Oct 2, 2006
i am dating another hiv poz guy and we are starting to have intercourse. He tells me that we can have unprotected intercourse with out worrying especially if we are not having orgasms inside of each other. Please tell me your thoughts and guidelines. I have only been poz for a year and him for 6 years and we are both on MEds and have undetectable viral loads.
Response from Dr. Frascino
This issue comes up frequently (so to speak). The real worry here is the risk of acquiring a superinfection (another viral strain). We know this does occur, but we are sill uncertain as to how often it happens. There is no doubt that having an undetectable viral load and not ejaculating inside each other decrease the potential risk of HIV transmission; however, it does not completely eliminate the risk. Only you and your partner can decide if this is a risk you are willing to take, considering the risk can be essentially avoided by using condoms. Personally it's a risk I would not take, knowing that infectious virus can be isolated from per-cum. I'll reprint some information from the archives below that may help you decide whether this risk with potentially devastating consequences is one you are willing to accept. My advice: stay safe; stay well.
sex with two pozitoids
Sep 3, 2006
Hi, my boyfirend and myself are both HIV+, we have similar viral load fluctuations, similar low CD4 counts, resistant to the same meds and are on the same meds. Can we have unprotected sex or is there still a risk of super infection?
Cheers, Johnny & Sam.
Sorry, I think I may have said that we have similar low CD4 counts. We have similar high CD4 counts and low v.l.
Cheers, Johnny & Sam (again)
Response from Dr. Frascino
Sorry boys, even with "similar viral load fluctuations, similar low (or high) CD4 counts, resistance . . . ," the risk of superinfection remains a real risk. Recent reports from the International AIDS Conference in Toronto last month suggest the incidence of superinfection (reinfection) may be higher than we had suspected. (See below.) Consequently, this is a risk I personally would not be willing to take. However, like voting for Bush/Cheney, the decision is ultimately up to you. (But remember not voting for Bush/Cheney would have avoided a catastrophic outcome.)
Aug 25, 2006
Dear Robert, Thank you so much for the humor and gusto you build into your answers, it keeps me grounded and reminds me that laughter is just as much part of HIV treatment as is taking my meds and eating well.
I attend a group for positive gay men in Sydney, and have attached the link to the following article from the most recent conference in Canada, that I have posted on our group e-mail discussion board. Cases of HIV Infections With Multiple Strains More Common Than Previously Believed, Researchers Say August 17, 2006 http://www.thebody.com/kaiser/2006/aug17_06/multiple_strains.html?m164h
One of the participants responded by saying:- Thanks for bringing this article to our attention L, however the article quotes findings based on a study in Kenya, which I would imagine does not have the access to HAART that we do. This would mean that the study subjects most likely have a high viral load, therefore making them highly infectious compared to someone here who is on HAART and therefore has a low or hopefully, undetectable viral load.
This article only skims the surface and is very much in the style of 'magazine journalism'.
I would not be too worried personally about this article, as too many factors are unknown and like a number of us said at the last AH, if it where the case, we should have been dead years ago..! Do you know where I can find evidence of the research that this article was based on? I tried following the links they attached but am none the wiser. I am interested to know if his answer will stand up against science or if the continued bare backing that is advocated holds no risk of future damage to his immune system.
L Sydney 25/8/2006
Response from Dr. Frascino
I do not have all the details of this particular study. Often at medical conferences, information is presented in abstract form or in short oral presentations. The details of the study often are not available until the study is published in a peer-reviewed medical journal, which may be a number of months after it was first presented at a conference.
The take-home lesson (and caution) from this study is that dual infections/superinfection may indeed be more common than we had recently suspected. It is certainly true that someone whose viral load is suppressed to undetectable levels on HAART is less infectious than someone with a sky-high viral load; however, that was not the point of this study, nor should it impact the take-home lesson that barebacking is indeed dangerous. Superinfection is real and can have disastrous consequences. Is it worth the risk? Not on your life!
Cases of HIV Infections With Multiple Strains More Common Than Previously Believed, Researchers Say
August 17, 2006
Cases in which an HIV-positive person is infected with more than one strain of the virus are more common than previously believed, Canadian and U.S. scientists said Monday at the XVI International AIDS Conference in Toronto, CanWest News Service/Vancouver Sun reports. Researchers reported that eight so-called "superinfection" cases have been discovered among 57 HIV-positive women in Mombasa, Kenya. According to the study, many of the women contracted a second strain of the virus within one year of their first infection, while other infections occurred up to five years after their first infection. While it is unclear whether the risk of contracting multiple strains of HIV is as likely as being infected for the first time, data are "starting to suggest" that reinfection is a concern, Julie Overbaugh, associate program head at the Fred Hutchinson Cancer Research Center, said, adding that although the study is thought to be the largest of its kind, only 57 women were involved. The findings might be significant for HIV-positive people who seek other HIV-positive people for unprotected sex because they might become infected with a different strain, Overbaugh said. In addition, there also are indications that infection with multiple strains of HIV speeds the progression of the virus, according to CanWest News Service/Sun. As a result, it is important that even partners who are both HIV-positive use safer sex practices to prevent the virus passing between them, according to Bill Cameron, a professor of medicine at the University of Ottawa and the Ottawa Hospital. Related studies among sex workers in South Africa show that people who first test positive for the virus can have two different strains of HIV. "It may be that they got them from one partner, but it looks like they probably got sequentially infected," Overbaugh said. The findings of the superinfection studies might have negative implications for HIV/AIDS vaccine development because current research aims to protect against a "natural HIV infection," not a superinfection, according to CanWest News Service/Vancouver Sun. With multiple strains of the virus, it not only could be mutating but also combining with other forms of the virus to produce a strain "that looks different from either one," Cameron said (Kirkey, CanWest News Service/Vancouver Sun, 8/15).
Reinfection - Concern? Risk?
Aug 30, 2006
I'm 34, Viral load under 5,000, CD4 Cells over 800, Poz 3 years. Still not taking any meds at my MD's direction. My partner, 41, Undetectable, CD4 cells >500, Poz 21 years. I would like an honest third party answer. How much risk do we pose to each other when not practicing safer sex, and ejaculating inside of each other? His doctor is telling him it is wrong never do it again. My doctor says the risk is very low; do not make it a habit. What is your opinion on this? Neither of us wants to put each other at risk of re-infection. To be honest, I never hear of re-infection until he brought it up with me. We both have buried a lover and do not want to do that again by having been careless and re-infecting each other with a strain that could both of us harm. What should we do? Papito & Papi Chulo, Fort Lauderdale
Response from Dr. Frascino
Hello Papito and Papi Chulo,
Dual infection (reinfection/superinfection) is indeed a real phenomenon, although there is still considerable debate over how often this actually occurs. I'll reprint some information from the archives below.
Even if the incidence turns out to be relatively low, personally it's a risk I would not choose to take.
Stay safe to stay well.
HIV + Couple (POZ with POZ)
Jul 29, 2006
My partner and I have been together for 7 years and are monogomous. I got HIV from him and he began treatment 6 months ago. I'll start in about another year. I want to know the risks of unprotected sex. Condoms are painful to me so thats why we rarely use them. Since our diagnosis he has not ejaculated in me, or vice versa. But we do have unprotected sex. Also, he likes for me to ejaculate in his mouth. I have read there is no conclusive evidence that the same strain of HIV can mutate. What are the risks that we can make things worse for ourselves? We have no other STD's and are strictly monogomous. Thanks!
Response from Dr. Frascino
Condoms are painful???? Hmmm . . . . They can be inconvenient, but they really shouldn't be painful. If they feel too tight for that beer-can-sized trouser snake of yours, then maybe you were using the Dick Cheney teeny weenie sized variety. Try Trojan Magnums; then even fit Italians!
To address your specific question, I am not aware of any information that would suggest the same strain of HIV in two different people would not mutate. Also, since your partner began HAART six months ago and you did not, he now has additional pressure on his virus, which could lead to resistance (mutation). Turning this logic in the other direction, your partner's viral replication could be suppressed to undetectable levels by his HAART, thereby decreasing the chance his virus may spontaneously mutate. Conversely, you, not being on HAART, would more likely have a higher (unsuppressed) rate of viral replication, thereby increasing the chances of a spontaneous mutation. As you can see, this is a complex issue with many variables, not the least of which is that you and your partner have unique immune systems, which may mount very different responses to the same viral challenge.
That said, I will give you one piece of somewhat potentially encouraging news. Overall, the incidence of true superinfection remains low. New information suggests that superinfection, when it does occur, tends to do so during the first year or two after infection. This may be due to the fact that those of us who are chronically infected, i.e. have had HIV for a number of years, have stronger and broader antibody responses against HIV and can therefore ward off other strains.
There is also the complex question of separating out "dual infection" (contracting a second viral strain at the very beginning of HIV, before the immune response has kicked in) and "superinfection" (contracting a second virus after the immune system has responded fully to the first viral strain). I'll post several questions from the archives that address the issue of superinfection.
Finally, don't forget to try the larger size condoms for comfort, OK Big Guy?
POZ with POZ
Jul 18, 2006
I am a healthy POZ sexually active gay man, generally a bottom. I have always been of the opinion that condoms are a good idea, period. They reduce the chance of more than just HIV. But lately I have frequently heard POZ guys saying that they bareback with other POZ guys because everyone is getting treated and doing so well.
Comment please .
Response from Dr. Frascino
Hello Poz Guy,
I agree with your rational and would extend it somewhat. Condoms protect against a host of nasty STDs, many of which are on the upswing among men having sex with men. An active STD can indirectly cause your HIV viral load to skyrocket. As viral replication goes up, so does the chance that the virus may mutate into a form that may be resistant to one or more of the medications in your current regimen.
Next, the possibility of a dual infection or superinfection is real. Although, we do not know how often this actually occurs, we do know that it can occur. Is that a risk you're willing to take? It's one I certainly would not. I'll repost a few questions from the archives that give further details on this topic.
Stay safe. Stay well. Be here for the cure.
superinfection with low viral load Jun 5, 2006
What are the latest findings on superinfection? My boyfriend and I are both positive with undetectable viral loads and hight t cell counts. We were wondering if our meds reduce the risk of reinfecting eachother while barebacking.
Response from Dr. Frascino
While it is true that having a nondetectable viral load decreases the risk of transmitting HIV, the question remains whether it decreases it enough that you don't have to worry. Unfortunately we don't know the answer to that. Superinfection is real. It can occur. Exactly how often and under what circumstances we are still finding out. What you have to decide is if you are willing to take that risk. Personally, I would not be.
I'll reprint a few posts from the archives that address this topic. Stay well!
Is safe sex necessary if both partners are + Dec 28, 2005 My husband and I are both positive and I was infected by him. Our Dr. says we must have safe sex or we can make each other sick. Is this true? It seams weird. Also I saw people were having trouble getting insurance after that were diagnosed +. I work for Anthem and they cover pre-exhisting conditions like HIV. I had no problem adding my husband to my policy, even thought he had been positive for over 6 years.
Response from Dr. Frascino:
Your doctor is cautioning you against the possibility of superinfection or reinfection. Even if you were initially infected by the same strain of HIV, the virus can evolve differently in each person. Consequently, over time your virus may be quite different from your husband's. I'll post several articles and a question from the archives that address this topic. I hope you'll consider this information carefully. Stay well.
How safe does HIV+ couple have to be? Aug 26, 2004
You inspire and console many, and are appreciated by the positives and negatives in this fight.
Ok, here is my question, I have been dating another HIV+ man for over a year and we have entered a committed relationship. We are both in our 50's and look forward to a great long life together. Both of us are on a drug regiment and have undetectable viral loads. We both have a good T-cell count and both of us are very healthy. If we live in a committed and monogamous lifestyle, how dangerous would un-protected sex be if we both have the HIV virus already, and are both compliant on our drug regiments?
We are very happy with our current safe sex practices, but are curious what you would say to this question.
P.S. Our doctors are evasive, first telling us about the risks of super infection, but then eluding to the fact that it would be unlikely.
Thanks! Curious in Boston
Response from Dr. Frascino
Hello Curious Boston Boys,
Actually your doctors are right on target. There is indeed a risk of superinfection. Cases of superinfection have now been well documented. The question of how often it occurs remains unanswered. That might explain your doctor's seemingly "evasive" comments. In reality we don't have a lot of information about the frequency of HIV super-infection because it's not all that easy to document without rather extensive and costly analysis. Certainly the major concern is the acquisition of a more virulent (aggressive) strain of HIV, or one that is resistant to some of the drugs in your current regimen.
As two consenting adults, only you and your partner can decide if you are willing to take this risk. You mention you are "very happy with your current safe sex practices." All I can do is advise you that the risk of superinfection is real, very significant, and potentially devastating. Even though the chance of HIV transmission is decreased by having undetectable viral loads, HIV superinfection is not a risk I would not be willing to take personally. Good luck, Boys. There may be some more information on this topic presented at an HIV/AIDS medical meeting in your hometown scheduled for February 2005. Stay posted to this site and I'll keep you posted as well!
Re-Infection: Is It a Concern for People Living With HIV? May 2004
Re-infection is a term used to describe a new or secondary infection by a virus that has already infected a person. In most viral diseases, re-infection with the same virus doesn't occur because once the immune system conquers the original viral infection, it creates immunity against that virus. Re-infection occurs almost constantly, however, in some types of infection, such as the cold or flu viruses, because each new version of those new viruses is substantially different from the last. This is why a person may develop immunity to the flu strain that is common in one year, but still be at risk from the strain that becomes dominant the next year.
The question of re-infection with HIV has long been debated. There is no theoretical reason to think re-infection isn't possible, since the immune system never fully conquers the initial HIV infection. Still, many people, including many physicians, clung to the hope that re-infection with HIV either does not happen or that it only happens rarely. This view is the basis of the belief held by some HIV-positive people that having sex or sharing needles with another HIV-infected person poses little or no risks. Many if not most virologists, however, have long believed that re-infection is both possible and perhaps even likely. What is not known are the individual short- and long-term clinical consequences (which may vary from person to person for wholly unknown reasons). For many years, there were no clear cases of re-infection presented at scientific conferences, but this did not mean such re-infection wasn't occurring. Instead, we know that finding and documenting cases of re-infection is extraordinarily difficult, if for no other reason than that no structured program has looked for them. Finding a case of re-infection has largely been a matter of chance. Yet, several observations over the years support the notion that re-infection is possible, including observations of sex workers in Africa infected with several different recombined "clades" of HIV as well as detailed genetic analysis of a few people's virus suggesting that re-infection was possible. This research is very difficult to conduct. Perhaps the only simple example of re-infection is in western Africa, where people are routinely found who carry both HIV-1 and HIV-2. At the very least, this proves that having HIV-1 does not protect a person from infection with HIV-2. Recently, there has been considerable media attention about a few well documented cases of suspected re-infection with two versions of HIV-1. The most interesting case, presented by Dr. Bruce Walker, was the result of an almost accidental observation. While researching the effects of Structured Treatment Interruption (STI) in some newly infected volunteers, Walker's team was intrigued by one particular case in which the volunteer responded well to two initial cycles of STI. After each, the person's viral load remained undetectable for several months without treatment. Shortly after a third STI, however, the viral load remained low for only a brief period and then suddenly soared upward. The team wondered what made things different this time? After conducting extensive genetic analysis, they found their answer: the volunteer had become infected with a second, slightly different strain of HIV. Most striking, and discouraging, was that the genetic makeup of the new infection differed by only 12% compared to the original infection. Despite this small difference, the second infection had completely escaped control by the immune system, breaking through the suppression achieved against the original virus. This discovery, while important enough in regards to re-infection, also had discouraging implications for vaccine development, suggesting that as little as 12% variation between viruses might be enough to make a vaccine fail.
Several questions remain in regards to re-infection. Will re-infection lead to more rapid disease progression? Will re-infection with HIV result in transmission/acquisition of drug-resistant HIV that will limit a persons' anti-HIV treatment options? Both of these concerns are theoretically possible, and both have now been demonstrated in case studies. Currently there is not a large amount of data to assess the actual risk to the individual. Although only a little data currently exists and it is extremely difficult to gather more, it does not lessen the real potential for re-infection or its consequences.
There are several reasons why people living with HIV would want to maintain safer sex activities. While the clinical implications of re-infection remain unknown (and will likely be unknown for many years to come), there is some evidence of harm and no evidence of harmlessness. We also know for certain that safer sex does protect against many blood-borne infections that are major causes of life-threatening diseases and death in people with HIV. These likely include CMV, some forms of hepatitis virus, genital herpes, possibly the JC virus (cause of a particularly destructive condition known as Pml), to name a few.
Ultimately people living with HIV need to consider this information and make informed decisions about safer sex for themselves. In the early 1980s many did not want to believe that HIV was caused by unsafe sex. Many people have dearly paid the price for that belief. The optimal outcome here is for people not to fight against data and shy away from acknowledging the potential consequences of re-infection. Some people will come to a conclusion that it's better to be safe than sorry. Others will choose the risk of being sorry rather than safe and will continue to participate in unsafe sex with positive partners. What matters most is that people make a conscious decision based on the available information.
HIV Superinfection 5% in Newly Infected Gay Men
Coverage provided by Keith Henry, M.D. February 9, 2004
Dr. Smith and colleagues presented their experience looking for cases of HIV superinfection in the cohort of HIV-positive patients that they followed after identification of primary infection. The topic of superinfection is important for several reasons. First, it provides important insight into protective anti-HIV immunity. The issue is whether the innate anti-HIV immunity that evolves in an infected person can prevent infection with a second strain of HIV. That is important clinically since a few anecdotal reports have suggested that superinfection can lead to more rapid deterioration of a patient's immune status. It is also important from the public health perspective with implications for the potential efficacy of a vaccine to prevent infection.
Co-infection describes when someone is initially infected with two strains, while with superinfection a patient is infected with one strain and then with another strain. Superinfection has been observed in some chimpanzee models and has been inferred from recombination analysis but is still a rarely documented clinical event.
Smith reported the results of a retrospective analysis of trials of primary infection in a cohort of 78 men who have sex with men (MSM) during their first six months living with HIV infection. These men were not yet on antiretroviral therapy. Samples of virus underwent pol gene sequencing and if isolates didn't cluster then env sequencing was done.
Three cases of possible superinfection with another type B virus were identified and then confirmed by clonal sequencing of env and pol sequences. All three men had a change in the reverse transcriptase sequence that could impact drug sensitivity. When those three patients were evaluated six months after acquiring the second strain, a negative impact on the CD4 count and RNA level was seen.
The 5% rate of superinfection is about the same rate as at risk infection initial infection in high-risk populations in the U.S. The interpretation was that there was no protection afforded by the initial HIV infection against superinfection. Dr. Smith said that the lab approach may underestimate the true rate of superinfection due to sensitivity issues with the assays used. It seems to me that a group of MSM with fairly recent HIV infection may represent a group with a higher than average risk for acquiring additional HIV so that extrapolation to the general MSM population may overestimate the overall risk. Whatever the actual rate is, these data add to the literature about superinfection and support enhanced emphasis on harm reduction counseling. A question from the audience highlighted that of the three cases reported, two had been previously reported in other reports. Clearly the topic is of interest and more studies looking at the rate and impact of superinfection are needed.
barebacking risks Mar 19, 2006
Thanks for your response to my questions regarding barebacking. I looked up the BETA articles you suggested and I want to tell you, even though I know a lot about HIV and HIV transmission, I certainly learned a mountain of new information in these articles. I was, impressed with the details on safer sex as it relates to the various forms of sexual activities. But, I was most surprised to learn that there have been virtually no known cases of HIV dual infection in any HIV+ individual who has been positive for more than three years. That would explain why barebacking has not truned out to be the horror clinicians initially thought it would be. In my experience, the overwhelming number of barebackers out there seem to be long-term positives and probably positive for three or more years. Yes, STDs are still a risk. And, certainly, any responsible barebacker (if that is not an oxymoron) should stay away from partners who are newly infected. I also understand that this phenomenom of no coinfections after three years) is a source of great interest to scientists in finding a vaccine for HIV. I hope you will print this and suggest that everyone out there do their own research, as well. Keep up the good work.
Response from Dr. Frascino:
Yes, I agree BETA did a fine job with their article, which is why I gave you the whole reference rather than just trying to summarize the key points. I'll reprint it below for those readers who may have had difficulty downloading the reference. Stay well. Stay informed.
Dual HIV Infection
A number of individuals infected with more than one strain of HIV have been identified over the past few years. Should people already diagnosed with HIV be concerned? Given the limited number of cases seen so far, the risk of multiple infections (also called dual infection) appears to be quite low. And there are many more pressing health concerns facing people living with HIV/AIDS. Nevertheless, two trends are worth noting: dual infection seems more likely to happen under certain conditions, and it is associated with faster progression to AIDS-related events. This article describes current evidence and theories behind this emerging phenomenon. Coinfection, or infection with more than one viral strain at or near the same time, is believed to occur around the time of initial infection. (Initial infection is also known as acute or primary infectionthe period before seroconversion that usually lasts from a few weeks to a few months.) Reinfection with a different strain, also known as superinfection or serial infection, presumably takes place later on during early infection (the first few years of HIV disease, after seroconversion) or chronic (long-term) infection. Researchers make a distinction between two types of dual, or multiple, HIV infection: Gathering Evidence Experts once hoped that a single HIV infection would prevent further infections, much like a vaccination. In the mid-1990s, however, studies using analogous viruses in primates showed that sequential infections were possible. Some people believed it was only a matter of time before something similar would be seen in humans. Compelling evidence of dual HIV infection in humans appeared in 2002. A report in the Journal of Virology in August of that year strongly suggested reinfection in two injection drug users (IDUs) from Thailand (one female, one male). The woman was initially diagnosed with HIV subtype AE only, followed by detection of subtype B approximately two months later. The man was apparently reinfected with subtype AE virus approximately six to ten months after his primary diagnosis with subtype B virus. Neither individual was being treated for HIV during the study period. In the September 5, 2002 issue of the New England Journal of Medicine, researchers from the University of Geneva reported on a man initially diagnosed with subtype AE virus in November 1998 whose viral load became undetectable (below 50 copies/mL) with antiretroviral therapy. He stopped treatment in January 2001 and shortly thereafter traveled to In theory, any apparent case of reinfection could be a case of coinfection in which one of the coinfecting strains remains undetectable until it emerges sometime after seroconversion (the point at which HIV antibodies can be detected and a person can be diagnosed as being HIV positive). This is sometimes called sequentially expressed coinfection. Testing limitations that prevent detection of very small viral populations in the body make it difficult to distinguish between coinfection and reinfection. Researchers believe that until a source partner for dual infection is found and the timing of exposure confirmed, it is not possible to determine that the second virus was acquired after seroconversion. While finding source partners is a continual problem, determining the timing of exposure is aided in some cases by the emergence of acute retroviral syndrome (often flu-like symptoms, including fever and fatigue) in the person presumed to be reinfected. It is not known whether overgrowth of a previously dormant coinfecting strain might also trigger acute retroviral syndrome. COINFECTION AND REINFECTION WINTER 2006 BETA 37 Brazil, where he had multiple unprotected sexual contacts. In April 2001, three weeks after his return from South America, his viral load spiked to 400,000 copies/mL and he reported symptoms of acute retroviral syndrome, which can signal a new HIV infection. Lab tests subsequently detected a second strain of HIV subtype B, which is common in Brazil. The researchers concluded that reinfection had occurred. More recently, Davey Smith, MD, of the University of California at San Diego and colleagues reported in the August 12, 2005 issue of AIDS that a man with wild-type (drug-sensitive) subtype B virus was apparently reinfected about a year after his first infection with a different subtype B virus resistant to protease inhibitors, which he had never taken, and 3TC (lamivudine, Epivir), which he started only after the second infection. Another case of dual infection with two subtype B viruses with discordant drug sensitivity was reported by the same research group in 2003. In that case, however, the subject was first diagnosed with drug-resistant subtype B virus and then found to have wildtype HIV of the same subtype four months later. Like the man in the 2005 report, this individual had not taken antiretroviral therapy before the apparent reinfection event. Other cases of multiple HIV infection have been identified in the past four years, although the total number remains smallonly 16 apparent reinfections by one measure (a 2005 Medscape survey of the scientific literature done by a group from the Gladstone Institute of Virology and Immunology in San Francisco). The Gladstone researchers, however, did not consider cases of coinfection. In addition, dual infection rates may be higher than reported, since few people with HIV have been tested for multiple strains. Only larger future studies using more sophisticated technologies and better tracking of source partners can provide a clearer picture of the incidence (rate of new cases) and prevalence (total number of existing cases) of coinfection and reinfection in a given population. Impact on Disease Progression Dual infection in humans has been linked to disturbances in immune control and poorer prognosis. In the case of the man who traveled to Brazil, the emergence of his subtype B virus while off therapy coincided with a loss of 300 CD4 cells/mm3 and a dramatic rebound in viral load before he resumed highly active antiretroviral therapy (HAART) four months later. HIV Recombination Different varieties, or strains, of HIV are grouped in a hierarchy. At the broadest level are the two types of HIV: HIV-1 (most prevalent worldwide) and HIV-2 (rare except in West Africa). HIV-1 is divided into three groups:M (major), N (new), and O (outlier). Group M is by far the most common of the three, and is itself subdivided into different clades or subtypes: AD, F, G, H, J, and K. Different subtypes can infect a cell and create hybrid or recombinant forms, such as AC (or A/C). Circulating recombinant forms, or CRFs, are genetically mixed subtypes (such as CRF02_AG) that are found in more than one person. Types HIV-1 HIV-2 | Groups M N O | Subtypes A B C D [E]* F G H J K (Clades) | recombinant forms and CRFs * E does not exist on its own, although it appears in certain CRFs Most recombination events seen thus far are between different subtypes. But infection with two genetically distinct viruses of the same subtypefor example, two subtype B virusesis also possible. The potential for recombination among these is unknown. At the same time, science has yet to reveal what might result from viral mixing among different HIV groups or types. But research opportunities might come soon. At the 2005 Retrovirus conference, a French team claimed to have detected the first reinfection of a group O-infected woman with a virus from group M. Almost more remarkably, the research group located the source of her second infection, the gold standard for confirming secondary infection that has eluded other investigators. While it is generally believed that dual infection must occur for a recombinant virus to be formed, an unusual case of viral recombination in a singly infected woman was reported at the 3rd IAS conference this past July. B. Weiser of the New York State Department of Health and colleagues found that this individual's drug-sensitive HIV evolved differently in her plasma and genital tract after starting HAART and recombined into a multidrug-resistant strain within six months. Viral recombination might play a significant role in accelerating HIV disease (see sidebar on page 37). Recombination increases viral diversity more rapidly than mutations that evolve slowly through replication errors. Recombinant viruses may be less sensitive to anti-HIV drugs and are potentially more virulent than nonrecombinant viruses. This might result from altered tropismspecifically, the virus' ability to use the CXCR4 coreceptor to enter cells, as was the case in the New York man; CXCR4-using viruses are associated with worse disease outcomes than viruses that use the CCR5 coreceptor. Genetically mixed viruses might also be more adept at evading immune responses in a type of evolutionary strategy. At the 3rd International AIDS Society (IAS) conference this past July, Carolyn Williamson, PhD, from the University of Cape Town and colleagues reported finding recombinant virus in six of six dually infected subjects, along with evidence of viral evasion of cellular immune defenses and neutralizing antibodies. The South African team proposed that dual infection "enables recombination to contribute significantly to viral adaptation to immune responses...and may help explain rapid disease progression." Alternatively, the link between dual infection and disease progression might be a product of individual characteristics. Gottlieb has speculated about whether certain people who are inherently predisposed to faster disease progression may also be more susceptible to reinfection. His team noted in their 2004 report, for example, that the one subject believed to be reinfected "had rapid CD4 decline immediately after initial infection, suggesting a host susceptibility to infection with a second virus." Susceptibility and Protection As to when reinfection might occur, data collected so far show an interesting trend. Researchers at the Gladstone Institute pointed out in In a report from 2004, Smith and colleagues analyzed the two dual infection cases mentioned above plus a third man with apparent secondary infection (wild-type followed by drugresistant virus). Among the three men, CD4 cell counts dropped an average of 132 cells/mm3 within six months of acquiring the second strain, while viral load levels increased an average of 1.6 logsa 40-fold increase. Geoffrey Gottlieb, MD, of the University of Washington in Seattle and colleagues retrospectively located five individuals with dual infection (four U.S. gay men, one female sex worker from South Africa). Four were coinfected near the time of seroconversion, while the other was reinfected 1.3 years after initial infection. All five had rapid disease progression: from seroconversion to below 200 CD4 cells/mm3 within 3.1 years on average, and to an AIDS diagnosis or death within 3.4 years. Time from seroconversion to AIDS typically takes 810 years in untreated individuals. In a letter to The Lancet in June 2005, Gottlieb proposed that the case of unusually rapid HIV disease progression in a New York City man described by local health officials in February 2005 might also be due to dual infection rather than the emergence of a so-called "supervirus" (see "News Briefs" on page 4). Several factors might explain an association between dual infection and a surge in HIV disease progression. For now, these are hypothetical and could be related to viral dynamics and the way the second virus attacks the immune system or evades immune responses. Acquiring a drug-resistant viral strain, for instance, would increase the likelihood of losing a response to antiretroviral therapy. This was seen in Smith's 2005 report as well as others. For those not on treatment, overwhelming a drug-resistant virus (considered less able to replicate) with a new wild-type virus (considered more virulent) could result in a higher viral load and speed progression of disease. 38 BETA WINTER 2006 their survey of the literature that multiple infections have not been reported in anyone beyond three years after his or her first infection. (Only a female sex worker from Kenya with recombinant AC virus might have been reinfected after three years, but the exact date is unknown due to a nine-year gap in blood sampling.) This observation has been borne out in recent studies in which dual infection was not observed in chronically infected individuals, even among IDUs who consistently shared needles and HIV positive individuals who had partners with different strains and high risk of re-exposure. While this trend may be an inaccurate observation based on coincidence or testing errors, it has also been seen in primates. A study done in the late 1990s by Ron Otten, PhD, and colleagues from the Centers for Disease Control and Prevention (CDC) showed that macaque monkeys could be infected with two strains of HIV-2 up to four weeks after a first infection, but not between eight and 72 weeks afterwards. Humans might have a similar window of susceptibility to reinfection of approximately three years. The lack of evidence for dual infection during chronic (long-term) HIV disease suggests a protective mechanism at work, such as immune responses that evolve over time or "viral interference"the ability of the original virus to ward off acquisition of another. Any protective role played by anti-HIV therapy in chronic infection would appear to be negligible, since multiple infections have not been reported in untreated chronically infected people after three years. Dual infection therefore seems to occur only during acute or early infection and in these cases, anti-HIV therapy might well make a difference. Evidence suggests that multiple infections happen only in people with acute or early infection who are not being treated or only intermittently treated with anti-HIV drugs. This implies that antiretroviral therapy has WINTER 2006 BETA 39 given the small number of cases? Should people with early HIV disease be counseled to start treatment to avoid reinfection, even if their virus is under control? What impact will reinfection have on HIV positive individuals who "serosort," or choose to have sex only with other positive people? Will those with chronic infection feel freer to have unprotected sex despite the risk of acquiring other sexually transmitted infections (STIs)? As always, the best guide to risk management is reliable information. The Gladstone researchers wisely counsel that "clinicians and researchers should provide balanced and broad views of the risks of unprotected sex between HIV-1 infected persons, and avoid exaggerated or sensational claims about superinfection that could undermine behaviors such as serosorting and serodisclosure that can help to curtail the spread of HIV." Beliefs about multiple infections can affect behavior. In interviews with 193 HIV positive men who have sex with men (33% Latino, 29% African American), researchers from the San Francisco Department of Public Health reported in 2003 that the 83% who believed reinfection was damaging to health were significantly less likely to report unprotected anal sex with an HIV positive partner or any partner compared with those who did not share this belief. Vaccine Design Recent dual infection news has been sobering for vaccine researchers, who study the mechanisms the immune system uses to control pathogens (disease-causing organisms) and work to develop agents that will elicit the same immune responses. The specific protective mechanisms, or "correlates of protection," necessary to subdue HIV are unknown, which has been a major obstacle in HIV vaccine research since the beginning of the epidemic. The task is now made more difficult by the knowledge that the immune system cannot reliably prevent reinfection a protective effect, at least during early HIV disease, either in blocking secondary infections or in preventing certain coinfecting strains from asserting themselves. Antiretroviral agents used as pre-exposure prophylaxis (PREP), taken before a high-risk incident, might work in a similar way to block a first infection. However, using anti-HIV agents as PREP remains experimental and unproven. Although continuous antiretroviral therapy (during early disease) and chronic infection (regardless of treatment) each appear to provide protection against dual infection, more research is needed to understand and confirm these observations. Studies are likewise needed to identify any individual characteristics that might make some people more prone to acquiring a second virus. These factors are currently unknown, although cases such as the one described by Gottlieb in 2004 point to the possibility. Managing Dual Infection The appearance of genetically distinct viruses within an individual complicates the management of HIV disease. Because multiple infections often lead to signs of accelerated disease progression, the typical clinical response has been to begin or resume anti-HIV treatment. Some people among the recently documented cases have controlled their secondary infection with standard antiretroviral therapy. Others, even if responding well to a first regimen before reinfection, have required salvage or rescue regimens containing four or more drugs. Resistance tests may help guide clinicians in their choice of therapy. Newer drugs and drug classes might likewise improve the chances of treatment success, especially in cases of secondary infection with a drugresistant virus. The current understanding of dual infection raises complex questions for people with HIV, clinicians, and prevention workers alike. What approach, if any, should be taken even when responding vigorously to an initial infection. At the 2003 Retrovirus conference, for example, Todd Allen, PhD, of Massachusetts General Hospital and colleagues reported that a robust and specific immune response to one HIV subtype (B) did not inhibit reinfection with another. The fact that virus-specific immune responses are unable to stop other invading viruseseven those of the same subtype, as seen in the cases reported by Smith's groupsuggests that priming the immune system with a vaccine to control one viral subtype will not be sufficient, and that designing a vaccine broadly protective against a range of HIV strains might be impossible. Still, with the added challenge comes a silver lining: the apparent protection afforded by chronic infection, antiretroviral drugs, or individual characteristics. Figuring out how these or other factors allow the immune system to prevent dual infection could be a significant breakthrough and may help guide researchers toward their elusive goal. Given the moribund state of HIV vaccine development, no time should be wasted in exploring this possibility. Conclusion What little is known about dual infection has been sketched from a handful of case reports. Uncertainty will prevail until scientists resolve the issue of whether reinfection occurs independently of coinfection. If all dual infections are in fact coinfections acquired at or near the same time, there would theoretically be no risk of later being reinfected with a second strain of HIV. Studies would then focus on why, when, and in whom coinfection takes place, as well as why some coinfecting HIV strains emerge virulently and only during early infection. If, however, reinfection is a distinct phenomenon, researchers will need to determine precisely what conditions are necessary for multiple infections to occur, who might be 40 BETA WINTER 2006 more susceptible to them, and what are the clinical implications. Only a fuller understanding of dual infection can help people with HIV make informed decisions about risk. (For information about the Positive Partners study, which looks at whether reinfection occurs between sexual partners, see "Open Clinical Trials" on page 54.) And, with luck, investigating the dynamics of multiple infections might lead to the ultimate protection: an HIV vaccine. Nicholas Cheonis is the former editor of BETA. Selected Sources Allen, T.M. and others. HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus. 10th Conference on Retroviruses and Opportunistic Infections (CROI). Boston. February 1014, 2003. Abstract 307. Blackard, J.T. and others. Human immunodeficiency virus superinfection and recombination: current state of knowledge and potential clinical consequences. Clinical Infectious Diseases 34(8): 11081114. April 15, 2002. Gottlieb, G.S. and others. Dual HIV-1 infection associated with rapid disease progression. The Lancet 363(9409): 619622. February 21, 2004. Jost, S. and others. A patient with HIV-1 superinfection. New England Journal of Medicine 347(10): 731736. September 5, 2002. Marcus, J.L. and others. HIV superinfection vs dual initial infection: what clinicians and patients should know. Medscape 11(1). 2005. Accessed November 4, 2005. Otten, R.A. and others. Identification of a window period for susceptibility to dual infection with two distinct human immunodeficiency virus type 2 isolates in a Macaca nemestrina (pig-tailed macaque) model. Journal of Infectious Diseases 180(3): 673684. September 1999. Plantier, J.C. and others. HIV-1 group M superinfection in a HIV-1 group O-infected patient. 12th CROI. Abstract 288. Ramos, A. Intersubtype human immunodeficiency virus type 1 superinfection following seroconversion to primary infection in two injection drug users. Journal of Virology 76(15): 74447452. August 2002. Smith, D.M. and others. HIV drug resistance acquired through superinfection. AIDS 19(12): 12511256. August 12, 2005. Weiser, B. and others. Multidrug resistant HIV-1 resulting from intrapatient viral recombination. 3rd International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment. Rio de Janeiro. July 2427, 2005. Abstract MoFo0306. Williamson, C. and others. Lower rates of adaptive evolution in HIV-1 dual infections compared to single infections. 3rd IAS Conference. Abstract MoFo0305.
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