A randomized, controlled, double-blind study presented at the International AIDS Society conference in Mexico City compared the efficacy of pregabalin (Lyrica) with placebo for HIV-infected patients with painful peripheral neuropathy. A total of 151 patients were treated with pregabalin (150-600 mg total daily dosage, depending on tolerance; an average of 386 mg/day), and an equal number received placebo. The groups were well matched at baseline, and had comparable mean pain scores and duration of symptoms. At 14 weeks, both groups had improvements in pain, with a mean decrease in pain score of about 3 points in the pregabalin group and about 2.5 points in the placebo group. This difference was not statistically significant. About 40% of subjects in each group gained ≥50% decrease in their pain scores, with no significant difference between groups. Pregabalin in general was tolerated well, with reported adverse effects of somnolence, dizziness, euphoria, and peripheral edema.

Clinical Bottom Line

For patients with postherpetic neuralgia and diabetic neuropathy, pregabalin has significant benefit over placebo. In this study, among patients with HIV-related painful peripheral neuropathy, both the pregabalin and the placebo recipients experienced notable improvements in pain, but pregabalin was not more effective than placebo. The study investigators argued that the placebo response in this study was particularly robust, but were unable to explain that observation. The outcome is disappointing, as peripheral neuropathy brings substantial suffering to a high proportion of HIV-infected individuals.

References

Simpson DM, Murphy TK, Durso-De Cruz E, et al. A randomized, double-blind, placebo-controlled, multicenter trial of pregabalin vs placebo in the treatment of neuropathic pain associated with HIV neuropathy. In: Program and abstracts of the XVII International AIDS Conference; August 3-8, 2008; Mexico City. Abstract THAB0301.

ACTG 5202 is an ongoing 96-week Phase III 4-arm study of initial ART strategies. Patients were randomized to blinded abacavir/lamivudine or emtricitabine/tenofovir, and to open label atazanavir/ritonavir or efavirenz. Earlier this year, an interim analysis by the Data Safety and Monitoring Board noted higher rates of early virologic failure among abacavir/lamivudine recipients with baseline HIV RNA ≥100,000 copies/mL. This led to unblinding of the NRTI backbones of patients in this high baseline viral load stratum. The ACTG 5202 interim results were presented in August at the XVII International AIDS Conference in Mexico City.(1)

The study cohort comprises 1,858 patients, including 797 with HIV RNA ≥100,000 copies/mL at baseline. The primary virologic end point was time to virologic failure, defined as HIV RNA ≥1,000 copies/mL at 16-24 weeks or ≥200 copies/mL at ≥24 weeks. Among patients with baseline HIV RNA ≥100,000, time to virologic failure was significantly shorter for the abacavir/lamivudine recipients, and the rate of virologic failure was higher (14% among abacavir/lamivudine recipients vs 7% among emtricitabine/tenofovir recipients) (hazard ratio [HR] = 2.33; p = .0003). However, among patients who did achieve suppression of HIV RNA to <50 copies/mL (on 2 checks), there was no significant difference between groups in the rate of virologic rebound.

Additionally, patients who received abacavir/lamivudine had a shorter time to grade 3/4 adverse events (HR = 1.86; p < .0001), with a majority of reactions being generalized body aches and increased lipids. Rates of suspected abacavir hypersensitivity reaction were the same in both NRTI groups and did not appear to explain the differences in rates of virologic failure.

Applying the same efficacy and safety end points as the ACTG 5202 study, researchers from GlaxoSmithKline (the manufacturer of abacavir and lamivudine) analyzed results of 6 clinical trials that used abacavir/lamivudine as an NRTI backbone.(2) They found no significant differences in rates of virologic failure between patients with baseline HIV RNA ≥100,000 copies/mL and those with <100,000 copies/mL. Their analysis included the HEAT study, which compared abacavir/lamivudine directly with tenofovir/emtricitabine (both combined with lopinavir/ritonavir) and found no significant differences in rates of virologic failure between the NRTI backbones among patients with high pretreatment viral loads. It should be noted, though, that these studies involved small numbers of patients with high viral loads and may be limited in their ability to discern the same differences in response.

Clinical Bottom Line

Even as the ACTG 5202 interim results undergo further scrutiny, clinicians should be cautious in initiating abacavir/lamivudine for patients with high baseline viral loads, particularly those for whom tenofovir/emtricitabine is an appropriate alternative. The DHHS Adults and Adolescents Antiretroviral Treatment Guidelines Panel considers both abacavir/lamivudine and tenofovir/emtricitabine "preferred" NRTI components of initial ARV therapy.

References

Sax P, Tierney C, Collier A, et al. ACTG 5202: shorter time to virologic failure (VF) with abacavir/lamivudine (ABC/3TC) than tenofovir/emtricitabine (TDF/FTC) as part of combination therapy in treatment-naive subjects with screening HIV RNA ≥100,000 c/mL. In: Program and abstracts of the XVII International AIDS Conference; August 3-8, 2008; Mexico City. Abstract THAB0303. Pappa K, Hernandez J, Ma B, et al. Abacavir/lamivudine (ABC/3TC) shows robust virologic responses in ART-naive patients for baseline (BL) viral loads (VL) of ≥100,000c/mL and <100,000c/mL by endpoint used in ACTG5202. In: Program and abstracts of the XVII International AIDS Conference; August 3-8, 2008; Mexico City. Abstract THAB0304.

Earlier this year, the D:A:D study group reported that current or recent use of abacavir or didanosine were associated with elevated rates of myocardial infarction (MI); see HMQ Summer 2008 . Since then, other research groups have been attempting to evaluate the cardiovascular effects of NRTIs in their own study populations. The SMART study group recently presented results analyzing MI risks associated with NRTIs.

The SMART study was designed to assess an HIV treatment strategy of continuous ARV therapy compared with CD4-guided ARV treatment. The present analysis evaluated cardiovascular end points and inflammatory biomarkers in 2,752 patients on continuous ARV therapy. Current use of abacavir was associated with an excess risk of cardiovascular events, with a hazard ratio of 4.3 for MI and 1.8 for major cardiovascular disease (CVD) events (a composite end point that included MI, stroke, surgery for CVD, and CVD death) compared with NRTIs other than abacavir or didanosine. Didanosine was not associated with elevated risk of MI. The risk of MI among patients taking abacavir was especially elevated for those who had traditional cardiovascular risk factors, notably those with ≥5 risk factors or those with ischemic changes on baseline electrocardiogram.

In a small subset of patients, biomarker data were collected at baseline; IL-6 and C-reactive protein were noted to be higher for abacavir recipients than for others, though levels of other biomarkers were not elevated.

Clinical Bottom Line

These results appear to confirm the findings of the D:A:D group, but the possible role of abacavir in cardiovascular disease events requires further investigation. Despite attempts to control for the fact (confirmed in the D:A:D report) that patients with cardiovascular risks were preferentially treated with abacavir, channeling bias remains a possible explanation for the study findings. Pending confirmation, clinicians probably should avoid use of abacavir with patients at high risk of CAD events, if appropriate alternatives are available. Additionally, clinicians should work with closely patients to reduce their traditional cardiovascular risk factors. The DHHS Adults and Adolescents Antiretroviral Treatment Guidelines Panel designates abacavir as a "preferred" component in initial therapy (for patients who test negative for HLA-B*5701), and states that ARV selection should be individualized for each patient.

References

D:A:D Study Group, Sabin CA, Worm SW, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration . Lancet. 2008 Apr 26;371(9622):1417-26. SMART/INSIGHT and the D:A:D Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients . AIDS. 2008 Sep 12;22(14):F17-24.

The atazanavir product label has been updated to include new information on several important drug interactions.

		Efavirenz: Efavirenz is known to decrease atazanavir levels substantially. In order to offset this interaction, previous recommendations indicated that atazanavir 300 mg should be combined with ritonavir 100 mg once daily. The manufacturer now recommends a higher atazanavir dosage for ARV-naive patients who take efavirenz: atazanavir 400 mg once daily + ritonavir 100 mg once daily. For treatment-experienced patients, the manufacturer warns that atazanavir should not be coadministered with efavirenz.

		Nevirapine: Two-way interactions between atazanavir and nevirapine cause decreases in serum atazanavir levels and increases in nevirapine levels. The manufacturer warns that these drugs should not be used in combination.

		Oral hormonal contraceptives: Atazanavir, like most protease inhibitors, interacts significantly with both ethinyl estradiol (EE) and norethindrone (NE). Unboosted atazanavir increases serum EE levels, and increases the risk of EE adverse effects. Ritonavir-boosted atazanavir decreases serum EE levels, and increases the risk of contraceptive failure. Atazanavir, whether combined with ritonavir or not, also increases NE levels, risking NE adverse effects. The atazanavir package label provides recommendations for dosage of EE in patients taking atazanavir, but few efficacy or safety data on the use of hormonal contraceptives with atazanavir or other protease inhibitors are available; alternative methods of contraception should be considered. If oral hormonal contraceptives are given to women who take atazanavir, the efficacy and safety of the contraceptive should be monitored carefully. Few data regarding the effects of atazanavir with other, non-oral hormonal contraceptives are available.

For further information on atazanavir drug interactions, see the atazanavir product label or the HIV InSite Database of Antiretroviral Drug Interactions .