Being Alive 1996 Aug 5: 11
While protease inhibitors captured the Conference spotlight,
another new class of antiviral drugs was shown to have a
significant impact upon HIV infection: non-nucleoside reverse
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
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
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
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.