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HIV Meds Quarterly, 2011-12 Winter, Entire Issue

for Health Care Providers

HIV Meds Quarterly, 2011-12 Winter, Entire Issue

Once-Daily Etravirine

The NNRTI etravirine is approved for twice-daily dosing in both treatment-naive and treatment-experienced patients. The pharmacokinetic characteristics of etravirine suggest it may be given once daily, and several recent trials have examined the efficacy of QD etravirine. In particular, the SENSE trial randomized 157 treatment-naive individuals to either etravirine (400 mg QD) or efavirenz, in combination with 2 NRTIs selected by the investigator (60% received tenofovir/emtricitabine). The median baseline HIV RNA level was 4.8 log10 copies/mL and the level was >100,000 copies/mL in 23% of subjects. At screening, no resistance to study ARVs was detected, though NNRTI or NRTI mutations were found in 16% of etravirine recipients and in 5% of efavirenz recipients on testing conducted at baseline.

At 48 weeks, the HIV RNA level was <50 copies/mL in 75.9% of the etravirine group and in 74.4% of the efavirenz group, by TLOVR analysis. Results appeared to be similar for subjects with pretreatment HIV RNA levels of >100,000 copies/mL. Increases in CD4 counts were approximately 234 cells/ÁL in each arm. The study was not powered to evaluate noninferiority. Among the 11 subjects who experienced virologic failure, 4 were etravirine recipients. None of those in the etravirine group had emergent resistance mutations, whereas 3 of 7 who experienced virologic failure on efavirenz developed NRTI or NNRTI mutations. Virologic failure was not associated with the mutations observed at baseline.

Neuropsychiatric adverse effects were substantially more common in the efavirenz arm, both in the early weeks of the study and throughout the follow-up phase (21.5% vs 6.3%, respectively, at 48 weeks), and lipid elevations also were more common in the efavirenz group (grade 3-4 LDL elevations were seen in 10% vs 3%, respectively, of subjects); rates of rash were the same in the 2 groups.

Clinical Bottom Line

This study suggests that once-daily etravirine is effective and well tolerated in initial therapy. Although it is not currently approved for once-daily dosing, etravirine may be a reasonable treatment option for select individuals, particularly those for whom other NNRTIs may not be appropriate. Additional evaluations of once-daily etravirine are under way.

References

Gazzard B, Duvivier C, Zagler C, et al. Phase 2 double-blind, randomized trial of etravirine versus efavirenz in treatment-naive patients: 48 week results. AIDS. 2011 Nov 28;25(18):2249-58.

Switching from Efavirenz to Rilpivirine

It has been reported previously that efavirenz reduces serum levels of rilpivirine and that this effect may be prolonged, even after discontinuation of efavirenz (see "Sustained Effect of Efavirenz on Rilpivirine Serum Concentrations"). A small, nonrandomized study was designed to answer the question of whether it is possible to switch directly from efavirenz to rilpivirine without loss of virologic control. Forty-nine subjects who complained of adverse effects on efavirenz/tenofovir/emtricitabine (Atripla) were changed to rilpivirine/tenofovir/emtricitabine (Complera). Subjects were on their first antiretroviral regimen with virologic suppression for =3 months (most had >1 year of suppressed HIV RNA), and had no baseline reverse transcriptase (RT) mutations. Twelve weeks after the switch, all subjects maintained HIV RNA levels of <50 copies/mL (that was the primary end point). Pharmacokinetic analysis showed that rilpivirine trough levels were suppressed initially but, within 2-4 weeks had risen to the levels that were seen in the Phase 3 studies of rilpivirine, whereas efavirenz levels remained in therapeutic range for several weeks after discontinuation.

Clinical Bottom Line

This small study provides some reassurance that switching directly from efavirenz to rilpivirine may be a successful treatment strategy, at least for the specific group of patients who have wild-type HIV and have long-term virologic control on efavirenz-based ART. For other patients, including those who have detectable viremia on efavirenz (eg, during the early weeks of ART) and those who have been virologically suppressed for only a short time, these results may not be applicable. Optimal strategies for managing the interaction between efavirenz and rilpivirine have yet to be identified, and if direct switches are made from efavirenz to rilpivirine, they should be made with caution.

References

Mills A, Cohen C, Dejesus E, et al. Switching from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) single tablet regimen (STR) to emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) STR in virologically suppressed, HIV-1 infected subjects. In: Program and abstracts of the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 17-20, 2011; Chicago. Abstract H2-794c.

Darunavir + Raltegravir without NRTIs, Revisited

In early 2011, a single-arm study of the NRTI-sparing regimen of darunavir/ritonavir (800/100 mg QD) plus raltegravir (400 mg BID) reported worrisome rates of virologic failure, particularly among subjects with baseline HIV RNA levels of >100,000 copies/mL.(1) At ICAAC, researchers involved in a second study to evaluate this combination presented their 24-week results.

In the small RADAR trial (n=80), treatment-naive subjects were randomized to receive darunavir/ritonavir (QD) with either raltegravir (BID) or tenofovir/emtricitabine. The median baseline HIV RNA was 4.72 log10 copies. At 24 weeks, rates of HIV RNA suppression to <50 copies/mL were 86% and 87%, respectively, with 2 subjects in the NRTI-sparing arm and none in the comparator arm experiencing virologic failure. Increases in CD4 counts were 149 cells/ÁL and 125 cells/ÁL, respectively.(2) The study was not powered to make statistical comparisons between treatment arms.

Clinical Bottom Line

In the RADAR study, treatment with darunavir/ritonavir + raltegravir resulted in rates of virologic suppression at 24 weeks that were high, and they were equivalent to those achieved with standard therapy. It is not clear, however, why the results of this study are so different from those reported in the ACTG trial. Accordingly, pending further study, this and most other NRTI-sparing combinations should be used with caution in individual patients.

References

1. Taiwo B, Zheng S, Gallien S, et al; ACTG A5262 Team. Results from a single-arm study of DRV/r + RAL in treatment-naive HIV-1-infected patients (ACTG A5262). In: Program and abstracts of the 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston. Abstract 551.

2. Bedimo R, Drechsler H, Turner D, et al. RADAR study: raltegravir combined with boosted darunavir has similar safety and antiviral efficacy as tenofovir/emtricitabine combined with boosted ritonavir in antiretroviral-naive patients. In: Program and abstracts of the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011); July 17-20, 2011; Rome. Abstract MOPE214.