HIV Can Remain in Semen despite Effective Antiretroviral Therapy

By Liz Highleyman

Effective antiretroviral therapy (ART) that suppresses HIV in the blood and semen dramatically reduces the risk of transmission. In 2008, the Swiss Federal Commission for HIV/AIDS sparked controversy when they stated that fully adherent HIV positive individuals on antiretroviral therapy who maintain an undetectable viral load for at least 6 months and have no concurrent sexually transmitted diseases (STDs) essentially cannot transmit HIV via sexual contact -- or at least via heterosexual vaginal intercourse.

Some researchers have suggested that universal treatment might be used as a prevention strategy, but this is not a completely reliable strategy since HIV can remain in semen despite undetectable plasma viral load.

Several studies presented at the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) this month in Montreal shed further light on the relationship between HIV treatment and transmission.

Heterosexual Couples in Africa

Two studies looked at HIV transmission risk among heterosexual couples in Africa. Steven Reynolds from the National Institute of Allergy and Infectious Diseases (NIAID) presented findings from Rakai, a rural district in Uganda that produced some of the earliest data that antiretroviral treatment could reduce transmission.

The present analysis included stable serodiscordant heterosexual couples from the Rakai Community Cohort Study. Between 2004 and 2007, 205 serodiscordant couples were identified, and 12 HIV positive men and 8 women started free ART when they had a CD4 count < 250 cells/mm3 or WHO stage IV disease. Participants were followed for 12-18 months on average.

A total of 34 instances of HIV transmission occurred during 396 person-years (PY) of follow-up prior to ART initiation, an incidence rate of 8.6 per 100 PY. In contrast, no transmissions occurred during 25 PY of follow-up while on the positive partner was on ART. Prior to ART, the median viral load was about 44,000 copies/mL. After starting treatment, 79% achieved undetectable HIV viral load (< 40 copies/mL) at 6 months and 95% had at least 1 detectable measurement within the first 18 months.

No significant differences in sexual variables (e.g., number of partners, condom use, circumcision status, STDs) were observed between treated and untreated couples. The researchers concluded that, "ART reduced HIV transmission among discordant couples during the period ART was provided free in this rural treatment cohort."

Patrick Sullivan and colleagues conducted a similar but larger study of 2993 serodiscordant heterosexual couples in Kigali, Rwanda and Lusaka, Zambia followed from 2002 through 2008. HIV positive partners started ART when they had < 200 CD4 cells/mm3 or WHO stage III or IV disease. Negative partners were tested for HIV and received HIV risk reduction counseling every 3 months.

During a median follow-up period of 17 months, 175 new HIV infections occurred -- 171 from untreated partners (3.4% per 100 PY) and 4 from partners on ART(0.7% per 100 PY). Couples with the infected partner on ART were actually less likely to have risky sex (as determined by self-report and testing for semen in vaginal fluid) than untreated couples.

"Reduction in risk of HIV transmission was observed when HIV positive partners were on ART," the researchers concluded, adding that "the reduced risk was likely due to a combination of ART effects and lower risk behaviors." Sullivan noted that the transmission rate was 3-fold to 5-fold lower among couples receiving treatment.

HIV in Semen

Prameet Sheth presented data from a study comparing HIV positive men in Toronto, 25 of whom were just starting ART and 13 of whom had been on effective therapy for at least 4 years and had undetectable (< 50 copies/mL) plasma viral load.

In the newly treated group, plasma viral load became persistently undetectable in all cases by week 16. Most (70%) had undetectable (< 300 copies/mL) semen viral load by week 4, but some still had detectable HIV RNA in their semen at 24 weeks. A higher proportion (48%) had detectable semen viral load on at least 1 test after starting therapy -- usually isolated "blips" -- and 14% of the time HIV RNA was detectable in semen but undetectable in plasma.

Among the men on long-term ART, 31% had detectable semen HIV RNA. This was more likely in men with higher baseline semen viral load. But baseline plasma viral load, CD4 cell count, and herpes simplex virus status did not predict HIV shedding in semen.

"Although effective HAART often eliminated HIV RNA from the semen, isolated HIV semen shedding was common, even after extremely prolonged suppression of blood viral load," the researchers concluded. "Public health messages and policy must be tailored carefully to reflect this reality."

In a related study, Anne-Genevieve Marcelin and colleagues looked at 264 paired plasma and semen samples from 145 HIV positive men participating in an assisted reproduction program at the Pitie-Salpetriere Hospital in Paris that used "sperm washing" to enable conception without putting HIV negative female partners at risk. HIV RNA was measured in seminal fluid after sperm cells were removed by centrifugation.

In 85% of sample pairs, HIV RNA was undetectable in both plasma (< 40 copies/mL) and semen (< 200 copies/mL), while in 3.4% of pairs it was detectable in both. In 8.7% of sample pairs, however, HIV RNA was undetectable in semen despite being detectable in plasma, while in 2.7% of pairs (coming from 4.8% of the men), HIV was detectable in semen but not plasma; in all the latter cases, the men were on stable ART and had fully suppressed plasma HIV RNA for at least 6 months. Here too, detectable semen viral load often occurred as transient "blips."

"These results show that 5% of patients had detectable HIV-1 RNA in semen although they had concomitantly undetectable HIV-1 RNA in blood while they were under HAART," the researchers concluded. "These results should be taken into account in public health messages. Indeed, while effective antiretroviral therapy is likely to substantially reduce HIV transmission at a population level, residual HIV RNA shedding can occur."

Cell-free Virus

Finally, David Butler from the University of California at San Diego presented data showing that HIV may be free-floating in seminal fluid, not only as genetic material in infected semen lymphocytes.

Butler and colleagues studied 4 previously serodiscordant male-male couples in which the negative partner was recently infected. In all 4 cases, the newly infected individual's HIV was closely related to cell-free HIV RNA, but not cell-associated HIV DNA, from the positive partner.

"Recipients' blood HIV RNA sequences clustered completely and with 100% bootstrap support with their respective sources' [cell-free RNA] sequences and separately from [cell-associated DNA] sequences in all cases," they reported.

The investigators also found 6 amino acids "signature" sequences that were associated with transmission, which might provide potential targets for a preventive HIV vaccine.

2/24/09

Reference

S Reynolds, F Makumbi, J Kagaayi, and others. ART Reduced the Rate of Sexual Transmission of HIV among HIV-discordant Couples in Rural Rakai, Uganda. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 52a.

P Sullivan, K Kayitenkore, E Chomba, and others. Reduction of HIV Transmission Risk and High Risk Sex while Prescribed ART: Results from Discordant Couples in Rwanda and Zambia. CROI 2009. Abstract 52bLB.

P Sheth, C Kovacs, K Kemal, and others. Persistent HIV RNA Shedding in Semen despite Effective ART. CROI 2009. Abstract 50.

A-G Marcelin, R Tubiana, S Lambert-Niclot, and others. Detection of HIV-1 RNA in Seminal Plasma Samples from Treated Patients with Undetectable HIV-1 RNA in Blood Plasma. CROI 2009. Abstract 51.

D Butler, M Lakdawala, D Richman, and others. Cell-free Virus in Seminal Plasma is the Origin of Sexually Transmitted HIV among Men Who Have Sex with Men. CROI 2009. Abstract 49LB.