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Document 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 http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_68.html [4/5/2004 4:50:47 PM]
Document Page 69 determining the mechanism(s) underlying drug resistance and, from this understanding, to devise ways for identifying combinations of drugs which might provoke drug-resistance mutations incompatible with viral survival. Several protocols have been designed for combination therapy using a variety of anti-HIV-1 drugs (see reviews [5,11]). Combinations of different drugs that interact with the same binding site of the same viral protein but lead to mutually antagonistic or suppressive resistance mutations have been studied extensively, especially for the combined uses of different but structurally related NRTIs (see for example [136–138]) or NNRTIs [139–141]. Combinations of drugs or inhibitors that target different sites of the same viral protein, primarily the combination of NRTIs and NNRTIs of HIV-1 RT, show enhanced inhibition of HIV-1 RT polymerase activity and suppression of the emergence of drugresistance mutations (for example [142–146]). Experiments have also been conducted with combinations of drugs that target different viral proteins, e.g., inhibitors of virus adsorption, virus-cell fusion, and/or uncoating proteins have been tested in combination with protease inhibitors and/or RT inhibitors. Combinations of AZT with the glycosylation inhibitor castanospermine [147], or with the Tat inhibitor Ro 24-7429 [148], or with the protease inhibitor Ro 31-8959 [149] have been shown to potently inhibit HIV-1 viral replication in vitro. Combination therapy can increase the effectiveness of inhibition and significantly impair efficiency of viral replication. However, both NRTI- and NNRTI-resistance mutations can affect the positioning of the nucleic acid and/or the overall structure of HIV-1 RT [23]. These two sets of resistance mutations can communicate with each other and can result in cross resistance. Moreover, new drug-resistance mutations that confer cross-resistance to both NRTIs and NNRTIs can be selected, which reduce the effectiveness of some drug combinations (see reviews [5,11,26]). Biochemical studies showed that both HIV-1 RT mutants [150] and viral variants [151] could be obtained that are resistant to the combination of AZT, ddI, and nevirapine. In clinical trials, treatment with AZT and ddI or AZT and ddC led to a different spectrum of NRTI-resistance mutations [152,153]. The most notable of these new mutations is Gln151Met, which is located at a position close to the dNTP-binding site. Structural analysis of the HIV- 1 RT/DNA/Fab complex suggests that the side chain of Gln151 in the wild-type enzyme may interact with the first unpaired template nucleotide. The side chain of this residue may play a role in selecting the correct base for the incoming nucleotide [72]. Since the RT mutant containing only the Gln151Met mutation can confer high-level resistance to a number of NRTIs, including AZT, ddI, and ddC, it is not clear why this mutation did not emerge in monotherapy of these NRTIs. However, Gln151 is relatively well conserved and mutations at this position may have an unfavorable impact on HIV-1 RT. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_69.html [4/5/2004 4:50:49 PM]
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Page 103 and 104: Document dine) and didanosine (dide
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