This question is just one way that we who live with HIV and those provide medical care and public health interventions express our concern and curiosity about HAART and transmission risk. At the personal level, we wonder if responding well to therapy renders us much less likely to transmit the virus to others should we slip and not use protection when we should have. At the community level, we worry about whether or not overly rosy views about treatment are used by some people, positive or negative, to do away with protection and other harm reduction measures. At the public health level, it would certainly be fortuitous if effective treatment did substantially reduce the number of new HIV infections. Focusing on finding and providing access to effective treatments, for all that is our right and should indeed be a public health goal, would also meet the key prevention goal. Care equals prevention, as well as longer and better lives.

But is it true? Or, since science-in-progress can seldom answer our questions so definitively, what is the state of the evidence? What factors should we take into account in thinking about these issues, planning our personal strategies and our public ones?

Dr. Kenneth Mayer of Brown University (Providence, RI) and the Fenway Community Health Clinic (Boston) gave a thoughtful assessment as a plenary talk at the recent National HIV Prevention Conference in Atlanta. Ken is not only a top-notch researcher, but also a compassionate clinician and leader in the gay community who has worked in AIDS for 20 years.

The Rationale
It is very plausible to consider HAART as a prevention strategy, certainly at the community level, and to believe that it is at least a significant harm reduction measure for a positive person concerned about protecting his/her partners. A number of recently published studies have found that HAART decreases the concentration of HIV in the genital tract, that is, in semen and cervicovaginal fluid. People with decreased genital tract HIV are less likely to transmit HIV.

An oft-cited study of heterosexual serodiscordant couples in Uganda showed that there were almost no cases of transmission to the negative partner over an 18-month period when the positive partner's serum plasma (blood) viral load was under 1500 copies. The risk of transmission increased about two and a half times for every log increase in serum plasma viral load. Positive partners whose initial viral load was over 50,000 were 12 times as likely to transmit HIV to their partners as were positive partners with viral loads under 3500.

This is promising news! However, Dr. Mayer pointed out that we cannot assume that these findings from the Rakai, Uganda study apply directly to the situations of people treated with HAART. Why? For one thing, this was a study of people who were not getting antiretroviral therapy. (The ethics of doing such a study even or especially in a poor country have been widely debated, but I will leave that discussion for another time.) So there may well be other factors that protected the negative partners who remained negative in addition to their partners' lower viral loads. Likewise, there may have been other factors in the positive partners besides viral load that determined whether or not that partner passed on the virus.

Complicating Factors
We know about some of the factors that complicate the relationship between serum viral load and degree of infectiousness. The correlation of HIV viral load in blood and in the genital tract is relatively weak. While we can say there is an overall effect, averaged across people, that HAART reduces genital as well as blood viral load, there is not a one-to-one correspondence. Some individuals have relatively high viral loads in their semen while having relatively low viral loads in their blood, and vice versa. There also seems to be greater variation of the concentration of HIV in the genital tract than in the blood, both from one person to another and within one person at different times.

Also, the evolution of the virus over time in an individual may be different in HIV harbored in the genital tract from that in the blood and lymph nodes, etc. This could be important if those evolutionary changes affect the infectivity of the virus.

Other infections localized to the genital tract may increase the amount of HIV there. For instance, while a herpes infection or flare-up in one's system might generally increase the amount of circulating HIV, a genital herpes infection with many sores (and therefore an increase of T-cells in the area to help fight them) might mean that the increase of HIV in the semen or vaginal fluids is much greater than the increase in the blood.

Then, there is the problem that antiviral drugs vary in their ability to achieve high concentrations in the semen. NRTIs and NNRTIs may (though not in everyone) achieve high concentrations in the semen, especially AZT, 3TC, nevirapine (Viramune) and efavirenz (Sustiva). Protease inhibitors, on the other hand, vary widely. Indinavir (Crixivan) may achieve a relatively higher level while nelfinavir (Viracept), saquinavir (Fortovase) and amprenavir (Agenerase) attain lower levels. Less is known about concentrations and drug penetration into cervicovaginal fluids because it is more difficult to measure those than semen (or they haven't worked hard enough yet to solve the measurement issues!).

Other Important Factors In Transmission
The presence of other STDs in either the positive person or his/her partner increases the likelihood of HIV transmission during unprotected sex, and treating STDs helps reduce that risk. Certain phenotypes of HIV are more frequently transmitted, especially NSI (non syncytium inducing) types. Negative partners also vary considerably in their susceptibility to HIV infection. This has been particularly demonstrated in women where CD4+ receptors on the cervix have been found to be much more dense in some women and much sparser in others. It is plausible that the same goes for the anus and rectum, though this hasn't yet been demonstrated. Variation in other "host factors" in the receptive partner may well also be significant.

Adherence and Access Matters In This As Well as Other Ways
Nonadherence selects for resistant mutants, as we know, meaning that any new infection resulting from a slip may mean the partner starts fighting HIV with a handicap. Unfortunately, "drug holidays" and irregular adherence have been associated with significant rises in genital as well as plasma viral loads.

Lesser access to HAART and high-quality medical care means lesser adherence and lesser benefits to the community as well as lesser benefits to the infected individual.

Sexual Behavior Still Matters Most
As you can see, we do not really have good answers yet to the questions raised above. We can be reasonably confident in asserting that there is some level of benefit to the community in reducing HIV transmission as a result of lower HIV viral loads in large numbers of HIV+ individuals. For many individuals, there is probably some real reduction in transmission risk from a given unprotected contact. The problem is, we have no way as yet of knowing for whom this is true and for whom it is not!

Another consideration is that providers and positive people are tending to defer the beginning of antiretroviral therapy to a stage later in infection than was the norm a few years ago. This means that more and more people, including many very sexually active people, may legitimately make therapy choices that leave their natural viral loads as they are for the time being. Behavior change is the only harm reduction available.

We know that many people are making decisions to relax precautions... and these decisions are not really justified by what we know as of now. For instance, in one community sample in the Midwest, 18% of HIV+ people taking protease inhibitors said they practice safer sex less often since combination therapy came along. A study in West Hollywood in 1999 showed that more than 30% of both positive and negative gay men were using condoms for anal intercourse less often, explicitly because of the belief that medications reduced the risk and/or the consequences of infection.

I believe that we need to counter such thinking with the facts as they stand. Community and peer norms are important factors in determining individual choices. I believe that we have an obligation to establish and maintain norms that strongly promote and reward safer sex choices by positive persons every time we have sex with someone who is HIV-negative or whose status we do not know.

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