A High-Stakes Game

It seems the best way to be safe: If you are HIV-positive, have sex only with others who are also HIV-positive. But is this true? With reports of an increase in the incidence of drug-resistant strains of HIV among people who are newly diagnosed as well as among HIVers who have never even taken certain medications before'and in the face of the ongoing debate about superinfection'should HIVers feel safe having unprotected sex with other HIVers? It is a question scientists are trying to help people who are HIV-positive fully explore. Right now, though, there is no definitive answer'just a handful of studies and case reports that are undoubtedly sending conflicting messages to men and women trying to determine what is risky and what is not. Reported rates of transmission of drug-resistant strains of HIV vary according to who is being studied and where the studies take place. Even so, experts agree that the number of individuals now being diagnosed with drug resistance'meaning they have a strain of HIV that has mutated in such a way that it will not optimally respond to certain HIV medications'is rising and is of increasing concern. Anita Shet, MD, an infectious diseases physician at the Aaron Diamond AIDS Research Center in New York, has been following trends in the transmission of drug-resistant strains of HIV in New York City. 'In the past,' she says, 'we have seen that drug resistance was not such a big problem.' Ten years ago, she notes, about 13% of newly infected people in New York had a drug-resistant strain. Now, as she reported at this year's Infectious Diseases Society of America annual meeting, 'it has risen to an alarming number': 27%. Why Things Are Changing Rapid reproduction is one of HIV's key characteristics, so mutations, some of which are drug-resistant, occur easily. Superinfection'infection with a second strain of HIV'is possible not only because of these mutations but because of how HIV acts in the body. 'We know that HIV does not give you lasting immunity like other viruses do,' Shet explains. For example, 'with chicken pox, once you get an infection, you are protected. But with HIV, once the virus enters the body, the body begins to makes antibodies to the virus. But that does not protect against another infection.' It is far from clear how common superinfection is. Only a few cases have been thoroughly researched and reported. These include the first superinfection case in Canada'a man who was reinfected 10 months after he had first been infected, which was reported in August'and a report published in September by researchers at the University of California, San Diego, describing three men who had been superinfected six to 12 months after their initial infections. These cases put to rest any question of whether superinfection can occur. Yet alongside these case reports is research such as the Positive Partners Study, led by Robert Grant, MD, an investigator at the Gladstone Institute of Virology and Immunology at the University of California, San Francisco. The ongoing Positive Partners Study regularly tested 33 HIV-positive heterosexual and gay male couples who had unprotected sex and, as Grant reported at the International AIDS conference, held in Bangkok in July, the study did not find any evidence of superinfection [see “Study Finds No Sign of Superinfection,”HIV Plus, November 2004]. Some scientists are now floating the theory that there may be a limited period of time in which someone who has become infected with HIV is susceptible to superinfection. 'Early in infection,' says Dale Hu, MD, MPH, who is acting associate director for laboratory sciences at the Centers for Disease Control and Prevention's National Center for HIV, STD, and TB Prevention, 'the immune system may not have developed a strong enough response to prevent subsequent reinfection, or superinfection.' This theory could help explain why the reported cases of superinfection have occurred only in people infected for less than three years and why the Positive Partners Study, which followed individuals who had been infected for a long time, showed no cases of superinfection. How long such a period might be is not known. As Grant explains, animal studies conducted to explore this question found that a monkey could be superinfected only within the first four weeks after originally being infected. In humans, though, it has been reported that superinfection can occur almost three years after an initial infection. Alternative Theories There may be an explanation for this longer time frame indicated in humans. As Grant notes, the man who was superinfected 30 months after his initial infection was already on medication and may not have been taking his drugs correctly, which could mean that it was not a new virus that was found but actually a mutated form of his original virus. It is also possible, Grant says, that in all these cases in which superinfection was found after the first four months 'the virus was in the body earlier but only later became detectable.' Scientists say a person with a drug-resistant strain of HIV is not more likely than someone with the naturally occurring form'called the 'wild type''to experience superinfection. 'Whether or not a virus is resistant,' Shet says, 'does not reduce or enhance the chance of getting another infection.' In addition, a drug-resistant virus is not more likely than the wild-type virus to cause superinfection. 'Drug-resistant viruses are frequently less fit and less readily transmitted to previously uninfected people,' Grant says. It is possible, however, that superinfection with wild-type virus could cover up an original infection with a drug-resistant strain of HIV. Davey Smith, MD, the lead researcher in the UCSD study, notes that in two of the three patients his study identified as having been superinfected, the first virus the patients had was drug-resistant and the second was wild-type. When this occurs, Smith says, routine drug-resistance testing would find only the wild-type virus. This would mean there would be no indicator that another virus had been present, and it could lead to a person receiving antiretroviral therapy that would not be effective. Fear Factor Smith's scenario could also mean that superinfection is occurring more often than the data indicate, which some scientists suspect. Roger Pomerantz, MD, director of the Center for Human Virology at Jefferson Medical College in Philadelphia, believes that in some instances when a person's medications suddenly stop working it may be because of superinfection. 'Drugs have to stop working for a reason'they do not just stop,' says Pomerantz, whose own research has identified three cases of superinfection. 'It could be that the patient is not taking his drugs or that the patient has begun taking a drug that interacts with the HIV medications.' Another possibility is that 'the patient has been superinfected.' Others are not so sure. 'It is often difficult to ascertain what the causes of viral change are,' Hu says. 'I would be hesitant to assign superinfection as a common cause, since there are more reasons for viral load changes. Having said that, though, I have heard a number of physicians anecdotally report that they think someone might be superinfected because they suddenly have a new resistance profile that was not present before.' So what does this all add up to for HIVers? Some scientists, like Pomerantz, argue that because superinfection could be more common than researchers currently believe'and because there is always the risk of transmitting other diseases such as hepatitis, gonorrhea, and syphilis'people who are HIV-positive should wear condoms all the time, even when having sex with others who are HIV-positive. On the Other Hand Others believe there is quite a bit more leeway in which to evaluate risk. 'I think everyone is best served if we stick to the data,' Grant says. And although the data is limited, 'what we know at this point is that superinfection can occur,' that it may be more likely to occur in people recently infected, and that 'we have not, so far, seen it occur in the context of a coupled partnership,' he says. 'We have to think about what harm may come if we err on the side of caution and publicize widely that superinfection can occur and people should be worried about it,' Grant continues. 'We may make couples who should be focused on making their relationships healthy instead preoccupied with the risk of superinfection.'