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currently available antiviral agents are not significantly less fit than the wild-type virus and the clinical
benefits are not obvious. In this regard, new drugs should be designed that would be intended to select
HIV-1 RT variants that are significantly less fit and do not replicate efficiently.
XV. Combination Therapy Using Multiple ANTI-HIV-1 Drugs
Page 68
Monotherapy using either NRTIs or NNRTIs has led to the emergence of drug-resistant viral strains of
HIV-1. Though many drug-resistance mutations confer cross-resistance to other inhibitors belonging to
the same class, there are indications that some mutations conferring resistance to certain inhibitors are
incompatible (see reviews [5,11,131]). A multidrug clinical trial with HIV-1 infected patients has shown
that AZT resistance can be reversed by mutations that confer resistance to ddI [8]. The Leu74Val
mutation appears to suppress the effects of the Thr215Tyr mutation that confers resistance to AZT
[8,27]. The Met184Val mutation, which causes resistance to 3TC or other oxathiolane-cytosine analogs,
also appears to reverse the effects of the AZT-resistance mutations [27]. Recent clinical studies have
shown that a combination of AZT and 3TC led to a considerable decrease in viral load and a substantial
increase of CD4 cells when compared with monotherapy using AZT alone, even after emergence of the
Met184Val mutation [132]. Another example is the Pro236Leu mutation that confers resistance to
BHAP. The sensitivity of this HIV-1 RT variant to TIBO, nevirapine, and pyridinone is increased ten
fold [133]. Although the NRTIs and NNRTIs target two distinct binding sites of HIV-1 RT and lead to
different sets of resistance mutations, some of the NRTI- and NNRTI-resistance mutations also appear
to be incompatible. For example, the NNRTI-resistance mutations Leu100Ile and Tyr181Cys have been
shown to suppress the effects of some AZT-resistance mutations [11,134]. This has led to the suggestion
that a combination of anti-HIV-1 drugs would be more effective in inhibiting HIV-1 replication than
using individual drugs alone. In fact, both clinical and in vitro studies have shown that combination
therapy has considerable advantages over monotherapy. At least in some cases, the effectiveness of the
therapy increases with an increase in the number of drugs in the combination [5,135]. Combination
therapy may, in addition to increasing antiviral activity, also slow emergence of drug-resistant variants
and may have the added benefit that reducing the dosage of individual drugs can reduce toxicity. It is
generally believed that synergistic drug interactions arise from the fact that certain combinations of drugresistance
mutations are particularly detrimental for the enzyme (and, by extension, the virus). This has
focused attention on
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