Rethinking the heterosexual infectivity of HIV-1: a systematic review and meta-analysis

Summary

Studies of cumulative HIV incidence suggest that cofactors such as genital ulcer disease, HIV disease stage, and male circumcision influence HIV transmission; however, the heterosexual infectivity of HIV-1 is commonly cited as a fixed value (approximately 0·001, or one transmission per 1000 contacts). We sought to estimate transmission cofactor effects on the heterosexual infectivity of HIV-1 and to quantify the extent to which study methods have affected infectivity estimates. We undertook a systematic search (up to April 27, 2008) of PubMed, Web of Science, and relevant bibliographies to identify articles estimating the heterosexual infectivity of HIV-1. We used meta-regression and stratified random-effects meta-analysis to assess differences in infectivity associated with cofactors and study methods. Infectivity estimates were very heterogeneous, ranging from zero transmissions after more than 100 penile-vaginal contacts in some serodiscordant couples to one transmission for every 3·1 episodes of heterosexual anal intercourse. Estimates were only weakly associated with study methods. Infectivity differences, expressed as number of transmissions per 1000 contacts, were 8·1 (95 % CI 0·4–15·8) when comparing uncircumcised to circumcised susceptible men, 6·0 (3·3–8·8) comparing susceptible individuals with and without genital ulcer disease, 1·9 (0·9–2·8) comparing late-stage to mid-stage index cases, and 2·5 (0·2–4·9) comparing early-stage to mid-stage index cases. A single value for the heterosexual infectivity of HIV-1 fails to reflect the variation associated with important cofactors. The commonly cited value of 0·001 was estimated among stable couples with low prevalences of high-risk cofactors, and represents a lower bound. Cofactor effects are important to include in epidemic models, policy considerations, and prevention messages.

Introduction

More than 33 million people are infected with HIV worldwide, with 2·5 million new infections arising in the past year alone.¹ Every HIV infection results from a transmission event, and one of the fundamental parameters driving the spread of HIV is its infectivity, defined as the probability of transmission during a single potentially infectious contact between an infected and an uninfected individual. A commonly cited2, 3, 4, 5, 6 value of approximately 0·001 for the heterosexual infectivity of HIV-1 has led to claims in biomedical reports, prevention education materials, policy recommendations, and the popular press that HIV cannot be transmitted efficiently through heterosexual contact. These claims are difficult to reconcile with the large numbers of HIV infections that have been acquired through heterosexual contact since the epidemic began.1, 7, 8, 9

Infectivity estimation requires an accurate count of the transmission events resulting from a defined number of potentially infectious exposures experienced by a specified population of susceptible individuals. Reliable counts of potentially infectious sexual exposures are very difficult to obtain. Often, it is possible to estimate only an approximate number of unprotected sex acts occurring between one individual who is presumed to be infectious and another who is presumed to be susceptible over some specified interval of time. Overestimation of the number of potentially infectious exposures will deflate infectivity estimates; underestimation will have the opposite effect.

Infectiousness and susceptibility could be influenced by multiple factors, such as direction of transmission (male-to-female versus female-to-male),¹⁰ type of sexual act,11, 12 viral load,13, 14 male circumcision,15, 16, 17, 18 vaginal flora,¹⁹ age,²⁰ and sexually transmitted infections (STIs).21, 22, 23 The effects of these transmission cofactors on cumulative HIV incidence have been characterised; however, efforts to quantify their effects at the per-contact level have been rare, and practical applications of infectivity estimates often ignore the possibility of cofactor influence.

Accurate, detailed estimates of the heterosexual infectivity of HIV are essential for understanding the epidemic, evaluating potential interventions, and communicating risk. We undertook a systematic review and meta-analysis of observational studies estimating the heterosexual infectivity of HIV-1 to (1) summarise existing infectivity estimates, (2) relate these estimates to methodological features of the studies producing them, (3) quantify cofactor effects on infectivity, and (4) identify gaps in understanding.