Much of the support for the potential benefit of treating patients during primary or early HIV infection comes from Bruce Walker’s group in Boston, where preliminary data suggested that very early treatment, especially during high-level viremia prior to Western Blot seroconversion, might lead to an improved virologic set-point, ultimately improving the long-term prognosis. Data were particularly encouraging for structured treatment interruptions (STIs) in this setting. It was hypothesized that early treatment would preserve the HIV-specific CD4+ T-cell proliferative response. This key component of the immune response is absent in the majority of chronically infected patients but maintained in long-term non-progressors (LTNP) who remain immunologically stable without the need for chronic antiretroviral therapy [Rosenberg, et al. Nature. 2000 Sep 28;407(6803):523-6]. It was also felt that STIs would have an “auto-immunizing” effect, further improving HIV-specific cellular immunity. It was thus hoped that the combination of these two strategies would turn acute seroconverters into LTNPs. Patients in Walker’s cohort underwent STI in a protocol that mandated the re-initiation of HAART for a single viral load (VL) of >50,000 c/mL or 3 consecutive VL of >5000 c/mL. This strategy initially looked very promising, with 5 out of 8 patients maintaining VL of <5000 c/mL in the first year of the protocol [Rosenberg, et al. Nature. 2000 Sep 28;407(6803):523-6].

Unfortunately, longer-term data presented at CROI by the same group of investigators suggests that the resulting immune control of viral replication is of limited durability [Kaufmann K, et al. Abstract 24]. Fourteen patients have now undergone from 1 to 4 STIs over a median of 3 years since the beginning of the first STI. Only 3 of these patients have maintained VL of <3000 c/mL off therapy, and 1 of these 3 patients has had a significant drop in his CD4 count. The other patients all experienced a decline in CD4 count and a gradual rise in viral load, eventually leading to the re-initiation of HAART. Interestingly, the time between diagnosis and initiation of HAART, the baseline viral load, the number of STIs performed, and the breadth and magnitude of HIV-specific cytotoxic T-lymphocyte response all failed to show a correlation with protection. There were no distinguishing features or predictors that separated the three successes from the remainder of the subjects.

It’s not clear why the initially observed immune control of viremia is not sustained, but preliminary data presented by the same group at least year’s conference suggest that gradual genetic evolution of the virus may play a role [Walker BD, et al. Abstract 164, 10th CROI, Boston, 2003]. While the results of the study are disappointing, a randomized control study is needed to determine whether there is any clinical advantage to starting HAART during acute infection. There is a hypothetical advantage to early treatment, as it does preserve the HIV-specific proliferative CD4 T-cell immune response [Rosenberg, et al. Nature. 2000 Sep 28;407(6803):523-6]. Many studies have shown that this response plays a key role in helping cytotoxic T-lymphocytes control viral infections [Reviewed by Kaech and Ahmed, Science. 2003 Apr 11;300(5617):263-5]. Thus treatment during primary infection, followed by therapeutic vaccination when available, may be a viable strategy for improving long-term immune control of viral replication.

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