Structured Treatment Interruption in Patients Infected with HIV

Abstract

Current antiretroviral regimens are limited by issues of potency, adherence, toxicity, resistance and cost. With these limitations and the realisation that eradication of HIV infection currently is not possible, there is enthusiasm for strategies that allow discontinuation of medications, such as the structured treatment interruption (STI). STI is hypothesised to have benefits in three distinct clinical scenarios: acute treated infection, chronic treated infection with controlled viraemia, and chronic treated infection without controlled viraemia (salvage therapy).

In patients with acute treated HIV infection, STI may preserve or enhance cellular immune responses to allow continued virological suppression in the absence of ongoing treatment. The Berlin patient presented with acute HIV infection prior to seroconversion and received antiretroviral therapy. After two treatment interruptions (for intercurrent infections), he permanently discontinued therapy and remained virologically suppressed for 2 years. Investigators from Massachusetts General Hospital described eight patients with acute or early HIV infection who received treatment and then underwent one or two STI. After the STIs, five of eight patients showed enhanced cellular immune responses and continued with virological suppression off treatment for a median of 2.7 years.

In patients with chronic treated infection with controlled viraemia, STI may enhance immune responses as in the case of acute infection, or may allow decreased drug exposure and toxicity. Investigators from the National Institutes of Health enrolled 18 patients with chronic HIV infection and virological suppression while taking antiretroviral regimens. With a single STI, all patients rebounded, although one (6%) ultimately continued off therapy with virological suppression. The largest study of STI is the Spanish Swiss Intermittent Treatment Trial in which 128 patients with chronic suppressed HIV infection on antiretroviral therapy underwent four cycles of STI. At 52 weeks, 17% had suppressed viral load levels of <5000 copies/ml in the absence of therapy.

In patients with chronic treated infection without controlled viraemia (salvage therapy), STI promotes a shift from resistant to wild-type (i.e. no mutations) virus. In the Hamburg cohort, the shift to wild-type virus was seen in 28 of 45 heavily treatment-experienced patients after an STI. Seventy-two percent of these patients experienced a virological response on a subsequent regimen, although many ultimately experienced virological rebound. In the San Francisco cohort, a shift to wild-type virus was seen in 15 of 17 protease inhibitor-experienced patients and six of these patients achieved virological suppression to <200 copies/ml on a new regimen.

Risks associated with STI include increases in viral load levels with the risk of loss of virological control (i.e. failure to resuppress on therapy), repopulation of viral reservoirs and antiretroviral resistance, and decreases in CD4+ cell counts with the risk of loss or dysregulation of immune function and the occurrence of clinical events. Other risks include acute retroviral syndrome and the recurrence of short-term adverse effects.

Currently, STI cannot be recommended as part of routine clinical care. Prospective studies are needed to assess the risks and benefits of this strategy in all clinical settings.