Studying trends in HIV virulence
Luuk Gras is a statistician at the Stichting HIV Monitoring (SHM). His work involves supporting other researchers with their analyses, and doing his own research. This includes monitoring of markers of disease progression and comparing statistical methods in the analysis of HIV observational data. One of his interests is trends in HIV virulence, which the following article discusses in further detail.
Virulence is defined as the severity of disease. HIV is a unique model system for the study of virulence evolution, as its recent origin and high evolutionary potential suggest that it has adapted to humans rapidly. Whether HIV virulence has evolved, or is evolving still, can inform our understanding about past and possible future patterns of the HIV/AIDS pandemic.
As time from infection to death cannot be studied in the cART era, set-point viral load, the relative stable level of HIV-1 RNA concentration in plasma during the asymptomatic stage of disease, is often used as a marker of severity of HIV disease. With a higher set-point viral load, progression to AIDS is more frequent (1), as is the rate of HIV-1 transmission (2). A temporal rising trend in plasma HIV-1 RNA concentration at set-point (and before cART is initiated) might imply an increase in the efficiency of transmission (3, 4).and a shorter interval between HIV-infection and reaching the CD4 cell count threshold below which cART should be initiated.
In a past SHM study (5) we reported an increasing mean set-point viral load among men-who-have-sex-with-men from Western Europe or North-America with evidence of recent HIV seroconversion (from 4.5 log10 copies/ml in 1985 to 4.9 log10 copies/ml in 2007). The changing distribution of the viral load assays used over time is unlikely to explain this increase. We also found a complementary trend of a declining mean CD4 cell count at viral set-point (592 cells/mm3 between 1984 and 1995, and 502 cells/mm3 between 2003 and 2007). In a recent study we found some evidence for a trend over time of a faster rate of CD4 cell count decline before cART is started. Combining these results together, we estimated that the time between HIV infection and reaching 350 cells/mm3 has shortened from 3.9 years when HIV infection was between 1984 and 1995 to 2.6 years for someone infected between 2003 and 2007.
A recent meta-analysis including results from 12 observational cohorts from Western Europe and North America, and including the SHM cohort, found similar results; a set-point viral load increase of 0.39 log10 copies/ml and a decline in CD4 cell counts at viral set-point of 148 cells/mm3 between 1984 and 2010 (6). A limitation of this study was that the statistical methods, outcome definitions and study population varied widely between individual studies. Therefore, the HIV Virulence Trends Working Group has recently been established with the aim to repeat the meta-analysis using harmonized methodology and definitions.
Reference List
(1) Mellors JW et al. Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997; 126: 946-954.
(2) Wawer MJ et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J Infect Dis 2005; 191:1403-1409.
(3) Quinn TC et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000; 342:921-929.
(4) Fraser C et al. Variation in HIV-1 set-point viral load: epidemiological analysis and an evolutionary hypothesis. Proc Natl Acad Sci U S A 2007; 104:17441-17446.
(5) Gras L et al. Viral load levels measured at set-point have risen over the last decade of the HIV epidemic in the Netherlands. PLoS ONE 2009; 4:e7365. 10.1371/journal.pone.0007365 [doi].
(6) Herbeck JT et al. Is the virulence of HIV changing? A meta-analysis of trends in prognostic markers of HIV disease progression and transmission. Aids 2012; 26:193-205. 10.1097/QAD.0b013e32834db418 [doi].