Reassessment of HIV-1 Acute Phase Infectivity: Accounting for Heterogeneity and Study Design with Simulated Cohorts

Background: The infectivity of the HIV-1 acute phase has been directly measured only once, from a retrospectively identified cohort of serodiscordant heterosexual couples in Rakai, Uganda. Analyses of this cohort underlie the widespread view that the acute phase is highly infectious, even more so than would be predicted from its elevated viral load, and that transmission occurring shortly after infection may therefore compromise interventions that rely on diagnosis and treatment, such as antiretroviral treatment as prevention (TasP). Here, we re-estimate the duration and relative infectivity of the acute phase, while accounting for several possible sources of bias in published estimates, including the retrospective cohort exclusion criteria and unmeasured heterogeneity in risk. Methods and Findings: We estimated acute phase infectivity using two approaches. First, we combined viral load trajectories and viral load-infectivity relationships to estimate infectivity trajectories over the course of infection, under the assumption that elevated acute phase infectivity is caused by elevated viral load alone. Second, we estimated the relative hazard of transmission during the acute phase versus the chronic phase (RHacute) and the acute phase duration (dacute) by fitting a couples transmission model to the Rakai retrospective cohort using approximate Bayesian computation. Our model fit the data well and accounted for characteristics overlooked by previous analyses, including individual heterogeneity in infectiousness and susceptibility and the retrospective cohort's exclusion of couples that were recorded as serodiscordant only once before being censored by loss to follow-up, couple dissolution, or study termination. Finally, we replicated two highly cited analyses of the Rakai data on simulated data to identify biases underlying the discrepancies between previous estimates and our own. Conclusions: Previous EHMacute estimates relying on the Rakai retrospective cohort data range from 31 to 141. Our results indicate that these are substantial overestimates of HIV-1 acute phase infectivity, biased by unmodeled heterogeneity in transmission rates between couples and by inconsistent censoring. Elevated acute phase infectivity is therefore less likely to undermine TasP interventions than previously thought. Heterogeneity in infectiousness and susceptibility may still play an important role in intervention success and deserves attention in future analyses Using simulated cohorts that account for previously unmeasured bias, Steve Bellan and colleagues provide new estimates of the duration and relative infectivity of the HIV-1 acute phase based on data from the retrospective cohort of serodiscordant couples in Rakai, Uganda.Background.: About 35 million people are currently infected with HIV, the virus that causes AIDS, and more than 2 million people become newly infected with the virus every year, usually through having unprotected sex with an infected partner. Most people do not become ill immediately after infection, although some people develop a short flu-like illness. However, during this acute phase of infection, the amount of virus in the blood—the viral load—rises rapidly and peaks, before decreasing to a relatively stable lower level during the chronic phase of HIV infection. Chronic HIV infection, which may last for more than ten years, also has no major symptoms, but HIV slowly destroys immune system cells throughout this phase. Eventually, the immune system can no longer fight off infections by other disease-causing organisms, and HIV-positive people then develop one or more AIDS-defining conditions, including unusual infections and specific types of cancer; the HIV load also rises again during late phase infection. Why Was This Study Done?: Antiretroviral therapy (ART) can control, but not cure, HIV infection. By decreasing the viral load, ART not only improves the health of HIV-positive individuals, but also reduces their infectiousness. Consequently, experts believe that scaling up ART could substantially reduce the rate of new HIV infections. But the successful implementation of “treatment as prevention” faces several challenges. Notably, HIV testing and treatment programs need to be widely available, and people who are HIV-positive need to adhere to ART. Another major challenge that faces treatment as prevention is that HIV transmission that occurs during the acute phase of infection is likely to evade the intervention, and it is widely accepted that HIV-positive individuals are highly infectious during this phase of infection. However, acute phase infectivity has been directly measured only once: in a retrospectively identified group of serodiscordant heterosexual couples (couples in which only one partner was HIV-positive) in Rakai, Uganda. The authors of the current study found that existing estimates of acute phase infectivity failed to take account of important aspects of the Rakai study design or of heterogeneity (variability) in infectiousness or susceptibility among the study participants. Here, the researchers use mathematical modeling to compare simulated cohorts with the Rakai data to provide new estimates of the duration and relative infectivity of the acute phase that take into account study design and heterogeneity. What Did the Researchers Do and Find?: The researchers first used viral load trajectories and viral load–infectivity relationships to estimate infectivity trajectories over the course of infection. Using this approach, they estimated that the total additional risk attributable to the acute phase expressed as EHMacute (excess hazard-months attributable to the acute phase of infection above the hazard generated by constant untreated chronic phase infectivity) was 5.6, which is considerably lower than previous estimates (which range from 31 to 141). Next, by fitting a mathematical model designed to simulate HIV infection and transmission within couples to the Rakai data, they estimated that the relative hazard of transmission during the acute phase versus the chronic phase (RHacute) was 5.3, that the acute phase duration (dacute) was 1.7 months, and that EHMacute was 8.4. Finally, by replicating two highly cited analyses of the Rakai data on simulated data, the researchers show that the previous overestimates of acute phase infectivity likely stemmed from a failure to account for risk heterogeneity among study participants (some participants were more likely to transmit HIV or contract HIV than others because of underlying biological or behavioral differences in their infectiousness or susceptibility, respectively) and from bias arising from the retrospective cohort design of the Rakai study (serodiscordant couples who were lost to follow-up were excluded). What Do These Findings Mean?: In common with previous estimates of acute phase infectivity, the accuracy of these findings depends on the many assumptions made by the researchers in developing their mathematical models and on the quality of the data fed into these models. Nevertheless, these findings suggest that previous estimates of the infectivity of acute phase HIV infection are substantial overestimates. Thus, the researchers suggest, elevated infectiousness early in infection alone is unlikely to undermine treatment as prevention campaigns, and the population-level benefits of treatment as prevention may be larger than predicted from earlier estimates. These revised estimates—and the impact of heterogeneity of HIV infectiousness and susceptibility to infection on HIV transmission within populations revealed by this analysis—should now be considered when designing population-scale interventions and when communicating individual-level risk of HIV transmission and infection in clinical and community settings. Additional Information.: Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001801.