Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 3: Antiretroviral Therapy

Antiretroviral Therapy

Background

Potent combination antiretroviral therapy (ART), consisting of 3 or more antiretroviral drugs (ARVs), has greatly improved the health and survival rates of HIV-infected patients in areas of the world with access to ARVs.

More than 20 individual ARVs are available in the resource-sufficient world, in addition to several fixed-dose combination preparations. These can be combined to construct a number of effective regimens for initial and subsequent therapy. ART is not without limitations, however. ART does not cure HIV infection and it requires that multiple medications be taken for very long periods of time (usually for the duration of life). It is expensive, may cause a variety of adverse effects (some severe), requires close adherence to be effective and to prevent the emergence of resistance, and often fails (because of the patient's imperfect adherence or other factors). The failure of an ARV regimen when accompanied by drug resistance usually means that subsequent regimens are less likely to succeed.

Greatly overshadowing the limitations of ART, however, is the overwhelming evidence that ART saves lives and improves or restores immune system function. Mortality and morbidity benefits are particularly obvious in patients with relatively advanced immune suppression or with symptoms related to HIV infection. For asymptomatic patients with relatively high CD4 cell counts (>350 cells/µL), it is less clear whether or when to start ART. In deciding when to start ART for any patient, practitioners must weigh the expected benefits of ART for that individual (in terms of morbidity and mortality) against the possible risks (eg, toxicity, drug resistance, adverse drug interactions).

Although implementing ART is complex, a number of guidelines from expert panels are available to help practitioners select effective regimens for particular patients. The U.S. Department of Health and Human Services (DHHS) keeps a repository of "living documents" of frequently updated recommendations on the use of ARV medications in children, adults and adolescents, and pregnant women. All clinicians treating HIV-infected patients should be familiar with the most current versions of these treatment guidelines. They are available on the Internet at the AIDSinfo Web site "Clinical Guidelines" section (http://aidsinfo.nih.gov/Guidelines ). This chapter frequently references the Adult and Adolescent ARV Guidelines. (U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006.)

S: Subjective

Obtain the patient's history, including the following:

• CD4 cell count history, including nadir
• HIV viral load history, including before therapy if the patient is currently taking ARVs
• History of HIV-related conditions
• Previous and current ARV regimens, including regimen efficacy, toxicity, resistance, start and stop dates
• Current medications, including herbal preparations, supplements, and over-the-counter medications
• Medication allergies, intolerances, or prominent adverse effects
• Comorbid conditions (eg, hepatitis C, hepatitis B, depression)
• Occupation and daily schedule
• Current and previous substance use, including alcohol and recreational drugs
• Self-assessment of adherence to previous regimens
• Desire to start or continue an ARV regimen
• Commitment to adherence (see chapter Adherence)
• Indicators of ability to adhere to various types of regimens (eg, once daily, twice daily, every 8 hours, with or without food) given current life situation
• For women of childbearing potential: last menstrual period, current method of birth control (if any), current pregnancy status, thoughts on whether or when to have children
• History and review of systems (see chapter Initial History)

O: Objective

Perform the following objective tests:

• Complete physical examination (see chapter Initial Physical Examination)
• Current CD4 count and HIV viral load: preferably 2 or more separate results approximately 1 month apart
• Drug resistance profiles (genotype, phenotype, or both), past and present (if available) (see chapter Resistance Testing)
• Complete blood count (CBC) and platelet count, liver function tests (LFTs), renal function tests, fasting lipid panel (see chapter Initial and Interim Laboratory and Other Tests) fasting glucose, rapid plasma reagin (RPR), tuberculin skin test, hepatitis serologies

A: Assessment

Make the following basic decisions:

• The patient is or is not likely to benefit from ART at this time (ie, do potential benefits outweigh the risks)? See the Adult and Adolescent ARV Guidelines noted above, which thoroughly address the issue. A brief summary is included in the tables in the chapter Determining Risk of HIV Progression and in the chapter CD4 Monitoring and Viral Load Testing.
• The patient is or is not willing to start ARVs at this time (the choice to accept or decline therapy ultimately lies with the patient).
• The patient is or is not likely to adhere to an ARV regimen (an adherence counselor, with or without a mental health clinician, may be able to assist with this assessment and should be called upon if available). No patient should be automatically excluded from consideration of ART; the likelihood of adherence must be discussed and determined individually.

P: Plan

After educating the patient about the purpose and logistics of the proposed regimen and assessing the patient's potential for adherence, the ART regimen can be initiated, changed, or postponed accordingly.

The goals of therapy are to achieve maximal and durable viral suppression, restore or preserve immune function, improve quality of life, and reduce HIV-related morbidity and mortality.

Considerations before Initiating ART

No "average patient" exists. Some patients will do better during treatment and some will do worse than clinical studies would predict. Health care providers must work with each patient to develop a treatment strategy that is both clinically sound and appropriate for that individual's needs, priorities, and circumstances of daily life. Not all patients will be able to tolerate all drugs, and the patients understanding, readiness to commit to the regimen, and history of adherence to previous regimens must be considered when choosing ARV combinations. Major considerations are as follows:

• Willingness of the individual to begin therapy, coupled with understanding of the purpose and the mechanics of the planned regimen, and how it will fit into his or her life
• Degree of immunodeficiency and risk of disease progression as reflected by the CD4 count and HIV RNA level (see tables in the chapter Determining Risk of HIV Progression and the chapter CD4 Monitoring and Viral Load Testing)
• Potential benefits and risks of ARV drugs
• Likelihood of adherence to the prescribed regimen
• Resistance, if any, to ARV medications (obtain resistance testing prior to ARV initiation in ARV-naive patients)

The patient has the right to decline or postpone ART. This decision should not affect any other aspect of care, and ART should be offered again at each visit to patients who meet the criteria for treatment. If mental health issues, addiction, or the patient's social situation are barriers to adherence, initiate appropriate referrals and reassess adherence barriers at regular intervals.

Initiating Therapy: DHHS ARV Guidelines

The following recommendations have been adapted from the DHHS Adult and Adolescent ARV Guidelines.

• ART is recommended for all patients with a history of AIDS-defining illness or severe symptoms of HIV infection regardless of the CD4 cell count.
• ART is also recommended for asymptomatic patients with a CD4 count of <200 cells/µL.
• Therapy should be offered to asymptomatic patients with CD4 counts of 201-350 cells/µL. The urgency of treatment recommendations may be based on various factors, including the following:
  • Rate of CD4 cell decline
  • Plasma HIV RNA >100,000 copies/mL
  • Patient's interest
  • Risk of toxicity
• Therapy should probably be deferred for asymptomatic patients with CD4 counts of >350 cells/µL and plasma HIV RNA <100,000 copies/mL.

The question of when to initiate ART in asymptomatic patients remains an area of research and debate. It is clear that ART should be initiated before the CD4 count declines to <200 cells/µL, if at all possible. However, it is not yet known at what CD4 threshold ≥200 cells/µL therapy should be started, because the long-term risks of ARVs may be substantial in some patients. With the increasing availability of ARV regimens that are more tolerable, include fewer pills, and offer easier dosing schedules, some clinicians are choosing to initiate therapy earlier in the course of HIV infection.

Special Situations

• Pregnancy (see chapter Care of HIV-Infected Pregnant Women)
• Acute or primary HIV infection (see chapter Primary HIV Infection)
• Postexposure prophylaxis (see chapters Occupational Postexposure Prophylaxis and Nonoccupational Postexposure Prophylaxis)

Preparing the Patient for ART

Before starting ART, it is necessary to have a detailed discussion with the patient about his or her readiness to commit to a difficult, potentially toxic medication regimen, and to return for the required follow-up visits. The patient also must understand that the first treatment regimen offers the best opportunity for effective viral suppression, and immune reconstitution, which are the primary goals of ART.

Supporting Adherence

Numerous strategies are being tested for their effectiveness in supporting patients' adherence to the ART regimen. These may include extensive patient education, telephone contact with office staff members who can answer questions about adverse effects or other difficulties, family meetings, and peer support. Trust and accessibility appear to be important predictors of adherence, and some practitioners see the patient for 2 or 3 appointments before starting ART. Patients also may be given "test regimens" for a few weeks using inactive pills or mints, to help them understand how the medication schedule may fit into their lives before starting the actual ARVs. The choice to accept or decline ART ultimately lies with the patient (see chapter Adherence).

Anticipating Difficulties

Choosing an initial regimen that fits the patients lifestyle and that is likely to be tolerable will improve the likelihood of long-term success with that regimen. If patients develop toxicities to 1 or more components of an initial regimen, substitutions typically can be made without limiting the success of the regimen. Close monitoring and "check-in" appointments allow these adjustments to be made under clinical supervision. Close monitoring also can help to identify medication toxicities that may limit treatment and to detect early signs of inadequate medication adherence; early intervention to treat adverse effects and to support adherence may increase the likelihood of treatment success.

Considerations in Regimen Selection

Regimens should be selected with consideration of both patient factors and medication factors. The patient's schedule, adherence history, and self-defined goals of ARV therapy should be considered in selecting a regimen to which the patient will best adhere. The patient's comorbid conditions and potentially interacting medications should be evaluated for potential contraindications or synergism. The ARV history and any available resistance profiles should be reviewed carefully to choose a regimen that will be likely to achieve durable viral suppression. The CD4 cell count should be considered, especially if nevirapine will be used. In women who are pregnant or likely to become pregnant, ARV pregnancy categories and ARV teratogenicity should be taken into account. Table 6 of the Adult and Adolescent ARV Guidelines reviews the advantages and disadvantages of various drug classes and individual drugs in initial therapy.

Use of Multiple Classes of Drugs

For initial therapy, the Adult and Adolescent ARV Guidelines recommend the use of 2 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Drug combinations that include only NRTIs generally do not reduce virus levels as effectively as 2-class combinations. The question of whether to use an NNRTI or a PI in initial therapy is a matter of debate. Some clinicians advocate using 2 NRTIs with an NNRTI to preserve the PI class for later and avoid PI-related toxicities. Others are more concerned about the potential toxicities of NNRTIs and their low genetic barrier to resistance and instead recommend starting with a PI-containing regimen. In the end, the regimen should be selected with the individual patient in mind because the only effective combination is the one that the patient is willing and able to take on a consistent basis. See the information on drug resistance and toxicities below as well as the full text of the Adult and Adolescent ARV Guidelines for more complete discussions.

Boosted Protease Inhibitors

Ritonavir may be used at low doses in combination with several other PIs to enhance or "boost" the serum level and prolong the half-life. This strategy generally decreases the dosing frequency and the number of pills required, and improves the activity of some PIs.

Preferred Starting Regimens

More than 20 ARVs in 4 drug classes are approved (see Tables 10, 11, and 12 in the Adult and Adolescent ARV Guidelines). There are 4 nucleoside or nucleotide fixed-dose combinations and 1 PI coformulation. These guidelines suggest "preferred" and "alternative" regimens for initial therapy (Table 1).

Table 1. Initial Antiretroviral Regimens

Class Antiretroviral Agents Preferred Regimens NNRTI-Based Efavirenz* + (lamivudine or emtricitabine) + (zidovudine or tenofovir) PI-Based Lopinavir/ritonavir (coformulation) + (lamivudine or emtricitabine) + zidovudine Alternative Regimens NNRTI-Based Efavirenz* + (lamivudine or emtricitabine) + (abacavir or didanosine or stavudine) Nevirapine# + (lamivudine or emtricitabine) + (zidovudine or stavudine or didanosine or abacavir or tenofovir) PI-Based Atazanavir + (lamivudine or emtricitabine) + (zidovudine or stavudine or abacavir or didanosine) or (tenofovir + ritonavir 100 mg/d) Fosamprenavir + (lamivudine or emtricitabine) + (zidovudine or stavudine or abacavir or tenofovir or didanosine) Fosamprenavir/ritonavir + (lamivudine or emtricitabine) + (zidovudine or stavudine or abacavir or tenofovir or didanosine) Indinavir/ritonavir + (lamivudine or emtricitabine) + (zidovudine or stavudine or abacavir or tenofovir or didanosine) Lopinavir/ritonavir + (lamivudine or emtricitabine) + (stavudine or abacavir or tenofovir or didanosine) Nelfinavir + (lamivudine or emtricitabine) + (zidovudine or stavudine or abacavir or tenofovir or didanosine) Saquinavir (hard-gel capsules or tablets)/ritonavir (100-400 mg/d) + (lamivudine or emtricitabine) + (zidovudine or stavudine or abacavir or tenofovir or didanosine) 3 NRTI-Based Abacavir + zidovudine + lamivudine (only when a preferred or an alternative NNRTI-based or PI-based regimen cannot or should not be used)

Key to abbreviations: NNRTI = nonnucleoside reverse transcriptase inhibitor; PI = protease inhibitor; NRTI = nucleoside reverse transcriptase inhibitor. Adapted from U.S. Department of Health and Human Services. Table 6. Antiretroviral Regimens Recommended for Treatment of HIV-1 Infection in Antiretroviral-Naive Patients. In: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006. * Efavirenz is not recommended for use in first trimester of pregnancy or in women with high pregnancy potential. # A high incidence of symptomatic hepatic events was observed in women with pre-nevirapine CD4 counts >250 cells/µL and men with CD4 counts >400 cells/µL; nevirapine should not be initiated in these patients unless the potential benefit clearly outweighs the risk.

Practitioners should note that these recommendations change over time as new data regarding efficacy or toxicity become available. Among regimens with adequate potency (taking into account possible ARV resistance), regimen selection should be guided by factors such as anticipated tolerability, pill burden, drug interactions, and the patient's comorbid conditions.

Avoiding Drug Resistance

ARV medications never should be given as single agents, in 2-drug regimens, in suboptimal regimens, or in lower doses than recommended because of the potential for development of resistance. High-level resistance to NNRTIs, as well as to emtricitabine and lamivudine, may develop quickly (ie, within days to weeks) in these situations. It may take longer for high-level resistance to develop with other NRTIs and PIs. Patients must be instructed to take the full dosage of all medications on schedule, and to avoid skipping doses or taking "days off" from their regimens. Careful medication dosing is important because resistance to 1 drug within a particular class may transfer to other drugs in the same class (cross-resistance). Cross-resistance can limit the options for future therapy significantly or require very complicated regimens in the future. Resistant viral strains, once developed, may be transmitted to other people.

Acquired or "primary" resistance, in which a patient is infected with ARV-resistant virus, is common in parts of the United States. Because both multi- and single-class resistance has been found among drug-naive persons in many U.S. cities, it is recommended that individuals with newly diagnosed HIV infection and those new to care should receive a baseline resistance test as early as possible, and before initiation of ART (see chapter Resistance Testing).

Drug Interactions

Many of the ARVs interact with one another as well as with other common medications. When starting or changing an ARV regimen, review all the patient's current medications carefully for possible drug interactions. See chapter Drug-Drug Interactions with HIV-Related Medications for a summary of this issue and for references and resources to review medication lists and combinations. For further information on drug interactions involving ARVs, see Tables 19, 20, and 21 in the Adult and Adolescent ARV Guidelines.

Once-Daily Regimens

Convenient and simplified dosing is an obvious strategy to improve adherence, particularly with the availability of coformulations that reduce pill burden. The Adult and Adolescent ARV Guidelines currently include the once-daily combination of efavirenz + tenofovir + lamivudine or emtricitabine as a "recommended" regimen, and list several other possibilities are listed among the "alternative" regimens.

The combinations indicated below (2 NRTIs + 1 NNRTI or PI) are likely to be effective in initial therapy (Table 2). Some of these combinations, however, have not been studied in clinical trials.

Table 2. Once-Daily Regimens for Initial Therapy

NRTI Combinations plus NNRTI or PI Lamivudine or emtricitabine + abacavir Lamivudine or emtricitabine + didanosine Lamivudine or emtricitabine + tenofovir Didanosine + tenofovir*# + Efavirenz* Nevirapine* Atazanavir# Atazanavir/ritonavir Fosamprenavir/ritonavir Indinavir/ritonavir Lopinavir/ritonavir

Key to abbreviations: NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = nonnucleoside reverse transcriptase inhibitor; PI = protease inhibitor * Didanosine + tenofovir should not be used with efavirenz or nevirapine. #Tenofovir cannot be used with unboosted atazanavir. Adapted from Coffey S. Options for Once-Daily Dosing of Antiretrovirals. AETC National Resource Center Web site. Available at http://aidsetc.org/aidsetc?page=et-03-00-01.

Drugs and Drug Combinations That Should Not Be Used

Drugs with similar mechanisms of action and resistance mutations (eg, lamivudine and emtricitabine, or efavirenz and nevirapine) offer no significant advantage when combined and may increase toxicities. Drugs with additive or overlapping toxicities, such as stavudine and didanosine, should not be combined. Zidovudine and stavudine, which compete intracellularly and therefore cause antagonism, should not be used together. Most clinicians in the United States avoid using the NRTI stavudine if other options are available because of the high rate of metabolic abnormalities associated with that drug. Certain 3-drug combinations have suboptimal efficacy and are not recommended (eg, tenofovir + didanosine + NNRTI). Some ARVs require specific dosing intervals in particular patients. For example, once-daily dosing of lopinavir/ritonavir is not recommended patients receiving concomitant efavirenz or nevirapine, and some once-daily PIs or combinations should not be used in treatment-experienced patients.

Follow-Up of Patients Starting ART

Patients who start a new ARV regimen should be seen at least twice within the first month to assess effectiveness, adherence, tolerability, and adverse effects of the regimen.

At 2 weeks on a new regimen, practitioners should check the following:

• CBC with platelets, especially for patients starting a zidovudine-containing regimen, to monitor for anemia
• LFTs, especially for patients starting a nevirapine-containing regimen, to monitor for hepatotoxicity

At 4-8 weeks on a new regimen, and every 3 months on a stable regimen, check the following:

• HIV viral load, to monitor initial virologic response to therapy
• CD4 cell count, to monitor initial CD4 response to therapy (note that CD4 response may lag behind virologic response)
• CBC with platelets (as above)
• LFTs (as above) and renal function tests

Patients should have glucose and lipid profiles (preferably when fasting) checked at baseline and, if normal, repeated every 4-6 months after starting ART. If the results are abnormal or if the patient has cardiac risk factors, recheck every 3-4 months while on the regimen.

Regimen Failure

A treatment regimen may fail for several reasons.

Inadequate virologic response

• Viral load does not decline below the level of detection (<50-75 copies/mL, especially in patients taking initial therapy) within 6 months of initiating therapy. (In patients with previous treatment experience and in those with ARV resistance, it may not be possible to decrease plasma HIV viral load to undetectable levels, and stabilization of viral load below the previous baseline may be an appropriate goal of therapy.)

Virologic rebound

• Virus is repeatedly detected in plasma after initial suppression to undetectable levels. The degree of increase should be considered, however. Repeat testing is required to rule out "blips" of virus (isolated elevations in viral load of less than about 1,000 copies/mL) that are not clinically significant and to ensure that the increase is not due to infection, vaccination, or problems with test methodology.
• A reproducible, significant increase occurs in viral load, reaching 3-fold or greater from the lowest plasma HIV RNA level, that is not due to intercurrent infection, vaccination, or problems with test methodology.

Immunologic failure

• The CD4 cell count, measured on at least 2 separate occasions, shows a persistent decline.
• The CD4 cell count fails to increase by at least 25-50 cells/µL above baseline in the first year of ART.

Clinical deterioration or progression

• Recurrent, persistent, or new HIV-related illness occurs after at least 3 months on ART. Note that new or recurrent symptoms of opportunistic illness occurring in the first weeks to months after starting ART, especially in patients with severe immunosuppression, may not reflect a failure of ART. Rather, these symptoms could be due to persistence of severe opportunistic infections that may require longer treatment, or they could be due to an immune reconstitution syndrome (see chapter Immune Reconstitution Syndrome).

Responding to Apparent Treatment Failure

Refer to the Adult and Adolescent ARV Guidelines and consult with HIV-expert clinicians about the use of resistance testing and alternative regimens before discontinuing therapy.

Carefully assess patient adherence, because inadequate adherence to ARVs is a common reason for regimen failure. In some cases, adherence support, treatment of adverse drug effects, substitution for poorly tolerated ARVs, or other measures to enhance adherence may result in virologic suppression. In other cases, ARV resistance may have developed. Poor adherence may affect the decision to change therapy, and adherence issues should be addressed before a new regimen is initiated.

The availability of effective alternative ARVs is critical consideration in deciding whether or when to change therapies. If treatment possibilities are limited or nonexistent, it may be necessary to weigh the value of partial virologic suppression with the current regimen against the likelihood of further resistance. Consultation with an experienced HIV provider and use of HIV resistance testing are appropriate when considering changes in therapy. When no treatment options remain among currently approved drugs, refer the patient to an appropriate clinical trial if possible.

Susceptibility or Resistance Testing

It is fairly common for a first regimen to fail because of resistance to only 1 or 2 drugs in a multidrug combination (see chapter Resistance Testing). Resistance testing, although expensive and time consuming, can identify drugs that are less likely to be effective against the patient's virus. During resistance testing, the patient should still be taking the failing regimen so that resistant viral populations will be present in detectable numbers. Resistance testing is recommended before changing regimens because of virologic rebound during ARV therapy or suboptimal suppression of viral load on ARV therapy.

Cross-resistance exists among ARVs, such that resistance to 1 drug in a class of agents often extends to other agents in that class. For example, cross-resistance between efavirenz and nevirapine is almost complete, and resistance mutations to NRTIs and to PIs often decrease viral susceptibility to other drugs in those classes. As a result, selecting a new ARV regimen can be complicated because it requires knowledge of expected resistance patterns. The likelihood of sustained viral suppression is lower when resistant virus is present even if a subsequent regimen contains new ARVs.

Guidelines for Changing an ARV Regimen for Suspected Drug Failure

The following recommendations are adapted from the Adult and Adolescent ARV Guidelines.

• Distinguish between the need to change a regimen because of drug intolerance or inability to adhere to the regimen and the failure to achieve the goal of sustained viral suppression. In the event of intolerance, single agents usually can be changed without resistance testing.
• In general, do not change a single drug or add a single drug to a failing regimen; it is important to use at least 2 or, preferably, 3 active drugs. If resistance testing (performed while the patient is taking the failing regimen) shows resistance to only 1 agent in a regimen, it may be possible to replace only that drug; however, this approach requires clinical validation.
• Many patients have limited options for new regimens that will achieve durable virologic suppression. In some of these cases it is rational to continue the same regimen if partial virologic suppression and clinical and immunologic stability were achieved.
• In some cases, it is rational to continue regimens identified as suboptimal for initial therapy in patients with limitations imposed by toxicity, intolerance, or nonadherence, especially in late-stage disease. Even when these patients fail to achieve durable viral suppression on these regimens, they may remain clinically stable, with stable CD4 cell counts. Discontinuing ARVs can lead to reversion of more virulent wild-type virus and to clinical progression.
• Data are limited on the value of restarting a drug that the patient has previously received. Resistant virus can be archived and will reemerge for patients who are rechallenged with regimens on which they had previously developed resistance. As a result, resistance tests from previous regimens should be used with current resistant tests to determine what drugs might be active in a new regimen.
• If virologic failure occurs on an NNRTI-containing regimen, avoid changing among NNRTIs because high-level cross-resistance is likely.
• The decision to change therapy and the choice of a new regimen require that the clinician have considerable expertise in the care of people with HIV infection. Those less experienced in the care of persons with HIV are strongly encouraged to obtain assistance by consulting with or referring to an expert clinician.

For a general strategy for selecting a new regimen after virologic failure of an initial regimen, see Table 25 in the Adult and Adolescent ARV Guidelines. Note that other possibilities exist, and resistance testing and expert consultation should be sought to help guide treatment choices.

Follow-Up of Patients Not Started on ART

Patients who may benefit from ART, but are not on therapy

These patients should continue their regular visits for monitoring, prophylaxis, and other medical treatment. Changes in laboratory results and the patients' condition should be taken as opportunities to reassess their decisions about ARVs, to educate them about new medications and research findings, and to discuss the risks of delayed treatment, including the risk of progression to AIDS or death. ARVs should be discussed again and offered at regular intervals to anyone who initially refuses treatment. If lack of readiness or probable adherence difficulties are issues, an adherence counselor (if available) or a mental health provider should be engaged to bolster the patients support and coping mechanisms (see the Adult and Adolescent ARV Guidelines or check tables in the chapter CD4 Monitoring and Viral Load Testing).

Patients who do not meet the DHHS criteria for starting ARVs

These patients should be monitored regularly with laboratory tests and physical examination (see Section 1, Testing and Assessment for chapters on physical examinations and laboratory tests), offered prophylaxis as appropriate, and reassessed for ARV therapy when they do meet the criteria for starting treatment.

Special Situations for ART

ART during acute or primary HIV infection

Patients with acute or primary HIV infection may experience symptoms such as rash, fever, lymphadenopathy, fatigue, weight loss, nausea, and headache within the first few weeks after becoming infected, and still have a negative or indeterminate result on the HIV antibody test. If a careful HIV risk history reveals the patient to be at significant risk for recent HIV infection, an HIV RNA test can be performed to ascertain whether viremia is present. (Note that a low viral load may suggest a false-positive result.) It is not yet known whether ART has a long-term benefit when started during primary HIV infection. However, for the appropriate patient, it is reasonable to consider starting therapy, with the goal of maximal virologic suppression. Before starting an ARV regimen, patients must be counseled carefully about potential limitations, such as toxicity, pill burden, cost, and the possible development of drug resistance. Patients should be monitored with HIV viral load, CD4 counts, and other parameters, as in patients with established infection who are taking ARV therapy. Because no definitive data exist on the clinical benefit of early treatment and because ART involves certain risks, including drug toxicity and resistance, persons with acute HIV infection ideally should be treated in controlled clinical trials. (See chapter Primary HIV Infection.)

Pregnant women

Since 1994, zidovudine has been recommended to reduce the risk of mother-to-child transmission of HIV, but zidovudine monotherapy is less effective than combination therapy in reducing perinatal transmission and is inadequate for treatment of the pregnant woman. Combination ARV regimens are now used during pregnancy, if possible, to reduce the risk of transmission to the infant and to treat HIV infection in the mother. Certain ARVs are recommended during pregnancy, whereas others should be avoided. Because of potential teratogenic effects, efavirenz should not be used. (See chapters Reducing Maternal-Infant HIV Transmission and Care of HIV-Infected Pregnant Women; also refer to CDC. Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States. July 6, 2006. Available online at http://aidsinfo.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=9.)

ARV treatment in resource-limited settings

The discussion of ARV management is futile for the majority of people in the world today who are living with HIV/AIDS. According to the Joint United Nations Programme on HIV/AIDS, as of June 2005, only 11% of those needing ARV therapy in low- and middle-income countries were receiving treatment.

ARV medications are becoming available in many parts of the developing world, but the increase in availability is slow and in no way is occurring at the pace and with the efficiency warranted in this dire situation. Medication choices are limited by the availability and cost of drugs. Most resource-limited countries that are able to provide ARVs use an NNRTI-based combination for initial therapy. This regimen typically includes nevirapine or efavirenz plus 2 NRTIs such as zidovudine or stavudine plus lamivudine. Second-line therapies or substitutions needed because of toxicities or intolerance often are not readily available.

Widespread use of nevirapine to prevent mother-to-child transmission of HIV has lowered the rate of HIV transmission to infants, but the drug resistance that may emerge after even single-dose administration to the mother during labor has raised many concerns regarding effective treatment options for the mother. Without the availability of resistance testing, many women are subsequently started on an ARV regimen that includes an NNRTI. For women who have developed NNRTI resistance during previous nevirapine exposure, these regimens probably will be ineffective. In addition, NRTI resistance is likely to develop, further limiting treatment options.

Concern about adherence in resource-limited settings, although often cited as a treatment-limiting factor, has proven to be less of an issue than it is in the United States and western Europe. Many treatment programs require a lengthy educational process before ARVs are initiated. In addition, the limited availability of treatments paired with the widespread devastation of entire communities and countries has enhanced the motivation for strict adherence to therapies among patients able to acquire ARV therapy.

CD4 count and viral load testing to identify patients who should begin ART, and to monitor ARV effectiveness and potential drug toxicities, are severely limited by the lack of sufficient laboratories, equipment, and funds to perform costly blood tests. In some settings, patients are started on therapy based on clinical presentation alone, and monitoring is based solely on clinical criteria. Success of treatment may be assessed by clinical response, such as resolution of opportunistic infections, weight gain, and improvements in quality of life. ARV toxicity may be assessed by clinical signs and symptoms of adverse effects such as anemia or hepatitis.

Comorbid conditions such as tuberculosis and malaria, and potential drug interactions associated with their treatments, often complicate therapy choices. Competing priorities of poverty, lack of clean water or sanitation, and overburdened health care settings and health care providers combine to complicate the distribution of effective ARV treatment. Regardless of the numerous challenges to treatment in resource-limited settings, human compassion and responsibility dictate that we find a way to provide care for those who require treatment.

Expert Consultation

The National HIV/AIDS Clinicians' Consultation Center (NCCC) is a valuable resource for any clinician seeking expert advice about ART, HIV clinical manifestations, laboratory evaluations, and other issues. Its National HIV Telephone Consultation Service (Warmline) is staffed by HIV-experienced physicians and pharmacists. The Warmline operates Monday through Friday, 8 am to 8 pm EST and is available free of charge in the United States at 800-933-3413.

Patient Education

• Starting ARVs is rarely an emergency. Before starting ARVs, health care providers must work with patients to determine how important therapy would be for them, what goals of therapy are likely to be achieved, and which personal issues are pertinent for selecting the best regimen to fit their lifestyles.
• Providers should review the proposed drug regimen with their patients. Be sure patients understand the instructions about dosage, scheduling, food requirements or restrictions, drug storage, adverse effects, toxicities, and type of reactions that must be reported immediately, as well as remedies for common adverse effects.
• Providers should explain to patients that ART requires a commitment to taking the medications precisely as prescribed. There is a limited number of ARVs, and if they are taken incorrectly, the virus can quickly become resistant to the medications. This will mean even fewer choices and less effective treatment in the future. It might also mean that they could transmit resistant virus to a partner or, if they are pregnant, to an infant.
• Patients should know that HIV medications do not prevent transmission of infection to others. Safer-sex recommendations must be followed and other high-risk activities (eg, needle sharing) must be carefully avoided to keep from spreading the virus to others (see chapter Preventing HIV Transmission/Prevention with Positives for more information).
• Experts recommend using latex barriers during sex (safer sex) and not sharing needles or other drug-using equipment, even with other HIV-infected persons. Patients should know that if their virus develops resistance to some ARVs and they pass that virus on to another person, HIV medications may not be effective in that person. If a patient's partner happens to have a drug-resistant strain of HIV, it is possible for the patient to become infected with a resistant virus in addition to the one he or she has already, and this may limit treatment options.
• Hepatitis C, hepatitis B, and other sexually transmitted infections such as syphilis and gonorrhea can be transmitted between partners who both have HIV.
• If ARVs must be discontinued, it is usually best to stop all ARVs at once. The exception to this recommendation may be NNRTI-containing regimens; in this case, the NRTIs should be continued for about 1 week after discontinuation of the NNRTI, if possible. Even carefully managed interruptions can cause drug resistance mutations. Again, this will limit future treatment options, and should be avoided if possible.
• Discuss contingencies in the event that the client is unable to take ARVs for a day or more (eg, illness, severe adverse effects, hospitalization, or other unexpected circumstances).

References

• Centers for Disease Control and Prevention. Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HIV and Recommendations for Postexposure Prophylaxis. MMWR Recomm Rep. 2005 Sep 30; 54(RR09); 1-24. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=10.
• Centers for Disease Control and Prevention. Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States. July 6, 2006. Available online at aidsinfo.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=9.
• Coffey S. Options for Once-Daily Dosing of Antiretrovirals. AETC National Resource Center Web site. Available online at http://aidsetc.org/aidsetc?page=et-03-00-01. Accessed May 19, 2006.
• Kojic E, Carpenter C. Initiating Antiretroviral Therapy. In: Peiperl L, Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [textbook online]; San Francisco: UCSF Center for HIV Information; 2006.
• Hirsch M. Highly Active Antiretroviral Therapy in 2005: Recent Data for Clinical Practice. MedScape.com Web site. Accessed February 7, 2006.
• New York AIDS Institute. Criteria for the Clinical Care of Adults with HIV Infection: Antiretroviral Therapy; revised June 2005. HIVGuidelines.org. Available online at www.hivguidelines.org/public_html/a-arv/a-arv.htm. Accessed February 7, 2006.
• U.S. Department of Health and Human Services. Antiretroviral Postexposure Prophylaxis After Sexual, Injection-Drug Use, or Other Nonoccupational Exposure to HIV in the United States. MMWR Recomm Rep. 2005 Jan 21;54(RR02);1-20. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=11.
• U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. May 4, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=7.
• World Health Organization. Progress on Global Access to Antiretroviral Therapy: An Update on "3 X 5"; June 2005.