Table 1. Challenges associated with the current paradigm of antiretroviral agents.

 

Selected challengesComments
Integration of provirus and viral latency for the lifetime of the patient • Viral rebound follows discontinuation or interruption of treatment in the current treatment paradigm. Therefore, available drugs (often in fixed-dose combinations) must be administered for a lifetime. No curative intervention is now known.
Drug resistance, remarkable genetic diversity of HIV-1, and the ongoing risk of cross-species infections (transpeciation) with new pathogenic retroviruses • Resistance to many available drugs has emerged. The current paradigm of antiretroviral therapy, starting with AZT [β-d-(+)-3′-azido-3′-deoxythymidine, zidovudine], has relied very heavily on targets encoded by the viral pol gene. Other targets are clearly needed.
• Non-B HIV-1 subtypes (clades) are becoming more prevalent. Typically, the diversity of influenza sequences worldwide in any given year appears to be roughly comparable to the diversity of HIV-1 sequences found within a single infected individual at any one time point.
• Certain assays for quantifying circulating amounts of HIV-1 may underquantify viral load. Ideally, the performance of such assays should tolerate mismatches and accurately report all known group M, group O, and group N viruses, as well as unexpected and unusual polymorphisms, over a very wide dynamic range.
• There is also a natural reservoir of retroviruses in nonhuman primates that could create opportunities for cross-species jumping (transpeciation) of new retroviruses. Careful epidemiological surveillance programs are essential. Three independent cross-species transmissions of SIVcpzPtt from chimpanzees are known to have given rise to HIV-1.
The ultimate role of pre-exposure prophylaxis in uninfected individuals• The treatment of individuals at high risk of HIV-1 infection with antiretroviral therapy using available drugs holds promise as a method of primary prevention. But the long-term safety, efficacy, compliance, and costs associated with this strategy have not been resolved.
Cardiac and metabolic complications of current antiretroviral regimens• Infectious disease specialists must now routinely manage dyslipidemias, insulin resistance, smoking cessation, and other preventable causes of heart disease. The long-term public health impact of the cardiometabolic side effects of current antiretroviral drugs remains an open issue.