Special Feature

What's New in the HIV Treatment Guidelines?

By Stan Deresinski, MD, FACP, FIDSA, Clinical Professor of Medicine, Stanford University, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.

Synopsis: Most of the changes in the guideline deal with the choice of antiretroviral therapy in the previously treatment-naïve patient.

Source: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 14, 2011. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed Nov. 8, 2011.

A revision to the Jan. 10, 2011, Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents was published on Oct. 14, 2011. This update focuses on the choice of an initial regimen for antiretroviral treatment-naïve HIV patients: "What to Start: Initial Combination Regimens for the Antiretroviral-Naïve Patient." The changes recommednded by the Panel are summarized here.

Non-nucleoside Reverse Transcriptase Inhibitor (NNRTI)-Based Regimens

Rilpivirine (RPV) was added as an alternative NNRTI option for initial therapy in treatment-naïve patients.

Background: On the basis of clinical trial results and safety data, the Panel recommends that efavirenz (EFV), RPV, or nevirapine (NVP) may be used as part of an initial regimen. In most instances, EFV is preferred, based on its potency and tolerability. RPV may be used as an alternative NNRTI option in treatment-naïve patients (B; see Table, below, for rating scheme for recommendations), whereas NVP may be used as an acceptable NNRTI option (C) in women with pretreatment CD4+ counts ≤ 250 cells/mm3 or in men with pretreatment CD4+ counts ≤ 400 cells/mm3.

Table. Rating scheme for recommendations.
Strength of Recommendation Quality of Evidence for Recommendation
A: Strong recommendation for the statement I: One or more randomized trials with clinical outcomes and/or validated laboratory endpoints

B: Moderate recommendation for the statement II: One or more well designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes

C: Optional recommendation for the statement III: Expert opinion

Source: Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 14, 2011. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed Nov. 8, 2011.

Although RPV demonstrated overall non-inferiority to EFV, among participants with higher pre-treatment HIV RNA (> 100,000 copies/mL), virologic failure occurred more frequently in those randomized to receive RPV. Subjects with virologic failure on RPV were also more likely to have genotypic resistance to other NNRTIs (EFV, ETR, and NVP) and to have resistance to their prescribed NRTIs. For those reasons, the guideline indicates that RPV should be used with caution in patients with pre-treatement HIV RNA > 100,000 copies/mL.

The drug interaction tables were also updated to include information regarding RPV. Table 14 indicates that the following should not be coadministered with this NNRTI: rifamycins, proton pump inhibitors, St. John's wort, other NNRTIs, carbamazepine, oxcarbazepine, phenobarbital, and phenytoin. Table 15b indicates that antacids may be administered at least 2 hours before or 4 hours after RPV, and H2 antagonists may be given at least 12 hours before or 4 hours after. The use of proton pump inhibitors is totally contraindicated, as are carbamazepine, phenobarbital, phenytoin, rifampin, and rifabutin. Because of a likely interaction with clarithromycin, azithromycin is recommended as an alternative in patients receiving RPV. More than a single dose of dexamethasone is contraindicated in patients on the NNRTI.

Dosing of RPV was also addressed. Appendix B, Table 2 recommends a daily 25 mg dose (alone or as part of Complera®, which also contains emtricitabline and tenofovir). It was noted that RPV is a CYP3A4 substrate with serum half-life of 50 hours and that the adverse events most commonly associated with its use are rash, depression, insomnia, and headache. In addition, Appendix B, Table 7 indicates that no dosage adjustment is indicated in patients with renal insufficiency, including those undergoing chronic peritoneal dialysis or hemodialysis. Finally, no dosage recommendation is indicated for patients with Childs Class A or B hepatic impairment, while no recommendation is made for those in Childs Class C.

All nevirapine-based regimens were reclassified as acceptable options for treatment-naïve patients (females with pretreatment CD4+ count < 250 cells/mm3 or males with pretreatment CD4+ count < 400 cells/mm3). Previously, "nevirapine + zidovudine/lamivudine" was classified as an alternative regimen and "nevirapine + abacavir/lamivudine" and "nevirapine + tenofovir/emtricitabine" were recommended as regimens that may be acceptable but should be used with caution.

Background: Patients who experience CD4+ count increases to levels above the thresholds indicated above in response to NVP-containing therapy can safely continue therapy without an increased risk of adverse hepatic events. At the initiation of NVP, a 14-day lead-in period at a dosage of 200 mg once daily should be instituted before increasing to the maintenance dosage of 400 mg per day (as an extended-release 400 mg tablet once daily or 200 mg immediate-release tablet twice daily). Some experts recommend monitoring serum transaminases at baseline, at 2 weeks, then 2 weeks after dose escalation, and then monthly for the first 18 weeks. Clinical and laboratory parameters should be assessed at each visit.

Protease Inhibitor (PI)-based Regimens

"Ritonavir (RTV)-boosted darunavir (DRV) + abacavir/lamivudine" was reclassified as an alternative regimen (BIII). This regimen had previously been recommended as one that may be acceptable, although more definitive data were needed (CIII).

Background: The Panel uses the following criteria to distinguish between preferred vs. alternative PIs in ART-naïve patients: 1) demonstrated superior or non-inferior virologic efficacy when compared with at least one other PI-based regimen, with at least published 48-week data; 2) RTV-boosted PI with no more than 100 mg of RTV per day; 3) once-daily dosing; 4) low pill count; and 5) good tolerability. Using these criteria, the Panel recommends atazanavir (ATV)/r (once daily) and DRV/r (once daily) as preferred PIs.

The ARTEMIS study compared DRV/r (800/100 mg once daily) with LPV/r (once or twice daily), both in combination with tenofovir (TDF)/emtricitabine (FTC), in a randomized, open-label, non-inferiority trial. At 96 weeks, virologic response to DRV/r was superior to response to LPV/r. Based on these data, the Panel recommends DRV/r + TDF/FTC as a preferred PI-based regimen (AI). No randomized controlled trial exists to evaluate the efficacy of DRV/r with the other two-NRTI combinations. A small retrospective study suggested that DRV/r + ABC/3TC may be effective in treatment-naïve patients for up to 48 weeks. Based on this preliminary information, the Panel recommends this combination as an alternative PI-based regimen (BIII).

• Regimens with unboosted fosamprenavir were removed as PI options for treatment-naïve patients because they have inferior potency compared with other PI-based regimens and because of the potential for selection of mutations that confer resistance to darunavir in patients who experience virologic failure while on these regimens.

Raltegravir-based Regimens

"Raltegravir + abacavir/lamivudine (RAL)" was reclassified as an alternative regimen (BIII). This regimen was previously classified as a regimen that may be acceptable, but more definitive data are needed (CIII).

Background: Comparisons of RAL-based regimens with other regimens in ART-naïve subjects have not yet been reported, and experience with RAL is less than with EFV or boosted PIs for initial therapy. In addition, RAL must be administered twice daily, a potential disadvantage when compared with some other regimens. RAL, like EFV, has a lower genetic barrier to resistance than RTV-boosted PIs, and resistance mutations were observed at approximately the same frequency in the comparative trial.

Dual-nucleoside Reverse Transcriptase Inhibitor (NRTI) Options

"Zidovudine + lamivudine" was reclassified from an alternative dual-NRTI option to an acceptable option because the combination has greater toxicities compared with tenofovir/emtricitabine and abacavir/lamivudine and requires twice daily dosing. However, zidovudine + lamivudine remains as the preferred dual-NRTI for pregnant women receiving antiretroviral therapy for prevention of perinatal transmission of HIV.

"Didanosine + lamivudine" was removed as a dual-NRTI option for initial therapy because the combination has the least clinical trial experience and greater toxicity compared with other available dual-NRTI options.

Discussion on the association between abacavir use and the risk of a cardiovascular event was updated.

Background: The D:A:D observational study found that recent (within 6 months) or current use of abacavir, but not TDF, was associated with an increased risk of myocardial infarction, particularly in participants with pre-existing cardiac risk factors. Since this study, however, multiple studies have explored this association and come to varying conclusions. To date, no consensus has been reached either on the association of abacavir use with myocardial infarction risk or a possible mechanism for the association.