Antiretroviral Therapy

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.

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. Clinicians must weigh the anticipated benefits of immune reconstitution against the possible risks of ARV toxicity and the likelihood of emergent ARV resistance, in the individual patient. With the increasing availability of ARV regimens that are more tolerable, consist of fewer pills, and offer easier dosing schedules, many clinicians are choosing to initiate therapy earlier in the course of HIV infection.

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.

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).

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.

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 9 of the Adult and Adolescent ARV Guidelines reviews the advantages and disadvantages of various drug classes and individual drugs in initial therapy.

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.

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.

More than 20 ARVs in 4 drug classes have been approved by the FDA (see Tables 11, 12, and 13 in the Adult and Adolescent ARV Guidelines). In recent years, an increasing number of fixed-dose combinations (FDCs) have become available to simplify dosing and reduce pill burden. These include 4 NRTI combinations:

	abacavir + lamivudine (Epzicom)
	abacavir + lamivudine + zidovudine (Trizivir)
	emtricitabine + tenofovir (Truvada)
	lamivudine + zidovudine (Combivir)

and 1 PI coformulation:

	lopinavir + ritonavir (Kaletra)

An FDC comprising 2 NRTIs and 1 NNRTI is also available, and constitutes a 1-pill once-daily regimen.

Also available is a 1-pill-per-day formulation of 2 NRTIs and 1 NNRTI:

	emtricitabine + tenofovir + efavirenz (Atripla)

The DHHS guidelines suggest "preferred" and "alternative" components for initial therapy (Table 1). Clinicians 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. Other agents or combinations may be appropriate in individual patients (see Table 6b of the Adult and Adolescent ARV Guidelines).

Table 1. Recommended Components of Initial Antiretroviral Treatment

Table 1. Recommended Components of Initial Antiretroviral Treatment Key to abbreviations: PI = protease inhibitor; NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTI = nucleoside/nucleotide analogue; BID = twice daily; QD = once daily. a. Efavirenz is not recommended for use by women in the 1st trimester of pregnancy or by sexually active women with childbearing potential who are not using effective contraception. b. The pivotal study that led to the recommendation of lopinavir/ritonavir as a preferred PI component was based on twice-daily dosing. A smaller study has shown similar efficacy with once-daily dosing but also showed a higher incidence of moderate to severe diarrhea with the once-daily regimen (16% vs. 5%). c. Nevirapine should not be initiated for use by women with CD4 counts of >250 cells/µL or by men with CD4 counts of >400 cells/µL because of increased risk of symptomatic hepatotoxicity. d. Atazanavir must be boosted with ritonavir if used in combination with tenofovir. Adapted from U.S. Department of Health and Human Services. Table 6a. Antiretroviral Components Recommended for Treatment of HIV-1 Infection in Treatment Naive Patients. In: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 10, 2006. Column A: NNRTI or PI Options (listed in alphabetical order) + Column B: Dual-NRTI Options (listed in alphabetical order) To construct a regimen, choose 1 component from column A and 1 from column B Preferred Components NNRTI efavirenza or PI atazanavir + ritonavir fosamprenavir + ritonavir (BID) lopinavir/ ritonavir (BID) + Preferred Components tenofovir/ emtricitabineb zidovudine/ lamivudineb Alternative to Preferred Components NNRTI nevirapinec or PI atazanavird fosamprenavir fosamprenavir + ritonavir (QD) lopinavir/ ritonavir (QD) + Alternative to Preferred Components abacavir/ lamivudine didanosine + (emtricitabine or lamivudine)

Key to abbreviations: PI = protease inhibitor; NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTI = nucleoside/nucleotide analogue; BID = twice daily; QD = once daily. a. Efavirenz is not recommended for use by women in the 1st trimester of pregnancy or by sexually active women with childbearing potential who are not using effective contraception. b. The pivotal study that led to the recommendation of lopinavir/ritonavir as a preferred PI component was based on twice-daily dosing. A smaller study has shown similar efficacy with once-daily dosing but also showed a higher incidence of moderate to severe diarrhea with the once-daily regimen (16% vs. 5%). c. Nevirapine should not be initiated for use by women with CD4 counts of >250 cells/µL or by men with CD4 counts of >400 cells/µL because of increased risk of symptomatic hepatotoxicity. d. Atazanavir must be boosted with ritonavir if used in combination with tenofovir. Adapted from U.S. Department of Health and Human Services. Table 6a. Antiretroviral Components Recommended for Treatment of HIV-1 Infection in Treatment Naive Patients. In: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 10, 2006.

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).

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.

Convenient and simplified dosing is an obvious strategy to improve adherence, particularly with the availability of coformulations that reduce pill burden (see Preferred Starting Regimens, above). The Adult and Adolescent ARV Guidelines currently include 2 once-daily combinations among "preferred" regimens, and list several other possibilities as "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

Table 2. Once-Daily Regimens for Initial Therapy 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. ^ Nevirapine is not FDA approved for once-daily dosing. #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. 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 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. ^ Nevirapine is not FDA approved for once-daily dosing. #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 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. For further information, see Table 7 and Table 8 of the Adult and Adolescent ARV Guidelines.

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.

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).

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.

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.

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.

In general, the goal of ART is to suppress HIV RNA to undetectable levels, in order to improve or maintain immune function. This is increasingly possible even for patients with resistance to multiple drugs as new ARV agents and new classes of ARVs become available.

However, 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 reasonable 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. The risk of maintaining patients on a partially suppressive regimen, however, is the emergence of additional resistance mutations.

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 resistance 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.

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.