Studies of zidovudine in combination with didanosine and zalcitabine.

A number of antiviral agents have been developed to treat individuals with HIV infection. Monotherapy treatment with the licensed reverse transcriptase (RT) inhibitors zidovudine (AZT), zalcitabine (ddC), and didanosine (ddI) has been shown to delay disease progression in the short term. However, after prolonged treatment viral resistance to these agents emerges. To overcome this development of resistance and subsequent destruction of the immune system leading to disease progression, combination therapies of two or more RT inhibitors have been investigated. In the past, studies have demonstrated that the antiviral drugs ddI and ddC have overlapping toxicities and show cross-resistance. Together, therefore, they are unlikely to prove successful as combination therapy. Conversely, AZT and ddI, and AZT and ddC, have additive or synergistic activities. Recent clinical trials have shown that these two combination therapies are well tolerated and are more effective than monotherapy in delaying the progression of HIV disease. Data from these studies suggest that the maximal benefit from combination therapies can be derived only if they are initiated early in the course of infection, e.g., when CD4 counts are greater than 150 cells/mm3. In clinical studies, AZT/ddI in combination, tended to have a more positive effect on CD4 cell count than the AZT/ddC combination, although the difference was statistically significant only when baseline CD4 count was greater than 100 cells/mm3. No serious side effects have been observed with either combination therapy (AZT/ddC or AZT/ddI) although not surprisingly, patients receiving ddI were more likely to suffer gastrointestinal side effects and those receiving ddC were more likely to suffer from peripheral neuropathy.