SUMMARY: Starting combination antiretroviral therapy (ART) early -- at CD4 cell counts higher than those recommended by global treatment guidelines -- led to a decrease in HIV transmission between serodiscordant (one positive, one negative) heterosexual couples in Africa, researchers reported at the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010) last month in San Francisco. One case of transmission did occur from a treated individual, however, indicating that ART does not eliminate risk.

By Liz Highleyman

It is well known that effective combination ART can suppress HIV to a low or undetectable level in the blood. Blood viral load typically (but not always) correlates with levels in semen and female genital fluids, suggesting that treatment could reduce the risk of sexual transmission.

Mathematical models indicate that widespread early treatment of all people who test HIV positive could dramatically reduce or even eliminate transmission, and there is some early evidence that this may be happening in certain populations; however, it has not been studied in formal clinical trials.

Deborah Donnell reported findings from a sub-study of the Partners in Prevention trial, a large randomized study designed to assess whether treating herpes simplex virus 2 (HSV-2), the usual cause of genital herpes, could reduce HIV transmission. As previously reported, the study found that daily acyclovir did not reduce the likelihood of HIV transmission, even though it was associated with lower plasma HIV viral load and fewer genital ulcers.

Partners in Prevention also included a non-randomized observational component looking at the effect of ART on HIV transmission.

The analysis included more than 3000 serodiscordant heterosexual couples from 7 countries in sub-Saharan Africa (Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, and Zambia). The average ages were 29 for women and 37 for men 37. In about two-thirds of the couples, the woman was HIV positive and the man was initially negative. All HIV positive partners also had HSV-2. At study entry, one-third of participants reported having unprotected sex with their primary partner during the previous month.

The mean baseline CD4 count was about 400 cells/mm3. Trial eligibility criteria required that none of the HIV positive partners have a CD4 cell count low enough to meet national criteria for starting ART (<250 cells/mm3), but they began therapy if their CD4 count fell to that threshold. (When the trial began, global guidelines called for treatment when the CD4 count fell bellow 200 cells/mm3, but this was recently raised to 350 cells/mm3.

Participants were followed for up to 24 months. HIV negative partners received HIV tests every 3 months and HIV positive partners had their CD4 counts measured every 6 months. If a person became infected, their virus was genetically sequenced to ascertain whether it was the same as that of their partner, in order to verify whether transmission occurred within a couple.

Results

	During the study, 349 HIV positive participants (10%) started ART:
	52% with < 200 cells/mm3; 33% with 200-349 cells/mm3; 15% with ? 350 cells/mm3 (about one-third for prevention of mother-to-child HIV transmission).
	A higher proportion of men than women started therapy (12% vs 9%, respectively), at median CD4 counts of 192 and 204 cells/mm3, respectively.
	Reported unprotected sex decreased after an HIV positive partner started ART (from 6.2% to 3.7%), but frequency of sex remained stable.
	151 total new infections occurred, of which 108 were verified as transmissions within a couple; 5 were excluded because it was not known if the partner was on ART or because the HIV positive partner was taking drugs to prevent mother-to-child transmission.
	102 cases of verified HIV transmission occurred from participants not taking ART, for an incidence rate of 2.23 per 100 person-years.
	Only 1 verified transmission occurred from an individual while on ART, for an incidence rate of 0.39 per 100 person-years.
	The relative risk of transmission from a partner on ART compared with no ART (adjusted for CD4 count) was 0.08, or a 92% risk reduction (although the single data point rendered the statistically analysis not very robust).
	For the single HIV transmission after ART initiation, the HIV positive partner had a CD4 count in the 200-350 cells/mm3 range and had initiated ART 18 days prior to their partner's first seropositive test.
	For transmissions from people not on ART, partners with a CD4 count < 200 cells/mm3 were about 5-fold more likely to transmit HIV than those with > 350 cells/mm3:
	< 200 cells/mm3: annual incidence rate 8.79; 200-350 cells/mm3: annual incidence rate 2.79; 350-500 cells/mm3: annual incidence rate 1.70; > 500 cells/mm3: annual incidence rate 1.82.

Based on these findings, the investigators concluded, "This large prospective study demonstrates that ART use is associated with substantially lower risk for HIV transmission among heterosexual, African, HIV serodiscordant couples, where the HIV-infected partner did not meet national criteria for ART initiation at enrollment."

Noting that 1 transmission did occur while on ART, Donnell said that serodiscordant couples should be advised to continue safer sex practices even if the HIV positive partner starts treatment.

Fred Hutchinson Cancer Res Ctr, Seattle, WA; Univ of Nairobi and Kenyatta Natl Hosp, Kenya; Univ of Washington, Seattle, WA; Univ of California, San Francisco, CA.

3/2/10

Reference
D Donnell, J Kiarie, K Thomas, and others. ART and Risk of Heterosexual HIV-1 Transmission in HIV-1 Serodiscordant African Couples: A Multinational Prospective Study. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 136.