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Selecting antiretroviral regimens for the treatment naive HIV-infected patient
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2012. | This topic last updated: Mar 30, 2012.

INTRODUCTION — The treatment of human immunodeficiency virus (HIV) infection has been revolutionized by potent antiretroviral therapy (ART). Use of these multidrug regimens has resulted in substantial reductions in progression to AIDS, opportunistic infections, hospitalizations, and deaths [1].

Drug selection is becoming increasingly complex, with more than 20 antiretroviral medications available in six major classes [2,3]. This topic will address the goals of therapy, the various drug classes, and the efficacy of different regimens for initial treatment.

Indications for initiating antiretroviral therapy in treatment-naive patients, appropriate patient evaluation prior to initiation of therapy, individual patient considerations (including counseling about adverse effects) prior to starting therapy, and laboratory monitoring are discussed elsewhere. (See "When to initiate antiretroviral therapy in HIV-infected patients" and "Considerations prior to initiating antiretroviral therapy" and "Counseling HIV-infected patients regarding potential side effects of antiretroviral therapy" and "Patient monitoring during HIV antiretroviral therapy".)

Treatment of the HIV-infected woman during pregnancy is discussed elsewhere. (See "Antiretroviral therapy for the pregnant HIV-infected patient in resource-rich settings".)

GOALS OF THERAPY — When ART is administered, the following goals are desired [3,4]:

  • Durable suppression of HIV viral load to less than 50 copies/mL
  • Restoration of immune function (as indicated by the CD4 cell count)
  • Prevention of HIV transmission
  • Prevention of drug resistance
  • Improvement in quality of life

UNDERSTANDING COMBINATION ANTIRETROVIRAL REGIMENS

General principles — Regimens are described as having a "backbone" and a "base". The backbone typically consists of two nucleoside reverse transcriptase inhibitors (NRTIs). The base has traditionally included either a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI). In December 2009, raltegravir, from the integrase inhibitor class, was also added to the list of potent antiretroviral medications recommended by the DHHS Guidelines for initial treatment of the HIV-infected patient in combination with a backbone of two NRTIs [5]. The International AIDS Society-USA Panel also made a similar recommendation in July 2010 [4].

ART regimens should have at least three active antiretroviral medications. Activity against HIV is determined by drug resistance testing prior to initiation of therapy; however, these tests will not detect resistant HIV in low concentrations. Detailed information regarding drug resistance testing and interpretation is discussed separately. (See "Drug resistance testing in the clinical management of HIV infection".)

In general, regimens with four active drugs are not recommended since they are not more efficacious than three-drug regimens in treatment-naive patients and are associated with more adverse events [6,7]. In addition, regimens composed of three classes of drugs are no more potent than regimens comprised of two different classes [8]. In general, three-drug regimens that include three drugs from the same class (ie, nucleoside analogs) are not as effective as regimens that combine drugs from different classes and are not recommended. (See "Clinical trials of HIV antiretroviral therapy: Three versus four-drug regimens" and 'Antiretroviral combinations to avoid' below.)

Antiretroviral classifications

Drug classes used in treatment-naive patients — The classes of antiretroviral drugs used in initial regimens include (table 1):

  • Nucleoside (and nucleotide) reverse transcriptase inhibitors (NRTIs)
  • Nonnucleoside reverse transcriptase inhibitors (NNRTIs)
  • Protease inhibitors (PIs)
  • Integrase strand transfer inhibitors (INSTIs)
  • CCR5 antagonists

The United States Food and Drug Administration (FDA) approved maraviroc, a CCR5 antagonist for treatment-naive patients, in November 2009 based on a trial that showed that maraviroc plus two NRTIs was noninferior to efavirenz plus two NRTIs [9]. Maraviroc is considered an “alternative” choice for treatment-naive patients [4]. (See 'NNRTI-based ART versus CCR5-based ART' below.)

Drug classes not used in treatment-naive patients — Fusion inhibitors (eg, enfuvirtide) are not approved for treatment-naive patients. (See "Clinical trials of HIV antiretroviral therapy: Integrase inhibitors".)

Abbreviations used — The table shows the abbreviations for medications used in this topic (table 1).

Pharmacokinetic boosting with ritonavir — If a PI is selected, pharmacokinetic boosting with low-dose ritonavir is standard and preferred, whenever possible [4].

Ritonavir is a potent inhibitor of hepatic microsomal enzyme CYP (450) 3A4. This characteristic is used to "boost" the serum concentration of other protease inhibitors (PIs). Use of pharmacokinetic boosting improves trough serum concentrations and rates of viral suppression; use of ritonavir also enables lower dosing of the parent drug, thereby decreasing pill burden (table 2).

At doses of 400 mg/day or less, ritonavir is not counted as an active individual agent in any ART regimen; in this dose range, it is only a "pharmacologic enhancer." Full-dose ritonavir (600 mg twice daily) is virtually never used to treat HIV due to significant adverse effects at this dose.

The major drawbacks of using ritonavir boosting are related to an increased risk of gastrointestinal intolerance, hyperlipidemia, and drug interactions. All of these adverse effects are dose related. Pharmacokinetic boosting is discussed in detail elsewhere. (See "HIV protease inhibitors", section on 'Pharmacokinetic boosting'.)

Provider expertise — The drugs now used have brought a host of new concerns including expense, side effects, drug interactions, and emergence of drug resistance.

The management of antiretroviral therapy (ART) is complex and should be delivered by providers with specific training. Multiple older studies showed that provider experience correlates with better patient outcome [10-12]. The potential magnitude of this effect was illustrated in a study of 403 HIV-infected men diagnosed between 1984 and 1994 [10]. After controlling for disease severity and year of diagnosis, patients of physicians with the most clinical experience (based on HIV clinic panel size) had a 31 percent reduction in the risk of death.

EFFICACY BY DRUG CLASS

Overview — As a general statement, NNRTI, PI, or integrase inhibitor-based regimens are all considered effective for initial HIV therapy, although advantages and disadvantages differ [3,4].

NNRTIs have been the major comparator in most large treatment efficacy trials during the last several years. The discussion below is divided into two parts:

  • NNRTIs versus PI-based ART
  • NNRTIs versus integrase inhibitor-based ART

NNRTIs have also been compared with maraviroc-based ART for the initial treatment of HIV-infected patients. However, as noted above, there are limited clinical data upon which to recommend a CCR5 antagonist (ie, maraviroc) at present for the treatment-naive patient [3]. At present, maraviroc is considered an “alternative” agent for the treatment-naive patient [3,4]. (See "Clinical trials of HIV antiretroviral therapy: CCR5 antagonists".)

An overview of the use of various classes of antiretroviral agents is given below. More specific data on the individual agents themselves is given later in this topic within the specific sections on the various drug classes.

NNRTI-based ART versus PI-based ART — Comparative trials have demonstrated that regimens based on NNRTIs or ritonavir-boosted PIs, with a backbone of two NRTIs, are nearly comparable for initial treatment of HIV infection [3,4]. Most of these trials have utilized efavirenz as the NNRTI agent because of its overall potency, toxicity profile and convenient dosing, compared with other NNRTI agents (eg, nevirapine). (See 'Non-nucleoside reverse transcriptase inhibitors' below.)

A meta-analysis of 12 comparative trials in antiretroviral-naive patients found that NNRTI-based therapy is associated with similar rates of death and disease progression as with PI-based ART [13]. Similar findings were noted in a subsequent randomized trial in 1397 treatment-naive patients with a five-year follow-up: PI and NNRTI-based strategies were equivalent in clinical efficacy and immunologic outcomes, although viral suppression to <50 copies/microL was achieved more rapidly in the NNRTI arm [8]. (See "Clinical trials of HIV antiretroviral therapy: Protease inhibitors versus non-nucleoside reverse transcriptase inhibitors".)

The AIDS Clinical Trial Group (ACTG) 5142 trial also demonstrated significantly better virologic responses with an efavirenz-based regimen compared with a lopinavir/ritonavir-based regimen at 96 weeks (89 versus 77 percent) [14]. However, better CD4 cell count responses and less drug resistance were noted in the boosted PI arm. (See "Clinical trials of HIV antiretroviral therapy: Protease inhibitors versus non-nucleoside reverse transcriptase inhibitors".)

Issues regarding drug resistance and adverse events profiles that should be considered in drug selection include the following:

  • Drug resistance to most PIs requires multiple mutations and seldom develops after a first regimen failure with boosted PI-based regimens. In contrast, resistance to both efavirenz and nevirapine is conferred by a single mutation (eg, K103N).
  • One study of 7891 patients demonstrated that the cumulative risk of drug resistance by eight years of therapy was 28 percent [15]. However, the probability of developing drug resistance was lower in patients who initiated PI-based ART compared with those who initiated NNRTI-based ART (adjusted relative hazard, 0.35; 95% CI 0.26-0.50).
  • Some PIs are associated with gastrointestinal intolerance and metabolic disturbances, whereas efavirenz use is associated with more rash and central nervous system side effects. These side effects usually abate within approximately two to three weeks.

Preferred and alternative agents within the PI and NNRTI classes are discussed within the specific sections below.

NNRTI-based ART versus INSTI-based ART — Raltegravir is the only drug available within the integrase inhibitor class for use in combination ART with two NRTIs. Two trials suggest that raltegravir (RAL) is effective first-line therapy in treatment-naive patients when compared to efavirenz-based ART, although the experience with RAL as initial therapy is less extensive than efavirenz (EFV) and many boosted PI-based regimens [16].

The STARTMRK trial compared EFV versus RAL, each in combination with tenofovir and emtricitabine (TDF/FTC) [16]. At 48 weeks of follow-up, the patients in the raltegravir arm had similar rates of viral suppression (<50 copies/mL) as those in the efavirenz group (86 versus 82 percent). The results at 96 weeks also showed comparable rates of viral suppression, although the RAL recipients had a greater CD4 cell count increase and fewer adverse reactions [17].

Disadvantages to RAL-based ART as initial treatment are the limited data on durability, the need for twice daily dosing, and its low genetic barrier to resistance. (See "Clinical trials of HIV antiretroviral therapy: Integrase inhibitors".) The advantages of RAL are better overall tolerance and limited potential for drug interactions. Some experts prefer to use raltegravir in patients with multidrug-resistant virus rather than for initial therapy in the treatment-naive patient [4].

NNRTI-based ART versus CCR5-based ART — Maraviroc, a CCR5 antagonist, has also been compared to EFV in treatment-naïve patients. A post-hoc analysis found that maraviroc was noninferior to efavirenz in virologic efficacy when both were combined with zidovudine/lamivudine (ie, Combivir) [18,19]. In this trial the rate of adverse reactions requiring treatment discontinuation was greater in the EFV recipients (16 percent versus 6 percent), while the rate of virologic failure was greater in the MVC recipients (13 percent versus 6 percent) [18,19]. These data are discussed in detail elsewhere [9]. (See "Clinical trials of HIV antiretroviral therapy: CCR5 antagonists".)

Maraviroc appears to be well tolerated. However, concerns remain regarding the high cost of the screening tropism assay (nearly $2000), which is needed to determine treatment eligibility with a CCR5 antagonist. Maraviroc also requires twice-daily dosing. Larger trials with longer follow-up will also be needed to assess efficacy and long-term safety and potency in the treatment-naive patient. Clinicians should also note that maraviroc has only been studied in combination with zidovudine/lamivudine.

Summary — Clinicians can consider a NNRTI, PI, or integrase inhibitor-based regimen in combination with dual NRTIs for initial HIV therapy. CCR5 inhibitors are not currently recommended for the treatment-naive patient pending the availability of further published data.

The particular choice of agents may depend on side effect profiles, comorbidities, potential drug interactions, results of resistance testing, allergy history, pregnancy status, or patient convenience. Preferred agents within the individual classes are discussed below. (See "Considerations prior to initiating antiretroviral therapy".)

PROTEASE INHIBITORS — Protease inhibitors are potent antiretroviral agents, which have the advantage of having a relatively high genetic barrier to resistance compared with NNRTIs and integrase inhibitors; the development of resistance to protease inhibitors in previously antiretroviral-naïve individuals is uncommon even with less than optimal adherence [20].

Preferred agents — Lopinavir/ritonavir was considered a preferred agent within the PI class for several years. However, increasing concerns about adverse events associated with lopinavir/ritonavir including metabolic effects (eg, hypertriglyceridemia), cardiovascular events (eg, myocardial infarction), and significant gastrointestinal toxicity led to a renewed focus on alternative PI agents.

In 2009, the Department of Health and Human Services (DHHS) panel selected ritonavir-boosted atazanavir or darunavir as preferred agents within the PI class because of their overall efficacy, dosing convenience, and side effect profiles [5]. In 2010, the IAS-USA guidelines also recognized boosted atazanavir and darunavir as preferred options within the PI class; however, the IAS-USA guidelines also acknowledge that some clinicians may defer the use of boosted darunavir in treatment-naive patient populations because of its efficacy in patients with multidrug-resistant virus [4].

Both boosted atazanavir and boosted darunavir have shown greater antiviral efficacy than boosted lopinavir (LPV/r) with long-term follow-up:

  • The CASTLE trial compared once-daily atazanavir/ritonavir with twice-daily lopinavir/ritonavir, each in combination with tenofovir/emtricitabine [21]. Atazanavir/ritonavir was superior to lopinavir/ritonavir with respect to viral suppression (74 percent versus 66 percent) at 96 weeks [21].
  • A similarly designed trial (ARTEMIS) demonstrated that patients treated with darunavir/ritonavir (DRV/r) achieved significantly higher rates of viral suppression than with lopinavir/ritonavir at 96 weeks (79 versus 72 percent) [22].

Both atazanavir and darunavir also have the advantage of requiring only 100 mg daily of ritonavir compared with 200 mg of ritonavir when given with lopinavir. (See "Clinical trials of HIV antiretroviral therapy: Protease inhibitors".)

As noted above, the ACTG 5142 trial demonstrated that efavirenz-based ART was virologically superior to boosted lopinavir. However, the observation that boosted atazanavir and darunavir-based regimens were both virologically superior to lopinavir/ritonavir has raised questions as to whether efavirenz-based ART is virologically superior to all PI regimens. To date, there are no comparative trials of efavirenz versus atazanavir or darunavir-based ART. (See 'NNRTI-based ART versus INSTI-based ART' above.)

Adverse events and dosing of atazanavir and darunavir are discussed below.

Atazanavir (Reyataz) — The two Food and Drug Administration (FDA) approved dosing regimens are a) atazanavir 400 mg (two 200 mg capsules) once a day unboosted, and b) atazanavir 300 mg (one 300 mg capsule) once a day plus ritonavir 100 mg once a day (ie, boosted atazanavir). The 2011 DHHS guidelines and the 2010 IAS-USA guidelines recommend "boosted" atazanavir as a "preferred" PI for naïve patients; unboosted atazanavir is listed in the "alternative" category [3].

This agent has the advantages of better gastrointestinal tolerance than most other PIs, once-daily dosing, and good potency. Atazanavir is not associated with the development of insulin resistance, as compared with other agents, such as lopinavir/ritonavir. Lipid profiles show mild increases in cholesterol and triglycerides that are mainly related to ritonavir [23].

Disadvantages include the need for gastric acid and food for optimal absorption; thus concomitant use of drugs that alter stomach pH (eg, proton pump inhibitors) may impair absorption of atazanavir. Atazanavir can also lead to an increase in the indirect serum bilirubin concentration, which is benign, but may cause jaundice. (See "HIV protease inhibitors".)

Darunavir (Prezista) — Dosing of darunavir for treatment-naïve patients is 800 mg once daily; (given as two 400 mg tablets) plus ritonavir (100 mg) once daily.

The principle adverse effects associated with darunavir include nausea, diarrhea, increased transaminases, hepatotoxicity, headache and rash, including Stevens-Johnson syndrome. Some patients who developed rash also had fever and/or transaminase elevations. Darunavir contains a sulfonamide moiety and should be used with caution in patients with a known sulfonamide allergy. (See "HIV protease inhibitors".)

Alternative agents — Alternative PI agents include ritonavir-boosted fosamprenavir, or lopinavir. These agents are classified as alternative PI agents because of issues related to potency, toxicity, or convenience. Both the IAS-USA and DHHS guidelines specifically recommend against using saquinavir because of concerns regarding QT-interval prolongation announced by the FDA [3,24].

Requirements for ritonavir dosing for pharmacologic boosting have also been considered since ritonavir’s associated side effects are dose related. Atazanavir and darunavir only require 100 mg of ritonavir daily as compared with some protease inhibitors, which require higher concomitant dosing of ritonavir (eg, lopinavir, fosamprenavir, or saquinavir). (See "HIV protease inhibitors" and "Clinical trials of HIV antiretroviral therapy: Protease inhibitors".)

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS — The NNRTIs are potent agents, but have the limitation of a low genetic barrier to resistance; efavirenz, nevirapine, and delavirdine require only a single mutation to confer drug resistance. Furthermore, a major mutation (such as K103N) leads to cross-resistance to other members of the class with one exception.

Etravirine has in vitro activity against some viruses with mutations that confer resistance to the other NNRTIs in this class, but is used within salvage regimens for treatment-experienced patients. Delavirdine is no longer used due to frequency of dosing and numerous associated drug interactions. (See "Primer on interpretation of HIV drug resistance testing".)

Preferred agents

Efavirenz (Sustiva) — Of the NNRTIs, efavirenz (EFV) is the preferred agent within this class because of its overall demonstrated potency, convenience, and toxicity profile [3].

Efavirenz has been used extensively since 1998 and has the advantages of excellent potency, low pill burden, and durability in treatment-naive patients [4,6,25-32]. Efavirenz has demonstrated comparable virologic efficacy to nevirapine, atazanavir and raltegravir-based ART; efavirenz has also demonstrated superior virologic activity to lopinavir/ritonavir, indinavir, and nelfinavir. (See "Clinical trials of HIV antiretroviral therapy: Integrase inhibitors" and "Clinical trials of HIV antiretroviral therapy: Non-nucleoside reverse transcriptase inhibitors" and "Clinical trials of HIV antiretroviral therapy: Protease inhibitors".)

The efficacy of efavirenz has also been demonstrated among patients with high pretreatment viral loads and low CD4 cell counts [33].

The main problems with EFV include:

  • Side effects: Central nervous system toxicity is common, although usually restricted to the first two to three weeks of initiation. Patients should be counseled regarding this side effect before initiating therapy. Higher rates of intolerance are noted in black patients due to delayed metabolism that is genetically determined. Some experts prefer other alternatives to EFV in patients with a history of depression and persons with selected high-risk occupations (eg, airplane pilots).
  • Teratogenic potential: Efavirenz is the only class D antiretroviral agent and must be avoided in the first trimester of pregnancy or in women who may become pregnant.
  • Potential for drug interactions, since efavirenz is an inducer of cytochrome P450

Alternative agents

Nevirapine (Viramune) — In one large randomized controlled trial comparing NNRTIs (2NN trial), there were no significant differences in virologic or immunologic outcomes among treatment-naive patients assigned to nevirapine (NVP) or efavirenz-containing regimens [4,25]. Nevirapine was also noninferior to both ritonavir-boosted atazanavir and lopinavir-containing ART in two trials that included patients with low CD4 cell counts (<250/microL) [34,35]. (See "Pharmacology of non-nucleoside reverse transcriptase inhibitors".)

However, nevirapine is more toxic during the first three months of therapy in the treatment-naive patient; complications have included hepatic necrosis and serious cutaneous reactions, including deaths due to hepatic necrosis or Stevens-Johnson Syndrome.

Nevirapine is considered an “acceptable” alternative to efavirenz for the treatment of HIV infection [36]. However, NVP should NOT be initiated in women with a baseline CD4 count >250 cells/mm3 or in men with a CD4 count >400 cells/mm3 since these CD4 thresholds represent major risk factors for hepatotoxicity. Nevirapine is also a suitable choice when efavirenz use is contraindicated (eg, pregnancy). (See "Considerations prior to initiating antiretroviral therapy" and "Clinical trials of HIV antiretroviral therapy: Non-nucleoside reverse transcriptase inhibitors" and "Pharmacology of non-nucleoside reverse transcriptase inhibitors".)

When starting nevirapine, a dose of 200 mg once daily is prescribed for 14 days prior to increasing to the maintenance dose of 200 mg twice daily. Some experts recommend monitoring serum aminotransferases at baseline, prior to and two weeks after dose escalation, then monthly for the first three months. Patients should also be counseled about symptoms of hepatotoxicity. (See "Counseling HIV-infected patients regarding potential side effects of antiretroviral therapy".)

Rilpivirine (Edurant) — Two controlled trials (ECHO and THRIVE) compared rilpivirine with efavirenz in treatment-naive patients in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) [37-39]. The pooled results demonstrated that the proportion of patients with viral suppression at 48 weeks was comparable in the rilpivirine and efavirenz-containing arms. Rilpivirine was also well tolerated and associated with minimal changes in lipids.

However, among those subjects with a baseline viral load >100,000 copies/mL, the risk of virologic failure was higher in the rilpivirine arm compared with the efavirenz arm. Virologic failure on rilpivirine may also compromise the anti-HIV activity of other NNRTIs, including etravirine, which may be useful for patients with HIV multi-drug resistance. An increased risk of nucleoside analog resistance mutations (eg, M184V/I) was also noted in these trials [38,39]. (See "Clinical trials of HIV antiretroviral therapy: Non-nucleoside reverse transcriptase inhibitors", section on 'Efavirenz versus rilpivirine' and "Primer on interpretation of HIV drug resistance testing", section on 'Non-nucleoside reverse transcriptase inhibitors (NNRTIs)'.)

For these reasons, rilpivirine should be considered as an alternative agent and should only be used in treatment-naïve patients with a baseline viral load less than 100,000 copies/mL [40].

INTEGRASE STRAND TRANSFER INHIBITORS

Raltegravir — Raltegravir is the only FDA-approved drug within this class. Raltegravir was shown to be comparable to efavirenz with respect to viral suppression in a double-blind non-inferiority trial in treatment-naïve patients over 192 weeks of follow-up. Raltegravir is noted for its overall excellent tolerance and its lack of impact on lipids. One of its main disadvantages is the need for twice-daily dosing (ie, 400 mg twice daily). Clinicians should note that this agent has been studied only in combination with tenofovir and emtricitabine as an NRTI backbone. (See "Clinical trials of HIV antiretroviral therapy: Integrase inhibitors".)

Like efavirenz, raltegravir also has a low genetic barrier to resistance; N155H is its signature mutation. (See "Primer on interpretation of HIV drug resistance testing".)

The use of raltegravir in pregnancy is currently under evaluation. Clinicians are advised to report instances of prenatal exposure to antiretroviral therapy drugs to the Antiretroviral Pregnancy Registry at www.APRegistry.com; Telephone 1-800-258-4263. (See "Antiretroviral medications in pregnancy: Entry and integrase inhibitors".)

NUCLEOSIDE ANALOGS — Nucleoside analogs, or nucleoside reverse transcriptase inhibitors (NRTIs), are considered the "backbone" of ART and are generally used in combination with a NNRTI, PI, or integrase inhibitor. NRTIs are usually given in pairs, such as tenofovir (TDF) and emtricitabine (FTC); abacavir (ABC) and lamivudine (3TC); and zidovudine (ZDV) and lamivudine (3TC) [3,4]. All of these combinations are available as coformulations; Truvada (FTC and TDF), Combivir (ZDV and 3TC) and Epzicom (ABC and 3TC), respectively. Coformulations enable decreased pill burden and possibly improve patient adherence.

Preferred agents — The DHHS guidelines panel recommends tenofovir/emtricitabine (TDF/FTC) as the preferred nucleoside analog coformulation in combination ART for the treatment-naive patient because of its overall potency, favorable toxicity profile, and convenience of dosing.

Tenofovir/emtricitabine — An open-label, noninferiority trial was performed among 517 treatment-naive patients who were randomly assigned to either tenofovir/emtricitabine (TDF/FTC) or zidovudine/lamivudine (ZDV/3TC), both in combination with efavirenz [27]. Viral suppression rates were significantly higher among patients taking tenofovir/emtricitabine compared with zidovudine/lamivudine (84 versus 73 percent, respectively). Also, through 144 weeks of follow-up, significantly more patients in the TDF/FTC arm reached and maintained viral suppression than in the ZDV/3TC arm (71 versus 58 percent) with significantly less lipoatrophy [41]. The emergence of the signature mutation for lamivudine/emtricitabine resistance (M184V) was also less common in patients assigned to the TDF/FTC than to those assigned to ZDV/3TC. Furthermore, the signature mutation of tenofovir (K65R) did not emerge in any patient [42].

TDF/FTC is also the preferred agent for HIV-infected patients with concomitant HBV infection. (See "Considerations prior to initiating antiretroviral therapy" and "Treatment of hepatitis B in the HIV-infected patient".)

Renal impairment, characterized by increases in serum creatinine, glycosuria, hypophosphatemia, and acute tubular necrosis has been reported in association with tenofovir [43]. Risk factors include advanced HIV infection, diabetes, and hypertension. TDF should be avoided in patients with a baseline creatinine clearance of <50 cc/mL and renal function should be monitored during use of this agent.

TDF/FTC is given as a single tablet daily with or without regard to food.

Alternative agents — The DHHS guidelines recommend either Epzicom (ABC/3TC) or Combivir (ZDV/3TC) as alternative nucleoside analog backbones for combination ART.

Abacavir/lamivudine — The pendulum has swung back and forth with respect to the use of Epzicom as the nucleoside analog backbone of ART.

The use of Epzicom (abacavir/lamivudine) gained favor in 2007 when the risk of the abacavir-associated hypersensitivity reaction (fever, rash, and abnormal aminotransferases) was largely eliminated by screening for the genetic marker HLA-B*5701 [44]. At that time, Epzicom was considered to be comparable to Truvada in terms of virologic efficacy and toxicity profile in two non-inferiority trials [45,46].

However, ABC/3TC is now considered an alternative agent by the DHHS guidelines panel because of concerns regarding its virologic potency, particularly among those with high-level viremia (>100,000 copies/mL) [47,48], and because of its possible contribution to cardiovascular disease risk [49].

  • Virologic failure — In a randomized, blinded equivalence trial (ACTG 5202) involving 1858 eligible patients, four once-daily ART regimens were compared in treatment-naive patients [47]. These regimens included abacavir-lamivudine or tenofovir-emtricitabine plus either efavirenz or ritonavir-boosted atazanavir.

    Among the 797 patients with screening plasma HIV RNA levels of ≥100,000 copies/mL, there were twice as many virologic failures among those treated with abacavir-lamivudine compared with those assigned to tenofovir-emtricitabine at a median follow-up of 60 weeks. No differences were seen with respect to CD4 cell count changes at week 48. These results have raised concerns about potency, although other prospective and retrospective studies of smaller size or without blinding have not confirmed these findings [45,50].

    Abacavir should also not be dispensed with tenofovir. Virologic failure occurred in approximately half of the study patients participating in a clinical trial of abacavir/tenofovir/lamivudine combination therapy in treatment-naive patients [51]. In a follow-up pharmacodynamic study, abacavir plus tenofovir did not have additive antiviral activity, despite adequate intracellular drug concentrations [52]. The mechanism for these observations is unclear, but the combination of abacavir/tenofovir, with or without lamivudine, is not recommended as a nucleoside analog backbone for HIV treatment.
  • Cardiovascular events — Prospective data from the D:A:D trial and the ACTG 5202 trial and a retrospective analysis of the SMART data suggest that abacavir may be associated with an increase risk of hyperlipidemia [47] and cardiovascular events. (See "Epidemiology and pathogenesis of dyslipidemia and cardiovascular disease in HIV-infected patients".)
  • Summary — Use of ABC should be limited to persons who have a negative HLA-B5701 screening test. Pending further data, abacavir/emtricitabine should not be administered to persons with significant risk factors for coronary artery disease. (See "Considerations prior to initiating antiretroviral therapy" and "Abacavir hypersensitivity reaction" and "Epidemiology and pathogenesis of dyslipidemia and cardiovascular disease in HIV-infected patients".)

Combivir — The coformulation of zidovudine/lamivudine was a preferred choice when it was first introduced in 1997, but is now considered an alternative regimen to tenofovir/emtricitabine for the following reasons [3,4]:

  • Combivir requires twice-daily dosing whereas Truvada is dosed once daily.
  • Zidovudine is associated with gastrointestinal intolerance, fatigue, lactic acidosis, anemia and loss of limb fat [42,53].
  • Combivir has been shown to have inferior virologic potency compared to Truvada-based ART [27,42].

SELECTING A REGIMEN — Groups such as the International AIDS Society-USA Panel (IAS-USA) [4] and the US Department of Health and Human Services (DHHS) [3] have published guidelines for initial ART based on data from randomized controlled trials, which demonstrate potency based on surrogate endpoints, such as viral suppression and improvements in CD4 cell counts. A summary of the DHHS guidelines is found below.

DHHS guidelines — The 2011 DHHS guidelines indicate preference for the following regimens for initial treatment selected on the basis of demonstrated potency in clinical trials, relatively low frequency of serious adverse reactions, substantial clinical experience, and dosing frequency [3].

OR

OR

  • An integrase inhibitor, raltegravir (400 mg twice daily) with two NRTIs.
  • The recommended NRTI coformulation is TDF/FTC in all of the above combinations.

Efavirenz should NOT be administered to women who are pregnant or may become pregnant (see below). For more detailed information on these regimens, see table 6 of the DHHS Antiretroviral Guidelines for Adults and Adolescents, which can be accessed at http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1.

Other options — Based on individual patient characteristics and needs, an alternative regimen may actually be a preferred regimen [3]. Alternatives to the above recommendations are included for use in selected patients (table 3 and table 4).

IAS-USA guidelines — The 2010 IAS-USA guidelines are generally in agreement with the DHHS guidelines noted above [4]. For example, the IAS-USA guidelines also recommend fixed-dose TDF/FTC as the preferred NRTI backbone for combination ART, with abacavir/lamivudine as an alternative choice if HLA B5701 testing is negative.

Although the panel generally supported the use of efavirenz, atazanavir/ritonavir, darunavir/ritonavir or raltegravir as a potential third agent for treatment-naive patients, the members noted that more clinical data are available for the use of efavirenz and boosted atazanavir in treatment-naive patients than for the other agents [4].The panel also noted that many HIV experts consider darunavir or raltegravir as less attractive options for initial therapy because these two agents have an important role in the treatment of patients with multidrug-resistant virus.

ANTIRETROVIRAL COMBINATIONS TO AVOID — Certain combinations of antiretroviral medications should be avoided either because of toxicity, lack of efficacy, or drug antagonism. Clinicians need to always check for potential drug interactions before prescribing an ART regimen (table 5). For more detailed information on drug interactions, see tables 8, 9, and 16b of the DHHS Antiretroviral Guidelines for Adults and Adolescents, which can be accessed at http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1.

NRTI combinations — NRTI combinations to avoid include:

Triple nucleoside analog combinations — In general, three-drug regimens that include three drugs from the same class (ie, nucleoside analogs) are not as effective as regimens that combine drugs from different classes and are not recommended [51,64,65].

Non-nucleoside reverse transcriptase inhibitors — The combination of EFV and NVP together produces more side effects and is less efficacious than either drug alone [25]. (See "Clinical trials of HIV antiretroviral therapy: Non-nucleoside reverse transcriptase inhibitors".)

A combination of nevirapine plus tenofovir plus emtricitabine (or lamivudine) is not recommended because of efficacy concerns [3].

Rilpivirine should not be used in patients with baseline HIV RNA levels >100,000 copies/mL due to the risk of virologic failure and drug resistance [37].

Etravirine has not been studied in large randomized clinical trials in treatment-naive patients and is thus not recommended [3].

Protease inhibitors — Nelfinavir, IDV (boosted or unboosted) and saquinavir are no longer recommended by any guideline for initial treatment of HIV-infected patients [5].

Double PI combinations are not routinely recommended for initial HIV therapy. These combinations are often associated with significant lipid abnormalities.

A combination of unboosted atazanavir plus didanosine plus emtricitabine is not recommended because of efficacy concerns [3,66].

APPROACH TO TREATMENT

Illustrative examples — Appropriate initial ART regimens can be constructed using the above guidelines. For more detailed information on these regimens, see table 7 of the DHHS Antiretroviral Guidelines for Adults and Adolescents, which can be accessed at http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1.

The following are examples of such regimens that may be appropriate in many patients:

  • EFV 600 mg daily plus TDF/FTC (300 mg/200 mg) daily

The above regimen, coformulated as Atripla, requires only one pill taken once daily. EFV should not be used in women who are pregnant or are likely to become pregnant. The patient must be warned of the CNS side effects that are frequently noted in the initial few days after dosing. Many recommend that efavirenz be taken initially on an empty stomach since food promotes absorption and the CNS complications are dose related. (See "Pharmacology of non-nucleoside reverse transcriptase inhibitors".)

Potential PI-based regimens include:

  • DRV/r (800 mg/100 mg) once daily with food plus TDF/FTC or ABC/3TC (600 mg/300 mg) daily. This regimen might be preferred in the patient who is chronically taking proton pump inhibitors since atazanavir has significant drug interactions with PPIs.
  • ATV 300 mg daily plus RTV 100 mg daily with food plus TDF/FTC (300 mg/200 mg) daily or ABC/3TC (600 mg/300 mg) daily. This regimen may be preferred in the patient with a history of a sulfa allergy since darunavir should be avoided in this circumstance.

Another potential ART regimen includes raltegravir, an integrase inhibitor:

This is a particularly attractive option for patients with either abnormal lipid profiles or risk factors for coronary artery disease, since raltegravir has a neutral effect on cholesterol and triglycerides compared with efavirenz, which is associated with greater lipid abnormalities. (See "Clinical trials of HIV antiretroviral therapy: Integrase inhibitors".)

Drug resistance testing — Baseline resistance needs to be included in decisions on agents selected for initial treatment. The major concern is the K103N and other mutations that confer complete resistance to efavirenz and nevirapine and can be seen in treatment-naive patients due to transmission of a resistant strain.

This topic is discussed in detail elsewhere. (See "Drug resistance testing in the clinical management of HIV infection" and "Overview of HIV drug resistance testing assays" and "Primer on interpretation of HIV drug resistance testing".)

CONSIDERATIONS IN SELECTED CLINICAL SETTINGS — Patient considerations in choosing ART also include issues regarding pregnancy, methadone treatment, substance abuse patterns, probability of adherence, and comorbidities such as hyperlipidemia, liver disease, heart disease, psychiatric conditions, and renal insufficiency. This is discussed in detail elsewhere. (See "Considerations prior to initiating antiretroviral therapy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

  • The goal of ART is viral suppression to <50 cells/mL; secondary goals are immunologic restoration and prevention of HIV-related complications and prevention of adverse drug reactions. (See 'Goals of therapy' above.)
  • ART regimens for treatment-naïve patients are composed of a "base" and a "backbone". The base is either an non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). The backbone typically consists of two nucleoside reverse transcriptase inhibitors (NRTIs). Two and preferably three active drugs are desired when possible. (See 'Understanding combination antiretroviral regimens' above.)
  • Four-drug regimens are no more effective than three-drug regimens and may be associated with greater toxicity. Two of the three drugs used in combination ART should be selected from different classes of agents to improve efficacy and decrease the risk of resistance. (See 'Understanding combination antiretroviral regimens' above.)
  • Selected non-nucleoside reverse transcriptase inhibitor-, protease inhibitor-, or integrase inhibitor-based regimens are all considered comparable and effective for initial HIV therapy. The particular choice of agents may depend on side effect profiles, comorbidities, potential drug interactions, results of resistance testing, allergy history, pregnancy status, or patient convenience. (See 'Efficacy by drug class' above.)
  • Ritonavir-boosting of PIs is preferred because of increased serum concentrations which lead to greater efficacy and decreased rates of resistance. We recommend either boosted atazanavir or darunavir as a first-line protease inhibitor, rather than boosted lopinavir (Grade 1A). Atazanavir and darunavir have superior efficacy and improved side effect profiles. (See 'Protease inhibitors' above.)
  • We recommend efavirenz as the first-line NNRTI, rather than nevirapine (Grade 1A). Efavirenz (EFV) has superior virologic efficacy, a more favorable toxicity profile, and offers the convenience of once-daily dosing. However, efavirenz should not be administered to women of child-bearing potential or who are pregnant; nevirapine is the preferred NNRTI agent in this situation. Caution is necessary in patients with major psychiatric conditions. (See 'Non-nucleoside reverse transcriptase inhibitors' above.)
  • We recommend tenofovir/emtricitabine as a first-line nucleoside analog coformulation, rather than other nucleoside analog coformulations (eg, zidovudine/lamivudine or abacavir/lamivudine) (Grade 1A). Tenofovir/emtricitabine has a more favorable toxicity profile and superior efficacy than the alternative agents. Baseline renal disease with a creatinine clearance <50 mL/min is a contraindication to tenofovir. (See 'Nucleoside analogs' above.)
  • Raltegravir is the only agent available within the integrase class. It is generally well-tolerated and does not adversely affect lipids. (See 'Integrase strand transfer inhibitors' above.)
  • Abacavir/lamivudine (Epzicom) should only be administered if HLA-B*5701 screening for abacavir hypersensitivity is negative. This combination should be avoided in patients at high risk of coronary artery disease and should be used with caution if the patient's baseline HIV RNA level is >100,000 copies/mL. (See 'Nucleoside analogs' above.)
  • Certain combinations of antiretroviral medications should be avoided either because of toxicity, lack of efficacy, or drug antagonism. (See 'Antiretroviral combinations to avoid' above.)

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