Drug resistance

Probably the greatest efforts in recent years have been devoted to the development of antiretroviral agents to combat the replication of HIV. Effective treatments for this virus must involve combinations of drugs to attempt to overcome the problem of virus resistance to antivirals. The high rate of virus replication in a host means that there is a high rate at which mutations occur in the virus genome – compounded in RNA viruses by the lack of any proofreading activity in RNA polymerases. As a result, changes occur in the amino acid sequences of virus proteins, including those that serve as targets of antivirals. Drug binding and activity are diminished or abolished and hence the virus adapts to become resistant to drugs that had previously been effective. The development of resistance to antivirals is a persistent problem with HIV, where the integration of the HIV genome into the chromosome of host cells makes for very long-term replication over months and years.  HIV mutations that give rise to resistance to AZT occur with a very high frequency, and treatment of HIV infection requires combining drugs that target different virus enzymes, e.g.  Two nucleoside analogs combined with an anti-protease inhibitor. Such regimes have been highly effective in reducing virus loads and raising CD4 cell counts in HIV-infected individuals and in reducing the risk of viral resistance. Most important are measures that insure that patients adhere to the regime of drug taking, which in some cases is highly complex and involves a number of different drugs routinely. Due to genomic integration, antiviral agents are unlikely to eliminate HIV from the patient, but they are effective in reducing symptoms, delaying the progression of infection to AIDS by several years.