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John W. Mellors, M.D.
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University of Pittsburgh Schools of the Health Sciences

Clinical Trial Evaluates First-Line Approaches For Treating HIV; Finds “Nuke”-Sparing Regimen Safe And Effective

Results of first trial to compare two standard therapies and NRTI-sparing approach presented at AIDS 2006

TORONTO, August 12, 2006 —– In the first head-to-head comparison between two commonly used HIV treatments, researchers found one triple-drug therapy was significantly more effective at reducing HIV viral load in the blood when used as a first-line treatment. Results of the clinical trial, which sought to determine from among three different therapies the optimal approach for patients beginning HIV treatment for the first time, will be reported at the XVI International AIDS Conference (AIDS 2006).

Of the two triple-drug approaches evaluated in the randomized trial, the therapy consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) with efavirenz, a non-nucleoside reverse transcriptase inhibitor (NNRTI), suppressed the virus to undetectable levels in more participants than the three-drug combination of two NRTIs and a protease inhibitor called lopinavir/ritonavir. Moreover, a third regimen, efavirenz and lopinavir/ritonavir, performed nearly as well as the three-drug cocktail with efavirenz, suggesting initial therapy need not include NRTIs, a class of drugs that can produce intolerable side effects in some patients.

“Our findings suggest that the efavirenz plus two-NRTI regimen was the best of the three approaches as initial therapy, even in patients with relatively advanced HIV disease,” said Sharon Riddler, M.D., M.P.H., assistant professor of medicine in the division of infectious diseases at the University of Pittsburgh School of Medicine, who will present the findings at AIDS 2006.

“Also, we found that the NRTI-sparing two-drug combination of efavirenz and lopinavir had a similar level of effectiveness to the efavirenz plus two-NRTI regimen. When we started this study, we heard from physicians with concerns about using efavirenz in the absence of NRTIs. Now that we’ve completed the trial, there should be little doubt that patients can benefit from this ‘nuke’-sparing treatment regimen when NRTI side effects are a problem,” she added.

The NRTI-sparing combination of lopinavir/ritonavir and efavirenz had never before been studied as first-line therapy in a large randomized clinical trial, in part because a general belief that combining an NNRTI with a protease inhibitor could result in resistance to two important classes of drugs. But earlier studies with other drug combinations suggested the approach would be safe. Thus, in designing the trial, Dr. Riddler and her national co-chair, Richard Haubrich, M.D., at the University of California, San Diego (UCSD) School of Medicine, felt it important to include this less conventional regimen so it could be evaluated under the rigors of a clinical trial.

The study included 753 participants at 55 centers and was conducted under the auspices of the AIDS Clinical Trials Group (ACTG), considered the world’s largest HIV clinical trials organization. ACTG receives its funding from the National Institute of Allergy and Infectious Diseases.

At the start of the study, just more than half of the participants had viral loads greater than 100,000 copies of HIV RNA per milliliter of blood. The median CD4+ T cell count was just 182 cells per cubic milliliter. Each participant was randomly assigned to one of the three treatment arms: 250 were selected to receive the efavirenz-based triple drug therapy, 253 the lopinavir/ritonavir-based triple drug therapy, and 250 were assigned to the group receiving the NRTI-sparing regimen of efavirenz and lopinavir/ritonavir. Participants in the triple-drug therapy groups each received two NRTIs: lamivudine, plus their choice of stavudine, zidovudine or tenofovir disoproxil fumarate.

The researchers found all three of the treatment regimens were potent, producing substantial increases in CD4+ T cell counts and decreases in HIV viral load. After 96 weeks of treatment, 89 percent of the participants randomized to the efavirenz arm had “undetectable” levels of HIV, meaning viral load was less than 50 copies per milliliter; 77 percent of the lopinavir/ritonavir arm participants and 83 percent of the participants on the NRTI-sparing regimen had low viral loads. Interestingly, the CD4+ T cell count increase was greater in the two study arms containing lopinavir/ritonavir as compared to the efavirenz regimen. At week 96, the CD4+ T cells increased from baseline to 285 cells in the lopinavir/ritonavir group, 268 cells in the nucleoside-sparing group and 241 cells for the efavirenz regimen.

More participants in the lopinavir/ritonavir group experienced virologic failure – a rebound in the HIV virus load to detectable levels – during the study compared to the efavirenz group. After 96 weeks of treatment, 33 percent of participants in the lopinavir/ritonavir group had virologic failure compared to 24 percent of the participants receiving the efavirenz-based therapy and 27 percent of those in the NRTI-sparing group.

It was no mistake that the two particular triple-drug therapies were selected for the study. Both are listed as “preferred” options in the U.S. Department of Health and Human Service’s treatment guidelines for HIV infection.

“We were surprised that the lopinavir plus two-NRTI regimen did not perform as well as the efavirenz-based treatment because lopinavir/ritonavir is considered one of the most potent drugs that we have available for HIV treatment at this time. It may be that the lopinavir/ritonavir regimen, which was dosed twice daily using the soft gel capsule form, was less convenient or less well tolerated by patients. We will continue to evaluate our study data to try to assess the reasons for these findings,” noted Dr. Haubrich, professor of medicine in the division of infectious diseases at UCSD School of Medicine.

All of the drugs used in the clinical trial are approved for the treatment of HIV. Nucleoside reverse transcriptase inhibitors, or NRTIs, prevent healthy T cells from being infected by blocking a process called reverse transcription that HIV uses to convert its RNA into DNA. By inserting faulty building blocks, HIV can’t copy its DNA. NNRTIs, the non-nucleoside reverse transcriptase inhibitors, target the same mechanism but block the reverse transcriptase enzyme by attaching to a different site than NRTIs. The class of drugs known as protease inhibitors blocks the maturation of proteins that HIV needs to assemble itself into an infectious virus.

In addition to Drs. Riddler and Haubrich, other authors of the abstract include: Gregory DiRienzo, Ph.D., and Lynne Peeples, M.S., from Harvard School of Public Health, Boston; William Powderly, M.D., from University College, Dublin, Ireland; Karin Klingman, M.D., of the National Institute of Allergy and Infectious Diseases, Division of AIDS, Bethesda, Md.; Kevin Garren, Ph.D., of Abbott Laboratories, Abbott Park, Ill.; Tania George, Pharm.D., of Bristol-Myers Squibb, Plainsboro, N.J.; James Rooney, M.D., of Gilead Sciences, Foster City, Calif.; Barbara Brizz, M.S.H.Ed., B.S.N., from Social & Scientific Systems, Inc., Silver Spring, Md.; Diane Havlir, M.D., from the University of California, San Francisco; and John W. Mellors, M.D., of the University of Pittsburgh School of Medicine.

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