Hey Dr. Bob,
What's the latest scoop on HIV viral load and the risk od HIV transmission. Was the Swiss Study correct?
The latest scoop? Well it's not so much of a scoop as a bunch of little news nuggets. Taken together all the recent reports continue to suggest that effective combination antiretroviral therapy that drives HIV plasma viral load to undetectable levels significantly decreases the risk of HIV transmission. However, the risk is not nonexistent. One of the issues recently getting more attention is the now confirmed fact that even though the plasma viral load is suppressed to undetectable limits, folks can still have detectable virus in seminal fluid (and presumably anal secretions and vaginal/cervical secretions as well). (See below for a summary of some of the recent findings.)
VIRAL LOAD AND HIV TRANSMISSION RISK
A January 2008 statement by the Swiss Federal AIDS Commission sparked considerable controversy, suggesting that HIV positive individuals on antiretroviral therapy who are fully adherent, maintain an undetectable viral load (below 40 copies/mL) for at least six months, and have no concurrent sexually transmitted infections are "not sexually infectious" (at least via heterosexual vaginal intercourse).
At the Mexico City conference, commission president Pietro Vernazza maintained that under the specific circumstances described, unprotected sex with a person with undetectable viral load carried a risk similar to that of sex using a condom: not 100% safe, but within a "comfortable range." But the risk is not non-existent, given that people on effective therapy may experience occasional transient viral load increases, or "blips," and that HIV may be present in genital and anal secretions even if it is undetectable in the blood.
As described in the July 26, 2008, issue of The Lancet, Australian researchers used a mathematical model to quantify the small transmission risk under the circumstances described in the Swiss statement. Assuming that each couple engaged in 100 sexual acts per year, they calculated the cumulative annual probability of transmission as .22% for female-to-male transmission, .43% for male-to-female transmission, and 4.3% for male-to-male transmission. In a population of 10,000 serodiscordant couples, this would translate to 215 expected instances of female-to-male transmission, 425 instance of male-to-female transmission, and 3,524 instances of male-to-male transmissionabout four times greater than the risk when using condoms.
"Although we agree that effective antiretroviral treatment which leads to undetectable viral load is likely to have a substantial effect on reducing infectiousness," the researchers concluded, "our analyses suggest that it should not replace condoms."
Along similar lines, researchers at the University of Bern set out to conduct a systematic review of medical literature to verify the Swiss statement (AIDS 2008 abstract THAC0505). Looking at more than 200 published articles and 100 abstracts, they found none that exactly mirrored the conditions described in the statement. In the one study that included treated patients with undetectable viral load, no cases of HIV transmission were reported. In four studies of untreated patients with HIV RNA below 400 copies/mL, only one transmission occurred (from an individual with a viral load of 362 copies/mL). No transmissions were identified from individuals with HIV RNA below 40 copies/mL.
At the Retrovirus conference, Steven Reynolds from NIAID presented findings from an analysis of 205 serodiscordant heterosexual couples in Rakai, Uganda (CROI 2009 abstract 52a). Participants were eligible for free antiretroviral therapy if they had a CD4 count below 250 cells/mm3 or advanced immunocompromise according to WHO disease-stage criteria; 12 HIV positive men and eight women started treatment. During 396 person-years (PY) of follow-up prior to treatment initiation, 34 cases of HIV transmission occurred, for an incidence rate of 8.6 per 100 PY. No transmissions occurred during 25 PY of follow-up while the positive partner was on therapy.
In a similar but larger study, Patrick Sullivan and colleagues followed 2,993 serodiscordant heterosexual couples in Kigali, Rwanda, and Lusaka, Zambia, from 2002 to 2008 (CROI 2009 abstract 52bLB). HIV positive partners started antiretroviral therapy when their CD4 count dropped below 200 CD4 cells/mm3 or they developed moderate or advanced disease (again according to WHO criteria). During a median 17 months of follow-up, 175 cases of HIV transmission occurred, 171 from untreated partners (3.4% per 100 PY) and four from treated partners (0.7% per 100 PY). Couples in which the HIV positive partner was on antiretroviral therapy were actually less likely to engage in high-risk sex, leading the researchers to conclude that the reduced risk was likely due to a combination of antiretroviral therapy and reduced risk behaviors.
In additional to mathematical models and epidemiological studies, researchers have also measured HIV shedding in semen as a predictor of potential transmission. In a letter in the September 12, 2008, issue of AIDS, French researchers described a man with persistent HIV RNA shedding into his semen despite his blood viral load being fully suppressed on HAART. The man's initial antiretroviral regimen brought his blood viral load to undetectable within four months (indicating good adherence), but his semen viral load remained unchanged. After a year, he switched drugs to try to reduce HIV shedding in his semen. His blood viral load remained undetectable, but his semen viral load did not begin to decrease until six months later, and did not fall below 400 copies/mL until 11 months after the switchor 22 months after first starting HAART.
In the August 20 issue of AIDS and at the Retrovirus Conference (CROI 2009 abstract 51) another French team reported data from an analysis of paired blood plasma and semen samples from 145 HIV positive men with negative female partners enrolled in an assisted reproduction program that used "sperm washing" to enable conception without putting the woman at risk. They found that 5% of the men had detectable virus in their semen despite being on antiretroviral therapy and having a blood viral load less than 40 copies/mL (conversely, 6% had detectable HIV in their blood but not in their semen). All of these men had some semen samples with undetectable HIV, indicating that levels fluctuated over time and a single test might miss potentially infectious virus.
Similarly, Prameet Sheth reported on a study comparing 25 HIV positive Toronto men who were starting antiretroviral therapy and 13 who had been on suppressive therapy for at least four years (CROI 2009 abstract 50). In all of the newly treated men, plasma HIV RNA became persistently undetectable (below 50 copies/mL) by week 16. While 70% had undetectable semen viral load (below 300 copies/mL) by week 4, some still had detectable HIV RNA in their semen at 24 weeks. Even more (48%) had at least one detectable semen viral load test after starting therapy; 14% of the time HIV RNA was detectable in semen but not blood plasma. Among the men on long-term treatment, about one-third had detectable semen HIV RNA. This was more likely to occur 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 investigators concluded. "Public health messages and policy must be tailored carefully to reflect this reality."
Finally, a study looking at stable male-male couples in which the negative partner was recently infected, genetic testing of viral strains in both partners showed that infectious HIV may be free-floating in the seminal fluid, not just sequestered as cell-associated DNA in infected semen lymphocytes (CROI 2009 abstract 49LB).
Taken together, these findings indicate that while antiretroviral treatment clearly lowers the risk of HIV transmission and may play a role in reducing the scope of the epidemic, it is not a guarantee against infection in individual cases.