Abstract
Single-Tablet Quad Regimen Achieves High Rate of Virologic Suppression
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Elvitegravir is an investigational integrase inhibitor for HIV, whereas cobicistat is a pharmacoenhancing agent. Truvada is a combination of emtricitabine and tenofovir disoproxil fumarate. Cobicistat (formerly GS 9350) is a potent mechanism-based inhibitor of cytochrome P450 3A (CYP3A). It is being studied as a stand-alone boosting agent for other antiretroviral medications such as atazanavir. Data from a phase II clinical trial evaluating the safety and efficacy of cobicistat-boosted atazanavir plus Truvada compared with ritonavir-boosted atazanavir plus Truvada have also been released and were presented at the 17th Conference on Retroviruses and Opportunistic Infections (CROI).
Study 236-0104 is a double-blind, multicenter, randomized (2:1), active-controlled 48-week clinical trial evaluating the safety and efficacy of the Quad (n = 48) versus Atripla (n = 23) among HIV-infected treatment-naïve adults with viral load ≥5,000 copies/milliliter and CD4 cell counts >50 cells/mm3 at baseline. Study participants in the Quad arm had a mean viral load of 4.59 log10 copies/milliliter and a median CD4 cell count of 354 cells/mm3. Patients in the Atripla arm of the study had a mean viral load of 4.58 log10 copies/milliliter and a median CD4 cell count of 436 cells/mm3 at baseline.
At 24 weeks, 90% of patients in the Quad arm and 83% of patients in the Atripla arm achieved the study's primary objective of HIV RNA levels of <50 copies/milliliter. Patients taking the Quad experienced a median increase in CD4 cell count of 123 cells/mm3, compared with a median increase of 124 cells/mm3 among Atripla patients at 24 weeks. Discontinuation rates and adverse events were similar in both arms of the study. Three patients discontinued treatment in each arm of the study. The Quad arm had fewer drug-related adverse events, particularly fewer central nervous system (CNS) adverse events. The most commonly observed treatment-emergent adverse events occurring in >5% of patients in either treatment arm were abnormal dreams/nightmares, dizziness, fatigue, somnolence, diarrhea, and headache. A similar incidence of laboratory abnormalities (grades 2–4) was found across both arms of the study. Laboratory abnormalities occurring in >5% of patients in either treatment arm included increases in amylase, decreased neutrophils, increases in total cholesterol, and proteinuria. Median increases in cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides were small and similar in both arms of the study.
Study 216-0105 is a double-blind, multicenter, randomized (2:1), active-controlled 48-week clinical trial evaluating the safety and efficacy of cobicistat-boosted atazanavir (n = 50) compared with ritonavir-boosted atazanavir (n = 29), each in combination with Truvada, in HIV-infected treatment-naïve adults with viral load ≥5,000 copies/milliliter and CD4 cell counts >50 cells/mm3 at baseline. At baseline, study participants in the cobicistat arm had a mean viral load of 4.56 log10 copies/milliliter and a median CD4 cell count of 341 cells/mm3. Patients in the ritonavir arm of the study had a mean viral load of 4.69 log10 copies/milliliter and a median CD4 cell count of 367 cells/mm3 at baseline.
At 24 weeks, 84% of patients in the cobicistat group and 86% of those in the ritonavir group met the primary objective of achieving HIV RNA levels of <50 copies/milliliter. Patients taking a cobicistat-boosted regimen experienced a median increase in CD4 cell count of 206 cells/mm3, compared with a median increase of 190 cells/mm3 among patients taking a ritonavir-boosted regimen at 24 weeks. Discontinuation rates were similar between study arms. Two cobicistat patients discontinued treatment because of adverse events (vomiting and rash), as did one ritonavir patient (scleral icterus). The most commonly observed treatment-emergent adverse events occurring in >5% of patients in either treatment arm were nausea, diarrhea, and fatigue. A similar incidence of laboratory abnormalities (grades 2–4) was found across both arms of the study. Laboratory abnormalities (grades 2–4) occurring in >5% of patients in either treatment arm included elevations in bilirubin (>2.5 × ULN), increases in amylase, and increases in total cholesterol. Median increases in cholesterol, LDL, HDL, and triglycerides were small and similar in both arms of the study.
Data from both studies were presented at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco (Abstract #58LB).
Disappointing Results for Vicriviroc
Vicriviroc has failed to meet its primary efficacy end point in two p, according to its developer, Merck. As a result, FDA approval for the drug in treatment-experienced patients has been suspended. Despite the setback, Merck plans to continue development of vicriviroc in naive patients. Vicriviroc belongs to a new class of antiretrovirals called the chemokine co-receptor 5 (CCR5) inhibitors.
The antiretroviral was evaluated in treatment-experienced patients. A high percentage of participants were taking three or more other active HIV drugs as part of the optimized background regimen with vicriviroc. This could have undermined the ability of vicriviroc to demonstrate superiority over placebo.
Both of the two phase III trials (VICTOR-E3 and VICTOR-E4) compared the safety and efficacy of 30-mg once-daily vicriviroc in combination with an optimized background regimen (ritonavir-boosted PI plus at least two active drugs) against placebo. Participants were treatment experienced with documented resistance to at least two antiretroviral drug classes. Vicriviroc may have failed to achieve superiority because of the inclusion of two to three active drugs in the background regimen. Efficacy rates as high as 90% have been observed in this population with the combination of currently available options.
Merck is now investigating vicriviroc in combination with atazanavir and eliminating the traditional nucleoside backbone. Long-standing concerns over NRTI toxicity have led to interest in such regimens. Two-agent regimens may also be more economical than three-agent regimens.
Elvucitabine Data Released at CROI
A poster presentation at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) released new data from a phase 2 trial of elvucitabine. The trial studied elvucitabine versus lamivudine with tenofovir and efavirenz in antiretroviral-treatment–naïve HIV-1–infected patients. Results were released from a 96-week analysis.
Elvucitabine is an
ACH443-015 is a randomized, double-blind study in patients infected with wild-type HIV-1 virus. The trial included a 12-week blinded treatment period, after which responders (patients with viral loads of <400 copies/milliliter, or <2 log10 decrease) continued to an 84-week open-label extension period. The trial enrolled 78 subjects who were randomized 1:1 into two treatment groups. One group received 10 mg/day elvucitabine with 600 mg/day efavirenz and 300 mg/day tenofovir. A second group received 300 mg/day 3TC with 600 mg/day efavirenz and 300 mg/day tenofovir.
The objectives of the trial, ACH443-015, included the assessment of safety, tolerability, and antiviral activity with a once daily 10 mg dose of elvucitabine, as compared with 3TC (lamivudine), in a standard triple-combination regimen. The results at 96 weeks demonstrated that elvucitabine had a substantial antiviral effect similar to 3TC. Ninety-five percent of patients in the elvucitabine-treated group who reached 96 weeks of treatment achieved undetectable viral loads of ≤50 copies/milliliter). This compared with 93% in the 3TC group. A mean change was found in HIV-RNA from baseline in the elvucitabine treatment group of −3.0 log10 (+0.6) versus −3.2 log10 (+0.7) in the 3TC treatment group in the as-treated patient analysis. Elvucitabine was well tolerated and demonstrated a safety profile comparable to 3TC for both incidence and severity of adverse events. In addition, no resistance to elvucitabine was documented at 96 weeks of therapy.
Results were presented at the 17th Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco.
Truvada May Prevent Anal Sex and Intravenous Transmission of HIV
New research in mice suggests that TruvadaR may prevent HIV transmission through the common routes of receptive anal intercourse and intravenous drug use. Earlier research demonstrated that Truvada may be able to prevent vaginal transmission. The combination of tenofovir and emtricitabine is already used by health care workers who experience needle-stick injuries.
Researchers at the University of North Carolina at Chapel Hill had earlier found that Truvada prevents vaginal transmission of HIV in mice. In their new study, they examined mice known as “BLT,” which have had human bone marrow, liver, and thymus cells transplanted into their bodies. As a result, the mice were able to have immune systems similar to those found in humans.
In total, 17 mice were given Truvada. These were compared with mice that did not receive the antiretroviral. All of the mice participating in the study were exposed to HIV rectally or intravenously at a higher level than typical in human exposure. Of the 17 mice given Truvada, only one became infected. This particular mouse has been exposed to HIV intravenously. Several mice that did not take Truvada became infected after exposure.
Further details about the study can be found in the January 21 issue of the online journal PloS One, 2010.
HIV Vaccine in Healthy Volunteers Gets Testing Approval
Approval from the Swedish Medical Products Agency has been given to Cyto Pulse Sciences to evaluate an HIV/DNA vaccine. The company will work with the Karolinska Institutet (KI) and the Swedish Institute for Infectious Disease Control (SMI) to conduct a phase I clinical trial evaluating the vaccine in healthy volunteers. Delivery will be done via a needle-free injection system in combination with an intradermal electroporation system.
The combination of intradermal injection and electroporation is thought to potentiate and broaden the response of the vaccine. The low-dose (1 mg) intradermal DNA injections induce stronger and broader priming to HIV antigens than “standard” (4-mg) intramuscular priming. According to the researchers, dermal electroporation of HIV/DNA may further increase this effect.
Acyclovir Reduces the Progression of HIV
Researchers from the University of Washington in Seattle have found that acyclovir has the ability to reduce the risk of HIV progression. Specifically, they found in a study of 3,300 patients in Africa that acyclovir reduced the risk of HIV progression by 16%. However, the herpes treatment does not appear to reduce the infectiousness of patients with HIV.
The randomized, placebo-controlled trial was conducted at 14 sites in southern and east Africa. It enrolled 3,381 heterosexual people who were dually infected with herpes simplex virus (HSV) type 2 and HIV-1. All were randomly assigned in a 1:1 ratio to acyclovir, 400 mg orally twice daily, or placebo, and followed up ≤24 months. The participants had CD4 cell counts of 250 cells per microliter or higher and were not taking antiretroviral therapy. The effect of aciclovir on HIV-1 disease progression was defined by a primary composite end point of first occurrence of CD4 cell counts of <200 cells per microliter, antiretroviral therapy initiation, or non–trauma-related death. The researchers also assessed the end point of CD4 decreasing to <350 cells per microliter as an exploratory analysis. At enrollment, the median CD4 cell count was 462 cells per microliter, and median HIV-1 plasma RNA was 4 · 1 log10 copies per microliter.
Aciclovir reduced the risk of HIV-1 disease progression by 16%. A total of 284 participants assigned aciclovir versus 324 assigned placebo reached the primary end point. The researchers looked specifically at participants who had CD4 counts of ≥350 cells per microliter. In these individuals, aciclovir delayed the risk of CD4 cell counts decreasing to <350 cells per microliter by 19%.
The complete study was published in the February 15 online edition of The Lancet.