A short course of potent HIV therapy during primary infection may slow longer-term disease progression

A case-control study has shown that CD4 cells may decline more slowly in HIV-positive people who take a three-month course of potent anti-HIV therapy shortly after seroconversion. The study was based on data from a recently HIV-infected cohort in London, UK, and published in the June issue of AIDS. From these non-randomised data, the researchers could not conclude that treatment during primary infection led to improved outcomes, but believe there is a pressing need to test the hypothesis in randomised clinical trials.

Primary HIV infection (PHI) is the brief interval immediately following HIV seroconversion (generally taken to be six months) during which HIV-specific immune responses are stronger and the virus is still establishing itself within bodily reservoirs. There have been hypotheses that intervening with HIV therapy during primary infection may help to preserve immune function and slow disease progression. It has also been shown that HIV disease tends to progress more slowly in individuals who have better control very early control of HIV viral load. However, there are many arguments against initiating long-term HIV therapy immediately after infection, and there is no clinical evidence that doing so is beneficial.

This study investigated a different approach than beginning long-term treatment – beginning potent anti-HIV treatment during primary infection but limiting treatment to a short course, with the goal of limiting the initial latent pool of infected cells. Out of 105 recently infected individuals at London’s St. Mary’s Hospital (with laboratory evidence of seroconversion within the previous six months), 90 accepted enrolment into the study, and began a three-month short course of antiretroviral therapy (SCART). Therapy was initiated between November 1999 and October 2003 and consisted of a nucleoside backbone of AZT (zidovudine) and 3TC (lamivudine, Epivir) for all participants; plus nevirapine (Viramune ), efavirenz (Sustiva) or lopinavir/ritonavir (Kaletra). Treatment makeup differed according to when treatment was initiated, with roughly equal numbers of participants on nevirapine, efavirenz and lopinavir. Those who took efavirenz also received abacavir (Ziagen). One person was excluded due to incomplete data; the remaining 89 of this SCART group were analysed.

For comparison, 179 controls were selected from the 8,908 participants in the European CASCADE collaboration cohort. Controls were matched for age, sex, HIV risk factor, and year of estimated seroconversion; all were treatment-naïve for at least six months after seroconversion. The SCART and control groups were therefore very similar demographically and clinically: median values were, respectively: age at seroconversion — 30.1 and 32.9 years, baseline CD4 count — 510 and 544 cells/mm³, baseline viral load — 4.96 and 4.92 log₁₀. Participants were mostly men – 92% and 89%, respectively.

Member of the SCART group began therapy 1.5 months after seroconversion, on average, with a median CD4 cell count of 500 cells/mm³, and remained on treatment a median of 3.3 months. As expected, as SCART was started and discontinued, most (although not all) experienced transient, steep CD4 cell increases followed by declines, as well as transient viral load decreases. Viral load dropped below 50 copies/ml during SCART in 80% of the group.

Analysis focused on the longer term trends in CD4 count and viral load. Follow-up periods were a median of 2.45 years for the SCART group and 1.20 for the controls. No significant differences between the two groups were found in terms of changes in viral load. However, CD4 cell counts declined more quickly in the untreated control group than in those who received SCART. Projected out to three years after seroconversion, the treated group lost 51 cells/mm³ annually [95% confidence interval (CI), 32-69] and the untreated controls, 77 cells/mm³ [95% CI, 65-89] (p = 0.011).

According to the investigators, “this is the first report showing an apparently significant alteration in the rate of CD4 cell decline in persons treated with SCART at PHI when compared with a matched untreated population”. Possible confounding factors included the different labs used to assess CD4 counts and other parameters (although this was judged unlikely), and the lack of knowledge of participant genetic factors which might affect disease progression. Given these and other possible confounders, the relatively short time frame and the lack of a randomised study design, the team “[could not] conclude that a 3 month short course of [potent anti-HIV therapy] is superior to no therapy”. However, the findings “may at least indicate that there is a transient beneficial effect over a period longer than has hitherto been described,” and highlight “the urgent need for a randomized clinical trial in acute and early HIV disease.” (Such a trial, SPARTAC, is currently underway: www.ctu.mrc.ac.uk/studies/spartac.asp.)