IAVI Report - February / March 2001
 

In a special lecture, Bruce Walker (Mass. General Hospital, Harvard University, Cambridge), a leader in studies of cellular immune responses during HIV infection, reviewed his lab's work on supervised treatment interruption (STI). Also called "strategic" or "structured" treatment interruption by some researchers, STI is a promising but still unproven new front in HIV therapy. Walker's talk focused on the potential of STI to stimulate HIV-specific T-cell responses that can control virus replication in the absence of drug treatment. Since many HIV vaccine candidates also aim to induce cellular immune responses that control viral load, STI research may yield information highly relevant to vaccine development.

Walker is testing STI in people identified during the acute stage of infection, prior to full seroconversion. He stressed that the average baseline viral load of his study participants was around 10 million copies per ml, which distinguishes them from many other cohorts of newly infected people with lower viral loads (indicating a longer duration of infection). The idea is to start antiretroviral drugs very early, thereby preserving nascent HIV-specific T-cell responses, and then to stop drug therapy and monitor whether the immune system can take over control of HIV.

In his presentation, Walker updated the encouraging data recently published by his group (Nature 2000 Sep 28;407(6803):523-6) on 14 volunteers who received combination antiretrovirals for an average of 18 months before interrupting treatment. The study protocol calls for resumption of drug therapy in participants who do not control HIV after the interruption (those with viral load over 50,000 on any one test, or above 5,000 for more than three weeks).

Walker reported that after the first treatment cessation, four participants have remained off therapy for 71-445 days (the duration of follow-up at the time of the meeting) while maintaining viral loads ranging from <50 to 4,157. Two other individuals have kept viral loads below 5,000 for nearly a year after restarting and then stopping treatment a second time, while another volunteer showed similar results after a third cycle of treatment. In all cases, CD4 counts have been preserved. The seven remaining study participants are awaiting viral load test results or undergoing a second or third cycle of treatment.

Analysis of T-cell responses in the seven volunteers who are successfully controlling HIV replication revealed potent HIV-specific CD4 helper and CD8 CTL activity, a finding that bodes well for vaccines which induce cellular immunity. But, as Walker took pains to emphasize, a crucial question is how long this immunological control will last. He showed two examples of "late breakthroughs"-people who experienced significant increases in viral load after prolonged periods of control. In one person, viremia spiked to 25,000 after four months below 5,000, although within two weeks it dropped again and has remained low for about a year without therapy. In the second case, viral load suddenly climbed to over 50,000 after eight months at low levels, triggering reinitiation of drug therapy. The significance of these viral load fluctuations in the context of otherwise effective immune control is unclear: although non-progressing HIV infection is associated with a persistently low viral load, it is not known whether these levels can fluctuate over time. Clarity on this point will be important for assessing both STI and vaccine-induced immune responses, to determine whether they affect disease progression in vaccinees who later become infected. Continuing follow-up of Walker's cohort should help better define the immune correlates of effective long-term HIV control (and of loss of control).

Several other STI studies were presented at the conference, but did not involve individuals treated as early in infection as Walker's cohort. Lack of consistency in STI duration and study populations make any conclusions about the overall efficacy of the approach premature. Several groups (including Walker's) hypothesize that therapeutic vaccination combined with STIs may facilitate long-term withdrawal of drug therapy. As Marty Markowitz from Aaron Diamond AIDS Research Center ruefully pointed out, researchers have been waiting for a vaccine candidate that reliably induces cell-mediated immunity in humans before pursuing this idea.

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©2001. The IAVI Report.

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