Being Alive; August 1996
Christopher Griffin

In order to replicate once inside a CD4 cell, HIV depends upon several enzymes that it brings into the cell or makes inside the cell. Antiretroviral drugs for treating HIV disease currently fall into three classes (with a fourth in early stages of development), according to the stage of viral replication they target and the enzyme involved in that stage:

1) Nucleoside analog reverse transcriptase inhibitors ("nucleosides"), such as AZT, ddC, ddI, d4T and 3TC, which interfere with an enzyme (reverse transcriptase) involved in an early stage of the virus' reproductive cycle;

2) Non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and loviride) which also attack the reverse transcriptase stage of the cycle, but in a different way-while the nucleoside analogues prevent the growth of the virus' DNA chain, non-nucleosides directly inactivate the enzyme itself;

3) Protease inhibitors-saquinavir (Invirase), indinavir (Crixivan) and ritonavir (Norvir), which prevent the protease enzyme from doing its job at a later stage in the reproductive cycle;

4) Integrase inhibitors (still in an early phase of development), which will target yet another enzyme crucial for the HIV replication process.

Nevirapine and Combination Therapy

On June 24, the FDA granted accelerated approval to the non-nucleoside drug nevirapine (Viramune, from Boehringer Ingelheim) for use in adults in combination with other antiretrovirals. It is expected to be available this month. While monotherapy with nevirapine alone has proved to result in quick viral resistance, combination therapy with other nucleoside drugs has produced some promising results.

Prior to approval several trials were conducted. One (ACTG 241) compared the combination of AZT, ddI and nevirapine to the combination of AZT, ddI and placebo. All participants had under 350 CD4 cells and had received extensive prior nucleoside therapy. The triple combination therapy was significantly more successful in increasing CD4 cell counts and reducing viral load.

An international trial (BI 1046) investigated nevirapine in previously untreated patients. This study compared the combinations of AZT, ddI and nevirapine; AZT and ddI; and AZT and nevirapine. The triple-drug regimen decreased the viral load below detectable levels (below 500 copies) in about two-thirds of the participants, which was significantly greater than either double-therapy regimen.

Dr. Julio S. G. Montaner of Vancouver's Canadian HIV Trials Network presented data at the Conference which showed that nevirapine combined with AZT and ddI in people with no prior history of antiviral use reduced viral load to undetectable levels. After 52 weeks approximately 50% of the study participants registered viral levels below the limit of detection (under 200 copies).

Dr. John Sullivan of the University of Massachusetts provided evidence of the utility of triple combination therapy-AZT, ddI and nevirapine-in two HIV+ infants under three months old. After twelve months of therapy both children had viral loads under detectable limits and had no detectable HIV antibody and were ELISA negative.

Protease Inhibitor Combination

No drug interaction studies have yet been completed to show that nevirapine is safe in combination with protease inhibitors. A pharmacological study of saquinavir plus nevirapine is now being done, primarily to determine if nevirapine will significantly reduce plasma levels of saquinavir, or vice versa. Until more data is available concerning the safety of combining nevirapine with protease inhibitors, caution is advised.

Short-Term Nevirapine Therapy

Dr. Joel Lange of the Academic Medical Center in Amsterdam spoke at a Conference symposium about how non-nucleosides could prove useful in specific circumstances when only short-term therapy is required, such as during the perinatal period (see below), and as post-exposure prophylaxis following accidental exposure to HIV. Nevirapine might also be of use in pre-exposure prophylaxis-for a surgeon who is going to perform an operation on an HIV+ individual, for example.

Pregnant Women and Newborns

One promising aspect of nevirapine is its potential for inhibiting the passing of HIV infection from mother to newborn. Preliminary data from a study of the administration of a single dose of nevirapine to HIV infected pregnant women when they begin labor, followed by a single dose later given to the newborn suggests that the drug might be highly useful in this area. Since the drug crosses the placenta easily and is found in therapeutic concentrations in the umbilical cord, and its half-life is comparably long (meaning it will remain in the blood stream of the mother and hopefully the child for a relatively long period of time), nevirapine may provide protection against mother-to-infant transmission comparable to that widely reported recently with the perinatal administration of AZT. Preliminary data indicate that effective levels of nevirapine are maintained in the mother's first breast milk after only one dose of the drug.

Other Non-Nucleoside Drugs in Development

Both delavirdine and loviride are in the late stages of Phase III study; both drugs will be submitted for review to the FDA this year. They are both being considered as of potential use in combination therapy only. Another non-nucleoside in an earlier stage of development is HBY097 (from Hoechst Roussel and Bayer). The drug produces (in the test tube) a specific genetic mutation in HIV that may correlate with the emergence of a less virulent virus.

A Nevirapine Cocktail: Who Should Take It?

As ever more anti-HIV drugs become available, people with HIV/AIDS are faced with an ever-growing menu of possible combinations. It is still too early to tell which combinations will prove, in the long run, to be the most efficacious and safe. Nevirapine may well have a place in HIV therapy, but certainly not as monotherapy, which results in rapid selection of resistant strains and a loss of antiviral activity. Much more experience with all the drugs is needed before we can accurately determine which combination of drugs will be best tolerated, most effective and safest. Until then, one can simply consult one's physician and make an educated determination of what is best suited to one's individual needs.

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