Combination therapy from a clinician's perspective

A number of important scientific questions have been answered in recent years concerning how HIV causes disease and whether combinations of antiretroviral agents might be more effective than monotherapies. However, a considerable number of questions remain unanswered regarding when to start treatment and what regimen to start with. It is also obvious that significant disparity exists between what is possible in therapeutic terms, in the clinic, and what has been demonstrated in in vitro studies and clinical trials. In translating what we have learned about combination therapy in clinical trials to application in a clinical setting, it is necessary to consider a number of important factors. First, the availability of antiretroviral agents as licensed products varies considerably between countries, as do the indications for these agents. Physicians in many countries are presently faced with prescribing therapeutic regimens that are already known to be suboptimal. With the speed of release of new data, there is growing disparity between our therapeutic knowledge and what is possible in the clinic. Patient compliance is also a very important consideration in the development of combination therapy, as patients may be expected to take large numbers of tablets for very long periods of time. Trials of combination therapies to date have already provided some insight into patients' willingness to comply with dosing regimens. A further consideration for physicians treating early-stage patients for prolonged periods is the prevention of development of HIV-associated CNS disease. Zidovudine is effective in preventing the onset of AIDS-dementia complex but little is known about the efficacy of other antiretroviral agents. To prevent the re-emergence of this disease to levels seen before the introduction of zidovudine (AZT) in 1987, it might be important to include AZT in all combination therapy regimens. For combination therapy to be approved and used on a widespread basis, effective tools or markers for monitoring the efficacy of therapeutic regimens are required. Tools such as viral load measurements require regulatory approval on a worldwide scale and should be economically and logistically accessible for regular use in the clinic. The increase in cost of HIV management associated with combination therapy is a significant factor in determining its widespread acceptance. It is heartening to see that collaborative efforts are already under way to address this important issue.