This is the current release of the guideline.

This guideline updates a previous version: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Bethesda (MD): Department of Health and Human Services (DHHS); 2011 Oct 14. 167 p.

Adults and adolescents infected with human immunodeficiency virus (HIV) or at risk of infection

Note: These guidelines focus on treatment for HIV-infected adults and adolescents. Separate guidelines outline the use of antiretroviral therapy (ART) for other populations, such as pregnant women and children. There is a brief discussion of the management of women of reproductive age and pregnant women in this document. For a more detailed and up-to-date discussion on this group of women and other special populations, the Panel defers to the designated expertise offered by panels that have developed those guidelines.

Evidence Collection

The recommendations in the guideline are generally based on studies published in peer-reviewed journals. On some occasions, particularly when new information may affect patient safety, unpublished data presented at major conferences or prepared by the U.S. Food and Drug Administration (FDA) and/or manufacturers as warnings to the public may be used as evidence to revise the guidelines.

Search Strategy

When new information becomes available that warrants a change in the guideline recommendations, the database search depends on the type of revision that is needed. For example:

1. New U.S. Food and Drug Administration (FDA) drug approval that leads to inclusion as recommendation for initial antiretroviral therapy (ART) regimen: review of data from pivotal studies that led to the drug approval; published data on the randomized controlled trials; data submitted to the FDA for approval, as well as the FDA's evaluation; package insert information; and comparison with other existing data in the literature. In addition, a PubMed search is done on the new drug and any comparator drugs. In most instances, the data from the comparator trials have already been reviewed in the guideline document.
2. Recommendations for the use of drug resistance testing prior to initiation of ART: the Panel searches PubMed on data supporting improved virologic outcomes if baseline genotype testing is used to guide therapy. In most instances, data from randomized controlled trials, observational cohort studies, and cost-effectiveness analyses are reviewed.

Time Frame

Some portions of the guidelines are updated annually. In general, the time frame for the searches is for new publications within the most recent 3 to 5 years. As the field of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) moves very rapidly, data reported more than 5 years prior are generally outdated and do not reflect the contemporary practice.

Inclusion/Exclusion Criteria and Search Terms

Selection of inclusion and exclusion criteria depends on the sections that need to be updated. For instance, data related to recommendations for certain treatment regimens include randomized controlled trials between an experimental arm compared with what is considered as standard of treatment. The trials have to be large enough to demonstrate non-inferiority or superiority. The studies have to be published in peer reviewed journals or have been used by the FDA for drug approval.

In the case for reporting when to start ART, since there are no randomized controlled trials to address this question to date, the Panel uses large observational cohort data (generally >5000 patients) that have long term (>3 years) follow-up data evaluating clinical outcomes (survival, lack of disease progression, safety) or surrogate marker (CD4, viral load) endpoints. In most cases, the Panel compares these outcomes with or without ART.

In cases where the Panel makes revisions of recommendations based on safety data, the information that may prompt a change can be based on FDA drug warnings and label changes. In that case, the published literature for similar case reports will also be reviewed.

Search terms depend on the type of recommendation that is examined. For antiretroviral drug regimen recommendations, search terms include the drug names, treatment-naïve or treatment-experienced, virologic responses, toxicities, immunologic responses, efficacy, and randomized controlled trials. For recommendations on when to start treatment, search terms include antiretroviral therapy, outcomes, survival, when to start, CD4 count, and AIDS. For toxicity-related issues, search terms include drug names, toxicities, adverse effects, outcomes, and specific adverse effects that are relevant to the case (e.g., hepatotoxicity, QT prolongation, arrhythmia).

Not stated

Quality of Evidence for Recommendation

1. One or more randomized trials with clinical outcomes and/or validated laboratory endpoints
2. One or more well designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes
3. Expert opinion

Not stated

The Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) is a working group of the Office of AIDS Research Advisory Council (OARAC). The primary goal of the Panel is to provide recommendations for human immunodeficiency virus (HIV) care practitioners based on current knowledge of antiretroviral drugs used to treat adults and adolescents with HIV infection in the United States. The Panel reviews new evidence and updates recommendations when needed. The primary areas of attention have included baseline assessment, treatment goals, indications for initiation of antiretroviral therapy (ART), choice of the initial regimen in ART-naïve patients, drugs or combinations to be avoided, management of adverse effects and drug interactions, management of treatment failure, and special ART-related considerations in specific patient populations.

Method of Synthesizing Data

Each section of the guidelines is assigned to a working group of Panel members with expertise in the area of interest. The members of the working group synthesize the available data and propose a recommendation to the Panel. All proposals are discussed at monthly teleconferences and then voted on by the Panel members before being endorsed as official recommendations.

Update Plan

The Panel meets monthly by teleconference to review data that may warrant modification of the guidelines. Updates may be prompted by new drug approvals (or new indications, dosing formulations, or frequency), new significant safety or efficacy data, or other information that may have a significant impact on the clinical care of patients. For cases in which significant new data become available that may affect patient safety, a warning announcement with the Panel's recommendations may be made on the AIDSinfo Web site until appropriate changes can be made in the guidelines document. Updated guidelines are available at the AIDSinfo Web site.

Strength of Recommendation

1. Strong recommendation for the statement
2. Moderate recommendation for the statement
3. Optional recommendation for the statement

Using Drug-Resistance Assays

No definitive prospective data exist to support using one type of resistance assay over another (i.e., genotypic vs. phenotypic) in different clinical situations. In most situations genotypic testing is preferred because of the faster turnaround time, lower cost, and enhanced sensitivity for detecting mixtures of wild-type and resistant virus. However, for patients with a complex treatment history, results derived from both assays might provide critical and complementary information to guide regimen changes.

Cost of Early Initiation of Antiretroviral Therapy (ART)

In resource-rich countries, the cost of ART exceeds $10,000 per year (see Appendix C of the original guideline document). Several modeling studies support the cost effectiveness of HIV therapy initiated soon after diagnosis. One study reported that the annual cost of care is 2.5 times higher for patients with CD4 counts <50 cells/mm³ than for patients with CD4 counts >350 cells/mm³. A large proportion of the health care expenditure in patients with advanced infection is from non-antiretroviral drugs and hospitalization. However, no comparisons of costs for patients starting ART with CD4 count 350 to 500 cells/mm³ and those for patients starting ART at >500 cells/mm³ have been reported.

After release of an update on the AIDSinfo Web site, the public is given a 2-week period to submit comments to the Panel. These comments are reviewed, and a determination is made as to whether or not revisions are indicated. The public may also submit comments to the Panel at any time at contactus@aidsinfo.nih.gov.

Recommendations usually are followed by levels of evidence (I-III) identifying the type of supporting evidence and strength of recommendation grades (A-C). Definitions for these are presented at the end of the "Major Recommendations" field.

Note from the National Guideline Clearinghouse (NGC) and the Department of Health and Human Services (DHHS): These guidelines were updated by the developer on March 27, 2012. Following are the major changes that have been made to the October 14, 2011, version of the guidelines, followed by the guideline recommendations. Please refer to the original guideline document at the AIDSinfo Web site  for further details (see also the "Guideline Availability" field).

What's New in the Guidelines?

Revisions to the October 14, 2011, version of the guidelines include both new sections and key updates to existing sections. The additions and updates, which are highlighted throughout the original guidelines, are summarized below.

New Sections

The following two new sections have been added to the guidelines.

Human Immunodeficiency Virus (HIV) and the Older Patient

Effective antiretroviral therapy (ART) has led to greater longevity in HIV-infected individuals resulting in an increasing number of older individuals living with HIV infection. Compared with younger HIV-infected patients, older patients may have more comorbidities, which can complicate treatments of HIV and other diseases. This section focuses on HIV diagnosis and treatment considerations in the older HIV-infected patient.

Antiretroviral Drug Cost Table (Appendix C)

This new table lists the monthly average wholesale price (AWP) for U.S. Food and Drug Administration (FDA)-approved brand and generic antiretroviral (ARV) drugs, including fixed-dose combination products. (The AWP listed for an ARV may not represent the pharmacy acquisition price or the price paid by consumers for that drug.)

Key Updates to Existing Sections

Following are key updates to existing sections of the guidelines.

Initiating Antiretroviral Therapy in Treatment-Naive Patients

The Panel updated its recommendations on initiation of ART in treatment-naive patients. The changes are primarily based on increasing evidence showing the harmful impact of ongoing HIV replication on acquired immune deficiency syndrome (AIDS) and non-AIDS disease progression. In addition, the updated recommendations reflect emerging data showing the benefit of effective ART in preventing secondary transmission of HIV. The updated section includes more in-depth discussion on the rationale for these recommendations and on the risks and benefits of long-term ART.

The Panel's recommendations are listed below.

• ART is recommended for all HIV-infected individuals. The strength of this recommendation varies on the basis of pretreatment CD4 cell count:
  • CD4 count <350 cells/mm³ (AI)
  • CD4 count 350 to 500 cells/mm³ (AII)
  • CD4 count >500 cells/mm³ (BIII)
• Regardless of CD4 count, initiation of ART is strongly recommended for individuals with the following conditions:
  • Pregnancy (AI) (see perinatal guidelines for more detailed discussion)
  • History of an AIDS-defining illness (AI)
  • HIV-associated nephropathy (HIVAN) (AII)
  • HIV/hepatitis B virus (HBV) coinfection (AII)
• Effective ART also has been shown to prevent transmission of HIV from an infected individual to a sexual partner. Therefore, ART should be offered to patients who are at risk of transmitting HIV to sexual partners (AI [heterosexuals] or AIII [other transmission risk groups]).
• Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence (AIII). Patients may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy on the basis of clinical and/or psychosocial factors.

HIV-Infected Women

This revised section includes an expanded discussion on the use of hormonal contraception in HIV-infected women. The discussion focuses on drug-drug interactions between combined oral contraceptives and ARV drugs as well as on recent data showing a possible association between hormonal contraceptive use and acquisition or transmission of HIV.

HIV/Hepatitis C Coinfection

Updates to this section focus on the newly approved hepatitis C virus (HCV) NS3/4A protease inhibitors (PIs) boceprevir and telaprevir, the known interactions between these drugs and ART, and interim results from current ongoing research in HIV/HCV coinfected patients. The updated section includes preliminary recommendations on coadministration of the HCV NS3/4A drugs and ART.

Mycobacterium tuberculosis Disease with HIV Coinfection

This update provides recommendations for timing of initiation of ART in HIV-infected patients who have been diagnosed with tuberculosis (TB) and are not receiving ART. The recommendations are based on results from randomized controlled trials showing survival benefits (1) when ART was initiated during rather than after TB treatment and (2) when ART was started within 2 weeks of TB treatment in patients with pretreatment CD4 count <50 cells/mm³. The updated section provides more in-depth discussions on the evidence and rationale supporting the recommendations.

The Panel's recommendations are as follows:

• For patients with CD4 counts <50 cells/mm³, ART should be initiated within 2 weeks of starting TB treatment (AI).
• For patients with CD4 counts ≥50 cells/mm³ with clinical disease of major severity as indicated by clinical evaluation (including low Karnofsky score, low body mass index [BMI], low hemoglobin, low albumin, organ system dysfunction, or extent of disease), the Panel recommends initiation of ART within 2 to 4 weeks of starting TB treatment (BI for CD4 count 50–200 cells/mm³ and BIII for CD4 count >200 cells/mm³).
• For other patients with CD4 counts ≥50 cells/mm³, ART can be delayed beyond 2 to 4 weeks but should be initiated by 8 to 12 weeks of TB therapy (AI for CD4 count 50–500 cells/mm³; BIII for CD4 count >500 cells/mm³).

Drug Interaction Tables (Tables 14-16b)

These tables are updated with recent data on pharmacokinetic (PK) interactions between ARV drugs and other drugs commonly prescribed for HIV-infected patients and the Panel's recommendations on coadministration of these drugs. The key updates include:

• Change in recommendation on dosing of rifabutin with HIV PIs
• New recommendation to not use HIV PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) with rifapentine
• Addition of information on interactions of boceprevir and telaprevir with different ARV drugs and related recommendations
• Update of interactions between different ritonavir-boosted PI and HMG-CoA reductase inhibitors

Prevention of Secondary HIV Transmission

This section is updated to discuss the role of effective ART in preventing HIV transmission. The updated section also indicates evidence-based interventions available to assist providers with HIV risk behavior identification and counseling.

Additional Updates

Minor revisions have also been made to the following sections:

• Treatment Goals
• What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient (new information regarding adverse effects of raltegravir)
• HIV and Illicit Drug Users (new drug interaction added to Table 11 included in the section)
• Adherence to Antiretroviral Therapy
• Adverse Effects of Antiretroviral Agents (and accompanying Table 13)
• Drug Characteristics Tables (Appendix B)

Baseline Evaluation

Each HIV-infected patient entering into care should have a complete medical history, physical examination, and laboratory evaluation, and should be counseled regarding the implications of HIV infection. The goals of the initial evaluation are to confirm the presence of HIV infection, obtain appropriate baseline historical and laboratory data, ensure patient understanding about HIV infection and its transmission, and initiate care as recommended by established guidances such as the HIV primary care guidelines and the guidelines for prevention and treatment of HIV-associated opportunistic infections. Baseline information can then be used to define management goals and plans.

The following laboratory tests performed during initial patient visits can be used to stage HIV disease and to assist in the selection of ARV drug regimens:

• HIV antibody testing (if prior documentation is not available or if HIV ribonucleic acid [RNA] is below the assay's limit of detection) (AI)
• CD4 T-cell count (AI)
• Plasma HIV RNA (viral load) (AI)
• Complete blood count, chemistry profile, transaminase levels, blood urea nitrogen (BUN) and creatinine, urinalysis, and serologies for hepatitis A, B, and C viruses (AIII)
• Fasting blood glucose and serum lipids (AIII)
• Genotypic resistance testing at entry into care, regardless of whether ART will be initiated immediately (AIII). For patients who have HIV RNA levels <500 to 1,000 copies/mL, amplification of virus for resistance testing may not always be successful (BII).

In addition, other tests, including screening tests for sexually transmitted infections and tests for determining risk for opportunistic infections and need for prophylaxis, should be performed as recommended by HIV primary care and opportunistic infections guidelines.

Patients living with HIV infection must often cope with multiple social, psychiatric, and medical issues that are best addressed through a patient-centered, multidisciplinary approach to the disease. The evaluation also must include assessment of high-risk behaviors, substance abuse, social support, mental illness, comorbidities, economic factors (e.g., unstable housing), medical insurance status and adequacy of coverage, and other factors that are known to impair adherence to treatment and to increase the risk of HIV transmission. Once evaluated, these factors should be managed accordingly.

Education about HIV risk behaviors and effective strategies to prevent HIV transmission to others should be provided at each patient visit. (See "Preventing Secondary Transmission of HIV" below.)

Laboratory Testing

Laboratory Testing for Initial Assessment and Monitoring While on Antiretroviral Therapy

A number of laboratory tests are important for initial evaluation of HIV-infected patients upon entry into care, during follow-up if ART has not been initiated, and prior to and after initiation or modification of therapy to assess virologic and immunologic efficacy of ART and to monitor for laboratory abnormalities that may be associated with ARV drugs. Table 3 in the original guideline document outlines the Panel's recommendations for the frequency of testing. As noted in the table, some of the tests may be repeated more frequently if clinically indicated.

Two surrogate markers are used routinely to assess the immune function and level of HIV viremia: CD4 T-cell count (CD4 count) and plasma HIV RNA (viral load). Resistance testing should be used to guide selection of an ARV regimen in both ART-naïve and ART-experienced patients; a viral tropism assay should be performed prior to initiation of a C-C chemokine receptor (CCR5) antagonist; and human leukocyte antigen (HLA)-B*5701 testing should be performed prior to initiation of abacavir (ABC). The rationale and utility of these laboratory tests are discussed below.

CD4 T-Cell Count

Use of CD4 Count for Initial Assessment

The CD4 count is one of the most important factors in the decision to initiate ART and/or prophylaxis for opportunistic infections. All patients should have a baseline CD4 count at entry into care (AI). Recommendations for initiation of ART based on CD4 count are found below in the "Initiating Antiretroviral Therapy in Treatment-Naïve Patients" section.

Use of CD4 Count for Monitoring Therapeutic Response

An adequate CD4 response for most patients on therapy is defined as an increase in CD4 count in the range of 50 to 150 cells/mm³ per year, generally with an accelerated response in the first 3 months. Subsequent increases in patients with good virologic control show an average increase of approximately 50 to 100 cells/mm³ per year for the subsequent years until a steady state level is reached. Patients who initiate therapy with a low CD4 count or at an older age may have a blunted increase in their count despite virologic suppression.

Frequency of CD4 Count Monitoring

In general, CD4 counts should be monitored every 3 to 4 months to (1) determine when to start ART in untreated patients; (2) assess immunologic response to ART; and (3) assess the need for initiation or discontinuation of prophylaxis for opportunistic infections (AI).

The CD4 cell count response to ART varies widely, but a poor CD4 response is rarely an indication for modifying a virologically suppressive ARV regimen. In patients with consistently suppressed viral loads who have already experienced ART-related immune reconstitution, the CD4 cell count provides limited information, and frequent testing may cause unnecessary anxiety in patients with clinically inconsequential fluctuations. Thus, for the patient on a suppressive regimen whose CD4 cell count has increased well above the threshold for opportunistic infection risk, the CD4 count can be measured less frequently than the viral load. In such patients, CD4 count may be monitored every 6 to 12 months, unless there are changes in the patient's clinical status, such as new HIV-associated clinical symptoms or initiation of treatment with interferon, corticosteroids, or anti-neoplastic agents (CIII).

Plasma HIV RNA Testing

Plasma HIV RNA (viral load) should be measured in all patients at baseline and on a regular basis thereafter, especially in patients who are on treatment, because viral load is the most important indicator of response to ART (AI).

Optimal viral suppression is generally defined as a viral load persistently below the level of detection (<20–75 copies/mL, depending on the assay used). However, isolated "blips" (viral loads transiently detectable at low levels, typically <400 copies/mL) are not uncommon in successfully treated patients and are not thought to represent viral replication or to predict virologic failure. In addition, low-level positive viral load results (typically <200 copies/mL) appear to be more common with some viral load assays than others, and there is no definitive evidence that patients with viral loads quantified as <200 copies/mL using these assays are at increased risk for virologic failure. For the purposes of clinical trials the AIDS Clinical Trials Group (ACTG) currently defines virologic failure as a confirmed viral load >200 copies/mL, which eliminates most cases of apparent viremia caused by blips or assay variability. This definition may also be useful in clinical practice. (See "Virologic and Immunologic Failure" below.)

For most individuals who are adherent to their ARV regimens and who do not harbor resistance mutations to the prescribed drugs, viral suppression is generally achieved in 12 to 24 weeks, even though it may take a longer time in some patients. Recommendations for the frequency of viral load monitoring are summarized below.

At Initiation or Change in Therapy

Plasma viral load should be measured before initiation of therapy and preferably within 2 to 4 weeks, and not more than 8 weeks, after treatment initiation or after treatment modification (BI). Repeat viral load measurement should be performed at 4- to 8-week intervals until the level falls below the assay's limit of detection (BIII).

In Patients Who Have Viral Suppression But Therapy Was Modified Due to Drug Toxicity or Regimen Simplification

Viral load measurement should be performed within 2 to 8 weeks after changing therapy. The purpose of viral load monitoring at this point is to confirm potency of the new regimen (BIII).

In Patients on a Stable ARV Regimen

Viral load should be repeated every 3 to 4 months or as clinically indicated (BII). Some clinicians may extend the interval to every 6 months for adherent patients who have suppressed viral loads for more than 2 to 3 years and whose clinical and immunologic status is stable (BIII).

Monitoring in Patients with Suboptimal Response

In addition to viral load monitoring, a number of additional factors, such as adherence to prescribed medications, altered pharmacology, or drug interactions, should be assessed. Patients who fail to achieve viral suppression should undergo resistance testing to aid in the selection of an alternative regimen, as discussed in the "Drug Resistance Testing" and "Virologic and Immunologic Failure" sections below (AI).

Drug Resistance Testing

See Table 4 in the original guideline document for recommendations and rationale regarding drug-resistance assays in various clinical settings.

HLA-B*5701 Screening

Coreceptor Tropism Assays

Treatment Goals

The primary goals for initiating ART are to:

• Reduce HIV-associated morbidity and prolong the duration and quality of survival
• Restore and preserve immunologic function
• Maximally and durably suppress plasma HIV viral load (see "Plasma HIV RNA Testing" above)
• Prevent HIV transmission

Strategies to Achieve Treatment Goals

Achieving treatment goals requires a balance of sometimes competing considerations, outlined below. Providers and patients must work together to define individualized strategies to achieve treatment goals. See the original guideline document for more information on these topics:

• Selection of initial combination regimen
• Pretreatment drug-resistance testing
• Improving adherence

Initiating Antiretroviral Therapy in Treatment-Naïve Patients

See the original guideline document for a discussion of conditions favoring more rapid initiation of therapy.

The current recommendations are based on greater evidence supporting earlier initiation of ART than was advocated in previous guidelines. The strength of the recommendations varies according to the quality and availability of existing evidence supporting each recommendation. In addition to the benefit of earlier initiation of therapy for the health of the HIV-infected individual, the reduction in sexual transmission to HIV-uninfected individuals provides further reason for earlier initiation of ART. The Panel will continue to monitor and assess the results of ongoing and planned randomized clinical trials and observational studies, which will provide the Panel with additional guidance to form future recommendations.

What to Start: Initial Combination Regimens for the Antiretroviral-Naïve Patient

More than 20 approved ARV drugs in 6 mechanistic classes are available to design combination regimens. These 6 classes include the nucleoside reverse transcriptase inhibitors (NRTIs), NNRTIs, PIs, fusion inhibitors (FIs), CCR5 antagonists, and integrase strand transfer inhibitors (INSTIs).

The Panel provides recommendations for preferred, alternative, and acceptable regimens; regimens that may be acceptable but more definitive data are needed; and regimens that may be acceptable but should be used with caution (see tables below). Potential advantages and disadvantages of the components recommended as initial therapy for ARV-naïve patients are listed in Table 6 of the original guideline document to guide prescribers in choosing the regimen best suited for an individual patient. Table 7 of the original guideline document provides a list of agents or components not recommended for initial treatment.

Factors to Consider When Selecting an Initial Regimen

Regimen selection should be individualized and should be based on a number of factors, including the following:

• Comorbid conditions (e.g., cardiovascular disease, chemical dependency, liver disease, psychiatric disease, renal diseases, or tuberculosis [TB])
• Potential adverse drug effects
• Potential drug interactions with other medications
• Pregnancy or pregnancy potential
• Results of genotypic drug resistance testing
• Gender and pretreatment CD4 count if considering nevirapine (NVP)
• HLA-B*5701 testing if considering ABC
• Coreceptor tropism assay if considering maraviroc (MVC)
• Patient adherence potential
• Convenience (e.g., pill burden, dosing frequency, and food and fluid considerations)

Considerations for Therapies

Appendix B, Tables 1–6 of the original guideline document provide a listing of characteristics, such as formulations, dosing recommendations, pharmacokinetics, and common adverse effects, of individual ARV agents. Additionally, Appendix B, Table 7 of the original guideline provides clinicians with ARV dosing recommendations for patients who have renal or hepatic insufficiency.

Table. Preferred and Alternative Antiretroviral Regimens for Antiretroviral-Therapy Naïve Patients

A combination ART regimen generally consists of two NRTIs + one active drug from one of the following classes: NNRTI, PI (generally boosted with ritonavir [RTV]), INSTI, or a CCR5 antagonist. Selection of a regimen should be individualized based on virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance testing results, and the patient's comorbid conditions.

The regimens in each category are listed in alphabetical order.

¹3TC may substitute for FTC or vice versa.
²For more detailed recommendations on ARV use in an HIV-infected pregnant woman, refer to the NGC summary of the DHHS guideline Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States.

The following combinations in the recommended list above are available as coformulated fixed-dose combinations: ABC/3TC, EFV/TDF/FTC, LPV/r, RPV/TDF/FTC, TDF/FTC, and ZDV/3TC.

Abbreviations: 3TC = lamivudine, ABC = abacavir, ART= antiretroviral therapy, ARV = antiretroviral, ATV/r = atazanavir/ritonavir, DRV/r = darunavir/ritonavir, EFV = efavirenz, FPV/r = fosamprenavir/ritonavir, FTC = emtricitabine, INSTI = integrase strand transfer inhibitor, LPV/r = lopinavir/ritonavir, NNRTI = non-nucleoside reverse transcriptase inhibitor, NRTI = nucleos(t)ide reverse transcriptase inhibitor, PI = protease inhibitor, RAL = raltegravir, RPV = rilpivirine, RTV = ritonavir, TDF = tenofovir, ZDV = zidovudine

Table. Acceptable Antiretroviral Regimens for Treatment-Naïve Patients

¹3TC may be substituted with FTC or vice versa.
²Refer to Appendix B, Table 7 in the original guideline document for the criteria for Child-Pugh classification.

Abbreviations: 3TC = lamivudine, ABC = abacavir, ART = antiretroviral therapy, ATV = atazanavir, ATV/r = atazanavir/ritonavir, AV = atrioventricular, DRV/r = darunavir/ritonavir, ECG = electrocardiogram, EFV = efavirenz, FPV/r = fosamprenavir/ritonavir, FTC = emtricitabine, HSR = hypersensitivity reaction, INSTI = integrase strand transfer inhibitor, LPV/r = lopinavir/ritonavir, msec = millisecond, MVC = maraviroc, NNRTI = non-nucleoside reverse transcriptase inhibitor, NVP = nevirapine, PI = protease inhibitor, RAL = raltegravir, RPV = rilpivirine, RTV = ritonavir, SQV = saquinavir, SQV/r = saquinavir/ritonavir, TDF = tenofovir, ZDV = zidovudine

What Not to Use

Some ARV regimens or components are not generally recommended because of suboptimal antiviral potency, unacceptable toxicities, or pharmacologic concerns. These are summarized below.

Antiretroviral Regimens Not Recommended

Monotherapy with NRTI

Single-NRTI therapy does not demonstrate potent and sustained antiviral activity and should not be used (AII). For prevention of mother-to-child transmission (PMTCT), zidovudine (ZDV) monotherapy is not recommended but might be considered in certain unusual circumstances in women with HIV RNA <1,000 copies/mL, although the use of a potent combination regimen is generally preferred (see the NGC summary of the DHHS guideline Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States).

Single-drug treatment regimens with a RTV-boosted PI, either LPV, ATV, or DRV are under investigation with mixed results, and cannot be recommended outside of a clinical trial at this time.

Dual-NRTI Regimens

These regimens are not recommended because they have not demonstrated potent and sustained antiviral activity compared with triple-drug combination regimens. (AI)

Triple-NRTI Regimens

In general, triple-NRTI regimens other than abacavir/lamivudine/zidovudine (ABC/3T/ZDV) (BI) and possibly lamivudine/zidovudine + tenofovir (3TC/ZDV + TDF) (BII) should not be used because of suboptimal virologic activity or lack of data. (AI)

Antiretroviral Components Not Recommended (in alphabetical order)

• Atazanavir + indinavir (AIII)
• Didanosine + stavudine (AII)
• Didanosine + tenofovir (AII)
• Two-NNRTI combinations (AI)
• Efavirenz in first trimester of pregnancy and in women with significant childbearing potential (AIII)
• Emtricitabine + lamivudine (AIII)
• Etravirine + unboosted PI (AII)
• Etravirine + ritonavir-boosted atazanavir or fosamprenavir (AII)
• Etravirine + ritonavir-boosted tipranavir (AII)
• Nevirapine initiated in ARV-naïve women with CD4 counts >250 cells/mm³ or in ARV-naïve men with CD4 counts >400 cells/mm³ (BI)
• Unboosted darunavir, saquinavir, or tipranavir (AII)
• Stavudine + zidovudine (AII)

See the original guideline document for more information on these components.

Management of the Treatment-Experienced Patient

Virologic and Immunologic Failure

Causes of Virologic Failure

Virologic failure in a patient can occur for multiple reasons. Data from older patient cohorts suggested that suboptimal adherence and drug intolerance/toxicity accounted for 28% to 40% of virologic failure and regimen discontinuations. More recent data suggest that most virologic failure on first-line regimens occurred due to either pre-existing (transmitted) drug resistance or suboptimal adherence. Factors associated with virologic failure include:

• Patient characteristics
  • Higher pretreatment or baseline HIV RNA level (depending on the specific regimen used)
  • Lower pretreatment or nadir CD4 T-cell count
  • Prior AIDS diagnosis
  • Comorbidities (e.g., active substance abuse, depression)
  • Presence of drug-resistant virus, either transmitted or acquired
  • Prior treatment failure
  • Incomplete medication adherence and missed clinic appointments
• ARV regimen characteristics
  • Drug side effects and toxicities
  • Suboptimal pharmacokinetics (variable absorption, metabolism, or, theoretically, penetration into reservoirs)
  • Food/fasting requirements
  • Adverse drug-drug interactions with concomitant medications
  • Suboptimal virologic potency
  • Prescription errors
• Provider characteristics, such as experience in treating HIV disease
• Other or unknown reasons

Management of Patients with Virologic Failure

Assessment of Virologic Failure

If virologic failure is suspected or confirmed, a thorough work-up is indicated, addressing the following factors:

• Change in HIV RNA and CD4 T-cell count over time
• Occurrence of HIV-related clinical events
• ARV treatment history
• Results of prior resistance testing (if any)
• Medication-taking behavior (including adherence to recommended drug doses, dosing frequency, and food/fasting requirements)
• Tolerability of medications
• Concomitant medications and supplements (with consideration for adverse drug-drug interactions)
• Comorbidities (including substance abuse)

In many cases the cause(s) of virologic failure will be identified. In some cases, no obvious cause(s) may be identified. It is important to distinguish among the reasons for virologic failure because the approaches to subsequent therapy differ. The following potential causes of virologic failure should be explored in depth.

• Adherence. Assess the patient's adherence to the regimen. For incomplete adherence, identify and address the underlying cause(s) (e.g., difficulties accessing or tolerating medications, depression, active substance abuse), and simplify the regimen if possible (e.g., decrease pill count or dosing frequency) (see "Adherence" in the original guideline document).
• Medication Intolerance. Assess the patient's tolerance of the current regimen and the severity and duration of side effects, keeping in mind that even minor side effects can impact adherence. Management strategies for intolerance in the absence of drug resistance may include:
  • Using symptomatic treatment (e.g., antiemetics, antidiarrheals)
  • Changing one ARV to another within the same drug class, if needed (e.g., change to tenofovir or abacavir for zidovudine-related toxicities; change to nevirapine or etravirine for efavirenz-related toxicities)
  • Changing from one drug class to another (e.g., from an NNRTI to a PI, from enfuvirtide [T-20] to raltegravir [RAL]) if necessary and no prior drug resistance is suspected
• Pharmacokinetic Issues. Review food/fasting requirements for each medication. Review recent history of gastrointestinal symptoms (such as vomiting or diarrhea) to assess the likelihood of short-term malabsorption. Review concomitant medications and dietary supplements for possible adverse drug-drug interactions (consult "Drug Interactions" section and tables in the original guideline document for common interactions) and make appropriate substitutions for ARV agents and/or concomitant medications, if possible. Therapeutic drug monitoring (TDM) may be helpful if pharmacokinetic drug-drug interactions or impaired drug absorption leading to decreased ARV exposure is suspected. (See also "Exposure Response Relationship and Therapeutic Drug Monitoring" in the original guideline document).
• Suspected Drug Resistance. Obtain resistance testing while the patient is taking the failing regimen or within 4 weeks after regimen discontinuation if the plasma HIV RNA level is >500 copies/mL (AII) (see "Drug-Resistance Testing" in the original guideline document). Evaluate the degree of drug resistance and consider the patient's prior treatment history and prior resistance test results. Drug resistance tends to be cumulative for a given individual; thus, all prior treatment history and resistance test results should be taken into account. Routine genotypic or phenotypic testing gives information relevant for selecting NRTIs, NNRTIs, and PIs. Additional drug-resistance tests for patients experiencing failure on fusion inhibitors and/or integrase strand transfer inhibitors (INSTIs) and viral tropism tests for patients experiencing failure on a CCR5 antagonist also are available (see "Drug-Resistance Testing" in the original guideline document).

Management of Virologic Failure

Once virologic failure is confirmed, generally the regimen should be changed as soon as possible to avoid progressive accumulation of resistance mutations.

Ideally, a new ARV regimen should contain at least two, and preferably three, fully active drugs on the basis of drug treatment history, resistance testing, or new mechanistic class (AI). Some ARV drugs (e.g., NRTIs) may contribute partial ARV activity to a regimen, despite drug resistance, while others (e.g., T-20, NNRTIs, RAL) likely do not provide partial activity. Because of the potential for drug-class cross resistance that reduces drug activity, using a "new" drug that a patient has not yet taken may not mean that the drug is fully active. In addition, archived drug-resistance mutations may not be detected by standard drug-resistance tests, emphasizing the importance of considering treatment history and prior drug-resistance tests. Drug potency and viral susceptibility are more important than the number of drugs prescribed.

Early studies of ART-experienced patients identified factors associated with better virologic responses to subsequent regimens. These factors included lower HIV RNA level and/or higher CD4 cell count at the time of therapy change, using a new (i.e., not yet taken) class of ARV drugs, and using RTV-boosted PIs in PI-experienced patients.

More recent clinical trials support the strategy of conducting reverse transcriptase (RT) and protease (PT) resistance testing (both genotype and phenotype) while an ART-experienced patient is taking a failing ARV regimen, designing a new regimen based on the treatment history and resistance testing results, and selecting at least two and preferably three active drugs for the new treatment regimen. Higher genotypic and/or phenotypic susceptibility scores (quantitative measures of drug activity) are associated with better virologic responses. Patients who receive more active drugs have a better and more prolonged virologic response than those with fewer active drugs in the regimen. Active ARV drugs include those with activity against drug-resistant viral strains, including newer members of existing classes (the NNRTI—etravirine [ETR], the PIs— DRV and tipranavir [TPV]) and drugs with new mechanisms of action (the fusion inhibitor—T-20, the CCR5 antagonist—MVC in patients with R5 but not X4 virus, and the INSTI—RAL). Drug-resistance tests for patients experiencing failure on fusion inhibitors (FIs) and/or INSTIs and viral tropism tests for patients experiencing failure on a CCR5 antagonist also are available. (See "Drug-Resistance Testing" in the original guideline document.)

Clinical Scenarios of Virologic Failure:

• Low-level viremia (HIV RNA <1,000 copies/mL). Assess adherence. Consider variability in HIV RNA assays. Patients with HIV RNA <48 copies/mL or isolated increases in HIV RNA ("blips") do not require a change in treatment (AII). There is no consensus regarding how to manage patients with HIV RNA levels >48 copies/mL and <200 copies/mL; HIV RNA levels should be followed over time to assess the need for changes (AIII). Patients with persistent HIV RNA levels >200 copies/mL often select out drug-resistant viral variants, particularly when HIV RNA levels are >500 copies/mL. Persistent plasma HIV RNA levels in the 200 to 1,000 copies/mL range should be considered as possible virologic failure; resistance testing should be attempted if the HIV RNA level is >500 copies/mL. For individuals with sufficient therapeutic options, consider treatment change (BIII).
• Repeated detectable viremia (HIV RNA >1,000 copies/mL) and NO drug resistance identified. Consider the timing of the drug-resistance test (e.g., was the patient off ARV for >4 weeks and/or nonadherent?). Consider resuming the same regimen or starting a new regimen and then repeating genotypic testing early (e.g., in 2–4 weeks) to determine whether a resistant viral strain emerges (CIII).
• Repeated detectable viremia (HIV RNA >1,000 copies/mL) and drug resistance identified. The goals in this situation are to resuppress HIV RNA levels maximally (i.e., to <48 copies/mL) and to prevent further selection of resistance mutations. With the availability of multiple new ARVs, including some with new mechanisms of action, this goal is now possible in many patients, including those with extensive treatment experience and drug resistance. With virologic failure, consider changing the treatment regimen sooner, rather than later, to minimize continued selection of resistance mutations. In a patient with ongoing viremia and evidence of resistance, some drugs in a regimen (e.g., NNRTI, T-20, RAL) should be discontinued promptly to decrease the risk of selecting additional drug-resistance mutations in order to preserve the activity of these drug classes in future regimens. A new regimen should include at least two, and preferably three, fully active agents (AII).
• Highly drug resistant HIV. There is a subset of patients who have experienced toxicity and/or developed resistance to all or most currently available regimens, and designing a regimen with two or three fully active drugs is not possible. Many of these patients received suboptimal ARV regimens (i.e., did not have access to more than one or two of the drugs at the time they became available) or have been unable to adhere to any regimen. If maximal virologic suppression cannot be achieved, the goals are to preserve immunologic function and to prevent clinical progression (even with ongoing viremia). There is no consensus on how to optimize the management of these patients. It is reasonable to observe a patient on the same regimen, rather than changing the regimen, depending on the stage of HIV disease (BII). Even partial virologic suppression of HIV RNA >0.5 log₁₀ copies/mL from baseline correlates with clinical benefits. There is evidence from cohort studies that continuing therapy, even in the presence of viremia and the absence of CD4 T-cell count increases, reduces the risk of disease progression. Other cohort studies suggest continued immunologic and clinical benefits if the HIV RNA level is maintained <10,000–20,000 copies/mL. However, these potential benefits all must be balanced with the ongoing risk of accumulating additional resistance mutations.

  In general, adding a single, fully active ARV in a new regimen is not recommended because of the risk of rapid development of resistance (BII). However, in patients with a high likelihood of clinical progression (e.g., CD4 cell count <100 cells/mm³) and limited drug options, adding a single drug may reduce the risk of immediate clinical progression, because even transient decreases in HIV RNA and/or transient increases in CD4 cell counts have been associated with clinical benefits (CI). Weighing the risks (e.g., selection of drug resistance) and benefits (e.g., ARV activity) of using a single active drug in the heavily ART experienced patient is complicated, and consultation with an expert is advised.

  Patients with ongoing viremia and with an insufficient number of approved treatment options to construct a fully suppressive regimen may be candidates for research studies or expanded access programs, or single-patient access of investigational new drug(s) (IND), as specified in FDA regulations: http://www.fda.gov/drugs/developmentapprovalprocess/default.htm .

  Discontinuing or briefly interrupting therapy in a patient with viremia may lead to a rapid increase in HIV RNA and a decrease in CD4 T-cell count and increases the risk of clinical progression. Therefore, this strategy is not recommended (AI). See "Discontinuation or Interruption of Antiretroviral Therapy" below.

• Prior treatment and suspected drug resistance, now presenting to care in need of therapy with limited information (i.e., incomplete or absence of self-reported history, medical records, or previous resistance data). Every effort should be made to obtain medical records and prior drug-resistance testing results; however, this is not always possible. One strategy is to restart the most recent ARV regimen and assess drug resistance in 2–4 weeks to help guide the choice of the next regimen; another strategy is to start two or three drugs known to be active based on treatment history (e.g., MVC with R5 virus, RAL if no prior INSTI).

Immunologic Failure: Definition, Causes, and Management

Immunologic failure can be defined as a failure to achieve and maintain an adequate CD4 response despite virologic suppression. Increases in CD4 counts in ARV-naïve patients with initial ARV regimens are approximately 150 cells/mm³ over the first year. A CD4 count plateau may occur after 4–6 years of treatment with suppressed viremia.

No accepted specific definition for immunologic failure exists, although some studies have focused on patients who fail to increase CD4 counts above a specific threshold (e.g., >350 or 500 cells/mm³) over a specific period of time (e.g., 4–7 years). Others have focused on an inability to increase CD4 counts above pretherapy levels by a certain threshold (e.g., >50 or 100 cells/mm³) over a given time period. The former criterion may be preferable because of data linking these thresholds with the risk of non-AIDS clinical events.

A persistently low CD4 count while on suppressive ART is associated with a small, but appreciable, risk of AIDS- and non-AIDS-related morbidity and mortality.

Factors associated with poor CD4 T-cell response:

• CD4 count <200/mm³ when starting ART
• Older age
• Coinfection (e.g., HCV, HIV-2, human T-cell leukemia virus [HTLV-1], HTLV-2)
• Medications, both ARVs (e.g., ZDV, TDF + didanosine [ddI]) and other medications
• Persistent immune activation
• Loss of regenerative potential of the immune system
• Other medical conditions

Assessment of Immunologic Failure

CD4 count should be confirmed by repeat testing. Concomitant medications should be reviewed carefully, with a focus on those known to decrease white blood cells or, specifically, CD4 T-cells (e.g., cancer chemotherapy, interferon, prednisone, ZDV, combination of TDF and ddI), and consideration should be given to substituting or discontinuing these drugs, if possible. Untreated coinfections (e.g., HIV-2, HTLV-1, HTLV-2) and serious medical conditions (e.g., malignancy) also should be considered. In many cases, no obvious cause for immunologic failure can be identified.

Management of Immunologic Failure

No consensus exists on when or how to treat immunologic failure. Given the risk of clinical events, it is reasonable to focus on patients with CD4 counts <200/mm³ because patients with higher CD4 counts have a lower risk of clinical events. It is not clear that immunologic failure in the setting of virologic suppression should prompt a change in the ARV regimen. Because ongoing immune activation occurs in some patients with suppressed HIV RNA levels, some have suggested adding a drug to an existing regimen. However, this strategy does not result in clear virologic or immunologic benefit. Others suggest changing the regimen to another regimen (e.g., from an NNRTI-based to a PI-based, INSTI-based, or CCR5 antagonist-based regimens), but this strategy has not shown clear benefit.

An immune-based therapy, interleukin-2, demonstrated CD4 count increases but no clinical benefit in two large randomized studies and therefore is not recommended (AI). Other immune-based therapies (e.g., gene therapies, growth hormone, cyclosporine, interleukin-7) are under investigation. Currently, immune-based therapies should not be used unless it is in the context of a clinical trial (AIII).

Regimen Simplification

Regimen simplification can be defined broadly as a change in established effective therapy to reduce pill burden and dosing frequency, to enhance tolerability, or to decrease specific food and fluid requirements. Many patients on suppressive ART may be considered candidates for regimen simplification, especially if (1) they are receiving treatments that are no longer recommended as preferred or alternative choices for initial therapy; (2) they were prescribed a regimen in the setting of treatment failure at a time when there was an incomplete understanding of resistance or drug-drug interaction data; or (3) they were prescribed a regimen prior to the availability of newer options or formulations that might be easier to administer and/or more tolerable.

This section of the original guideline document reviews situations in which clinicians might consider simplifying treatment in a patient with virologic suppression. Importantly, this section does not review consideration of changes in treatment for reducing ongoing adverse effects. Regimens used in simplification strategies generally should be those that have proven high efficacy in ARV-naïve patients (see "What to Start" above) or that would be predicted to be highly active for a given patient based on the individual's past treatment history and resistance profile.

Refer to the original guideline document for a detailed discussion about the rationale for regimen simplification, candidates for regimen simplification, types of treatment simplification, and monitoring after treatment simplification.

Exposure-Response Relationship and Therapeutic Drug Monitoring (TDM) for Antiretroviral Agents

Knowledge of the relationship between systemic exposure (or concentration) and drug responses (beneficial and/or adverse) is key in selecting the dose of a drug, in understanding the variability in the response of patients to a drug, and in designing strategies to optimize response and tolerability.

TDM is a strategy applied to certain antiarrhythmics, anticonvulsants, antineoplastics, and antibiotics that utilizes measured drug concentrations to design dosing regimens to improve the likelihood of the desired therapeutic and safety outcomes. The key characteristic of a drug that is a candidate for TDM is knowledge of the exposure-response relationship and a therapeutic range of concentrations. The therapeutic range is a range of concentrations established through clinical investigations that are associated with a greater likelihood of achieving the desired therapeutic response and/or reducing the frequency of drug-associated adverse reactions.

TDM for ARV agents, however, is not recommended for routine use in the management of the HIV-infected adult (CIII).

See the original guideline document for discussions of the following topics:

• TDM with PIs, NNRTIs, and integrase inhibitors
• TDM with CCR5 antagonists
• TDM with NRTIs
• Scenarios for use of TDM
• TDM in different patient populations (e.g., patients who have drug-susceptible virus, ART-experienced patients with virologic failure)
• Using drug concentrations to guide therapy

A final caveat to the use of measured drug concentrations in patient management is a general one—drug concentration information cannot be used alone; it must be integrated with other clinical and patient information. In addition, as knowledge of associations between ARV concentrations and virologic response continues to accumulate, clinicians who employ a TDM strategy for patient management should consult the most current literature.

Discontinuation or Interruption of Antiretroviral Therapy

Discontinuation of ART may result in viral rebound, immune decompensation, and clinical progression.

Short-term Therapy Interruptions

Reasons for short-term interruption (days to weeks) of ART vary and may include drug toxicity; intercurrent illnesses that preclude oral intake, such as gastroenteritis or pancreatitis; surgical procedures; or unavailability of drugs. Stopping ARV drugs for a short time (i.e., <1 to 2 days) due to medical/surgical procedures can usually be done by holding all drugs in the regimen. Recommendations for some other scenarios are listed below:

Unanticipated Need for Short-Term Interruption

• When a patient experiences a severe or life-threatening toxicity or unexpected inability to take oral medications—All components of the drug regimen should be stopped simultaneously, regardless of drug half-life.

Planned Short-Term Interruption (>2-3 Days)

• When all regimen components have similar half-lives and do not require food for proper absorption—All drugs may be given with a sip of water, if allowed; otherwise, all drugs should be stopped simultaneously. All discontinued regimen components should be restarted simultaneously.
• When all regimen components have similar half-lives and require food for adequate absorption, and the patient cannot take anything by mouth for a sustained period of time—Temporary discontinuation of all drug components is indicated. The regimen should be restarted as soon as the patient can resume oral intake.
• When the ARV regimen contains drugs with differing half-lives—Stopping all drugs simultaneously may result in functional monotherapy with the drug with the longest half-life (typically an NNRTI). Options in this circumstance are discussed below. (See "Discontinuation of EFV, ETR, or NVP".)

Interruption of Therapy after Pregnancy

ARV drugs for prevention of perinatal transmission of HIV are recommended for all pregnant women, regardless of whether they have indications for ART for their own health. Following delivery, considerations regarding continuation of the ARV regimen for maternal therapeutic indications are the same as for other nonpregnant individuals. The decision of whether to continue therapy after delivery should take into account current recommendations for initiation of ART, current and nadir CD4 T-cell counts and trajectory, HIV RNA levels, adherence issues, and patient preference.

Planned Long-term Therapy Interruptions

Planned therapy interruptions have been contemplated in various scenarios, listed below. Research is ongoing in several of the scenarios. Therapy interruptions cannot be recommended at this time outside of controlled clinical trials (AI).

• In patients who initiated therapy during acute HIV infection and achieved virologic suppression—The optimal duration of treatment and the consequences of treatment interruption are not known at this time. (See "Acute HIV Infection" section below.)
• In patients who have had exposure to multiple ARV agents, have experienced ARV treatment failure, and have few treatment options available because of extensive resistance mutations—Interruption is not recommended unless done in a clinical trial setting (AI). Several clinical trials, largely yielding negative results, but some with conflicting results, have been conducted to better understand the role of treatment interruption in these patients. The largest of these studies showed negative clinical impact of treatment interruption in these patients. The Panel notes that partial virologic suppression from combination therapy has been associated with clinical benefit; therefore, interruption of therapy is not recommended.
• In patients on ART who have maintained a CD4 count above the level currently recommended for treatment initiation and irrespective of whether their baseline CD4 counts were either above or below that recommended threshold—Interruption is also not recommended unless it is done in a clinical trial setting (BI) (see the original guideline document for discussion highlighting potential adverse outcomes seen in some treatment interruption trials).

If therapy has to be discontinued, patients should be counseled about the need for close clinical and laboratory monitoring. They should also be aware of the risks of viral rebound, acute retroviral syndrome, increased risk of HIV transmission, decline of CD4 count, HIV disease progression or death, development of minor HIV-associated manifestations such as oral thrush, development of serious non-AIDS complications, development of drug resistance, and the need for chemoprophylaxis against opportunistic infections depending on the CD4 count. Treatment interruptions often result in rapid reductions in CD4 counts.

Prior to any planned treatment interruption, a number of ARV-specific issues should be taken into consideration. These include:

• Discontinuation of EFV, ETR, or NVP. The optimal interval between stopping EFV, ETR, or NVP and other ARV drugs is not known. The duration of detectable levels of EFV or NVP after discontinuation ranges from less than 1 week to more than 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTIs because NNRTIs have much longer half-lives than other agents. This may increase the risk of selection of NNRTI-resistant mutations. It is further complicated by evidence that certain host genetic polymorphisms may result in slower rates of clearance. Such polymorphisms may be more common among specific ethnic groups, such as African Americans and Hispanics. Some experts recommend stopping the NNRTI but continuing the other ARV drugs for a period of time. The optimal time sequence for staggered component discontinuation has not been determined. A study in South Africa demonstrated that giving 4 or 7 days of ZDV plus 3TC after a single dose of NVP reduced the risk of postnatal NVP resistance from 60% to 10%-12%. Use of NRTIs with a longer half-life such as TDF plus FTC has also been shown to decrease NVP resistance after single-dose treatment. The findings may, however, differ in patients on chronic NVP treatment. An alternative strategy is to substitute a PI for the NNRTI and to continue the PI with dual NRTIs for a period of time. In a post-study analysis of the patients who interrupted therapy in the SMART trial, patients who were switched from NNRTI- to a PI-based regimen prior to interruption had a lower rate of NNRTI-resistant mutation after interruption and a greater chance of resuppression of HIV RNA after restarting therapy than those who stopped all the drugs simultaneously or stopped the NNRTI before the 2-NRTI. The optimal duration needed to continue the PI-based regimen after stopping the NNRTI is not known. Given the potential of prolonged detectable NNRTI concentrations for more than 3 weeks, some suggest that the PI-based regimen may need to be continued for up to 4 weeks. Further research to determine the best approach to discontinuing NNRTIs is needed. Clinical data on etravirine and treatment interruption is lacking but its long half-life of approximately 40 hours suggests that stopping ETR needs to be done carefully using the same suggestions for NVP and EFV for the time being.
• Discontinuation and reintroduction of NVP. Because NVP is an inducer of the drug-metabolizing hepatic enzymes, administration of full therapeutic doses of NVP without a 2-week, low-dose escalation phase will result in excess plasma drug levels and potentially increase the risk for toxicity. Therefore, in a patient who has interrupted treatment with NVP for more than 2 weeks, NVP should be reintroduced with a dose escalation period of 200 mg once daily for 14 days, then a 200 mg twice-daily regimen (AII).
• Discontinuation of FTC, 3TC, or TDF in patients with HBV coinfection. Patients with HBV coinfection (hepatitis B surface antigen [HBsAg] or hepatitis B e-antigen [HBeAg] positive) and receiving one or a combination of these NRTIs may experience an exacerbation of hepatitis upon drug discontinuation. (See "HBV/HIV Coinfection" section below.)

Considerations for Antiretroviral Use in Special Patient Populations

Acute HIV Infection

Diagnosis of Acute HIV Infection

Health care providers should maintain a high level of suspicion of acute HIV infection in patients who have a compatible clinical syndrome and who report recent high-risk behavior. However, in some settings, patients may not always disclose or admit to high-risk behaviors, or might not perceive their behaviors as high risk. Thus, symptoms and signs consistent with acute retroviral syndrome should motivate consideration of this diagnosis even in the absence of reported high-risk behaviors.

When acute retroviral syndrome is suspected, a plasma HIV RNA test should be used in conjunction with an HIV antibody test to diagnose acute infection (BII). Acute HIV infection is often defined by detectable HIV RNA in plasma in the setting of a negative or indeterminate HIV antibody test. A low-positive HIV RNA level (<10,000 copies/mL) may represent a false-positive test because values in acute infection are generally very high (>100,000 copies/mL). A qualitative HIV RNA test can also be used in this setting. Interest in routine screening for antibody-negative acute infection has led to select centers performing virologic testing on all antibody-negative specimens, including the use of pooled HIV RNA testing on all seronegative serum samples. In addition, a combination HIV antigen/antibody test (ARCHITECT), recently licensed by the FDA, could be used for this purpose. Patients diagnosed with acute HIV infection by a virologic test while still antibody negative or indeterminate should have confirmatory serologic testing performed over the next 3 months (AI). (See Table 10 in the original guideline document.)

Performance of Resistance Testing

Data from the United States and Europe demonstrate that transmitted virus may be resistant to at least one ARV drug in 6% to 16% of patients. If the decision is made to initiate therapy in a person with acute HIV infection, genotypic resistance testing at baseline to guide the selection of an ARV regimen will likely optimize virologic response; this strategy is therefore recommended (AIII). (See "Drug-Resistance Testing" section in the original guideline document.) If therapy is deferred, resistance testing should still be performed because the result may be useful in optimizing the virologic response when therapy is ultimately initiated (AIII).

Refer to the "Potential Benefits and Harms" fields in this summary for information on potential benefits and risks of treating acute HIV infection.

Treatment for Recent but Nonacute HIV Infection or Infection of Undetermined Duration

In addition to patients with acute HIV infection, some HIV clinicians also recommend consideration of therapy for patients in whom seroconversion has occurred within the previous 6 months (CIII). Although the initial burst of viremia among infected adults usually resolves in 2 months, rationale for treatment during the 2- to 6-month period after infection is based on the probability that virus replication in lymphoid tissue is still not maximally contained by the immune system during this time. In the case of pregnancy, use of a combination ARV regimen to prevent MTCT of HIV is recommended (AI). For nonpregnant patients the current guidelines have provided a rationale for recommending initiation of ART in ART-naive patients with CD4 count between 350 and 500 cells/mm3 as well as a recommendation to consider therapy for those with CD4 count >500 cells/mm³. (See "Initiating Antiretroviral Therapy" above.) Although these recommendations are primarily based upon data from patients with chronic infection, the potential benefit of early treatment on immune recovery and on attenuation of the pathologic effects of viremia-associated inflammation and coagulation could apply to those with early HIV infection as well. Based upon all of these considerations it is reasonable that clinicians share with patients the potential rationale for initiating ART during early HIV infection and offer treatment to those who are willing and able to commit to lifelong treatment.

Treatment Regimen for Acute or Recent HIV Infection

If the clinician and patient have made the decision to initiate ART for acute or recent HIV infection, the goal of therapy is to suppress plasma HIV RNA levels to below detectable levels (AIII). Data are insufficient to draw firm conclusions regarding specific drug combinations to use in acute HIV infection. Potential combinations of agents should be those used in chronic infection. (See "What to Start," above.) However, because clinically significant resistance to PIs is less common than resistance to NNRTIs in ART-naive persons, an RTV-boosted PI-based regimen should be used if therapy is initiated before drug-resistance test results are available (AIII). If resistance test results or resistance pattern of the source virus are known, this information should be used to guide the selection of the ARV regimen.

Patient Follow-up

Testing for plasma HIV RNA levels and CD4 count and toxicity monitoring should be performed as described in Laboratory Testing for Initial Assessment and Monitoring While on Antiretroviral Therapy (i.e., HIV RNA at initiation of therapy, after 2–8 weeks, then every 4–8 weeks until viral suppression, then every 3–4 months thereafter) (AII).

Duration of Therapy for Acute or Recent HIV Infection

Difficulties inherent in determining the optimal duration and therapy composition for acute or recent infection (and the potential need for lifelong treatment) should be considered when counseling patients prior to initiation of therapy. Patients need to know that there are limited data regarding the benefits of stopping treatment, whereas strong data from studies in patients with chronic HIV infection show that stopping ART may be harmful.

HIV-Infected Adolescents and Young Adults

Antiretroviral Therapy Considerations in Adolescents

Adult guidelines for ART are usually appropriate for postpubertal adolescents, because the clinical course of HIV-infected adolescents who were infected sexually or through injection drug use during adolescence is more similar to that of adults than to that of children. Adult guidelines can also be useful for postpubertal youth who were perinatally infected because these patients often have treatment challenges associated with the use of long-term ART that mirror those of ART-experienced adults, such as extensive resistance, complex regimens, and adverse drug effects.

Dosage of medications for HIV infection and opportunistic infections should be prescribed according to Tanner staging of puberty and not solely on the basis of age. Adolescents in early puberty (i.e., Tanner Stages I and II) should be administered doses on pediatric schedules, whereas those in late puberty (i.e., Tanner Stage V) should follow adult dosing schedules. However, Tanner stage and age are not necessarily directly predictive of drug pharmacokinetics. Because puberty may be delayed in children who were infected with HIV perinatally, continued use of pediatric doses in puberty-delayed adolescents can result in medication doses that are higher than the usual adult doses. Because data are not available to predict optimal medication doses for each ARV medication for this group of children, issues such as toxicity, pill or liquid volume burden, adherence, and virologic and immunologic parameters should be considered in determining when to transition from pediatric to adult doses. Youth who are in their growth spurt period (i.e., Tanner Stage III in females and Tanner Stage IV in males) and following adult or pediatric dosing guidelines and adolescents who have transitioned from pediatric to adult doses should be closely monitored for medication efficacy and toxicity. Therapeutic drug monitoring can be considered in selected circumstances to help guide therapy decisions in this context. Pharmacokinetic studies of drugs in youth are needed to better define appropriate dosing. For a more detailed discussion, see the NGC summary of the DHHS guideline Guidelines for the use of antiretroviral agents in pediatric HIV infection.

Adherence Concerns in Adolescents

HIV-infected adolescents are especially vulnerable to specific adherence problems based on their psychosocial and cognitive developmental trajectory. Comprehensive systems of care are required to serve both the medical and psychosocial needs of HIV-infected adolescents, who are frequently inexperienced with health-care systems and who lack health insurance. Many HIV-infected adolescents face challenges in adhering to medical regimens for reasons that include:

• Denial and fear of their HIV infection
• Misinformation
• Distrust of the medical establishment
• Fear and lack of belief in the effectiveness of medications
• Low self-esteem
• Unstructured and chaotic lifestyles
• Mood disorders and other mental illness
• Lack of familial and social support
• Absence of or inconsistent access to care or health insurance
• Incumbent risks of inadvertent parental disclosure of the youth's HIV infection status if parental health insurance is used

For a more detailed discussion on specific therapy and adherence issues for HIV-infected adolescents see the NGC summary of the DHHS guideline Guidelines for the use of antiretroviral agents in pediatric HIV infection.

See the original guideline document for information on special considerations for adolescents and transitioning care.

HIV and Illicit Drug Users (IDUs)

See the original guideline document for information about the treatment challenges of HIV-infected IDUs, treatment efficacy in HIV-infected illicit drug use populations, and antiretroviral agents and opioid substitution therapy.

The first step in provision of care and treatment for these individuals is to recognize the existence of a substance abuse problem. It is often obvious that the problem exists, but some patients may hide these problem behaviors from clinicians. Assessment of a patient for substance abuse should be part of routine medical history taking and should be done in a professional, straightforward, and nonjudgmental manner.

It is usually possible over time to support most active drug users such that acceptable adherence levels with ARV agents can be achieved. Providers must work to combine all available resources to stabilize an active drug user in preparation for ART. This should include identification of concurrent medical and psychiatric illnesses, drug treatment and needle and syringe exchange programs, strategies to reduce high-risk sexual behavior, and harm reduction strategies. A history of drug use alone is insufficient reason to withhold ART because individuals with a history of prior drug use have adherence rates similar to individuals who do not abuse drugs.

Important considerations in the selection of successful regimens and the provision of appropriate patient monitoring in this population include supportive clinical sites; linkage to substance abuse treatment; and awareness of the interactions between illicit drugs and ARV agents, including the increased risk of side effects and toxicities. Simple regimens should be considered to enhance medication adherence. Preference should be given to ARV agents that have a lower risk for hepatic and neuropsychiatric side effects, simple dosing schedules, and minimal interaction with methadone.

See also Table 11: "Drug Interactions between Antiretroviral Agents and Drugs Used to Treat Opioid Addiction" in the original guideline document.

HIV-Infected Women

Gender Considerations in Antiretroviral Therapy

In general, studies to date have not shown gender differences in virologic responses to ART, although a number of studies have suggested that gender may influence the frequency, presentation, and severity of selected ARV-related adverse events. Although data are limited, there is also evidence that pharmacokinetics for some ARV drugs may differ between men and women, possibly due to variations between men and women in factors such as body weight, plasma volume, gastric emptying time, plasma protein levels, cytochrome P (CYP) 450 activity, drug transporter function, and excretion activity.

It is generally recommended that NVP not be prescribed to ARV-naïve women who have CD4 counts >250 cells/mm³ unless there is no other alternative and the benefit from NVP outweighs the risk of hepatotoxicity (AI). See the original guideline document for additional adverse effects of ART.

Women of Childbearing Potential

All women of childbearing potential should be offered preconception counseling and care as a component of routine primary medical care. Counseling should include discussion of special considerations pertaining to ARV use when trying to conceive and during pregnancy (see the NGC summary of the DHHS guideline Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States). Sexual activity, reproductive desires and plans, HIV status of sexual partner(s), and use of effective contraception to prevent unintended pregnancy should be discussed. An HIV-infected woman who wishes to conceive with an HIV-uninfected male partner should be informed of options to prevent sexual transmission of HIV while attempting conception. Interventions include initiation of maximally suppressive ART, which has been shown to significantly decrease the risk of sexual transmission (see "Preventing Secondary Transmission of HIV" below and in the original guideline document), and artificial insemination including the option to self-inseminate with the partner's sperm during the periovulatory period. More extensive discussion can been found in the "Reproductive Options for HIV-Concordant and Serodiscordant Couples" section of the Perinatal Guidelines (see the NGC summary of the DHHS guideline Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States). As part of the evaluation for initiating ART, women should be counseled about the potential teratogenic risk of EFV-containing regimens should pregnancy occur. EFV-containing regimens should be avoided in women who are trying to conceive or who are or may engage in sexual activity that could result in pregnancy (AIII). The most vulnerable period in fetal organogenesis is early in gestation, often before pregnancy is recognized.

Hormonal Contraception

Safe and effective reproductive health and family planning services to reduce unintended pregnancy and perinatal transmission of HIV are an essential component of care for HIV-infected women of childbearing age. Counseling about reproductive issues should be provided on an ongoing basis.

Providers should be aware of potential interactions between ARV drugs and hormonal contraceptives that could lower contraceptive efficacy. Several PIs and NNRTIs have drug interactions with combined oral contraceptives (COCs). Interactions include either a decrease or an increase in blood levels of ethinyl estradiol, norethindrone, or norgestimate (see Tables 15a and b in the original guideline document), which potentially decreases contraceptive efficacy or increases estrogen- or progestin-related adverse effects (e.g., thromboembolism). In small studies of HIV-infected women receiving injectable depot-medroxyprogesterone acetate (DMPA) while on ART, there were no significant interactions between DMPA and EFV, NVP, nelfinavir (NFV), or NRTI drugs. Contraceptive failure of the etonogestrel implant in two patients on EFV-based therapy has been reported and a study has shown EFV may decrease plasma progestin concentrations of COCs containing ethinyl estradiol and norgestimate. Several RTV-boosted PIs decrease oral contraceptive estradiol levels. A small study from Malawi showed that NVP use did not significantly affect estradiol or progestin levels in HIV-infected women. Overall, data are relatively limited and the clinical implications of these findings are unclear. The magnitudes of change in drug levels that may reduce contraceptive efficacy or increase adverse effects are unknown. Concerns about pharmacokinetic interactions between hormonal contraceptives and ARVs should not prevent clinicians from prescribing hormonal contraceptives for women on ART. However, when women wish to use hormonal contraceptives and drug interactions with ARVs are known, additional or alternative contraceptive methods may be recommended (see drug interaction Tables 15a, 15b, and 15d in the original guideline and the NGC summary of the DHHS guideline Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States). Consistent use of male or female condoms to prevent transmission of HIV and protect against other sexually transmitted diseases (STDs) is recommended for all HIV-infected women and their partners, regardless of contraceptive use.

The data on the association between hormonal contraception and the risk of acquisition of HIV are conflicting. Further research is needed to definitively determine if hormonal contraceptive use is an independent risk factor for acquisition and transmission of HIV.

Intrauterine devices (IUDs) appear to be a safe and effective contraceptive option for HIV-infected women. Although studies have focused primarily on non-hormone-containing IUDs (e.g., copper IUD), several small studies have also found levonorgestrel-releasing IUDs to be safe.

Pregnant Women

Clinicians should review the NGC summary of the DHHS guideline Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States for a detailed discussion of the management of HIV-infected pregnant women. The use of combination ARV regimens is recommended for all HIV-infected pregnant women, regardless of virologic, immunologic, or clinical parameters (AI). Pregnant HIV-infected women should be counseled regarding the known benefits versus risks of ARV use during pregnancy to the woman, fetus, and newborn. A woman's decision regarding ARV use should be respected. Coercive and punitive policies undermine provider-patient trust and could discourage women from seeking prenatal care and adopting health care behaviors that optimize maternal, fetal, and neonatal well-being.

Prevention of Perinatal Transmission of HIV. Both reduction of HIV RNA levels and use of ARVs appear to have an independent effect on reduction of perinatal transmission of HIV. The goal of ARV use is to achieve maximal and sustained suppression of HIV RNA levels during pregnancy.

As in non-pregnant individuals, genotypic resistance testing is recommended for all pregnant women before ARV initiation (AIII) and for pregnant women with detectable HIV RNA levels while on therapy (AI). Optimal prevention of perinatal transmission may require initiation of ARV before results of resistance testing are available. If results demonstrate the presence of significant mutation(s) that may confer resistance to the prescribed ARV regimen, the regimen should be modified.

Long-term follow-up is recommended for all infants born to women who have received ARVs during pregnancy, regardless of the infant's HIV status (see the NGC summary of the DHHS guideline Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States).

Regimen Considerations. Pregnancy should not preclude the use of optimal drug regimens. Because recommendations on ARVs to use for treatment of HIV-infected pregnant women are subject to unique considerations, recommendations specific to the timing of therapy initiation and the choice of ARVs for pregnant women may differ from those for non-pregnant individuals. These considerations include the following:

• Potential changes in pharmacokinetics, and thus dosing requirements, which result from physiologic changes associated with pregnancy
• Potential ARV-associated adverse effects in pregnant women and the woman's ability to adhere to a particular regimen during pregnancy
• Potential short- and long-term effects of the ARV on the fetus and newborn, which are unknown for many drugs

Combination drug regimens are considered the standard of care in pregnancy, both for the treatment of HIV infection and for the prevention of perinatal transmission of HIV. ZDV by intravenous infusion to the mother during labor and neonatal ZDV prophylaxis for 6 weeks are recommended irrespective of antenatal regimen chosen. Recommendations on ARV choice in pregnancy are discussed in detail in the Perinatal Guidelines (see the NGC summary of the DHHS guideline Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States).

Clinicians who are treating HIV-infected pregnant women are strongly encouraged to report cases of prenatal exposure to ARVs (either administered alone or in combinations) to the Antiretroviral Pregnancy Registry (http://www.apregistry.com/ ). The registry collects observational data regarding exposure to FDA-approved ARV drugs during pregnancy for the purpose of assessing potential teratogenicity. For more information regarding selection and use of ART during pregnancy, refer to the NGC summary of the DHHS guideline Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States.

Postpartum Management

Following delivery, clinical, immunologic, and virologic follow-up should continue as recommended for non-pregnant adults and adolescents. Because maternal ART reduces but does not eliminate the risk of transmission of HIV in breast milk and postnatal transmission can occur despite maternal ART, women should also be counseled to avoid breastfeeding. HIV-infected women should avoid premastication of food for the infant because the practice has been associated with transmission of HIV from mother to child. Considerations regarding continuation of ART for maternal therapeutic indications are the same as considerations regarding ART use for other non-pregnant individuals. For more information regarding postpartum discontinuation of ART, refer to the NGC summary of the DHHS guideline Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Several studies have demonstrated that women's adherence to ART may worsen in the postpartum period. Clinicians caring for postpartum women receiving ART should specifically address adherence, including evaluating specific facilitators and barriers to adherence, and consider offering an adherence intervention (see "Adherence to Antiretroviral Therapy" in the original guideline document).

HIV-2 Infection

HIV-2 infection is endemic in West Africa. Although HIV-2 has had only limited spread outside this area, it should be considered in persons of West African origin or those who have had sexual contact or shared needles with persons of West African origin. The prevalence of HIV-2 infection is also disproportionately high in countries with strong socioeconomic ties to West Africa (e.g., France, Spain, Portugal, and former Portuguese colonies such as Brazil, Angola, Mozambique, and parts of India near Goa).

The clinical course of HIV-2 infection is generally characterized by a longer asymptomatic stage, lower plasma HIV-2 viral loads, and lower mortality rates compared with HIV-1 infection. However, HIV-2 infection can progress to AIDS, and thus ART may become necessary during the course of infection. Concomitant HIV-1 and HIV-2 infection may occur and should be considered in patients from an area with high prevalence of HIV-2. In the appropriate epidemiologic setting, HIV-2 infection should be suspected in patients with clinical conditions suggestive of HIV infection but with atypical serologic results (e.g., a positive screening assay with an indeterminate HIV-1 Western blot). The possibility of HIV-2 infection should also be considered in the appropriate epidemiologic setting in patients with serologically confirmed HIV infection but low or undetectable viral loads or in those with declining CD4 counts despite apparent virologic suppression on ART.

The Multispot HIV-1/HIV-2 Rapid Test (Bio-Rad Laboratories) is FDA approved for differentiating HIV-1 from HIV-2 infection. Commercially available HIV-1 viral load assays do not reliably detect or quantify HIV-2, and no HIV-2 commercial viral load assays are currently available. Most studies reporting HIV-2 viral loads use "in-house" assays that are not widely available, making it difficult to monitor virologic response in the clinical setting. In addition, no validated HIV-2 genotypic or phenotypic ARV resistance assays are available.

To date, there have been no randomized trials addressing the question of when to start ART or the choice of initial or second-line therapy for HIV-2 infection; thus, the optimal treatment strategy has not been defined. HIV-2 appears intrinsically resistant to NNRTIs and to enfuvirtide. In vitro data suggest HIV-2 is sensitive to the currently available NRTIs, although with a lower barrier to resistance than HIV-1. Variable sensitivity among PIs has been reported; lopinavir, saquinavir, and darunavir are more active against HIV-2 than other approved PIs. The integrase inhibitor, raltegravir, and the CCR5 antagonist, MVC, appear active against some HIV-2 isolates, although no approved assays to determine HIV-2 coreceptor tropism exist and HIV-2 is known to utilize multiple minor coreceptors in addition to CCR5 and CXCR4. Several small studies suggest poor responses among HIV-2 infected individuals treated with some ARV regimens, including dual-NRTI regimens, regimens containing two NRTIs + NNRTI, and some unboosted PI-based regimens including nelfinavir or indinavir plus zidovudine and lamivudine. Clinical data on the utility of triple-NRTI regimens are conflicting. In general, boosted PI-containing regimens have resulted in more favorable virologic and immunologic responses. One small study suggested satisfactory responses to lopinavir/ritonavir-containing regimens in 17 of 29 (59%) of ARV-naïve subjects.

Resistance-associated mutations develop commonly in HIV-2 patients on therapy. Genotypic algorithms used to predict drug resistance in HIV-1 may not be applicable to HIV-2, because pathways and mutational patterns leading to resistance may differ. CD4 cell recovery on therapy may be poor, suggesting that more reliable methods for monitoring disease progression and treatment efficacy in HIV-2 infection are needed.

Some groups have recommended specific preferred and alternative regimens for initial therapy of HIV-2 infection, though as yet there are no controlled trial data to reliably predict their success. Until more definitive data are available in an ART-naïve patient with HIV-2 mono-infection or with HIV-1/HIV-2 dual infection who requires treatment, clinicians should initiate a regimen containing two NRTIs and a boosted PI. Monitoring of virologic response in such patients is problematic because of the lack of a commercially available HIV-2 viral load assay; however, clinical and CD4 count improvement can be used to assess treatment response.

HIV and the Older Patient

Non-AIDS HIV-Related Complications and Other Comorbidities

At present, primary care recommendations are the same for HIV-infected and HIV-uninfected adults and focus on identifying and managing risks of conditions such as heart, liver, and renal disease; cancer; and bone demineralization.

Discontinuing Antiretroviral Therapy in Older Patients

Important issues to discuss with aging HIV-infected patients are living wills, advance directives, and long-term care planning including financial concerns. Health care cost sharing (e.g., co-pays, out-of-pocket costs), loss of employment, and other financial-related factors can cause interruptions in treatment. Clinic systems can minimize loss of treatment by helping patients maintain access to insurance.

For the severely debilitated or terminally ill HIV-infected patient, adding palliative care medications, while perhaps beneficial, further increases the complexity and risk of negative drug interactions. For such patients, a balanced consideration of both the expected benefits of ART and the toxicities and negative quality-of-life effects of ART is needed.

Conclusion

HIV infection may increase the risk of many major health conditions experienced by aging adults and possibly accelerate the aging process. As HIV-infected adults age, their health problems become increasingly complex, placing additional demands on the health care system. This adds to the concern that outpatient clinics providing HIV care in the United States share the same financial problems as other chronic disease and primary care clinics and that reimbursement for care is not sufficient to maintain care at a sustainable level. Continued involvement of HIV experts in the care of older HIV-infected patients is warranted. However, given that the current shortage of primary care providers and geriatricians is projected to continue, current HIV providers will need to adapt to the shifting need for expertise in geriatrics through continuing education and ongoing assessment of the evolving health needs of aging HIV-infected patients. The aging of the HIV-infected population also signals a need for more information on long-term safety and efficacy of ARV drugs in older patients.

Considerations for Antiretroviral Use in Patients with Coinfections

HBV/HIV Coinfection

Recommendations for HBV/HIV Coinfected Patients

• All patients with chronic HBV should be advised to abstain from alcohol, assessed for immunity to hepatitis A virus (HAV) infection (anti-HAV antibody total) and vaccinated if nonimmune, advised on methods to prevent HBV transmission (methods that do not differ from those to prevent HIV transmission), and evaluated for the severity of HBV infection as outlined in the NGC summary of the Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA) guideline Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents.
• Prior to initiation of ART, all persons who test positive for HBsAg should be tested for HBV DNA using a quantitative assay to determine the level of HBV replication (AIII). Persons with chronic HBV infection already receiving ART active against HBV should undergo quantitative HBV DNA testing every 6–12 months to determine the effectiveness of therapy in suppressing HBV replication. The goal of HBV therapy with NRTIs is to prevent liver disease complications by sustained suppression of HBV replication to the lowest achievable level.
• If not yet on therapy and HBV or HIV treatment is needed: In persons without HIV infection, the recommended anti-HBV drugs for the treatment of persons naïve to HBV therapy are TDF and entecavir. In HIV-infected patients, however, only TDF can be considered part of the ARV regimen; entecavir has weak anti-HIV activity and must not be considered part of an ARV regimen. In addition, only TDF is fully active for the treatment of persons with known or suspected 3TC-resistant HBV infection. To avoid selection of HBV-resistant variants, when possible, these agents should not be used as the only agent with anti-HBV activity in an ARV regimen (AIII).

  Preferred regimen. The combination of TDF + FTC or TDF + 3TC should be used as the NRTI backbone of a fully suppressive ARV regimen and for the treatment of HBV infection (AII).

  Alternative regimens. If TDF cannot safely be used, entecavir should be used in addition to a fully suppressive ARV regimen (AII); importantly, entecavir should not be considered to be a part of the ARV regimen (BII). Due to a partially overlapping HBV-resistance pathway, it is not known if the combination of entecavir + 3TC or FTC will provide additional virologic or clinical benefit compared with entecavir alone. In persons with known or suspected 3TC-resistant HBV infection, the entecavir dose should be increased from 0.5 mg/day to 1 mg/day. However, entecavir resistance may emerge rapidly in patients with 3TC-resistant HBV infection. Therefore, entecavir should be used with caution in such patients with frequent monitoring (~ every 3 months) of the HBV DNA level to detect viral breakthrough. Other HBV treatment regimens include peginterferon alfa monotherapy or adefovir in combination with 3TC or FTC or telbivudine in addition to a fully suppressive ARV regimen; however, data on these regimens in persons with HIV/HBV coinfection are limited (BII). Due to safety concerns, peginterferon alfa should not be used in HIV/HBV-coinfected persons with cirrhosis.

• Need to discontinue medications active against HBV: The patient's clinical course should be monitored with frequent liver function tests. The use of adefovir dipivoxil, entecavir, or telbivudine to prevent flares, especially in patients with marginal hepatic reserve such as persons with compensated or decompensated cirrhosis, can be considered. These alternative HBV regimens should only be used in addition to a fully suppressive ARV regimen.
• Need to change ART because of HIV resistance: If the patient has adequate HBV suppression, the ARV drugs active against HBV should be continued for HBV treatment in combination with other suitable ARV agents to achieve HIV suppression (AIII).

HIV/HCV Coinfection

Assessment of HIV/HCV Coinfection Before Initiation of Antiretroviral Therapy

• All HIV-infected patients should be screened for HCV infection using sensitive immunoassays licensed for detection of antibody to HCV in blood. HCV-seronegative patients at risk for the acquisition of HCV infection should undergo repeat testing annually. HCV-seropositive patients should be tested for HCV RNA using a qualitative or quantitative assay to confirm the presence of active infection.
• Patients with HIV/HCV coinfection should be counseled to avoid consuming alcohol and to use appropriate precautions to prevent transmission of HIV and/or HCV to others. HIV/HCV-coinfected patients who are susceptible to hepatitis A virus (HAV) or HBV infection should be vaccinated against these viruses.
• All patients with HIV/HCV coinfection should be evaluated for HCV therapy. HCV treatment is recommended according to standard guidelines. Strong preference should be given to commence HCV treatment in patients with higher CD4 counts. For patients with lower CD4 counts (e.g., <200 cells/mm³), it may be preferable to initiate ART and delay HCV therapy until CD4 counts increase as a result of HIV treatment.

Antiretroviral Therapy in HIV/HCV Coinfection

• When to start antiretroviral therapy: The rate of liver disease (liver fibrosis) progression is accelerated in HIV/HCV-coinfected patients, particularly in individuals with low CD4 counts (≤350 cells/mm³). Data largely from retrospective cohort studies are inconsistent regarding the effect of ART on the natural history of HCV disease. However, ART may slow the progression of liver disease by preserving or restoring immune function and reducing HIV-related immune activation and inflammation. Thus, for most coinfected patients, including those with high CD4 counts and those with cirrhosis, the benefits of ART outweigh concerns regarding DILI. Therefore, ART should be initiated for most HIV/HCV coinfected patients, regardless of CD4 count (BII). However, in HIV treatment-naive patients with CD4 counts >500 cells/mm³, some clinicians may choose to defer ART until completion of HCV treatment.
• What antiretroviral to start and what antiretroviral not to use: Initial ARV combination regimens for most HIV treatment-naive patients with HCV are the same as those for patients without HCV infection. Special considerations for ARV selection in HIV/HCV-coinfected patients include:
  • When both HIV and HCV treatments are indicated, the choice of ARV regimen should be guided by the HCV treatment regimen selected with careful consideration of potential drug-drug interactions and overlapping toxicities (as discussed below).
  • Cirrhotic patients should be carefully assessed for signs of liver decompensation according to the Child-Turcotte-Pugh classification system because hepatically metabolized ARV drugs may require dose modification or avoidance in patients with Child-Pugh class B and C disease. (See Appendix B, Table 7 in the original guideline document).
• Hepatotoxicity: Drug-induced liver injury (DILI) following ART is more common in HIV/HCV coinfection than in those with HIV monoinfection. The greatest risk of DILI may be observed in coinfected persons with advanced liver disease (e.g., cirrhosis or end-stage liver disease). Eradication of HCV infection may decrease the likelihood of ARV-associated DILI.
  • Given the substantial heterogeneity in patient populations and drug regimens, comparison of DILI incidence rates for individual ARV agents across clinical trials is difficult. In such studies, the highest incidence rates of significant elevations in liver enzyme levels (>5 times the upper limit of the laboratory reference range) have been observed during therapy with ARV drugs that are no longer commonly used in clinical practice, including stavudine (d4T) (with or without ddI), NVP, or full-dose RTV (600 mg twice daily). Additionally, certain ARV agents should be avoided if possible because they have been associated with higher incidence of serious liver-associated adverse effects, such as fatty liver disease with NRTIs such as d4T, ddI, or ZDV, noncirrhotic portal hypertension associated with ddI, and hepatotoxicity associated with RTV-boosted tipranavir.
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored at 1 month after initiation of ART and then every 3 to 6 months. Mild to moderate fluctuations in ALT and/or AST are typical in individuals with chronic HCV infection. In the absence of signs and/or symptoms of liver disease these fluctuations do not require interruption of ART. Significant ALT and/or AST elevation should prompt careful evaluation for signs and symptoms of liver insufficiency and for alternative causes of liver injury (e.g., acute HAV or HBV infection, hepatobiliary disease, or alcoholic hepatitis); short-term interruption of the ART regimen or of the specific drug suspected to be responsible for the DILI may be required.

Treating Both HIV and HCV Infection

Concurrent treatment of HIV and HCV is feasible but may be complicated by high pill burden, drug interactions, and overlapping drug toxicities. In this context, the decision to treat chronic HCV should also include consideration of the medical need for such treatment on the basis of an assessment of HCV disease stage. Some clinicians may choose to defer HCV therapy in HIV/HCV-coinfected patients with no or minimal liver fibrosis. If treatment with peginterferon and ribavirin (PegIFN/RBV) alone or in combination with one of the HCV NS3/4A PIs (boceprevir or telaprevir) is initiated, the ART regimen may need to be modified to reduce the potential for drug interactions and/or toxicities that may develop during the period of concurrent HIV and HCV treatment.

Refer to the original guideline document for considerations for using certain nucleoside reverse transcriptase inhibitors and HCV treatments and for the use of HCV NS3/4A protease inhibitors (boceprevir or telaprevir) and antiretroviral therapy.

Mycobacterium Tuberculosis Disease with HIV Coinfection

Treatment of Active TB in HIV Patients

HIV infection significantly increases the risk of progression from latent to active TB disease. The CD4 cell count influences both the frequency and severity of active TB disease. Active TB also negatively affects HIV disease. It may be associated with a higher HIV viral load and more rapid progression of HIV disease.

Active pulmonary or extrapulmonary TB disease requires prompt initiation of TB treatment. The treatment of active TB disease in HIV-infected patients should follow the general principles for persons without HIV (AI). Treatment of drug-susceptible TB disease should include a standard regimen that consists of isoniazid (INH) + a rifamycin (rifampin or rifabutin) + pyrazinamide + ethambutol given for 2 months, followed by INH + a rifamycin for 4 to 7 months. The NGC summary of the CDC, NIH, and HIVMA guideline Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents include a more complete discussion of the diagnosis and treatment of TB disease in HIV-infected patients.

All patients with HIV/TB disease should be treated with ART (AI). Important issues related to the use of ART in patients with active TB disease include: (1) when to start ART, (2) significant pharmacokinetic drug-drug interactions between rifamycins and some antiretroviral (ARV) agents, (3) the additive toxicities associated with concomitant ARV and TB drug use, (4) the development of TB-associated IRIS after ART initiation, and (5) the need for treatment support including DOT and the integration of HIV and TB care and treatment.

Antiretroviral Therapy in Patients with Active TB

Patients Diagnosed with TB While Receiving Antiretroviral Therapy

When TB is diagnosed in a patient receiving ART, the patient's ARV regimen should be assessed with particular attention to potential pharmacokinetic interactions with rifamycins (see discussion below). The patient's regimen may need to be modified to permit use of the optimal TB treatment regimen (see Tables 14–16 in the original guideline document for dosing recommendations).

Patients Not Yet Receiving Antiretroviral Therapy

Until recently, when to start ART in patients with active TB has been a subject of debate. Survival is improved when ART is started early following initiation of TB therapy, but a delay in initiating ART often was favored because of the potential complications of high pill burden, additive toxicities, drug interactions, adherence, and the potential for development of IRIS. Recent studies primarily conducted in resource-limited settings, including three randomized controlled trials, have helped clarify the question of when to start ART in patients with active TB. Refer to the original guideline for further discussion of these studies.

In each of these 3 studies, IRIS was more common in patients initiating ART earlier than in patients starting ART later, but the syndrome was infrequently associated with mortality. Collectively these 3 trials demonstrate that in patients with active TB and with very low CD4 cell counts (i.e., <50 cells/mm³), early initiation of ART can reduce mortality and AIDS progression, albeit at the risk of increased IRIS. These findings strongly favor initiation of ART within the first 2 weeks of TB treatment in patients with CD4 cell counts <50 cells/mm³ (AI).

The question of when to start ART in patients with CD4 counts ≥50 cells/mm³ is also informed by these studies. The STRIDE and SAPiT studies—in which the patients with CD4 cell counts ≥50 cells/mm³ were relatively healthy and with reasonable Karnofsky scores (note the SAPiT study excluded patients with Karnofsky scores <70) and BMIs—demonstrated that ART initiation in these patients can be delayed until 8 to 12 weeks after initiation of TB therapy (AI for CD4 counts 51–500 cells/mm³ and BIII for CD4 counts >500 cells/mm³).

However, the CAMELIA study, which included more patients who were severely ill than the STRIDE and SAPiT studies, showed that early initiation of ART improved survival both in patients with CD4 counts ≤50 cells/mm³ and in patients with CD4 counts from 51 to 200 cells/mm³. In a multivariate analysis, age >40 years, low BMI (<16), low Karnofsky score (<40), elevated aspartate aminotransferase (AST) level (>1.25 x the upper limit of normal [ULN]), disseminated and MDR TB were independently associated with poor survival; whereas in a univariate analysis, hemoglobin <10g/dl also was associated with poor survival.

Thus, recently published results from the three clinical trials are complementary in defining the need for ART and use of CD4 count and clinical status to inform decisions on the optimal time to initiate ART in patients with HIV and TB disease. Earlier initiation of ART within 2 to 4 weeks of TB treatment should be strongly considered for patients with CD4 cell counts from 50 to 200 cells/mm³ who have evidence of clinical disease of major severity as indicated by clinical evaluation, low Karnofsky score, low BMI, low hemoglobin, low albumin, or organ system dysfunction (BI). Initiation of ART within 2 to 4 weeks also should be considered for patients with CD4 counts >200 cells/mm³ who present with evidence of severe disease (BIII).

Mortality rates in patients with MDR or XDR TB and HIV coinfection are very high. Retrospective case control studies and case series provide growing evidence of better outcomes associated with receipt of ART in such coinfected patients, but the optimal timing for initiation of ART is unknown. However, given the high rates and rapid mortality, most experts recommend that ART be initiated within 2 to 4 weeks after confirmation of the diagnosis of drug resistance and initiation of second-line TB therapy (BIII).

All HIV-infected pregnant women with active TB should be started on ART as early as feasible, both for maternal health and to prevent perinatal transmission of HIV (AIII). The choice of ART should be based on efficacy and safety in pregnancy and take into account potential drug-drug interactions between ARVs and rifamycins (see the NGC summary of the DHHS guideline Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States for more detailed discussions).

TB meningitis often is associated with severe complications and high mortality rate. However, in the United States, where patients may be more closely monitored and treated for severe adverse events such as central nervous system (CNS) IRIS, many experts feel that ART should be initiated as for other HIV/TB-coinfected patients (CIII).

Drug Interaction Considerations

A rifamycin is a crucial component in treatment of drug-sensitive TB. However, both rifampin and rifabutin are inducers of the hepatic cytochrome P (CYP) 450 and uridine diphosphate gluconyltransferase (UGT) 1A1 enzymes and are associated with significant interactions with most ARV agents including all PIs, NNRTIs, MVC, and RAL. Rifampin is a potent enzyme inducer, leading to accelerated drug clearance and significant reduction in ARV drug exposure. Despite these interactions, some observational studies suggest that good virologic, immunologic, and clinical outcomes may be achieved with standard doses of EFV and, to a lesser extent, NVP when combined with rifampin. However, rifampin is not recommended in combination with all PIs and the NNRTIs ETR and RPV. When rifampin is used with MVC or RAL, increased dosage of the ARV is generally recommended. Rifabutin, a weaker enzyme inducer, is an alternative to rifampin. Because rifabutin is a substrate of the CYP 450 enzyme system, its metabolism may be affected by the NNRTI or PI. Tables 14, 15a, 15b, 15d, and 15e in the original guideline document outline the magnitude of these interactions and provide dosing recommendations when rifamycins and selected ARV drugs are used concomitantly. After determining the drugs and doses to use, clinicians should monitor patients closely to assure good control of both TB and HIV infections. Suboptimal HIV suppression or suboptimal response to TB treatment should prompt assessment of drug adherence, subtherapeutic drug levels (consider TDM), and acquired drug resistance.

Rifapentine is a long-acting rifamycin that can be given once weekly with INH for the treatment of active or latent TB infection. Similar to rifampin and rifabutin, rifapentine is also a CYP3A4 inducer. No systematic study has been performed to assess the magnitude of the enzyme induction effect of rifapentine on the metabolism of ARV drugs and other concomitant drugs. Significant enzyme induction can result in reduced ARV drug exposure, which may compromise virologic efficacy. Rifapentine is not recommended for treatment of latent or active TB infection in patients receiving ART, unless given in the context of a clinical trial (AIII).

Anti-TB/ARV Drug Toxicities

ARV agents and TB drugs, particularly INH, rifamycin, and pyrazinamide, can cause drug-induced hepatitis. These first-line TB drugs should be used for treatment of active TB disease, even with coadministration of other potentially hepatotoxic drugs or when baseline liver disease is present (AIII). Patients receiving potentially hepatotoxic drugs should be monitored frequently for clinical symptoms and signs of hepatitis and have laboratory monitoring for hepatotoxicity. Peripheral neuropathy can occur with administration of INH, ddI, or d4T or may be a manifestation of HIV infection. All patients receiving INH also should receive supplemental pyridoxine to reduce peripheral neuropathy. Patients should be monitored closely for signs of drug-related toxicities and receive alternative ARVs to ddI or d4T.

IRIS with TB and ARV Agents

Predictors of IRIS include CD4 count <50 cells/mm³, higher on-ART CD4 counts, high pre-ART and lower on-ART HIV viral loads, severity of TB disease, especially high pathogen burden, and less than 30-day interval between initiation of TB and HIV treatments. Most IRIS in HIV/TB disease occurs within 3 months of the start of TB treatment. Delaying the start of ART for 2 to 8 weeks may reduce the incidence and severity of IRIS. However, this possible advantage of delayed ART must be weighed against the potential benefit of earlier ART in improving immune function and preventing progression of HIV disease and mortality.

Patients with mild or moderately severe IRIS can be managed symptomatically or treated with nonsteroidal anti-inflammatory agents. Patients with more severe IRIS can be treated successfully with corticosteroids. A recent randomized, placebo-controlled trial demonstrated benefit of corticosteroids in the management of IRIS symptoms (as measured by decreasing days of hospitalization and Karnofsky performance score) without adverse consequences. In the presence of IRIS, neither TB therapy nor ART should be stopped because both therapies are necessary for the long-term health of the patient (AIII).

Immune Reconstitution with ART: Conversion to Positive Tuberculin Skin Test (TST) and Interferon-Gamma (IFN-γ) Release Assay (IGRA)

Immune reconstitution with ART may result in unmasking LTBI (i.e., conversion of a previously negative TST to a positive TST or a positive IGRA for Mycobacterium tuberculosis-specific proteins). A positive IGRA, similar to a positive TST, is indicative of LTBI in the absence of evidence of active TB disease. Because treatment for LTBI is indicated in the absence of evidence of active TB disease, clinicians should be aware of this phenomenon. Patients with a negative TST or IGRA and advanced HIV disease (i.e., CD4 count <200 cells/mm³) should have a repeat TST or IGRA after initiation of ART and CD4 count increase to >200 cells/mm³ (BII).

Caring for Patients with HIV and TB

Close collaboration among clinicians, health care institutions, and public health programs involved in the diagnosis and treatment of HIV-infected patients with active TB disease is necessary in order to integrate care and improve medication adherence and TB treatment completion rates, reduce drug toxicities, and maximize HIV outcomes. HIV-infected patients with active TB disease should receive treatment support, including adherence counseling and DOT, corresponding to their needs (AII). ART simplification or use of coformulated fixed-dose combinations also may help to improve drug adherence.

Limitations to Treatment Safety and Efficacy

Refer to the original guideline document for a discussion of the limits to treatment safety and efficacy, including adherence to antiretroviral therapy, adverse effects of antiretroviral agents, and drug interactions.

Preventing Secondary Transmission of HIV

Consistent and effective use of ART, resulting in a sustained reduction in viral load, in conjunction with consistent condom usage, safer sexual and drug use practices, and detection and treatment of STDs are essential tools for prevention of sexual and blood-borne transmission of HIV. Given these important considerations, medical visits provide a vital opportunity to reinforce HIV prevention messages, discuss sexual- and drug-related risk behaviors, diagnose and treat intercurrent STIs, and develop open communication between provider and patient.

Definitions:

Quality of Evidence for Recommendation

1. One or more randomized trials with clinical outcomes and/or validated laboratory endpoints
2. One or more well designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes
3. Expert opinion

Strength of Recommendation

1. Strong recommendation for the statement
2. Moderate recommendation for the statement
3. Optional recommendation for the statement

None provided

The type of supporting evidence is identified and graded for selected recommendations (see the "Major Recommendations" field).

An implementation strategy was not provided.

Not applicable: The guideline was not adapted from another source.

United States Government

Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents (a Working Group of the Office of AIDS Research and Advisory Council)

Panel Co-Chairs: John G. Bartlett, Johns Hopkins University, Baltimore, MD; H. Clifford Lane, National Institutes of Health, Bethesda, MD

Executive Secretary: Alice K. Pau, National Institutes of Health, Bethesda, MD

Scientific Members: John T. Brooks, Centers for Disease Control and Prevention, Atlanta, GA; Deborah L. Cohan, University of California–San Francisco, San Francisco, CA; Eric Daar, University of California-Los Angeles, Harbor-UCLA Medical Center, Los Angeles, CA; Steven G. Deeks, University of California-San Francisco, San Francisco, CA; Carlos del Rio, Emory University, Atlanta, GA; Robert T. Dodge, University of North Carolina, Chapel Hill, NC; Courtney V. Fletcher, University of Nebraska Medical Center, Omaha, NE; Gerald Friedland, Yale University School of Medicine, New Haven, CT; Joel E. Gallant, Johns Hopkins University, Baltimore, MD; Stephen J. Gange, Johns Hopkins University, Baltimore, MD; Christopher M. Gordon, National Institutes of Health, Bethesda, MD; Roy M. Gulick, Weill Medical College of Cornell University, New York, NY; W. Keith Henry, Hennepin County Medical Center & University of Minnesota, Minneapolis, MN; Martin S. Hirsch, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Michael D. Hughes, Harvard School of Public Health, Boston, MA; Bill G. Kapogiannis, National Institutes of Health, Bethesda, MD; Daniel R. Kuritzkes, Brigham and Women's Hospital & Harvard Medical School, Boston, MA; Richard W. Price, University of California–San Francisco, San Francisco, CA; Michael Saag, University of Alabama at Birmingham, Birmingham, AL; Paul Sax, Brigham and Women's Hospital & Harvard Medical School, Boston, MA; Mark Sulkowski, Johns Hopkins University, Baltimore, MD; Zelalem Temesgen, Mayo Clinic, Rochester, MN; David A. Wohl, University of North Carolina, Chapel Hill, NC

Community Members: Lei Chou, Treatment Action Group, New York, NY; Paul Dalton, San Francisco, CA; Heidi Nass, Madison, WI; Jeff Taylor, AIDS Treatment Activists Coalition, Palm Springs, CA; Nelson Vergel, Program for Wellness Restoration, Houston, TX

Members Representing the Department of Health and Human Services (DHHS) Agencies: Victoria Cargill, National Institutes of Health, Rockville, MD; Laura Cheever, Health Resources and Services Administration, Rockville, MD; Jonathan Kaplan, Centers for Disease Control and Prevention, Atlanta, GA; Kendall Marcus, Food and Drug Administration, Silver Spring, MD; Henry Masur, National Institutes of Health, Bethesda, MD; Lynne Mofenson, National Institutes of Health, Bethesda, MD; Kimberly Struble, U.S. Food and Drug Administration, Silver Spring, MD

Non-voting Observer: Monica Calderon, National Institutes of Health, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD

All members of the Panel submit a written financial disclosure annually reporting any association with manufacturers of antiretroviral (ARV) drugs or diagnostics used for management of human immunodeficiency virus (HIV) infections. A list of the latest disclosures can be found in the original guideline document.

This is the current release of the guideline.

This guideline updates a previous version: Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Bethesda (MD): Department of Health and Human Services (DHHS); 2011 Oct 14. 167 p.

Electronic copies: Available from the AIDSinfo Web site.

The guideline is also available for mobile devices from the AIDSinfo Web site.

Print copies: Available from the Centers for Disease Control and Prevention, National Prevention Information Network (NPIN), P.O. Box 6003, Rockville, MD 20850. Telephone: (800) 458-5231, TTY (800)-243-7012 International number (301)-562-1098. Web site: www.cdcnpin.org .

The following is available:

• Guide for HIV/AIDS clinical care. AIDS Education and Training Center (AETC) National Resource Center. 2012 Jun. 613 p. Electronic copies: Available from the AETC Web site .

Print copies: Available from Southeast AIDS Training and Education Center, Emory University School of Medicine, 735 Gatewood Road, NE, Atlanta, GA 30322. Telephone: (404) 727-2929; fax (404) 727-4562. E-mail: seatec@emory.edu. Web site: www.seatec.emory.edu .

The following slide sets based on the "Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents" are available:

• Guidelines for the use of antiretroviral agents in adults and adolescents: comprehensive summary. AIDS Education and Training Center (AETC) National Resource Center. 2012 Mar. 78 slides. Electronic copies: Available from the AETC Web site .
• Issues affecting ART success: adherence, ARV toxicity, drug interactions. AIDS Education and Training Center (AETC) National Resource Center. 2012 Mar. 44 slides. Electronic copies: Available from the AETC Web site .
• Management of the treatment-experienced patient. AIDS Education and Training Center (AETC) National Resource Center. 2012 Mar. 42 slides. Electronic copies: Available from the AETC Web site .
• Special issues. AIDS Education and Training Center (AETC) National Resource Center. 2012 Mar. 86 slides. Electronic copies: Available from the AETC Web site .

The following are also available:

• Antiretroviral therapy in adults and adolescents. Pocket reference cards. AIDS Educational and Training Center (AETC). 2012 Jun. Electronic copies: Available in PDF from the AETC Web site .
• A comprehensive Spanish-language Web site featuring information about HIV treatment and clinical trials is available at http://infosida.nih.gov/ .

The following are available:

• Drugs that fight HIV. Poster. Bethesda (MD): Department of Health and Human Services (DHHS); 2011 July. 1 p. Electronic copies: Available in Portable Document Format (PDF) from the AIDSinfo Web site.
• Drugs that fight HIV. Brochure. Bethesda (MD): Department of Health and Human Services (DHHS); 2011 Jan. 4 p. Electronic copies: Available in PDF from the AIDSinfo Web site.
• HIV and its treatment: what you should know. Brochure. Bethesda (MD): Department of Health and Human Services (DHHS); 2011 Nov. 24 p. Electronic copies: Available in PDF from the AIDSinfo Web site. See the related QualityTool summary on the Health Care Innovations Exchange Web site .

Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

This summary was completed by ECRI on July 20, 1999. The original information was verified by the guideline developer on August 10, 1999. Updated guidelines were issued on January 28, 2000, February 5, 2001, April 23, 2001, August 17, 2001, February 4, 2002, July 14, 2003, November 10, 2003, November 17, 2003, and March 29, 2004. This summary was updated on November 1, 2004. This summary was updated on January 21, 2005, following the release of a public health advisory from the U.S. Food and Drug Administration regarding the use of nevirapine. This summary was updated on April 12, 2005. An addendum was included on July 18, 2005. This NGC summary was updated on October 10, 2005 and May 10, 2006. This summary was updated by ECRI on July 3, 2006, following the U.S. Food and Drug Administration advisory on Aptivus (tipranavir). This summary was updated on October 12, 2006. This summary was updated by ECRI on April 16, 2007, following the U.S. Food and Drug Administration advisory on Baraclude (entecavir). This summary was updated most recently by ECRI Institute on May 2, 2007. This summary was updated by ECRI Institute on September 5, 2007, following the revised U.S. Food and Drug Administration advisory on Baraclude (entecavir). This summary was updated by ECRI Institute on October 2, 2007, following the U.S. Food and Drug Administration advisory on Viracept (nelfinavir mesylate). This NGC summary was updated by ECRI Institute on December 4, 2007. This NGC summary was updated by ECRI Institute on February 7, 2008. This summary was updated by ECRI Institute on March 28, 2008, following the FDA advisory on Prezista (darunavir). This summary was updated by ECRI Institute on August 11, 2008 following the U.S. Food and Drug Administration advisory on Ziagen (abacavir sulfate). This summary was updated by ECRI Institute on November 21, 2008. This summary was updated by ECRI Institute on September 4, 2009 following the U.S. Food and Drug Administration advisory on Intelence (etravirine). This NGC summary was updated by ECRI Institute on February 10, 2010. This summary was updated by ECRI Institute on February 26, 2010 following the U.S. Food and Drug Administration advisory on Videx (didanosine). This summary was updated by ECRI Institute on April 1, 2010 following the U.S. Food and Drug Administration advisory on Erythropoiesis-Stimulating Agents (ESAs). This summary was updated by ECRI Institute on January 12, 2011 following the U.S. Food and Drug Administration advisory on Invirase (saquinavir). This summary was updated by ECRI Institute on March 17, 2011. This NGC summary was updated by ECRI Institute on January 6, 2012. This summary was updated by ECRI Institute on April 13, 2012 following the U.S. Food and Drug Administration advisory on Statins and HIV or Hepatitis C drugs. This summary was updated by ECRI Institute on June 27, 2012.

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