Triple combinations: Present and future

Three or more therapeutic agents have commonly been used to treat chronic infections and many malignant diseases. It is clear that monotherapy treatment of HIV infection, although effective in the short term, is not a viable long-term management option because of incomplete suppression of viral replication and the subsequent development of viral resistance. It is therefore generally accepted that multidrug combination therapy represents the most promising strategy for HIV management. The rationale for this approach is based on an understanding of viral pathogenesis and preliminary results from in vitro studies. It is anticipated that combination therapy will achieve greater reductions in viral load, leading to reduced rates of viral replication and diversification, which, in turn, will result in the delayed emergence of drug-resistant and cytopathic variants. This will probably result in the prevention of both immune system destruction and subsequent disease progression. Preliminary in vitro studies have provided evidence that double combinations are more effective than monotherapy. In vivo results from clinical trials comparing double combinations with monotherapy, however, have not been as impressive as expected, and show that suppression of viral replication, even with two drugs, is incomplete. Further in vitro evidence from sensitivity studies suggests that triple combinations are likely to be more effective. Further clinical trials of the most promising combinations need to be conducted. However, the selection of these combinations is not an easy task owing to the large number of possible regimens to choose from. The Inter-Company Collaboration on AIDS Drug Development, among others, has established protocols for rapid identification of promising combinations that should make this task easier. At present, early treatment with combinations of three or even more drugs represents the only logical long-term management option for patients infected with HIV.