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Coverage provided by Howard Grossman, M.D.

July 10, 2001

• Greater Suppression of CD8 Activation with Four vs. Three Drugs in Early Stages of Primary HIV Infection (PHI) Despite Similar Plasma Virological Decay Rates (Abstract 61)
  Speaker: D. Smith
  Authored by Smith, D.; Zaunders, J.; Kauffman, G.; Cunningham, P.; Grey, P.; Goh, L.; Cooper, D.; University of NSW, Sydney, Australia

This was a study to determine the impact of antiretroviral therapy given during the early stages of primary HIV infection on CD4 + T-cell recovery, CD8+ T cell activation and HIV-RNA reduction. It was a non-randomized comparison of two cohorts, with treatment commenced within two weeks of identification of infection and all patients remaining on therapy for at least one year.

Patients were included who were symptomatic or asymptomatic, who had >1 HIV antigen and only early antibody responses. There was laboratory confirmation of positive p24 antigenemia and detectable viral replication by PCR. Acute HIV infection was determined by a negative antibody test by third generation EIA and <3 bands on the Western blot test, including <1 band with gp160, gp120 or gp41.

Patients were assigned to a three-drug group (n=17), commencing therapy with ZDV 300mg BID, 3TC 150mg BID and nelfinavir 750mg TID or indinavir 800mg TID, or to a four-drug group (n=10) and treated with combivir one pill BID, abacavir 300mg BID and amprenavir 1,200mg BID. Assessments were made of lymphocyte subsets using real time four-color flow cytometry. Determination of acutely activated (CD38+HLA-DR+), memory (CD45RO+), and effector (CD28-) T lymphocyte subsets at one- to two-monthly intervals. HIV RNA was determined using the Roche Ultrasensitive PCR (Amplicor 1.5).

Patients were well matched for sex, mode of infection, and age. The three-drug group had a mean CD4 of 345 (133-1140) and a plasma viral load (pVL) of 6.3 (3.2-7.2). The four-drug group had a mean CD4 of 529 (170-1104) and a mean pVL of 6.1 (2.4-7.8).

There was no significant difference in the first and second stage decay rates of the viral load, with a median pVL decrease from baseline of -4.6 and -4.8 logs by 48 weeks respectively (p>0.05). Median CD4 counts were also similar in the groups, 714 and 594 (p=0.2), and there was no difference in the CD4 activation marker CD38+HLA-DR+ cells. However, total CD8 cell numbers at week 48 (814 vs. 535) as well as the CD8 subsets CD38+ (411 vs. 129), CD38+HLA-DR+ (106 vs. 59) and CD45RO+ (255 vs. 134) cell numbers were all significantly higher (p<0.05) in the three-drug group compared to the four-drug group.

The authors concluded from this that although there was no difference in the viral load response with use of more drugs in these early cohorts, immunological markers of CD8 cell activation were significantly reduced, suggesting a greater suppression of HIV replication.

For some time now there has been a debate about the need to use more medications in patients during acute seroconversion to try to get the best outcomes. David Ho and colleagues at Aaron Diamond have demonstrated a greater slope to the viral load decay curve when more potent regimens are used. However, it is well known that even in many patients who appear suppressed by viral load testing, there is residual viral activity going on. This study did not confirm Ho's findings of a faster decay with four-drug therapy, but it indicated a decrease in CD8 activation. Using these markers may be a way to gain greater insight into the real degree of suppression of viral load when there it has been suppressed below the limits of our ability to detect it with Amplicor assays. In the question and answer session it was clearly indicated that this would be very helpful in being able to separate out patients with better responses to therapy.

This study also reinforces the idea that more drugs may be needed during very early HIV infection to get closer to full suppression, a necessary condition if we have any hope of eradicating or getting better control of the virus in this population.

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