BEING ALIVE: February 1995
Ronald Baker, PhD

The two Phase II/III studies of 352 people reported at the Glasgow Conference were designed to evaluate the effect of the AZT/3TC combination on laboratory markers of HIV disease progression, such as viral load and CD4 counts, not clinical endpoints, such as opportunistic infections and survival time. No clinical data on the effects of the AZT/3TC double combination were presented in Glasgow.

Effect on CD4 Counts

Professor Christine Katlama of the H|pital Piti Salp ti re in Paris reported on a study of 129 HIV+ patients with CD4 counts between 100 and 400 cells who had no previous anti-HIV threapy. Participants taking the AZT/3TC combination had an average gain of 85 CD4 cells after 8 weeks of therapy and sustained an 80 cell increase above baseline at week 24. Participants who stayed on the combination experienced a 49 CD4 cell increase over baseline at week 48. The patients who received AZT alone experienced a drop of 7 CD4 cells at week 24. However, those in the AZT monotherapy group who switched to the combination regiment showed an average increase of 40 CD4 cells above baseline at week 48.

Effect on HIV Levels in Blood Cells

Professor Katlama reported that participants taking the AZT/3TC combination experienced a 99% decrease below baseline of HIV levels in blood cells at week 24, as measured by cultures of peripheral blood mononuclear cells (PMBC). For participants who continued the combination regimen, the 99% reduction in virus levels was sustained at week 48. Among patients taking AZT alone, HIV levels in blood cells fell 70% at week 4, but returned to within 11% of baseline by week 24. Patients on AZT alone who switched to the combination at week 24 also experienced a 99% reduction in HIV levels in blood cells at week 48.

Effect on HIV Levels in Blood Plasma/Serum

As measured by quantitative PCR HIV RNA testing, levels of HIV in the bloodstream (viral load) of participants taking the AZT/3TC combination were reduced by 92% below baseline at week 2 and were sustained at 86% by week 24 and at 91% by week 48, according to Professor Katlama. HIV levels in those taking AZT alone were reduced by 76% at week 2, but by week 24 had reached 36% below baseline. Patients who switched from AZT monotherapy to combination therapy at week 24 experienced a 92% decrease in HIV levels from baseline by week 48.

Resistance

Early studies of 3TC as a single agent in HIV infection, showed that HIV rapidly develops resistance to the drug. Because of this, it quickly became apparent that 3TC monotherapy did not have a promising role in fighting HIV infection.

The rationale for combining 3TC with AZT was the discovery that the two drugs were synergistic in their anti-HIV activity. Researchers also theorize that 3TC, when used in combination with AZT, may help to prevent or significantly delay the development of HIV resistance to AZT. In fact, this may explain in part the ability of the AZT/3TC combination to reduce viral load more effectively and for a more sustained period of time than AZT alone.

German Study of AZT/3TC Combination

At the Glasgow Conference, Schlomo Staszewski, MD, of Goethe University in Frankfurt, Germany, reported results of a second study of combination treatment with AZT plus 3TC. That study compared 2 doses of 3TC in combination with AZT and AZT alone. Two hundred twenty-three HIV+ patients with 100-400 CD4 cells and with at least 24 weeks of prior AZT therapy took either 150 or 300 mg 3TC twice daily in combination with 600 mg/day AZT, or 600 mg/day AZT alone.

After 4 weeks, both doses of combination therapy increased CD4 cell counts from baseline by an average of 33 cells (high-dose combination) and 36 cells (low-dose combination). At week 24, participants on both combination regimens experienced an average increase of 33 CD4 cells. On average, patients taking AZT alone experienced decreases of 8 CD4 cells below baseline at week 24. The effect of the combination on CD4 counts beyond 24 weeks is not yet known. In addition, viral load data from the German study was not presented in Glasgow.

Adverse Side Effects

Overall, the combination of AZT and 3TC was well tolerated by patients, according to the investigators. Nausea and vomiting were reported in 26% of participants in the French study and in 15% of those in the German study. Headache was reported in 9% of patients in both studies. Neutropenia and anemia affected 4% and 5%, and 3% and 2% of patients in the French and German studies, respectively.

Access to 3TC

3TC is currently available free to HIV+ individuals through an Open Label Compassionate Use protocol. To be eligible,individuals must have failed or be intolerant to standard anti-HIV therapy (AZT, ddI, ddC, d4T) and have fewer than 300 CD4 cells. To enroll patients in the Open Label protocol, physicians may call Glaxo at 1.800.248.9757. Commentary

The data from the French and German studies are extremely promising. The French data, in particular, demonstrate clearly that the AZT/3TC combination significantly reduces HIV levels and significantly increases CD4 counts over a 48-week period. The AZT/3TC combination appears to have a more profound effect on decreasing viral load and increasing CD4 counts than the double combination of either AZT plus ddI or AZT plus ddC, or than the triple combination of AZT plus ddC plus saquinavir (a protease inhibitor drug). In addition, the beneficial effects of the AZT/3TC double combination on laboratory markers persisted for a year, without showing any sign of falling off.

These data strengthen the notion that combination treatment with certain nucleoside analogues is more effective than single agent therapy in increasing CD4 counts and reducing HIV levels in blood cells and in the bloodstream. Although these studies evaluated changes in laboratory markers, not clinical endpoints, there is a growing consensus among researchers that reduction of viral load correlates with clinical benefit. Trials to assess the clinical benefit of combination treatment with AZT/3TC will begin in North America and Europe in early 1995, according to Glaxo.

Implications of Study Results

The release of these data comes at an important moment in AIDS research. The results of these and other studies showing that the two and three drug combinations of anti-HIV agents can significantly reduce viral load add considerable weight to the argument that combination treatment offers the current best hope for slowing HIV disease progression.

After reviewing the promising data from the AZT/3TC combination studies, two questions immediately come to mind: (1) what would be the effect on laboratory and clinical markers of a triple combination using AZT plus 3TC plus a protease inhibitor? (2) what would be the effect of a four-drug combination using AZT plus 3TC plus a protease inhibitor plus nevirapine or a second protease inhibitor? It is hoped that the Inter-Company Collaboration of pharmaceutical firms will design short-term studies in the near future that can help to provide the answers to these questions. (This article is reprinted from the December 1994 issue of BETA, Bulletin of Experimental Treatment for AIDS, with the permission of the San Francisco AIDS Foundation. For subscription information, call 1.800.959.1059.)

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