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The Body Covers: The XIII International AIDS Conference

Clinical Trials of Antiretroviral Therapy

Coverage provided by Judith Feinberg, M.D.

July 12, 2000

The effects of hydroxyurea or placebo combined with efavirenz, didanosine, and stavudine in treatment of naive and experienced patients: preliminary 24-week results from the third study (WeOrB603)

Continuing Controversy About the Role of Hydroxyurea

A study that compared hydroxyurea, 600mg twice a day, to placebo in both naive and treatment-experienced patients -- all of whom were receiving ddI, d4T and efavirenz -- failed to show a significant difference in either CD4 percent or viral load. Although there was no difference in CD4 percents, the absolute CD4 cell counts were lower in the hydroxyurea arm because this drug, which was originally used to treat chronic leukemia, has toxic effects on white blood cells. Seventy-three percent of the previously untreated patients had viral loads less than 50 copies, and there was no added benefit from the inclusion of hydroxyurea in the regimen. However, there was a trend toward better viral load suppression in the experienced patients, with 76% having fewer than 50 copies compared to 50% in the placebo group.

This study was also stopped early by an independent safety monitoring board because excess toxicity was seen in the hydroxyurea group. There was a 3.5-fold increase in peripheral neuropathy. Hydroxyurea inhibits the enzyme inside our cells responsible for metabolizing ddI, so it results in high ddI levels inside cells. It is this excess amount of ddI that is the culprit for causing peripheral neuropathy. There were only two episodes of pancreatitis, one in each arm, a toxic effect that had stopped another hydroxyurea study in the U.S. last year.

The dose of hydroxyurea used in this study was high, and it cannot be said with certainty that hydroxyurea wouldn't have been more successful at a lower dose. However, the data from this study do not look promising, especially for use in patients who have never been treated.

An open-label study to compare the efficacy and safety of the triple nucleoside analog combination -- Combivir (COM)/Abacavir (ABC) versus a protease inhibitor (PI)-containing regimen in antiretroviral therapy (ART)-naive adults (CNAF3007/Ecureuil) (WeOrB605) and

Preliminary efficacy, adherence and satisfaction with COM/ABC versus COM/IDV, an open-label randomized comparative study (CNAB3014) (WeOrB606)

Three Nukes: AZT, 3TC and Abacavir (ABC)

Two comparative, randomized, open-label studies comparing AZT/3TC/ABC to AZT/3TC and a protease inhibitor were presented. One study used nelfinavir, 750mg three times a day, and the other used indinavir, 800mg every eight hours on an empty stomach. Virologic response was defined as the proportion (%) of patient who achieved a viral load less than 50 copies. The triple-nuke arm performed well in both studies, with good results in the patients with the highest viral loads (over 100,000 copies) at study entry.

Although these were the 24-week analyses of ongoing studies, the initial data indicate that these three NRTIs in combination may offer adequate potency for patients with a lot of virus. Whether this effect is durable remains to be seen.

NZT4002: 64-week analysis of Combivir (COM)-based triple and quadruple therapy in antiretroviral-naive, HIV-1-infected subjects (WeOrB608)

Four Drugs are Not Necessarily Better than Three

An open-label randomized trial in previously untreated patients with viral loads of at least 5000 copies and CD4 cell counts greater than 50 compared nelfinavir (750mg three times a day) to abacavir and amprenavir, both given at standard doses twice a day. Everyone in the study received AZT/3TC as the nucleoside "backbone." The hypothesis was that four drugs would be better at suppressing viral replication than three, and would result in a more long-lasting virologic response. There were 152 patients in the three-drug arm and 150 in the four-drug group. Virologic response was defined as a viral load less than or equal to 120 copies by week 24, using the NASBA NucliSens test. The final analysis was based on 60 weeks of data. The study was stopped early by an independent safety monitoring board, because the three-drug combination proved superior to the four-drug regimen.

More participants withdrew from the study or had toxicity that limited further treatment in the four-drug arm. Most of the toxicity was gastrointestinal in nature (nausea, vomiting, diarrhea, etc.). Toxicity was the Achilles heel of the four-drug regimen, proving that more drugs are not necessarily better if the combination is poorly tolerated.

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