Structured intermittent treatment for HIV disease: Necessary concession or premature compromise?

Abstract

The entree of potent antiretroviral therapy into the therapeutic armamentarium of HIV disease was an extraordinary moment in the history of the AIDS epidemic. Mortality declined, morbidity diminished, hospitalizations decreased, and the transition of HIV from a hospital-based to an outpatient disease commenced (1). The guiding principles of antiretroviral therapy were grounded on landmark studies of HIV viral dynamics and our understanding of drug resistance (2, 3). The production of 10 million particles of HIV daily combined with the knowledge that viral load predicted HIV disease progression provided the rationale to treat HIV with multidrug regimens that maximally suppressed viral replication (4, 5). Selection of HIV drug resistance and viral rebound were reduced by using therapies that initially suppressed HIV RNA levels in the plasma below 20 copies/ml (6). On the contrary, any reduction in regimen potency—either through simplification of therapy or through suboptimal patient adherence—led to rapid virologic failure and eventual drug resistance (7–10). Continuous lifelong therapy was thus adapted as the optimal treatment approach for HIV disease. Interventions may harm the host more than the virus before progression to AIDS. The clinical paradigm of treating HIV disease from the onset of infection, for life, is now under intense scrutiny. HIV therapy unequivocally reduces the risk for HIV-related complications. Yet HIV, despite early optimistic projections to the contrary, is unlikely to be eradicated even with decades of therapy (11–14). HIV therapy itself has produced an entirely new set of serious complications for HIV-infected patients including body deformities, insulin resistance, lactic acidosis, osteoporosis, neuropathy, osteonecrosis, lipid abnormalities, and cardiovascular disease (15). Most disconcerting is the fact that both the mechanisms of these toxicities as well as the long-term consequences are unknown. Several strategies are under investigation to address the conundrum that interventions may harm …