P1-S4.04 Biases in the design of studies assessing the role of sexually transmitted infections as HIV risk factors
Authors: O'Hagan J , Lipsitch M 
Published: July 2011

BackgroundFor over 20 yearss sexually transmitted infections (STIs) have been studied as risk factors for HIV infection. We show how the design of studies in this field has inherent biases due to inappropriate confounder definition, coinfection, and heterogeneity in exposure to HIV. We use herpes simplex virus 2 (HSV2) to illustrate these biases and show that use of a serodiscordant couple design can remove them. Such findings are timely given the interest in using HPV vaccination for HIV prevention based on similar data.MethodsWe developed an individual based model (IBM) using published data from an existing STI IBM (STDSIM). This model permits simulation of multiple cohort studies to show the direction and magnitude of these biases. The model is written in Matlab. Analyses were performed using Cox regression in SAS.ResultsWe identified four causes of bias. (1) While confounding by sexual behaviour is widely appreciated it is less well understood that perfect measurement of sexual behaviour will not permit adequate control of confounding as data on the frequency of HIV exposure is missing. We show that this bias can result in upward confounding. 2) As HSV2 is more infectious than HIV we expect HSV2 to be acquired from coinfected partners first followed by HIV. 3) As coinfection increases HIV viral load HSV2 infection may act as a proxy for a partner's elevated infectiousness with HIV. Both of these mechanisms result in upward bias, the magnitude of which depends on the prevalence of coinfection. 4) Between subject heterogeneity in the risk of disease has been shown to attenuate estimates for any risk factor. We show that this bias can result in significant attenuation of the HR and that it depends on the prevalence of HIV among subjects' partners and their sexual behaviour. We show that if HIV serodiscordant couples are enrolled all four biases can be removed see Abstract P1-S4.04 Table 1.Abstract P1-S4.04 Table 1Comparison of standard study design and serodiscordant couples study design for estimating the per-sex act risk of HIV infection among HSV2 infected individuals compared to HSV2 uninfected individualsNull Median HR (Lowest HR, Highest HR)Different transmissibility Median HR (Lowest HR, Highest HR)Coinfection increases hiv infectiousness Median HR (Lowest HR, Highest HR)Susceptibility Median HR (Lowest HR, Highest HR)Expected11110Standard Design1.32 (0.84, 2.26)1.58 (0.64, 1.44)1.26 (1.01, 1.56)4.38 (3.28, 5.65)Serodiscordant Couples1.03 (0.84, 1.44)1.07 (0.70, 2.11)1.03 (0.72, 1.25)10.33 (9.65, 12.77)20 simulations were performed for each bias scenario. Simulations were started in 1930. Cohort studies were conducted from 1992-95, which is the period during which the data used to parameterise the model were collected in rural Tanzania. The data from each run was analysed using Cox proportional hazards regression in two ways, both of which enrolled sexually active index subjects who were HIV negative and who could be HSV2 positive or negative:1) Standard design – data on exposure to infection was not incorporated into the analysis.2) Serodiscordant couples design – only those individuals who had an HIV infected partner were included and only for the length of time they were in the partnership.All analyses adjusted for age in 5-year intervals, gender, and the baseline number of lifetime partners. Results presented are the median, lowest, and highest point estimates for the HR calculated from these runs. HIV and HSV2 per-sex act transmission probabilities were both equal to 0.02 unless otherwise stated.Null: No interaction between HSV2 and HIV.Different Transmissibility: No interaction between HSV2 and HIV. HSV2 per-sex act transmission probability = 0.03.Coinfection Increases HIV Infectiousness: Coinfected individuals have twice the HIV per-sex act transmission probability than individuals infected with HIV alone (ie, 0.04 vs 0.02 respectively).Susceptibility: The HIV per-sex act transmission probability to an HSV2 infected individual is 10 times higher than to an HSV2 uninfected individual (ie, 0.2 vs 0.02 respectively).Note: Susceptibility is not affected in the first three scenarios. Also, parameter values have been changed from disease specific values to permit each bias to be presented separately. Concurrent partnerships are not permitted. Full sensitivity analysis results which relax these restrictions are not shown.ConclusionsThe standard design is affected by at least four biases that preclude causal interpretations of all such HSV2-HIV studies performed to date. Use of a serodiscordant couple study design can remove these biases. It is impossible to correct previous results as the biases are not all in the same direction and their magnitudes depend on the unknown prevalence and transmissibility of both HSV2 and HIV among partners. These findings are expected to generalise to other STI-HIV risk factor studies and can help inform the decision to test HPV vaccination as an HIV prevention measure.