| |
Risk of HIV transmission greatest during early-stage infection; risk by number of sex acts..
|
| |
| |
"....The overall rate of HIV transmission observed in these discordant couples, 0.0012/coital act, is consistent with previous estimates from Rakai, Europe, and North America. The present analysis, however, provides the first empirical data on the substantial variation in transmission by stage of HIV-1 infection...."
NEW YORK (Reuters Health) - Retrospective data show the rate of heterosexual HIV transmission varies substantially by stage of HIV-1 infection. The risk is greatest early after seroconversion, a period of time when few seroconverters know they are infected or are on antiretroviral therapy.
Dr. Maria J. Wawer from Columbia University in New York and an international team estimated rates of HIV-1 transmission per coital act in 235 monogamous couples in Uganda in whom only one partner was HIV-positive.
Over the course of the study, a total of 68 (28.9%) of 235 index partners transmitted HIV to their initially uninfected partners, they report in the May 1st issue of The Journal of Infectious Diseases.
A look at data collected at 10-month intervals for up to 40 months showed that the overall rate of HIV transmission via heterosexual sex was 1.2 per 1000 coital acts, consistent with previous estimates.
By stage of disease, the rate of HIV transmission was almost 12-fold higher early after infection (about 2.5 months after seroconversion) than during established infection, the team observed.
The transmission rate was 8.2 per 1,000 sex acts during early infection compared to 0.7 to 1.5 per 1000 sex acts during established infection. The transmission rate was 2.8 per 1,000 coital acts during late-stage infection (6 to 25 months before death)....
"... Furthermore, the risk ascribed to patients with early infection is likely an underestimate, given that the data collected did not allow for the detection of subjects with (preseroconversion) acute HIV infection, who are likely to have the highest blood and genital-tract HIV burden and who may have STIs as well. The authors estimate that the risk for HIV transmission from patients with acute infection might be as high as 1 case/50 coital actsgreater than the transmission risk associated with deep needlestick injuries.."
"In adjusted models, early- and late-stage infection, higher HIV load, genital ulcer disease, and younger age of the index partner were significantly associated with higher rates of (heterosexual) transmission," the team reports.
This study confirms the "remarkable threat of HIV transmission posed by people with newly acquired HIV infection," Dr. Myron S. Cohen and Christopher D. Pilcher from the University of North Carolina at Chapel Hill write in an editorial.
"The challenge now is to waste no time in finding the most creative strategies to incorporate these results into global HIV prevention efforts," they add.
J Infect Dis 2005;191:1391-1393,1403-1409.
Excerpts from Published Article
Rates of HIV-1 Transmission per Coital Act, by Stage of HIV-1 Infection, in Rakai, Uganda
Maria J. Wawer,1 Ronald H. Gray,2 Nelson K. Sewankambo,5 David Serwadda,6 Xianbin Li,2 Oliver Laeyendecker,3 Noah Kiwanuka,7 Godfrey Kigozi,7 Mohammed Kiddugavu,7 Thomas Lutalo,7 Fred Nalugoda,7 Fred Wabwire-Mangen,6 Mary P. Meehan,1 and Thomas C. Quinn3,4
1Heilbrun Department of Population and Family Health, Columbia University Mailman School of Public Health, New York, New York; 2Department of Population and Family Health Sciences, Johns Hopkins Bloomberg School of Public Health, 3Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, and 4National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; 5Faculty of Medicine and Clinical Epidemiology Unit and 6Institute of Public Health, Makerere University, Kampala, and 8Rakai Health Sciences Program, Uganda Virus Research Institute, Entebbe
(See the editorial commentary at end of this report by Cohen and Pilcher):
"....In their earlier work, the investigators demonstrated that the risk of HIV transmission correlated strongly with blood viral burden and the incidence of genital ulcer disease. In their current work, Wawer et al. make another critically important observation: nearly one-half of the HIV transmission events observed could be ascribed to a sex partner with newly acquired HIV infection...
.... When investigators have searched for people with acute HIV infection, they have been found. Rosenberg et al. reported that 1.0% of patients with negative tests for Epstein-Barr virus infectious mononucleosis had serological results consistent with acute HIV infection. Pincus et al. found that 1.0% of patients with "any viral symptoms" in a Boston urgent-care center had unsuspected acute HIV infection. In a Malawi STI clinic, 2.8% of all male clients with acute STIs had acute HIV infection. However, acute retroviral symptoms occur in only one-half of patients, and the signs and symptoms are nonspecific..."
ABSTRACT
Background. We estimated rates of human immunodeficiency virus (HIV)1 transmission per coital act in HIV-discordant couples by stage of infection in the index partner.
Methods. We retrospectively identified 235 monogamous, HIV-discordant couples in a Ugandan population-based cohort. HIV transmission within pairs was confirmed by sequence analysis. Rates of transmission per coital act were estimated by the index partner's stage of infection (recent seroconversion or prevalent or late-stage infection). The adjusted rate ratio of transmission per coital act was estimated by multivariate Poisson regression.
Results. The average rate of HIV transmission was 0.0082/coital act (95% confidence interval [CI], 0.00390.0150) within `2.5 months after seroconversion of the index partner; 0.0015/coital act within 615 months after seroconversion of the index partner (95% CI, 0.00020.0055); 0.0007/coital act (95% CI, 0.00050.0010) among HIV-prevalent index partners; and 0.0028/coital act (95% CI, 0.00150.0041) 625 months before the death of the index partner.
In adjusted models, early- and late-stage infection, higher HIV load, genital ulcer disease, and younger age of the index partner were significantly associated with higher rates of transmission.
Conclusions. The rate of HIV transmission per coital act was highest during early-stage infection. This has implications for HIV prevention and for projecting the effects of antiretroviral treatment on HIV transmission.
AUTHOR DISCUSSION
The overall rate of HIV transmission observed in these discordant couples, 0.0012/coital act, is consistent with previous estimates from Rakai, Europe, and North America. The present analysis, however, provides the first empirical data on the substantial variation in transmission by stage of HIV-1 infection. After seroconversion of the index partner, the rate of transmission (0.0082/coital act) within the first 2.5 months was almost 12-fold higher than that observed in prevalent index couples (0.0007/coital act). The rate then increased significantly again `2 years before the index partner's death. Risks of transmission per act remained significantly higher during early- and late-stage HIV infection, after adjustment for multiple covariates; this pattern is consistent with model estimates.
In the 46 couples with one seroconverting partner for whom we conducted molecular linkage, >91% of the seroconverting partners acquired a virus strain that was homologous to that found in the infected index partner: the 4 couples with nonhomologous virus strains were excluded from the analysis. None of the partners reported anal intercourse during follow-up, consistent with the fact that we observe virtually no evidence of anal or rectal trauma compatible with anal intercourse in Rakai Program STD clinics. In addition, reported receipt of injections is not associated with the acquisition of HIV in this population. The data thus reflect the effects of stage of HIV infection on heterosexual vaginal transmission.
We retained the 26 couples with proven transmission for whom we could not conduct molecular linkage (because of insufficient archival serum samples) in the analysis. Their characteristics did not differ from those of the 46 couples for whom linkage analysis was possible and for whom we observed a low rate (8.7%) of nonmarital HIV acquisition. It is thus possible that `2 of 26 couples also acquired HIV from outside the marital union, but this degree of misclassification would have only a minimal effect on study results.
The 40-month maximum follow-up period in our analysis did not permit observation of any couples for the entire period between seroconversion of the index partner and deatha period of 810 years, on average, in rural Uganda. However, we were able to reconstruct the probable pattern of transmission rates during the course of infection. In 23 couples, the index partner seroconverted within a known 10-month period. Although the timing of index infection was not known in the 161 couples with a prevalent index partner, most of them were monitored for at least 3 10-month intervals, and the rate of transmission was relatively stable over time, providing an estimate of the average transmission rate per act during latent HIV infection. A total of 51 index partners died; the rate of HIV transmission per coital act >2 years before death was not significantly different from that observed during latency or >6 months after seroconversion of the index partner, which suggests overlap among the 3 groups.
We were unable to observe the magnitude or the duration of the peak viremia or the rate of HIV transmission per coital act during the weeks immediately after HIV acquisition in the index partner. Although the median serum HIV load observed `5 months after seroconversion (30,000 copies/mL) was similar to levels observed in other populations at a comparable time point, recent data from Malawi have suggested a peak HIV load of 6.10 log10 copies/mL (>1 million RNA copies/mL) shortly after the acquisition of HIV. The rate of transmission per coital act may thus be very high for a short period immediately after HIV infection. In Rakai couples, if the average length of exposure between infection of the index partner and HIV transmission was only 1 month (encompassing `10 coital acts), rather than the 2.5 months that we estimated, the rate of transmission during this period could be as high as 0.02/coital act. In populations, the epidemiological effects of different magnitudes and durations of the peak rate of transmission would depend on the numbers of partners, coital frequency, and the structure of sexual networks.
Because we could not observe the effect of short-term variations in HIV load on transmission, this may underestimate the effects of HIV load in the multivariate model. The model suggests, however, that HIV load may not explain all of the increased risk seen during early-stage disease. Potential contributing factors could include higher susceptibility in newly exposed, uninfected partners and the presence of GUD. In Rakai, we observed high rates of genital ulcers, particularly among HSV-2seropositive persons, during early-stage HIV infection.
The likelihood of transmission within a partnership over time is likely to be heterogeneous and nonlinear. Our data do not capture the effects of short-term variations in infectivity and susceptibility but describe the average transmission rate per coital act during different stages of HIV infection in the index partner. In couples with prevalent index partners, the rate of transmission per coital act remained relatively constant during each 10-month period of the 40-month follow-up, which suggests that the average infectivity rate per coital act was stable during this period.
Of all the 741 Rakai couples with HIV infection who were retrospectively identified between 1994 and 1999, 414 (55.9%) were HIV discordant and 327 (44.1%) were concordant HIV positive at enrollment. In the present study, only 13 (57%) of 23 of initially negative partners remained uninfected `5 months after the index partner seroconverted. Couples in whom transmission did not occur during early infection, and those who remained persistently discordant over time, may represent a selected subgroup of "survivors" in whom either the index partners were less infectious and/or the seronegative partners were less susceptible [26]. We are undertaking additional studies to examine such potential factors.
The Rakai data were collected from stable heterosexual couples, whose primary risk was through vaginal intercourse, and additional studies are required to examine transmission by stage of HIV infection in other epidemic settings. Nonetheless, our data have a number of clinical and epidemiological implications.
The highest rate of transmission per coital act, as well as the highest proportion of transmissions, occurred during early-stage infection in index partners, a time when few seroconverters know their HIV status or receive ART. Although the rate was also higher during late-stage infection, the overall contribution of the latter to a heterosexual HIV epidemic is likely to be limited, because individuals with advanced HIV infection report less sexual intercourse and have fewer partners, and only a minority of couples remain discordant by this stage. Thus, ART, initiated relatively late during infection, under current guidelines, may have only a modest impact on HIV transmission. Also, because most HIV transmissions occur before index cases are eligible to receive ART, the heterosexual spread of drug-resistant HIV may be modest in this population. Measures that prevent primary HIV infection or reduce early viremia (as may occur with HIV vaccines) are likely to have a greater effect than ART on the spread of HIV. Increased efforts to identify persons with early-stage HIV infection are also warranted, to promote safe behaviors, and, where appropriate, to provide ART.
In conclusion, the empirical estimates of the rates of heterosexual HIV transmission per coital act, by stage of HIV infection in index partners, reported here show high rates of transmission during early- and late-stage disease, which may assist in epidemic modeling, in the design and evaluation of HIV prevention strategies, and in the assessment of the likely epidemiologic impact of ART.
EDITORIAL
Amplified HIV Transmission and New Approaches to HIV Prevention
Myron S. Cohen and Christopher D. Pilcher
Departments of Medicine, Microbiology, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill
HIV has infected 40,000,000 people, killed >6,000,000 people, and devastated whole sectors of societies [1]. HIV infection is rightly considered by the United Nations to be a major threat to global security and economy [2]. Prevention of the spread of HIV demands precise knowledge of the biology and epidemiology of transmission [3], a challenge that even now has not been completely met. Although several studies of HIV epidemiology (reviewed in [4]) have described heterosexual transmission as occurring in `1/1000 coital acts, this number seems far too low to explain the magnitude of the HIV pandemic.
In this issue of the Journal of Infectious Diseases, Wawer et al. [5] provide a new and important understanding of the transmission of HIV. Between 1994 and 1999, the investigators enrolled 15,127 subjects from 56 villages in the Rakai District of Uganda in a trial designed to determine whether intermittent mass therapy directed against sexually transmitted infections (STIs) could reduce the spread of HIV. Although this intervention did not reduce the incidence of HIV infection [6], meticulous and extensive collection of demographic, clinical, and historical data on the participants has led to a steady and compelling stream of analysis [79].
In their earlier work [8], the investigators demonstrated that the risk of HIV transmission correlated strongly with blood viral burden and the incidence of genital ulcer disease [9]. In their current work, Wawer et al. [5] make another critically important observation: nearly one-half of the HIV transmission events observed could be ascribed to a sex partner with newly acquired HIV infection.
Although several "couples studies" of HIV transmission [10, 11] have been undertaken in the past, such studies depend on the identification of an index patient with established HIV infection. However, the Rakai investigators retrospectively "constructed" couples from the entire study population based on the subjects' histories and (more recently) viral genetics [12]. This approach allowed them to detect the transmission of HIV within couples even when both partners were HIV seronegative at the beginning of the study.
The authors identified 235 couples for study. On the basis of the number of coital acts reported by both partners, they estimated the probability of HIV transmission from a subject with early infection (an average of 2.5 months after seroconversion) as 8.2 cases/1000 coital acts, with established infection as 715 cases/10,000 coital acts, and with advanced (unrestrained and untreated) infection as 2.8 cases/1000 coital acts. Furthermore, the risk ascribed to patients with early infection is likely an underestimate, given that the data collected did not allow for the detection of subjects with (preseroconversion) acute HIV infection, who are likely to have the highest blood and genital-tract HIV burden [13] and who may have STIs as well [9, 14, 15]. The authors estimate that the risk for HIV transmission from patients with acute infection might be as high as 1 case/50 coital actsgreater than the transmission risk associated with deep needlestick injuries [16].
These results strongly support earlier modeling predictions. Using blood and semen samples harvested from patients at different stages of disease, Chakraborty et al. [4] constructed a probabilistic model of HIV transmission. According to this model, the very high viral burden in semen that has been demonstrated in patients with acute HIV infection should result in an 810-fold increase in the risk of male-to-female transmission [13] (figure 1A). Coinfection with "classic" STI pathogens [17, 18] and high-risk behavior in acutely infected patients [19] would also amplify transmission in sexual networks [20] (figure 1B). As early as 1994, Koopman et al. [20] and Jacquez et al. [21] used population modeling to argue that the spread of HIV from patients with early, transient hyperinfectiousness could contribute disproportionately to the epidemic.
When investigators have searched for people with acute HIV infection, they have been found. Rosenberg et al. [22] reported that 1.0% of patients with negative tests for Epstein-Barr virus infectious mononucleosis had serological results consistent with acute HIV infection. Pincus et al. [23] found that 1.0% of patients with "any viral symptoms" in a Boston urgent-care center had unsuspected acute HIV infection. In a Malawi STI clinic, 2.8% of all male clients with acute STIs had acute HIV infection [18]. However, acute retroviral symptoms occur in only one-half of patients, and the signs and symptoms are nonspecific [24]. Furthermore, the clinical diagnosis of acute HIV has relied on tests (HIV p24 antigen or nucleic-acid amplification tests) that add significantly to the costs of testing and have been dogged by concerns with specificity. Recent innovations in high-throughput group testing for HIV RNA in antibody-negative specimens allow more efficient identification of people with acute infection, regardless of clinical presentation [25, 26]. Not surprisingly, such patients are most often detected in STI clinics [27], which supports the importance of cotransmission of HIV and STIs.
If patients with acute HIV infections can be more readily detected, the opportunities for novel care and prevention are considerable. The results of clinical trials have suggested that very early antiretroviral therapy and/or immune-based therapy may benefit the acutely HIV-infected patient [2830]. In addition, aggressive attempts to reduce the size of the latent HIV pool in these patients are likely to be forthcoming [31].
Prevention of HIV transmission is of paramount importance. Historically, HIV prevention efforts have focused on HIV-uninfected subjects, whereas prevention directed at infected subjects has only gained attention very recently [32, 33]. To respond adequately to the threat of amplified HIV transmission, HIV prevention strategies must use complementary diagnostic, behavioral, and biological tools. Unique partner notification, counseling and referral services [34], and novel biological interventions should be developed specifically for people with acute HIV infection. Wawer et al. [5] have confirmed the remarkable threat of HIV transmission posed by people with newly acquired HIV infection. The challenge now is to waste no time in finding the most creative strategies to incorporate these results into global HIV prevention efforts.
|
|
| |
| |
|
|
|
