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Structured Treatment Interruptions Workshop Summary

January 31, 2001

Progress in STI Research:
The Population View

Primary Infection

The most encouraging development in STI research is the possibility of durably modulating the intensity of an HIV infection by lowering the viral load setpoint for patients able to be treated at or near the time of seroconversion. Because this approach will be available only to the relatively few individuals diagnosed during primary HIV infection (PHI), the direct public health benefit of this research may not be large. Nevertheless, this work has other important implications. A beneficial intervention during primary infection will affect the design of preventive vaccine trials and may ethically restrict the observation of secondary endpoints after breakthrough infections. Potential clinical benefits aside, STI studies have opened a window onto the HIV disease process by manipulating the dynamics of immune responses that take place soon after infection. Despite this promise, much difficult work remains before the correlates of immune function and the meaning of HIV-1-specific immune activation assays are understood.

Chronic Suppressed Infection

For individuals with an established, chronic infection, the goal of bolstering immune response by vaccination with autologous virus after repeated cycles of STI remains elusive. There may be an emerging sense that, since durable HIV-1-specific immune stimulation has been difficult to replicate in chronically infected individuals, autovaccination may be a flawed approach to stimulating immune control. It could be that the pathogenic influence of HIV-1 on antigen presentation or cytokine production necessarily undermines the immune response to HIV in the presence of HIV. If this contradiction is not resolvable, then, as has been suggested, vaccination with exogenous antigens while remaining suppressed on antiretroviral therapy may give better results. In this context, vaccination may be used as a "prime" and STI as a "boost" approach.

A better-established clinical benefit of TI is for individuals who need a break from antiretroviral drugs due to toxicity, fatigue or an inability to adhere. A body of anecdotal experience, several prospective cohort studies, and a few small, randomized trials support the clinical safety of STI. Very few cases of resistance or breakthrough clinical events have been observed. Other risks need study before TI can be prescribed as easily as medications are. These include the risk of drug reactions on re-challenge and secondary acute retroviral syndrome (ARS). The current advice that STI should be undertaken in the context of clinical research remains prudent.

The development of metabolic abnormalities, fat redistribution, liver toxicities, and nerve damage has pressed the need for reducing or temporarily stopping drug exposure. Although some laboratory markers of toxicity seem to resolve after STI, it appears that symptoms of fat redistribution are refractory.

Intermittent Therapy

Clinical trials of intermittent treatment during chronic infection with the primary goal of reducing drug exposure and conserving resources are underway. Early reports suggest that good viral control can be maintained on several schedules of periodic dosing.

The effects of pulsed dosing on toxicity and drug clearance rates, the practicability of adherence to discontinuous schedules, and the risks of transmission while unsuppressed require careful study. Questions have also been raised about the cost savings of intermittent therapy if additional monitoring is required.

Chronic Unsuppressed

For a minority of individuals with multi-drug resistant (MDR) virus, a shift to the drug-susceptible wild type (WT) virus after TI is occasionally sustainable. However, most who restart treatment after shifting to WT soon experience treatment failure unless they have switched to previously untried drugs to which their virus is susceptible. Proposed studies of this intervention typically take the form of an immediate versus deferred treatment trial, with one arm waiting for a specified period before starting a new regimen and the other arm switching right away.

In some cases, however, the MDR virus may be less fit or less pathogenic than the WT and it may be as or more effective to remain on the failing regimen as it is to switch or take a break. Of course, for individuals who need to stop therapy due to toxicity, there are no clear solutions. Often, CD4+ cell loss speeds up dramatically after the viral population shifts to WT -- well before the effects of toxicity have abated.


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