Primary infection and sexual transmission

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%.

It is also understood that since untreated primary HIV infection only lasts a matter of weeks or months, the opportunity for transmission is 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.

Studies in Uganda¹ and the United States² established that viral load during untreated primary HIV infection is much higher – and therefore individuals are more infectious – than during untreated chronic infection.

A prospective study in heterosexual couples in Rakai, Uganda,³ 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 couples were followed for a mean of two and a half years.

The investigators also estimated that primary HIV infection increased the risk of HIV transmission per sexual act more than seven-fold. They also found that late/end-stage HIV infection (the five to fifteen months prior to death) increased the risk of HIV transmission per sexual act almost six-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 data⁴ 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). “From this perspective,” write the investigators, “primary infection plays only a minor role in transmission because of its very short duration relative to the other stages.”

Similarly, a 2007 US mathematical modelling study 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.⁵ The model was based upon the assumption that individuals who know that they are HIV-positive are 60% less likely to have unprotected sex that risks onward infection than individuals who are unaware of their infection status (which may not necessarily be the case amongst gay men, according to data from the UK⁶), and that patients taking antiretroviral therapy with a plasma viral load below 500 copies/ml are incapable of transmitting the virus (which may also not necessarily be the case).

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, and because individuals with acute HIV infection only represent 0.5% of all HIV-infected individuals in the US, “the impact of acute-phase transmission on the overall epidemiology of HIV in the US is minimized,” it concluded.

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,⁷ using phylogenetic analysis to track the impact of infection stage on sexual transmission from blood samples in Quebec’s genotypic resistance database, estimated that almost half of all sexually transmitted HIV infections were attributed to primary or early infection, (although some onward transmission took place within a month of infection, the average time between infection and onward transmission was 15 months).

They concluded that whilst primary/early HIV infection represented just 10% of the total sequenced samples in the genotypic resistance database, they accounted for 49% of all onward transmission events. In contrast, they found that treatment-naive and treatment-experienced chronically infected individuals accounted for 15% and 12% of onward transmission, respectively. The investigators do not account for the remaining quarter of infections, but note that they “doubtless missed some” primary HIV infection in Quebec during the study period.

A similar phylogenetic study, focused primarily on gay men attending London’s largest HIV clinic, estimates that around 25% of onward HIV transmission took place within six months of infection. However, the median estimated time between acquisition of HIV and onward transmission was fourteen months, and more than 90% of all onward HIV transmission events were estimated to have occurred within 42 months of infection – i.e. during early chronic, and most likely undiagnosed and/or untreated, HIV infection, rather than acute infection.⁸

Perhaps the most intriguing study on the relative impact of primary versus chronic infection comes from investigators from Imperial College, London,⁹ which again utilised mathematical modelling to estimate the impact of untreated HIV infection on transmission.

The main aim of the study was to quantify the relationship between viral load and infectiousness and to estimate its epidemiological impact. The first part of the study involved looking at viral loads of a group of gay men in Amsterdam followed between 1982 and 1993, before effective treatment, which found that the higher someone’s natural viral load was, the sooner they became ill.

The second part examined the link between viral load and transmission from a Zambian study of serodiscordant heterosexual couples. Putting these two pieces of information together, they 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.

They 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. They 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.

Testing during primary infection is covered in a later section.