Suppression of resistance to drugs targeted to human immunodeficiency virus reverse transcriptase by combination therapy

Abstract

There are currently thirteen drugs approved for the treatment of human immunodeficiency virus (HIV)-infected individuals. Seven of them are targeted against the virus-encoded reverse transcriptase (RT). Appearance of drug-resistant virus strains under the selective pressure of anti-HIV chemotherapy rapidly occurs as a consequence of the low fidelity of the RT-catalyzed DNA polymerisation reaction and the massive viral turnover. Resistance-associated mutations appear in the RT of virus strains that are under selective pressure of both nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). A variety of these mutations cause cross-resistance to several other NRTIs or NNRTIs and consequently may hamper the effectiveness of the other drugs. Other RT mutations are quite specific and selective in their drug-resistance spectrum and do not influence the potency of the majority of other available drugs. Moreover, drug-specific mutations are identified that are able to restore drug sensitivity again when concomitantly present with other drug-specific mutations. Combination therapy has proven to be able to markedly suppress virus replication (and subsequent appearance of drug resistance) for a relatively long time period. However, in a number of cases, multiple drug combination therapy results in the appearance of a different mutation spectrum than is expected to emerge under monotherapy. Also, it has been shown that drugs that alter cellular deoxynucleotide pools not only are able to potentiate the antiviral efficacy of some RT inhibitors, but also may influence the resistance spectrum of certain anti-HIV drugs. All available information argues for the use of a rational combination of different anti-HIV inhibitors with different resistance spectra to suppress virus replication efficiently and to delay the emergence of drug-resistant virus as long as possible, but it also indicates that there is a strong need for additional drugs to further optimize and improve the efficacy of long-term HIV treatment.