater intervals between presumed date of HCV infection and initiation of ARV therapy than those with none to moderate fibrosis (median duration of ARV treatment was the same). The mean rate of fibrosis progression was significantly slower among patients exposed to HAART.

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

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

34. Phillips A, Pezzotti P; CASCADE Collaboration. Short-term risk of AIDS according to current CD4 cell count and viral load in antiretroviral drug-naïve individuals and those treated in the monotherapy era. AIDS 2004;18:51-58. [PubMed] Age was significantly associated with AIDS rate, with older people experiencing a higher rate [rate ratio 1.23 per 10 years older].

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

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

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

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

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

40. Sulkowski MS, Thomas DL, Mehta SH, et al. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: Role of hepatitis C and B infections. Hepatology 2002;35;182-189. [PubMed]

41. Röling J, Schmid H, Fischereder M, et al. HIV-associated renal diseases and highly active antiretroviral therapy-induced nephropathy. Clin Infect Dis 2006;42:1488-1495. [PubMed]

42. Zimmerman AE, Pizzoferrato T, Bedford J, et al. Tenofovir-associated acute and chronic kidney disease: A case of multiple drug interactions. Clin Infect Dis 2006;42:283-290. [PubMed]

43. Karras A, Lafaurie M, Furco A, et al. Tenofovir-related nephrotoxicity in HIV-infected patients: Three cases of renal failure, Fanconi syndrome, and nephrogenic diabetes insipidus. Clin Infect Dis 2003;36:1070-1073. [PubMed]

44. Deeks SG, Hoh R, Neilands TB, et al. Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection. J Infect Dis 2005;192:1537-1544. [PubMed]

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APPENDIX A

CHARACTERISTICS OF ANTIRETROVIRAL DRUGS

FDA Pregnancy Categories

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

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

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

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

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

Click here to view Table A-1: Abacavir (ABC)

Click here to view Table A-2: Didanosine (ddI)

Click here to view Table A-3: Emtricitabine (FTC)

Click here to view Table A-4: Lamivudine (3TC)

Click here to view Table A-5: Stavudine (d4T)

Click here to view Table A-6: Tenofovir (TDF)

Click here to view Table A-7: Zidovudine (AZT, ZDV)

Click here to view Table A-8: Delavirdine (DLV)

Click here to view Table A-9: Efavirenz (EFV)

Click here to view Table A-10: Etravirine (ETR)

Click here to view Table A-11: Nevirapine (NVP)

Click here to view Table A-12: Atazanavir (ATV)

Click here to view Table A-13: Darunavir (DRV)

Click here to view Table A-14: Fosamprenavir (FPV)

Click here to view Table A-15: Indinavir (IDV)

Click here to view Table A-16: Lopinavir/Ritonavir (LPV/r)

Click here to view Table A-17: Nelfinavir (NFV)

Click here to view Table A-18: Ritonavir (RTV)

Click here to view Table A-19: Saquinavir (SQV)

Click here to view Table A-20: Tipranavir (TPV)

Click here to view Table A-21: Enfuvirtide (T-20)

Click here to view Table A-22: Maraviroc (MVC)