Treatment and heterosexual transmission risk

The first-ever randomised controlled trial to assess the impact of antiretroviral therapy on heterosexual transmission risk found that the efficacy of treatment as prevention was 96% – i.e. HIV-positive people taking antiretroviral therapy were more than 20 times less likely to infect their partners than untreated people.¹

The HPTN 052 trial reported results four years ahead of schedule in May 2011 and confirmed the suspected benefit of treatment on heterosexual transmission risk seen in earlier observational studies and reported in more recent studies.

The trial recruited 1763 serodiscordant couples – one HIV-positive, one HIV-negative – in which the HIV-positive partner had a CD4 cell count between 350 and 550 cells/mm³. The HIV-positive participants were randomised either to start treatment immediately, or to defer treatment until their CD4 counts fell into the range 250 to 200, the threshold for starting treatment in national guidelines at the time the study began recruiting.

A total of 39 individuals acquired HIV during the trial, four in the immediate-treatment arm and 36 in the deferred-treatment arm, during a median follow-up period of 1.7 years. However, 11 cases of transmission were attributed to sex outside the primary relationship, or else the source could not be confidently determined. Of the 28 infections remaining, only one occurred in the immediate-treatment arm, representing a highly statistically significant reduction in the risk of transmission of 96%.

The only transmission in the immediate-treatment arm took place during the early months of treatment, with HIV antibodies fully detectable 85 days after baseline in the partner who became infected. The transmitting partner had a baseline viral load of 87,202 copies/ml, and after 28 days a viral load below 400 copies/ml.

In 2013, Loutfy and colleagues published a systematic review of the three observational studies that had previously evaluated rates of sexual HIV transmission between heterosexual serodiscordant couples when the HIV-positive partner had blood plasma viral loads below detectable levels (which ranged between 500 and 50 copies/ml, depending on the study) on antiretroviral therapy.² The three studies – Melo and colleagues (2008),³ Del Romero and colleagues (2010)⁴ and Reynolds and colleagues (2011)⁵ were also analysed in a more comprehensive systematic review by Anglemyer and colleagues, described below.⁶

Loutfy and colleagues calculated that the rate of transmission in these three studies was 0 per 100 person-years (95% CI = 0-0.05).  However, there were several caveats to the analysis, including lack of data on same-sex couples, the type of sexual intercourse (vaginal vs anal), the direction of HIV transmission, exact viral load at the time of transmission, rates of sexually transmitted infections (STIs), extent of condom use, and limited follow-up time.

Despite the excitement over the results of HTPN 052, questions remain about the durability of the protective effect of antiretroviral therapy – the average follow-up for HPTN 052 was just 1.7 years – and whether it is feasible (and ethical) to rely solely on treatment – and more specifically an ‘undetectable’ viral load on treatment to reduce HIV transmission risk, especially since there are still incomplete data for anal sex (which does not only occur in sex between men).

Of note, in HPTN 052, reported condom use was high throughout the study, claimed by 94% of HIV-positive individuals at baseline, and there was no evidence of a decline in self-reported condom use as the study went on. In multivariate analysis, consistent condom use at baseline was found to be highly protective (HR 0.33, 95% CI 0.12-0.91) in both arms.

And, as detailed in the later section on viral load in semen, cervico-vaginal fluid and rectal secretions, it remains unclear as to why some people may occasionally have much higher viral loads in their genital tracts or rectal secretions than in their blood, and how important this is for sexual transmission risk.

In 2013, Anglemyer and colleagues undertook a systematic review to determine if the use of antiretroviral treatment by the HIV-positive partner in serodiscordant couples is associated with a lower risk of HIV transmission to the uninfected partner compared to the uninfected partner in untreated serodiscordant couples.⁶

As well as HPTN 052, which they described as “provid[ing] clear and compelling evidence” for the preventive effect of HIV treatment in HIV-positive individuals with CD4 cell counts between 350-550 cells/mm³, they reviewed nine observational studies in heterosexual serodiscordant couples, published between 1994 and 2012.

For the nine observational studies combined, they estimated a 44% reduction in HIV transmission risk when the HIV-positive partner was on treatment, although there was a great deal of variation between the studies – ranging from a (statistically significant) 92% reduction in risk (Donnell, 2010) to a (non-statistically significant) 44% increase in risk (Lu, 2010).

After excluding two studies with inadequate longitudinal data (Lu, 2010 and Mussico, 1994), they estimated a 64% reduction in HIV transmission risk when the HIV-positive partner was on treatment, although there was still substantial variation between the studies due, in part, to there not being enough information about viral load, condom use, other sexually transmitted infections and the amount and kind of sex couples had within (and outside) their relationships.

However, a further analysis of the preventive effect of treatment restricted to the three studies where the HIV-positive partner began treatment with a CD4 count at or above 350 cells/mm³ found 247 transmissions in untreated couples and 30 in treated couples, resulting in an estimated 88% reduction in HIV transmission risk – ‘real world’ findings that are not dissimilar to HPTN 052’s 96% reduction.

The following cohort studies were included in the review:

Musicco and colleagues (1994) published the first study to find a reduction in sexual HIV transmission risk in heterosexual couples when the HIV-positive partner was on treatment – in this case AZT monotherapy. This Italian study followed 436 monogamous HIV-negative female sexual partners of HIV-positive men over 740 person-years and observed 27 seroconversions, 21 in partners of men who were not receiving AZT monotherapy and 6 in partners of men who were. After adjusting for reported consistent condom use they found a 50% reduction in HIV transmission risk in the female partners of men treated with AZT compared to female partners of the untreated men.⁷

Melo and colleagues (2008) followed 93 heterosexual couples in Brazil over six years, and found that no transmissions in the 41 couples where the HIV-positive partner was on antiretroviral therapy with an undetectable viral load, compared with six transmissions in the couples where the HIV-positive partner was not on therapy.³

Sullivan and colleagues (2009) followed 2993 serodiscordant heterosexual couples in Zambia and Rwanda for a median of 512 days between 2002 and late 2008. However, no viral load testing was done. Of 175 transmissions confirmed (by phylogenetic analysis) to have taken place within the relationship, six transmissions occurred in couples where the HIV-positive partner was on treatment, although two of these took place in the first three months following treatment initiation. Excluding the two transmissions during early treatment, the HIV incidence rate on treatment was calculated to be 0.7 per 100 couple-years, compared to an incidence of 3.4 per 100 couple-years when HIV treatment was not being taken – a fivefold risk reduction.⁸

Del Romero and colleagues (2010) followed 424 serodiscordant heterosexual couples in Spain over 1355 couple-years. Whereas five transmissions were observed in untreated couples over 863 couple-years, no transmissions were observed among treated couples over 492 couple-years, resulting in a reduced risk of 79% when the partner was on treatment.⁴

Donnell and colleagues (2010) reported that antiretroviral treatment reduced the risk of HIV transmission by 92% in the randomised controlled Partners in Prevention trial (designed to examine whether aciclovir treatment of herpes in the HIV-positive partner reduced HIV transmission). This study recruited 3381 serodiscordant couples from seven countries from south and east Africa. The primary endpoint of the study showed that aciclovir treatment had no effect on HIV transmission. However, during the two-year study, 349 people, about 10% of the total, initiated HIV treatment. There were 103 new HIV infections in the study where the source of the HIV was the primary partner, but only one transmission from a partner on antiretroviral treatment. This involved a man who initiated treatment 18 days before his nine-month study visit. At the twelve-month visit his partner tested positive for HIV, having been negative at month nine. No viral load tests were done in this study.⁹

Reynolds and colleagues (2011) followed 250 heterosexual couples in Uganda between 2004 and 2009. They observed 42 seroconversions over 459 person-years of exposure to HIV-positive partners not on treatment, compared with no transmissions to the HIV-negative partners of the 32 HIV-positive partners on treatment during 53.6 person-years. However, couples where the HIV-positive partner was on treatment reported more consistent condom use.⁵

While the above observational studies found a significant protective effect of treatment, the following three studies – two from China and one from Uganda – found either a much less pronounced effect of treatment on transmission risk or no effect at all.

Between January 2003 and December 2011, Jia and colleagues followed 24,057 serodiscordant, predominantly heterosexual, couples where the HIV-positive partner was on treatment and compared them to 14,805 serodiscordant couples where the HIV-positive partner was not on treatment, resulting in 101,295 person-years of follow-up.¹⁰ Among treated couples, the HIV transmission rate was 1.3 per 100 person-years and among the untreated couples the transmission rate was 2.6 per 100 person-years. The investigators calculated that antiretroviral therapy reduced the risk of transmission by just 26%, a significantly lower rate than that seen in the HPTN 052 trial. The study covered a period when sub-optimal antiretroviral treatment was widespread in China, and the authors also note that potential for “treatment non-adherence, resistance and the potential for…non-linked HIV transmission”.

Lu and colleagues analysed data from a prospective cohort study that enrolled 1927 heterosexual couples between January 2006 and December 2008 for testing and treatment in China’s Henan province.¹¹ Approximately 80% of HIV-positive partners were treated with antiretroviral therapy, although no data were available regarding adherence or viral load. New infections were observed in the previously HIV-negative partner in 4.8% of treated couples and 3.2% of untreated couples. However, the authors note the many limitations of this study and highlight other studies from China which have found that a significant number of people on treatment were either non-adherent or on suboptimal regimens.

Birungi and colleagues (2012) followed 586 patients and their long-term partners in rural Uganda for a median of two years. During the study, 238 (41%) of the HIV-positive partners stayed off antiretroviral therapy because they did not meet treatment criteria (which at the time of the study was a CD4 count under 250 cells/mm³ or an AIDS-defining illness), 99 (17%) started treatment and 249 (44%) were already on treatment at enrolment. Ninety-three per cent of those on treatment had viral loads under 1000 copies/ml. During the study, there were 17 new HIV infections: eight in couples where the HIV-positive partner was not on treatment and nine in couples where the HIV-positive partner was on treatment.

Reporting the results at the International AIDS Conference in Washington DC in July 2012, lead author Josephine Birungi said that it was difficult to understand the results of the study. She noted, however, that viral load measurements were taken at least a month or two after infections occurred, and viral load in the transmitting partner may not have reflected the viral load at the time of infection. Other factors, such as undiagnosed STIs or significant under-reporting of extramarital sexual partners may have also impacted the study. "Our results do not question ART working as a prevention tool," she commented, "only that the effect can be undermined by social, biological and cultural factors that can underlie transmission."¹²

Nevertheless, a more recent longitudinal cohort study of married heterosexual couples in Uganda – not included in the Anglemyer and colleagues meta-analysis – provides further evidence of the protective effect of treatment on HIV transmission risk. This study observed 119 new HIV infections in 2334 couples over the course of the study, and 62 infections among the 254 couples that were initially or who became HIV serodiscordant. However, no transmissions were observed in couples where the HIV-positive partner was on antiretroviral therapy. The study also found that the rate of HIV infection between couples declined over time and that transmission likelihood was related to the HIV-positive partner’s viral load, although because widespread ART has only been available in Uganda relatively recently, neither of these findings reached statistical significance.¹³