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IAS 2009: ARIES Trial Shows Unboosted Atazanavir (Reyataz) Maintains Viral Suppression as well as Boosted Drug

The protease inhibitor atazanavir (Reyataz), taken with abacavir/lamivudine (Epzicom coformulation), was as likely to keep viral load undetectable after initial suppression as the same combination plus a boosting dose of ritonavir, researchers reported at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009) last month in Cape Town, South Africa. The unboosted regimen, however, was less likely to cause cholesterol and triglyceride elevations.

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IAS 2009: Can People in Low-income Countries Benefit from Antiretroviral Therapy without Routine Laboratory Monitoring?

Antiretroviral therapy (ART) should not be withheld from HIV patients in medium- and low-income countries due to lack of laboratory monitoring, according to results of the Development of Antiretroviral Therapy (DART) in Africa trial, presented last week at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009) in Cape Town, South Africa. The researchers also concluded that first-line treatment regimens can be given to people in resource-limited countries without the need for routine laboratory monitoring of toxicity.

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Shionogi-GlaxoSmithKline Pharmaceuticals Will Revise Inclusion Criteria for a Clinical Study of the Experimental Integrase Inhibitor S/GSK1349572 To Incorporate Concerns of HIV Treatment Advocates

Shionogi-GlaxoSmithKline is developing S/GSK1349572, an experimental HIV integrase inhibitor, for use as a first-line treatment in HIV patients. Following discussions with two AIDS treatment advocacy groups, the European AIDS Treatment Group and the AIDS Treatment Activists Coalition, the companies agreed to revise inclusion criteria for a dose-ranging study of the drug in HIV patients without prior antiretroviral treatment. The revision will raise the minimum allowable CD4+ count for entry to the study to 200 cells/mm3 or higher. The advocacy groups argued that HIV patients with CD4+ counts below 200 cells/mm3 should only be treated with FDA-approved standard of care therapies.

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IAS 2009: At Opening of International AIDS Conference in South Africa, Scientists Warn against Cutting Back Funding for AIDS Programs

As more than 5,000 researchers, people with HIV/AIS and HIV community advocates gathered in Cape Town, South Africa for the 5th IAS Conference on HIV Pathogenesis, Treatment an AIDS (IAS 2009), July 19 - 22, 2009, speakers at the open ceremonies warned against a loss of momentum in the global fight against the HIV pandemic. There is heightened concern that due to the global recession, governments and other donors are scaling back on their financial support for healthcare delivery systems.

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STARTMRK Trial Shows Raltegravir (Isentress) Works as Well as Efavirenz (Sustiva) in Treatment-naive HIV Patients

The first approved integrase inhibitor, raltegravir (Isentress), suppressed HIV viral load as well as efavirenz (Sustiva) over 48 weeks in the STARTMRK trial, a Phase 3 study of previously untreated patients. Participants taking raltegravir, however, experienced fewer drug-related adverse events.

As reported in the August 3, 2009 advance online edition of The Lancet, STARTMRK (sponsored by Merck) enrolled 566 participants from 67 research centers on 5 continents between September 2006 and June 2008.

Eligible patients had HIV RNA > 5000 copies/mL and no evidence of baseline resistance to efavirenz, tenofovir (Viread, also in the Truvada and Atripla coformulations), or emtricitabine (Emtriva). At baseline, 53% patients had viral load < 100,000 copies/mL and 47% had a CD4 count of 200 cells/mm³ or less.

Participants were randomly assigned in a 1:1 ratio to receive either 400 mg raltegravir twice-daily or 600 mg efavirenz once-daily, both in combination with 300/200 mg tenofovir/emtricitabine once-daily. To make sure the study was blinded, patients in the raltegravir arm also received placebo tablets matching efavirenz, while those in the efavirenz arm received raltegravir-matching placebos.

The primary efficacy endpoint was achievement of HIV RNA < 50 copies/mL at week 48, with a margin of non-inferiority of 12%.

Results

• In a 48-week non-completion = failure analysis, 86.1% of patients in the raltegravir arm and 81.9% in the efavirenz arm achieved HIV RNA < 50 copies/mL.
• The difference in efficacy was 4.2%, thereby meeting the criteria for raltegravir non-inferiority.
• The average time to achieve viral suppression, however, was significantly shorter for patients in the raltegravir arm compared with the efavirenz arm (P < 0.0001).
• Mean changes in CD4 count from baseline to week 48 were 189 cells/mm³ in the raltegravir arm and 163 cells/mm³ in the efavirenz arm (P = 0.0184)
• Patients in the raltegravir arm experienced significantly fewer drug-related clinical adverse events -- including central nervous system symptoms -- than those taking efavirenz (44.1% vs 77.0%; P < 0.0001).
• Serious drug-related clinical adverse events occurred in less than 2% of patients in both arms.
• Fewer laboratory-associated adverse events were recorded in the raltegravir arm compared with the efavirenz arm, but the difference did not reach statistical significance.
• Patients taking raltegravir experienced small increases in total cholesterol, LDL ("bad") cholesterol, HDL ("good") cholesterol, and triglycerides, but changes were significantly higher for efavirenz recipients.

Based on these findings, the study authors concluded, "Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48."

"Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients," they continued.

In their discussion, the researchers explained that non-inferiority of raltegravir "was not solely due to the higher number of discontinuations in the efavirenz group than in the raltegravir group."

"Both regimens had consistent efficacy across all baseline prognostic and stratification factors, including patients with high viral loads or low CD4 cell counts," they added

They also noted that more patients taking raltegravir reached undetectable HIV RNA levels by weeks 2-16 (studies typically do not report response prior to 24 weeks), but the clinical significance of this early response is not clear.

Virological failure was rare in both treatment groups, the researchers stated. Of the 8 patients in the raltegravir arm who experienced virological failure with > 400 copies/mL and an HIV integrase gene that could be analyzed, half had mutations known to confer raltegravir resistance.

A smaller Phase 2 study comparing similar regimens (but using lamivudine instead of emtricitabine) found that both raltegravir and efavirenz produced sustained viral suppression though 144 weeks (78% vs 76% < 50 copies/mL, respectively).

Emory University School of Medicine, Atlanta, GA; Orlando Immunology Center, Orlando, FL; Universita Vita-Salute San Raffaele, Milan, Italy; University of California at Davis, Sacramento, CA,; Centro de Referencia e Treinamento DST/AIDS, Sao Paulo, Brazil; Northstar Medical Center, University of Illinois at Chicago, Chicago, IL; Merck Research Laboratories, North Wales, PA.

8/11/09

Reference

JL Lennox, E DeJesus, A Lazzarin, and others (for the STARTMRK investigators). Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. The Lancet. August 3, 2009 (Epub ahead of print).

A Review of the Experimental NNRTI Rilpivirine

This review of the experimental NNRTI rilpivirine summarizes studies demonstrating that the drug has potent activity against HIV, including against NNRTI-resistant strains of the virus. After 96 weeks of treatment, rates of HIV suppression in treatment-naive patients compared favorably with those of efavirenz (Sustiva). The safety profile of rilpivirine was also favorable, with fewer central nervous system disturbances compared with efavirenz and, thus far, no concerns about its use during pregnancy.

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