HIV causes chronic infection and is associated with persistent viral replication and a high viral mutation rate. It is an illusion to think that monotherapy with any antiretroviral agent will have a major and lasting impact on this disease. Monotherapy with antitubercular agents led to dramatic improvements in treatment, but the development of drug resistance meant that these improvements were of only short duration, and hence it was concluded that drugs should be combined. The response to the limited efficacy of nucleoside analogue monotherapy in HIV infection has in many instances been the stance that ‘currently available antiretrovirals are no good; it is better not to treat’.
In addition, regulatory insistence on clinical end-points has also hampered antiretroviral drug development. It is implied that antiretrovirals must be tested in populations with fairly advanced HIV infection, in whom the least success may be expected. The regulatory bind has also resulted in artificial and counterproductive treatment guidelines.
Common sense and experience in infectious diseases dictate that treatment should hit hard and early. No study published thus far undermines the concept that early therapy is better than late therapy or that a tolerable combination of drugs with additive or synergistic anti-HIV activity is better than nucleoside monotherapy.
Promising data have been generated in trials on combinations of zidovudine plus didanosine or zalcitabine; a combination of zidovudine and lamivudine (3TC) may be even more promising. However, with 2-drug combinations there still is suboptimal suppression of HIV virus load. In vitro findings indicate that most 3-drug combinations are more effective at suppressing virus production than 2-drug combinations, and a good number of antiretroviral agents that could have a place in triple-drug regimens are available. Thus, we should proceed expeditiously with the clinical testing of triple-drug combinations. This can only be done efficiently in a systematic manner, in trials of limited size but with intensive virological and immunological monitoring and of sufficiently long duration. Only regimens that give the most profound and durable suppression of HIV virus load in such exploratory studies may be taken forward to be studied in large, clinical-end-point trials.
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Lange, J. Combination Antiretroviral Therapy. Drugs 49, 32–37 (1995). https://doi.org/10.2165/00003495-199500491-00008
- Human Immunodeficiency Virus
- Human Immunodeficiency Virus Type
- Human Immunodeficiency Virus Infection