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Estimating the Benefit of a HIV-1 Vaccine that Reduces Viral Load Set-point
Swati Gupta*1, L Jacobson2, C Rinaldo3, J Phair4, B Jamieson5, J Margolick2, D Mehrotra1, M Robertson1, and W Straus1
1Merck Res Labs, West Point, PA, US; 2Johns Hopkins Univ, Bloomberg Sch of Publ Hlth, Baltimore, MD, US; 3Univ of Pittsburgh, Graduate Sch of Publ Hlth, PA, US; 4Northwestern Univ Med Sch, Chicago, IL, US; and 5Univ of California Sch of Publ Hlth, Los Angeles, US
Background: Vaccines
designed to induce cell-mediated immune responses against HIV-1 are being
developed. Such vaccines may not provide sterilizing immunity, but are likely
to be associated with reduced viral set-points after infection. Using data derived
from a cohort study, we modeled the effct of a vaccine that reduces viral set-point
upon the natural history of HIV-1.
Methods: Data from the Multicenter AIDS Cohort Study, an ongoing,
prospective cohort study (initiated in 1984) of HIV infection in homosexual or
bisexual men, were used to model the natural history of HIV-1 based upon viral set-point,
defined as the viral load value 9 months post seroconversion. We evaluated the
clinical course of 311 seroconverters before December 31, 1992 (to avoid any confounding
effect of combination ART). Lognormal parametric regression models were
used to estimate the log median time and relative time to events of interest, such
as a CD4 cell count <350 cells/mm3 and loss of virological
control (defined as HIV-1 RNA ≥55,000 copies/mL). Relative times were estimated
for those with viral load set-points of 30,000 copies/mL (reference group) vs those
with lower viral set-point measurements.
Results: The median time to
a CD4 cell count <350 cells/mm3 was 3.4 years for those with a
viral set point of 30,000 copies/mL compared with 5.9 years for those with viral
set-point of 3000 copies/mL (relative time 1.7; 95%CI 1.4, 2.1). The median
times to HIV-1 RNA ≥ 55,000 copies/mL were 2.4 and 7.6 years for those
with viral set-points of 30,000 and 3000 copies/mL, respectively (relative time
3.1; 95%CI 1.9, 5.0). All event-free times were significantly longer for those
with early HIV-1 RNA measurements 0.5 to 1.25 log10 copies/mL lower
than the reference group.
Conclusions: The time to key
clinical events in the course of HIV-1 disease progression was significantly extended
for those with early HIV-1 RNA 0.5-1.25 log10 copies/mL lower than
the reference group. For those with a viral set-point of 3000 vs 30,000
copies/mL, the relative time to clinical events examined was approximately
double or higher, even for those events that occur earlier in disease
progression. By quantifying the anticipated clinical benefits associated with a
reduction in viral set-point, these findings provide support for the use of
virologic endpoints in HIV-1 vaccine trials.
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