The influence of primary infection on sexual transmission

During untreated primary HIV infection, people have exceptionally high viral loads and are extremely infectious. This has been cited as a limiting factor in test-and-treat programmes since, if a high proportion of infections are transmitted by people in primary infection, this places a limit on the degree to which diagnosing people with HIV and treating them promptly can reduce onward transmission. People in primary infection (within the first six months) are less likely to be diagnosed, at least until after their period of peak infectiousness has passed. Moreover, HIV-antibody tests will not usually detect infection in the first few weeks after exposure, and even p24 or RNA tests are not reliable in the first two to three weeks.

 However, primary infection only lasts a few weeks or months, so there are fewer opportunities for transmission than during many years of chronic infection. The opportunity for transmission is therefore lower compared with untreated chronic HIV infection, which can last for years or even decades.

Frequency of partner change will also have a major impact on the role of primary infection: the more frequently partners change within a high-risk population, the greater the potential for early onward transmission.

As a result, there is currently some disagreement regarding the impact of untreated primary (also called acute) HIV infection versus untreated chronic HIV infection on infectiousness and sexual transmission, and their relative contributions to onward transmission, with estimates of transmission following primary infection ranging from a low of 9% to a high of almost 50%. The proportion probably varies with the characteristics of the population studied, such as the rate of partner change, the proportion of HIV transmitted in stable couples and the proportion transmitted during casual sex.

A prospective study in heterosexual couples in Rakai, Uganda,¹ where one partner was HIV-positive at the start of the study, and one partner HIV-negative, further established that the likelihood of heterosexual HIV transmission is highest in the first two and a half months following initial infection with HIV, and that this correlates with higher viral load levels in early HIV infection. They estimated that 43% of transmissions in the study occurred within ten weeks of the index partner’s infection.

The investigators also estimated that primary HIV infection increased the risk of HIV transmission per sexual act more than seven-fold compared to the risk of HIV transmission per sexual act during the chronic (and longest) period of untreated HIV infection. Further analysis of these data² estimated that relative to chronic infection, infectiousness during primary infection was actually enhanced 26-fold (and 3.6-fold during late/end-stage infection).

However, taking into account primary infection’s relatively short duration, the study estimated that 14% of onward transmission occurred during primary infection (compared with 46% during the chronic stage and 40% during end/late-stage HIV disease).

Similarly, a 2007 US mathematical modelling study³ estimated that fewer than 9% of all new sexually transmitted HIV infections originated in people with untreated primary HIV infection, compared with 48% of new infections resulting from sexual contact with people with untreated chronic HIV infection.

Although it agreed with previous studies that individuals with primary HIV infection have exceptionally high viral loads, and estimated that they are 16 times more infectious than during chronic infection, because the period for which they are highly infectious is relatively short, typically no more than 49 days, individuals with acute HIV infection only represent 0.5% of all HIV-infected individuals in the US.

Studies in populations that include a higher proportion of gay men and other MSM (with potentially much more frequent partner change than heterosexual couples in Africa, even those with concurrent relationships), have come to slightly different conclusions, partially due to their more liberal interpretation of primary infection.

A 2007 study from Quebec, Canada,⁴ used phylogenetic analysis of blood samples in Quebec’s genotypic-resistance database. It estimated that almost half of all sexually transmitted HIV infections were attributed to primary or early infection. However, in this study, although some onward transmission took place within a month of infection, the average time between infection and onward transmission was 15 months.

The study concluded that whilst primary/early HIV infection represented just 10% of the total sequenced samples in the genotypic-resistance database, it accounted for 49% of all onward transmission events. In contrast, the study found that treatment-naive and treatment-experienced chronically infected individuals accounted for 15% and 12% of onward transmission, respectively, with the other 25% uncertain.

A similar phylogenetic study, focused primarily on gay men attending London’s largest HIV clinic,⁵ estimates that around 25% of onward HIV transmission took place within six months of infection.

A third study from Switzerland, using the same methods, concluded that about 30% of new infections showed signs of being transmitted in early infection.⁶

Perhaps the most intriguing study on the relative impact of primary versus chronic infection comes from investigators from Imperial College, London, which used mathematical modelling to estimate the impact of untreated HIV infection on transmission.⁷

The main aim of the study was to quantify the relationship between viral load and infectiousness and to estimate its epidemiological impact. The investigators examined the link between viral load and transmission from a Zambian study of serodiscordant heterosexual couples and found that the periods of highest viral load (during primary infection and again during late-stage HIV disease) did not actually have the highest transmission potential, because these lasted relatively short periods of time. Instead, they found that the viral load with the highest transmission potential (of a hypothetical average of 1.5 infections per person per lifespan) was found to be during chronic infection.

The study concluded that the 'ideal' viral load for HIV in its 'quest' for continued survival was 33,113 (4.52 log₁₀) copies/ml. At this viral load, someone could live for around ten years without becoming ill and still feel well enough to have sex, providing HIV with the longest transmission potential. The investigators hypothesise that HIV may have actually evolved so that average viral loads during chronic infection are finely balanced between being the optimal for HIV transmission and the optimal for human survival.