The effect of HIV subtype on disease progression in Rakai, Uganda

Previous Ugandan studies have found more rapid disease progression in people with subtype D than with subtype A.

In an oral presentation, Oliver Laeyendecker from the National Institutes of Allergies and Infectious Diseases and John Hopkins Medical Institute evaluated the effect of HIV subtype on rapid disease progression in a cohort in Rakai, Uganda.

The Rakai cohort is an annual survey of 12,000 HIV positive adults, identified between 1994 and 2001 in 50 communities in the Rakai district. This analysis included data from 340 serconverters with follow up information.

Subtypes were determined by Multi Region Hybridization Assay (MHA) for subtypes A,C and D. AIDS was defined as having a CD4 count <250 cells/mL (at which point study participants became eligible for antiretrovirals from PEPFAR).

Of the group studied, 53 (16%) people were subtype A, 203 (60%) were subtype D, 14 (4%) had multiple and 70 (20%) people had recombinant viruses. There were no differences in median age or viral load between the groups by subtype.

The investigators found that in the group with subtype A, 5 people progressed to AIDS and there were no deaths over a median follow up period of 2.9 years (range 1.7-5.3 years); in those with subtype D there were 40 cases of AIDS and 12 deaths over a similar period (median 3.2 years, range 1.7 -5.4 years). There were 5 and 10 cases of AIDS; 0 and 11 deaths over 2.7 (0.9-6.1) and 3.5 (1.7-5.0) years for those with multiple and recombinant viruses respectively.

Based on Kaplan-Meier survival curves they found a significant difference in median survival time: 8.8, 6.9 and 5.8 years for people with subtype A, subtype D and recombinant viruses respectively.

In a Cox regression analysis of AIDS or death, adjusted hazard ratios were 1.00, 2.89 (p=0.43) and 4.88 (p=0.005) for people with subtype A, subtype D and recombinant viruses respectively. Viral load was also significant in this model HR 1.83 (p=0.001) but gender, age or infection with multiple strains were not.

At the cut off point for the study the investigators reported only 40% with subtype D were healthy compared to 75% with subtype A. When they looked at rapid death, 8% of people with subtype D and 11% with recombinant strains were dead within three years. Dr Laeyendecker noted that there was a slightly higher viral load in those who died compared to those who did not but this was not significant.

There was also a small subset of 31 seroconverters for whom tropism data were available. The investigators found that 5/31 had dual tropic virus within two years of infection, all of which were subtype D and 4/5 were dead within three years of infection.

A further population analysis found that approximately 25% of people with subtype D (n=79) and 16% of people with recombinant viruses (n=22) had dual tropic virus (none were subtype A, n=21). And 68% of people with dual tropism were dead within three years.

From this study subtype D and recombinant strains incorporating subtype D both appear to be more pathogenic compared to subtype A.

The investigators found that viral load had a significant effect on disease progression over longer follow up times but viral load measured during the year of seroconversion did not predict death within three years.

They wrote: Determination of HIV subtype is important for the management of HIV-positive individuals because disease progression occurs more rapidly in individuals infected with subtype D and recombinant virus incorporating subtype D than other viral variants and Vaccine trials or trials of HAART which assess disease progression as an end point must consider subtype differences.

Laeyendecker O, Li X, Arroyo M, McCutchan F et al. The effect of HIV subtype on rapid disease progression in Rakai, Uganda. 13th CROI, Denver, 2006. Abstract 44LB.