Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
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GMHC Treatment Issues, Volume 10, Number 6/7 - June/July 1996
Theo Smart
The ease with which approval occurred stands in stark contrast to the drug's tortured development. Although potent, the drug has attracted little interest from either physicians or people with HIV because of the rapid emergence of nevirapine-resistant HIV in people treated with the drug. Probably as a result, nevirapine showed only marginal benefit when combined with AZT or AZT/ddI in trials involving people with extensive prior AZT. Nevirapine also caused frequent skin rash (17 percent of patients) which on a few occasions became life-threatening.
The case for nevirapine at the committee hearing was buoyed unexpectedly by interim results from a new study following 151 treatment-naive patients who are receiving either AZT/ddI, AZT/nevirapine or AZT/ddI/nevirapine (see table). The patient population is much less advanced than in the earlier studies, with a mean CD4 count of 376 cells and a mean viral load of 4.41 log (25,704 copies per milliliter of plasma).
At the week 28 interim analysis, the AZT/ddI and AZT/ddI/nevirapine arms outperformed the AZT/nevirapine arm in both CD4 and viral load responses (see table). There was a trend toward greater viral load and CD4 cell responses in the triple combination. This combination also reduced viral load to undetectable levels (below 200 copies per ml) in a significantly larger percentage of patients than in the other arms. Moreover, the CD4 cell response at one year was sustained for the triple combination arm while CD4 cell counts had begun to fall in the other two arms.
A resistance analysis performed on four patients in the three-drug arm at week 28 found resistance to nevirapine in two who discontinued one of the nucleoside analogs for more than four weeks, while isolates from two patients who were compliant to all three medications remained sensitive to nevirapine. This suggests that the antiviral effect of nevirapine may be sustained if used consistently in a potent enough combination.
Further support for nevirapine came from John Sullivan, M.D., of the University of Massachusetts, Worcester, who reported on the activity of AZT/ddI/nevirapine in eight infants older than two months and with baseline viral loads ranging between 40,000 and 1,600,000. All except one child had sustained reductions in viral load and normalization of CD4 cell counts. Viral load became undetectable in two children with baseline viral loads close to 300,000 copies per ml. By the 168th day, these two had begun testing negative on HIV antibody tests. Such data indicate that the two infants may be eliminating the HIV in their bodies. Although spontaneous remission has been previously observed in infants, it is not an everyday occurrence.
The data in naive patients were so much better than the earlier experience with nevirapine that many advisory panel members wanted the drug's labeling to stress that nevirapine should not be added to an ongoing nucleoside analog regimen, but initiated in combination with drugs to which the patient has not yet been exposed. Some suggested that it should not be used with AZT alone except as a last resort, given that combination's poor performance.
The FDA approved combining nevirapine with nucleoside analogs in adults but held off on protease inhibitors because nevirapine can accelerate the CYP3A liver pathway that metabolizes these drugs, especially saquinavir. Data released at the advisory hearing, though, revealed that nevirapine only lowered saquinavir's blood levels by seventeen percent (not considered significant) in the first eleven patients in a drug-interaction study. This bodes well for the potential use of this drug in combination with indinavir, which has the lowest rate of elimination by the liver. Complete data from interaction studies with saquinavir and indinavir should be available in the fall. Interaction data with ritonavir will take longer because of difficulty coordinating the study with Abbott Laboratories, ritonavir's manufacturer.
Table 1. AZT/ddI/Nevirapine: Trial BI 1046 Interim Results
| Regimen | Week 28 | Week 28 | Week 28 | One Year |
|---|---|---|---|---|
| CD4 Cells - | Viral Load - | Viral Load - | CD4 Cells | |
| change from | change from | percentage | change from | |
| baseline | baseline | undetectable | baseline | |
| AZT/Nev | +10-15 cells | -0.4 log | 0% | -2 cells |
| AZT/ddI | +70 cells | -1.3 log | 40% | +26 cells |
| AZT/ddI/Nev | +120 cells | -1.65 log | 70%* | +140 cells* |
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Copyright © 1996 - Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, Inc. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011 fredg@gmhc.org http://www.gmhc.org
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