Recent reports have documented increases in unprotected intercourse (UI) and sexually transmitted diseases (STDs) among men who have sex with men (MSM) and other at-risk populations. A further consequence of persons living with HIV engaging in unprotected intercourse or shared parenteral exposures with seroconcordant partners is HIV recombination and superinfection, possibly with a drug-resistant or more pathogenic virus. The epidemiologic, clinical, and therapeutic implications of recent case reports confirming superinfection in persons living with HIV, as well as research priorities aimed at providing a more thorough understanding of the consequences of unprotected sex among HIV-infected people, are explored here.
*Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; and the †Research and Evaluation Department, Fenway Community Health, Boston, Massachusetts, and Miriam Hospital/Brown University, Providence, Rhode Island
The authors thank the dedicated staff of Fenway Community Health, as well as countless volunteers who have made their work over the years possible.
Correspondence: Kenneth Mayer, MD, Research and Evaluation Department, Fenway Community Health, 7 Haviland Street, Boston, MA 02115. E-mail: Kenneth_Mayer@brown.edu
Received for publication October 30, 2003, and accepted November 7, 2003.
DESPITE REDUCTIONS IN THE most risky sexual practices among men who have sex with men (MSM) after the discovery of HIV/AIDS, recent reports show significant increases in unprotected intercourse (UI) and sexually transmitted diseases (STDs). 1 The ability of STDs to facilitate HIV transmission, 2,3 therefore, raises serious concerns that new HIV infections could shortly follow. Indeed, increases in HIV incidence have been reported recently among MSM for the first time since the mid-1990s. 4–7
A multitude of factors could explain recent increases in UI and STDs, including therapeutic optimism since the introduction of highly active antiretroviral therapy (HAART), pharmaceutical advertisements trivializing the consequences of long-term HIV infection and treatment, and changing attitudes and apathy regarding the severity of HIV infection and the perceived risks of UI. 1 Decreased AIDS-related deaths and increased AIDS-free survival times since HAART became widely available 8–10 could have fostered complacency regarding safer sexual practices and led many individuals, regardless of their HIV status, to increase their risk-taking activities. Indeed, several studies suggest that HIV optimism often coincides with less stringent safer sexual practices 11–13 and could differ according to one’s HIV status, 14 although causality cannot be firmly established.
Studies have shown that individuals using antiretroviral therapy practice safer sex less often in the HAART era compared with the pre-HAART era, 15,16 particularly in individuals using protease inhibitors. 17 Katz et al. found an increased HIV incidence among MSM during which increased unprotected intercourse and HAART use were also reported. 4 Changing perceptions and attitudes regarding antiretroviral medications and the associated likelihood of HIV transmission while on therapy could have potentiated this increased HIV incidence. 15,17,18 Moreover, HIV-infected persons with undetectable viral loads expressed less concern about infecting their sexual partners and reported increased UI compared with individuals with detectable viral loads. 19 Similarly, HIV-positive men who expressed the least concern about HIV transmission in light of HAART optimism were more likely to practice UI. 20 These data collectively suggest that risky sexual behaviors are increasing among HIV-infected people, in part as a result of optimism associated with the widespread use of potent antiretroviral therapies. Nonetheless, MSM at highest risk for transmitting HIV are no more likely to be counseled regarding safer sex practices than lower-risk men, 21 highlighting the need to provide ongoing risk reduction counseling for persons living with HIV that involves frank discussions of current treatment options, infectiousness, and prevention of secondary transmission.
Virologic and Clinical Consequences of HIV Superinfection
Persons living with HIV who continue to practice unprotected intercourse are not only at continued risk for new STDs, but they could also become reinfected with HIV. Coinfection with heterologous HIVs could occur during a single transmission event, whereas HIV superinfection refers to infection with a second heterologous HIV after primary infection or during the course of established infection. Although animal studies 22,23 and in vitro experiments 24,25 have demonstrated that coinfection with multiple strains of HIV is possible, only recently have data become available on whether superinfection occurs among humans. 26–29 Although the incidence of HIV superinfection has not yet been determined, relevant molecular and epidemiologic data clearly support the existence of this phenomenon. 30
The widespread existence of recombinant HIVs attests to the high frequency of superinfection, because simultaneous infection of a single cell by multiple virions is a necessary first step in the generation of recombinant viruses. Although the frequency at which superinfection occurs is unknown, the presence of multiple unique recombinant forms suggests that reinfection and recombination are common occurrences shaping the HIV pandemic. 31 Additionally, recent case reports of HIV superinfection underscore the importance of this much-ignored research topic (Table 1). Ramos et al were the first to publish definitive data demonstrating HIV superinfection in humans. 27 Using serologic and molecular approaches, superinfection was documented in 2 Thai intravenous drug users. Prospective sequence analysis demonstrated an HIV subtype at later time points that was distinct from that found during primary HIV infection (AE→AE + B in 1 case, B→B + AE in the other). A second report described the case of a 38-year-old man with acute retroviral syndrome. 26 On HAART initiation, his viral load dropped to undetectable levels; when treatment was interrupted, his viral load rebounded sharply. On further evaluation, it was determined that the primary HIV infection was the result of subtype AE, whereas the rebound virus belonged to subtype B (AE→AE + B). Altfeld et al. reported the case of virologic breakthrough after prolonged immunologic containment. 28 Sequencing demonstrated that superinfection with a second, distinct HIV-1 subtype B virus (B→B + B’) coincided with a loss of immunologic control, confirming that superinfection also occurs with viruses belonging to the same HIV-1 subtype despite virus-specific immune responses during primary HIV infection. A fifth case of HIV superinfection (B→B + B’) has also been reported in a patient with drug-resistant virus transmitted during primary infection; this was followed by a rapid increase in plasma viremia and a sharp decline in CD4 count on superinfection with a wild-type virus of the same subtype. 29 It is important to note that in most instances, superinfection coincided with a marked decline in CD4 cell count and a rise in plasma viremia.
What remains to be determined is the frequency of HIV superinfection and the risk it represents to the HIV-infected population as a whole. A preliminary study suggests that HIV superinfection is more common among high-risk persons (ie, those practicing intravenous drug use or unsafe sex) compared with low-risk persons; however, only 18 patients were analyzed, and a detailed report has not been published. 32 Alternatively, a recent study of 718 subjects followed over a 4-year period revealed no cases of superinfection, although the use of HAART in this cohort likely limited the ability to detect such events. 33 However, at the recent conference on retroviruses and opportunistic infections, Smith et al reported that 3 of 78 (5%) acutely infected participants in a Southern California study showed evidence of superinfection. 34 Indeed, the published reports represent only 5 cases of HIV superinfection. Each is limited by the fact that viral sequences from the putative “donor” are unavailable for definitive confirmation of superinfection and that the exact timing of superinfection is often unknown. Moreover, the simultaneous presence of both viruses could not always be firmly established, 28,29 suggesting potential limitations in detecting low-copy variants. Two reports provide comprehensive immunologic and serologic data allowing confirmation of HIV superinfection despite specific cellular and humoral responses to the primary virus. 27,28 Another report provides interesting in vitro viral growth data, suggesting that the superinfecting virus had a higher replicative capacity and rapidly replaced the initial virus, suggesting the possibility of enhanced virulence. 26 This was clinically corroborated by the patient’s rapid disease progression as demonstrated by persistence of high plasma HIV RNA levels and a rapid loss of CD4 cells within 4 months of superinfection.
The documentation of superinfection with 2 distinct subtypes of HIV suggests the crossreactivity among different subtypes could be minimal. More disturbing are concerns raised by intrasubtype superinfection (eg, B→B + B’) regarding the ability of subtype-specific vaccines to protect against challenge with a heterologous virus of the same subtype. Despite these concerns, evaluation of in vivo superinfection provides valuable insight into the quantity and quality of the immune response necessary to protect against viral challenge and prevent subsequent reinfection. Notwithstanding understanding how HIV superinfection impacts vaccine-induced protection against natural infection, 35,37 future therapeutic options, and the natural course of disease progression, is critical. Additionally, superinfection in treatment-experienced individuals could have serious consequences for subsequent treatment, particularly if 1 partner’s virus is drug-sensitive while the virus transmitted is drug-resistant. 30 Although these case reports highlight individual examples of HIV superinfection, they provide no data on the incidence of superinfection itself, and they do not provide more than anecdotal evidence of the clinical consequences of superinfection. A single published study has addressed the prevalence of superinfection in a cohort of subtype B-infected persons. 33 Using genetic measures of HIV diversity, Gonzales et al. found that sequence divergence during treatment was usually the result of sequence evolution rather than superinfection; however, it is unclear how antiretroviral therapy could influence the incidence of superinfection. Although this initial study could suggest a low rate of superinfection, distinguishing viral variants representing multiple transmission events from highly divergent variants that have evolved over several years of chronic infection could be exceedingly difficult in cohorts with a single circulating HIV subtype. Moreover, such cohorts provide no information on the incidence of superinfection in untreated persons or the long-term consequences of superinfection.
Research Initiatives to Reflect an Evolving Epidemic
Several strategies to identify individual cases of HIV superinfection have been used and represent ideal settings in which to measure its true incidence in different populations. Ramos et al. prospectively monitored a cohort of uninfected persons at high risk for HIV infection in a country with multiple HIV-1 subtypes. 27 Others have identified cases from well-characterized treatment/intervention trials. 26,28,29 Another strategy would be to determine the incidence of superinfection in seroconcordant-positive couples who continue to engage in unprotected intercourse despite intensive counseling about potential health consequences. Such prospective cohorts would allow researchers to define both the biologic and behavioral factors associated with superinfection, and would provide clinicians and patients with more concrete decision-influencing information regarding the likelihood of superinfection and the clinical consequences of continued high-risk behaviors. Longitudinal monitoring of clinical and laboratory values (ie, viral load testing, drug-resistance patterns, adherence to antiretroviral medications, and viral gene sequencing) complemented with detailed behavioral risk assessments every 3 to 6 months are critical for future investigations. This approach would effectively link epidemiologic factors thought to enhance one’s risk of HIV superinfection to actual laboratory values that provide the most sensitive measures of this phenomenon. To this end, the Positive Partners Study is currently enrolling seroconcordant-positive couples to assess the extent of drug-resistant HIV transmission in persons already infected with HIV, 38 whereas follow up of patients experiencing treatment failure without evidence of resistance mutations or nonadherence to treatment has been suggested. 31 Prospective monitoring of HIV genetic diversity in relation to antiretroviral treatment histories and risk behaviors would be necessary to appreciate fully the extent of HIV superinfection. Because identification of superinfection could be hampered by difficulties in distinguishing viral variants of the same subtype, establishing cohorts in whom at least 2 HIV-1 subtypes are circulating will also be critical. Once these cohorts have been established, several key research questions must be addressed, including:
1. What is the true incidence of intersubtype and intrasubtype superinfection according to both type and frequency of exposure?
2. What is the correlation, if any, between superinfection and exposure to antiretroviral medications?
3. What are the consequences, if any, that superinfection has for the development of antiretroviral drug resistance and altered disease progression as measured by persistently high HIV RNA levels and/or precipitous drops in CD4 cells?
4. What clues does superinfection despite primary immunologic control of HIV provide regarding the correlates of immunologic protection during natural infection?
5. What clues does superinfection provide regarding the optimal design and delivery of future HIV vaccines?
Optimism regarding HIV transmission and disease management in recent years has been heavily influenced by people’s perceptions of the benefits of HAART. However, the beneficial effects of HAART could quickly be offset by reported increases in sexual risk-taking behaviors. With a growing number of case reports documenting HIV superinfection, as well as the expansion of recombinant viruses, it is critical for the research community to respond quickly with longitudinal studies aimed at elucidating the potential ramifications of superinfection. A comprehensive agenda focused on behavioral, clinical, and laboratory assessment of high-risk individuals is critical to determine potential consequences of superinfection such as restricted treatment options as a result of the transmission of drug-resistant virus, inadequate or inappropriate therapeutic vaccine-induced immune responses, and accelerated disease course. These data could then be used by clinicians and public health practitioners to tailor risk reduction strategies to the ever-changing behaviors and needs of those affected by HIV. Given the inherent difficulties in distinguishing intrasubtype viruses from one another and the lack of “donor” sequences in many cases, detection of HIV superinfection will continue to be difficult. Nonetheless, recent increases in sexually transmitted infections, as well as other evidence that risk-taking behaviors could change coincident with highly active antiretroviral therapies, indicate that HIV superinfection will continue to occur in the foreseeable future. 5,6
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