PI Perspective #19

September 1996     View PDF

Nevirapine - First of a New Class of Drug

On June 26, 1996, the Food and Drug Administration (FDA) gave nevirapine (Viramune) accelerated approval for use with nucleoside analogues (e.g. AZT, ddI, ddC, d4T and/or 3TC) for treating HIV infection. Results from a number of studies show that nevirapine is best used with two other anti-HIV drugs. Like most new therapies, the role of nevirapine and its optimal use is not fully understood, but studies suggest that it might best be used for people with relatively healthy immune system who have not taken other anti-HIV drugs.

Nevirapine is the first of a new class of drugs, called non-nucleoside analogue reverse transcriptase inhibitors (NNRTI), to be approved. NNRTIs work at the same step of viral replication as existing nucleoside analogue reverse transcriptase inhibitors (NRTI) such as AZT, ddI, etc. But, they do so using a different mechanism. The NRTI drugs work by blocking the building of genetic material in the cell, while NNRTIs directly inactivate a part of the virus which allows it to take over the machinery of the cell. Other NNRTIs are in studies including delavirdine (Rescriptor), loviride, HBY097 and DMP266.

The approval of nevirapine was primarily based on results from two studies, though the drug has been used in more than two dozen studies over the last several years. Different lessons can be learned from each of the two studies. The first enrolled 398 people with CD4+ cell counts under 350 who had previously been on long-term antiretroviral therapy. People received either AZT + ddI or AZT + ddI + nevirapine. At the end of the 48 week study, people receiving the 3-drug therapy had significantly better CD4+ cell count and viral load responses compared to those receiving the 2-drug regimen.

A second and somewhat surprising study enrolled 151 people with CD4+ cell counts between 200 and 600 who had never previously taken antiretroviral therapy. People received either AZT + ddI, AZT + nevirapine or AZT + ddI + nevirapine. Preliminary data show that after 24 weeks on therapy, over 70% of people receiving the triple combination have viral load below the limit of detection (HIV RNA below 200). In contrast, only about 40% of those receiving AZT + ddI and no one receiving the AZT + nevirapine combination achieved this level of viral control after 24 weeks of therapy. After 48 weeks of the study, about 60% of people on the triple combination continued to have undetectable levels of virus, whereas about 30% of people on AZT + ddI had this level of continued viral suppression. Further analysis showed that virtually all of the people who continued to have detectable levels of virus had in fact stopped using one or another of their assigned drugs for a month or longer. Overall, the study suggests that the 3-drug therapy was able to achieve long-term control of viral replication whenever patients adhered to the prescribed treatment regimen.

One potentially life-threatening side effect is Stevens-Johnson syndrome, which is the result of severe rashes and may require skin grafts. In the studies about 8% of people developed severe rash. The rashes usually occurred within the first 4 weeks of therapy and then gradually disappear. Escalating the dose of nevirapine from a 200mg once daily dose for two weeks, to the standard 200mg twice daily dose, appears to reduce the risk of rashes, though it remains as yet unclear whether this will affect the development of drug resistance.

Research on nevirapine slowed a few years ago because data indicated that HIV quickly developed resistance to nevirapine when the drug was taken alone or with a previously used therapy. The results of these more recent studies indicate that nevirapine should always be used in combination with at least two other previously unused anti-HIV drugs. When used in this fashion it appears possible to delay and perhaps prevent the development of resistance to nevirapine as well as the other drugs in the combination. Another way of looking at the data suggests that, even for drugs which are prone to resistance, the problem can be brought under control by consistent use of a combination therapy powerful enough to suppress viral replication below the limit of detection.

Test tube data show considerable cross-resistance between the various NNRTIs. This means that once the virus has become resistant to nevirapine, other NNRTIs may have diminished, or even no, impact on HIV.

There are a number of possible drug interactions between nevirapine and other commonly used therapies (for a complete list of drug interactions, call the Project Inform Treatment Hotline). It is anticipated that there will be some level of drug interaction between nevirapine and the currently available protease inhibitors, indinavir (Crixivan), ritonavir (Norvir) and saquinavir (Invirase). It is not yet clear whether this will rule out nevirapine’s use in combination with protease inhibitors. Drug interactions are being studied but for now, a safe rule is to not combine nevirapine (or delavirdine) with protease inhibitors until more information is available.

The most common side effects associated with nevirapine include rash (37%), fevers (5%), nausea (6%), headaches (5%) and increases in liver enzymes (3%). Where/When to Use Nevirapine

Results from studies of 3-drug combination therapy with nevirapine show activity nearly as potent as combinations which include the better protease inhibitors and are very encouraging. These benefits may be best achieved in people just beginning therapy for the first time. Preliminary results of a study in children suggest that a similar 3-drug combination using nevirapine was particularly potent in treating HIV-infected infants.

A likely role for triple drug therapy with nevirapine may be for managing early-stage HIV disease, thus saving protease inhibitors for later use if needed. This is particularly attractive from a cost standpoint as well, since nevirapine is priced at less than one half to one third the cost of protease inhibitors.

The manufacturer, Boehringer Ingelheim, and the distributor, Roxanne Labs, should be commended for taking a very reasonable position on pricing at a time when some companies have chosen to set the prices of their new drugs in the stratosphere.

Antiviral Update

LAST      NEXT

Long-Term Strategies