Abstract
The extent to which receptive anal intercourse (RAI) increases the HIV acquisition risk of women compared to receptive vaginal intercourse (RVI) is poorly understood. We evaluated RAI practice over time and its association with HIV incidence during three prospective HIV cohorts of women: RV217, MTN-003 (VOICE), and HVTN 907. At baseline, 16% (RV 217), 18% (VOICE) of women reported RAI in the past 3 months and 27% (HVTN 907) in the past 6 months, with RAI declining during follow-up by around 3-fold. HIV incidence in the three cohorts was positively associated with reporting RAI at baseline, albeit not always significantly. The adjusted hazard rate ratios for potential confounders (aHR) were 1.1 (95% Confidence interval: 0.8–1.5) for VOICE and 3.3 (1.6–6.8) for RV 217, whereas the ratio of cumulative HIV incidence by RAI practice was 1.9 (0.6-6.0) for HVTN 907. For VOICE, the estimated magnitude of association increased slightly when using a time-varying RAI exposure definition (aHR = 1.2; 0.9–1.6), and for women reporting RAI at every follow-up survey (aHR = 2.0 (1.3–3.1)), though not for women reporting higher RAI frequency (> 30% acts being RAI vs. no RAI in the past 3 months; aHR = 0.7 (0.4–1.1)). Findings indicated precise estimation of the RAI/HIV association, following multiple RVI/RAI exposures, is sensitive to RAI exposure definition, which remain imperfectly measured. Information on RAI practices, RAI/RVI frequency, and condom use should be more systematically and precisely recorded and reported in studies looking at sexual behaviors and HIV seroconversions; standardized measures would aid comparability across geographies and over time.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Systematic reviews of cross-sectional studies have shown that heterosexual anal intercourse (RAI) is prevalent worldwide, with little apparent variation by key demographic characteristics such as age [1,2,3,4,5,6,7,8,9]. Our understanding of the contribution of RAI to HIV incidence is, however, limited by the variability of RAI measurements and exposure definitions across studies and by the scarcity of longitudinal data that tracks levels and persistence of RAI, and HIV seroconversions over time.
Current evidence suggests that RAI increases HIV risk. The pooled estimate of the per-act probability of HIV acquisition risk during one RAI sex act, from a systematic review of serodiscordant-couple studies, was 1.25% (95%CI 0.55–2.23%) [10], a figure ~ 3–20 times higher than that for one receptive vaginal intercourse (RVI) sex act (0.12%, 95%CI 0.08–0.20%)) [11]. However, the exact magnitude of the increase in HIV risk per RAI sex act for women remains uncertain given the large confidence intervals and because the pooled estimate relies on five studies, including four among men who have sex with men [10].
Mathematical model results suggest that, even infrequent RAI (e.g. assuming 7.5% of all acts are RAI) could account for a substantial fraction of new HIV infections among women (~ 23%) if it increases HIV risk by ~ 1.8-fold (equivalent to assuming a 5-fold increase of the acquisition probability at the per-sex-act level) [4, 12] and could influence the impact of prevention strategies such as vaginal microbicide or oral PrEP, which have varying efficacy by anatomical site [13,14,15]. Nevertheless, HIV trials and cohort studies alike often give little consideration to the impact of RAI practice on HIV incidence during follow-up.
A recent systematic review of longitudinal HIV studies that included some measure of RAI and HIV incidence estimated that women reporting RAI were, on average, 1.6 times more likely to acquire HIV than women not reporting RAI (with some variation in magnitude by risk population and region) [16]. As expected, this figure was lower than the increase in HIV risk per RAI sex act, since women reporting RAI do not practice it in all their sex acts and differences in per-act risk translates into smaller differences in cumulative incidence risk [7]. However, the review also highlighted limitations which could explain differences across studies and obscure the association, including variable definitions and recall periods for RAI exposures, the near systematic use of non-confidential interview methods potentially resulting in misclassification bias, absence of adjustment for important confounders such as condom use (less than a quarter were adjusted for possible confounders), and lack of accounting for changes in RAI practices during follow-up.
Existing knowledge of RAI practice among women has largely focused on reporting the prevalence of RAI over long recall periods (lifetime, past year) [8], with frequent variation in estimates across studies, likely influenced by reporting biases due to the use of non-confidential interview methods, such as face-to-face interviews and/or challenges with accurate translation of sexual terms [17]. Very few cohorts have considered the prevalence and persistence of RAI over time [18,19,20]. For example, of 31 systematically-reviewed studies on the practice of heterosexual anal intercourse in South Africa, only one reported RAI prevalence over two different time frames [3]. Further, in a systematic review looking at the increased HIV incidence due to RAI exposure, only a quarter of the estimates accounted for changes in RAI practices over time, which should influence the magnitude of HIV risk cumulatively over the study period [16] and could explain why longitudinal studies among women have estimated a lower increase in HIV acquisition risk due to RAI than per-act estimates which draw on serodiscordant partnerships studies or prospective cohorts of MSM.
To address this knowledge gap and better understand potential sources of variation in estimates of the magnitude of association between RAI and HIV across studies, we used longitudinal data from three recent cohort studies conducted in Africa (MTN-003 (VOICE) trial and RV 217) and in the Caribbean (HVTN 907) [21,22,23] to (1) examine the level and persistence of RAI practice (e.g. prevalence) among women over the study periods and to (2) assess the relationship RAI and HIV incidence using different RAI exposure definitions. Based on existing knowledge we hypothesized that HIV incidence will be higher among women reporting RAI than not reporting, and that the magnitude of association would be higher for women reporting RAI more consistently (RAI in the past few months before follow-up visits) and/or frequently (percentage of all acts that are RAI).
Methods
Description of the Three Longitudinal Studies (VOICE, RV 217, and HVTN 907)
We analyzed data from three recent longitudinal studies. The MTN-003 Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial recruited sexually active women aged 18–40 years (in South Africa, Uganda, and Zimbabwe; N = 5,029) who reported at least one act of RVI in the three months preceding the baseline interview [23]. We used data from all trial intervention and control arms, as none were associated with lower HIV incidence due to low product adherence [24]. The prospective study of acute HIV infections in adults (RV 217) recruited women aged 18–47 years with a higher risk profile (in Uganda and Kenya; N = 1,545) from locations associated with transactional sex (e.g. bars and clubs) [21]. Finally, the prospective cohort study HVTN 907 recruited Caribbean female sex workers (FSW) aged 18–45 years (in Haiti, the Dominican Republic, and Puerto Rico; N = 1,019) who had performed at least one condomless act of RVI or RAI in the last six months [25]. The main characteristics of the studies and participants are summarized in Table 1, with more complete descriptions, including protocols and ethics approvals, available elsewhere [21, 23, 25]. Further ethics approval for our secondary analysis was obtained from Imperial College London (approval # 16IC3667).
Study Variables
Behavioral data was collected via Audio Computer-Assisted Self-Interview (ACASI) at baseline and every three months (VOICE) or six months (RV 217), or via Face-to-face interviews at baseline and every six months (HVTN 907). History of sex work was reported for the prior year (VOICE), prior 3 months (RV 217), or prior 6 months (HVTN 907), while history of drug injection was recorded at baseline only for RV 217 (ever/never/recently injected) and HVTN 907 (in past 6 months; see Table 1). Information on RAI practice, at baseline and follow-up, was elicited over either the past 3 months (VOICE and RV 217), or the past 6 months (HVTN 907; see Table 1 and Figure S1). Although women enrolled in RV 217 were followed every six months, the study item used a recall period of three months (Figure S1). We therefore assumed participants’ report of RAI practice over the past six months was the same as over the past 3 months. RAI prevalence was defined as the proportion of the study population that reported having practiced RAI over a specific recall period. Information on the number of RAI acts during recall periods was available for VOICE and HVTN 907 participants (Table 1 and S1). RAI fraction was defined as the fraction of total sex acts (RVI plus RAI) that were RAI, only among those that reported this sexual behavior.
In VOICE, condom use at last RVI was reported only by participants who had a sex act in the last week, whereas condom use during RV 217 was reported for the last intercourse (RAI or RVI) by partner type (steady, casual, client); the prevalence of condomless RAI or fraction of condomless sex acts that are RAI in these two studies could not be ascertained because data only covered the last RAI. Information on condom use during sex acts was not collected during HVTN 907.
Incident HIV infections were measured by testing participants once a month in the VOICE trial using two different third-generation rapid tests (positive assays were confirmed by a GS HIV-1 western blot) [23] and every six months in the HVTN 907 study using ELISA tests [25]. HIV-negative women enrolled in RV 217 were tested twice a week using Aptima RNA tests on small-volume blood samples [21]. Because HIV testing protocols varied between studies, dates of HIV infection were inferred in different ways. The seroconversion time was assumed at mid-point between the last and current visit for VOICE and HVTN 907, and HIV infections of participants were assumed to have occurred one month before seroconversion time (Fig. 1 for VOICE). For participants of RV 217, we assumed that HIV infection occurred two weeks before the first positive HIV test to reflect the higher testing frequency and very short detection window of HIV RNA tests.
Statistical Analyses
Sociodemographic and behavioral differences between women reporting RAI at baseline (hereafter called “RAI + women”) and women only reporting RVI in each study at baseline (hereafter called “RVI-only women”) were evaluated using Pearson chi-squared and Wilcoxon signed-rank tests. The persistence of RAI practices over time was characterized using four outcomes: (1) cross-sectional RAI prevalence (proportion of women reporting RAI over the previous 3 months (6 months for HVTN)) at baseline and at each subsequent follow-up visit, (2) anytime RAI prevalence (proportion of women that reported RAI at baseline or any of the follow-up visits), (3) the proportion of women reporting RAI for the first time and (4) the proportion of women who stopped practicing RAI during follow-up. Outcome 1 was also stratified by participant socio-demographic characteristics. Outcome 3 was estimated from prevalence at the first follow-up visit, but only among women not reporting RAI at baseline. Outcome 4 was estimated from the prevalence at the first follow-up visit, but only among women reporting RAI at baseline. Total changes in RAI prevalence during the study were measured by comparing RAI prevalence at the first (baseline) and last visit and compared using chi-squared test for linear trend in proportions. Finally, we derived the cross-sectional fractions of all sex acts that were RAI and fractions of RAI and RVI acts involving condoms for VOICE and RV 217 over time.
Because only 12 seroconversions were observed in the HVTN 907 study, the association between RAI practice and HIV incidence was calculated as the ratio of crude cumulative incidences among RAI + and RVI-only women. Otherwise, the VOICE trial and the RV 217 studies were used for detailed analyses using five different RAI exposure definitions (D1-D5) commonly used in previous analyses [16]. The first one consisted of having reported RAI at baseline (D1; in the past three months for VOICE and RV 217). The second definition reflected RAI persistence during follow-up visits; each woman was classified as having never or ever reported RAI during follow-up (D2). The third RAI exposure definition classified participants as never, sometimes (D3a), or consistently (always) (D3b) reporting RAI during follow-up (excluding baseline information). The fourth RAI exposure definition was time-varying based on reports of RAI practice at each visit (D4; baseline and follow-up) [26, 27]. The last definition was based on the RAI fraction (for VOICE trial only) and was expressed as the proportion of all sex-acts that were RAI among those reporting RAI during follow-up (D5a: 1–30% vs. no RAI; D5b: >30% vs. no RAI). The associations between D1-D5 and incident HIV were first estimated using univariate Cox Proportional hazards models. Analyses were performed separately for the different studies due to differences in populations and study designs.
Potential confounders of the RAI-HIV relationships were adjusted for in multivariable analyses using available data from each study. For the VOICE trial, the multivariable model was adjusted for baseline data on age at enrolment (18–25, 25 + years), country (South Africa, Uganda, or Zimbabwe), trial arm (control vs. placebo), sex work (prior year), number of partners (1, 2, 3 + in the past 3 months), and condom use at last vaginal sex. The adjusted model for the RV 217 study included age (18–25, 25 + years), country (Uganda or Kenya), number of partners in the last 3 months (< 10, 10+), history of injecting drug use (never/ever), and condom use at last sex. None of the statistical models could be adjusted for condom use at last RAI because it was highly correlated with condom use at last RVI at the overall and individual level in VOICE (69% vs. 71%, with > 90% of women reporting using a condom at last RAI also reporting using a condom at last RVI) or correlated with condom use at last sex by partner type in RV 217 (e.g. 47% vs. 53% at last sex with a client, with 75% of women reporting using a condom at last RAI with a client also reporting using a condom at last sex with a client), and because condom use at last RAI was only reported by RAI + women.
A sensitivity analysis evaluated the impact of gradually introducing an improved version of the ACASI questionnaire during the VOICE trial (including improved translation of terms related to RAI practice) on the persistence of RAI by (1) comparing the cross-sectional RAI prevalence for each of the ACASI questionnaire version, and (2) re-estimating of the association between RAI exposure definitions and HIV incidence only among VOICE participants having used the improved questionnaire from baseline (23% of the total population). All statistical analyses were performed using the R software (version 3.5.1) [28].
Results
Prevalence, Frequency, and Persistence of RAI Practice in the Three Longitudinal Studies
The proportion of women reporting RAI over the last three months at baseline was 17.5% (95% confidence interval (95%CI): 16.5–18.6%) among VOICE participants and 16.0% (14.2–17.9%) among RV 217 participants (Fig. 2). For HVTN 907, prevalence of RAI over the past six months was 27.3% (24.4–30.2%). In VOICE, higher proportions of RAI + women lived in South Africa and were in the youngest age group, compared to RVI-only women (Table S2a). Women reporting RAI in RV 217 reported more frequent history of injecting drugs, more sexual partners, and less frequent condom use than RVI-only women (Table S2b). In contrast, higher proportions of RAI + women in HVTN 907 study were older than 25 years and reported having fewer clients compared to RVI-only women (Table S2c).
The anytime RAI prevalence at baseline and during follow-up was 31.1% (29.9–32.5%) for VOICE (over 3 years of follow-up), 23.1% (20.3–25.9%) for RV 217 (over 2 years), and 35.3% (32.1–38.4%) for HVTN 907 (over 18 months, Fig. 2b). RAI prevalence at follow-up visits significantly declined over time in all three studies (Chi-square test for trend: p-value < 0.001 for VOICE, RV 217, and HVTN 907) (Fig. 2a). RAI prevalence (past 3 months) decreased to 4.5% compared to baseline (i.e. by 74%) after 33 months of follow-up in VOICE, to 4.5% (by 72%) after 2 years of follow-up in RV 217, and to 16.6% (by 39%) after 18 months of follow-up in HVTN 907. The decline in reported RAI practice was most pronounced between baseline and first follow-up, with 50% of women in the VOICE sample who were RAI + at baseline no longer reporting RAI at the three-month follow-up (Fig. 2b). The decline was even steeper in RV 217, with 74% stopping after 6 months. In HVTN 907, the reductions were 46% between baseline and first follow-up – also occurring at six months. The RAI prevalence among these women continued to decrease after this initial follow-up visit, a difference not attributable to differential loss to follow-up among women reporting RAI. Results of the persistence of RAI practice, stratified by socio-demographic characteristics, are presented as supplementary material (Figures S2 to S6). Briefly, the decline in cross-sectional RAI prevalence across the 3 studies was largest for Kenyan participants of RV 217, declining from 14.1% (11.8–16.2%) at baseline, to 1.5% (0.5–2.8%) after two years of follow-up (Figure S2).
Most participants did not practice RAI at any time during follow-up (74.8% VOICE, 86.8% RV 217, and 72.8% for HVTN 907) (Figure S7), with 21.9% (VOICE), 11.1% (RV 217), and 16.3% (HVTN907) of participants, respectively, reporting RAI at least once during follow-up. Very few participants reported practicing RAI at all follow-up visits (3.3% VOICE, 2.1% RV 217, and 10.9% for HVTN 907). Among women ever-practicing RAI (25.2% VOICE, 13.2% RV 217, and 27.2% for HVTN 907), RAI was most often reported at only one follow-up visit.
Importantly, 7.2% (6.4–8.1), 5.0% (3.4–10.6), and 8.1% (5.9–10.6) of the women who did not report RAI at baseline in VOICE, RV 217 and HVTN 907 reported initiating RAI at the first follow-up visit (3, 6, 6 months after baseline, respectively) (Fig. 2b). RAI + women who ceased to report RAI at first follow-up were more likely to reside in Zimbabwe (VOICE), Kenya (RV 217), and Haiti (HVTN 907) (Figures S4a-6a). Conversely, being aged under 25 years (VOICE), or residing in either Uganda (RV 217) or Puerto Rico (HVTN), was most associated with reporting initiating RAI at first follow-up visit among RVI-only women (Figures S4b-S6b).
At baseline, the fraction of RAI (only calculated among those who reported RAI acts) was 34.2% (31.6–37.1) in VOICE and 16.0% (13.7–18.5) in HVTN 907. These proportions remained stable after initial HIV/STI risk reduction counselling and during follow-up in both studies (Fig. 3 and S8), whilst the fraction of condom use during RVI and RAI decreased slightly over time (Figure S9).
Incident HIV and RAI Association for Different RAI Exposure Definitions
Overall, we found positive associations between the different RAI exposure definitions and incident HIV across studies, albeit sometimes accompanied by wide confidence intervals (Table 2). Estimates of the magnitude of association with HIV during VOICE and RV 217 varied by definition of RAI exposure. For VOICE, reporting RAI in the three months before baseline was not associated with higher HIV incidence during the trial (aHR = 1.1; 0.8–1.5), however always reporting RAI during follow-up visits was (aHR = 2.0; 1.3–3.1 for D3b). The unadjusted time-varying definition (D4) yielded a slightly higher point-estimate of association than D1 (1.2 vs. 1.1), though, contrary to our hypothesis, the reported fraction of acts that were RAI (D5a,b) was not associated with HIV incidence. By contrast, and consistent with our hypothesis, in RV 217, reporting RAI in the three months before baseline was associated with a much higher HIV incidence (aHR = 3.3; 1.6–6.8). However, due to low incidence (22 infections) among individuals completing at least one round of follow-up questionnaire, we were not able to calculate adjusted hazard ratio (aHR) for D2-D4, nor use time-varying RAI variables, in this cohort. The association between reporting RAI at any time (D2) or consistently (D3b) during follow-up and HIV incidence were not statistically significant despite relatively high HR point-estimates (HR = 1.7; 0.4–7.2 and 2.6; 0.3–19.2 for D2 and D3b, respectively). Finally, the RAI HIV cumulative incidence ratio for HVTN 907 was 1.9 (0.6-6.0), based on 12 incident cases (5 among RAI+, 7 among RVI-only women, not shown).
Sensitivity Analysis to the RAI Questionnaire (VOICE)
The RAI prevalence at baseline and during the first year of follow-up was approximately only 1% point lower among VOICE participants using the second questionnaire version compared to the first version (Figure S10). However, the estimated magnitude of association between the different RAI exposure definitions and HIV incidence was similar for the analysis conducted only among study participants using the second questionnaire (23% of participants) than the whole sample (Figure S11).
Discussion
Our study shows that RAI was commonly reported, but not necessarily practiced regularly during follow up, by women recruited in three different HIV longitudinal studies. RAI practice declined markedly during study periods, but not the frequency of RAI among those reporting RAI. Despite its well-established, heightened per-act probability of HIV acquisition [10], the association between RAI practice and incident HIV infection was not always positive and varied across exposure definitions, settings and studies, highlighting persisting difficulties in precisely measuring unprotected RAI, a relatively infrequent and sensitive behaviour. Consistent with our hypothesis, higher estimates of the magnitude of the RAI and HIV association in VOICE were usually observed when using more precise exposure definitions, such as time-varying RAI exposure or ‘always practicing’ RAI, although the fraction of acts that are RAI was not associated with HIV incidence during VOICE, which departed from our hypothesis.
The prevalence of RAI among women at baseline was consistently higher than 15% across the three studies, and approximately 2-fold higher among HVTN 907 FSW participants (in the Caribbean), which is consistent with findings from a recent systematic review and meta-analysis of the prevalence of RAI among FSW [29], which was found to be around 15–20% among FSW in Africa compared to 20–28% in the Americas [29]. Furthermore, a survey among at-risk women living in 20 U.S. settings also found a 2-fold higher prevalence of RAI in the past year in San Juan (Puerto Rico) compared to other U.S. cities [30], yielding a much higher estimated relative contribution of RAI to new HIV infections in this population than on average over the whole sample (57% vs. 41%). Reporting of RAI by women at higher risk of HIV infection is known to be influenced by contextual factors such as violence and substance use, which vary across settings and populations [20]. Reported RAI consistently declined over follow-up, particularly at first follow-up visit, during all studies. Since the cohorts recruited women at high risk of infection, this may be partly explained by regression to the mean [31], HIV/STI risk-reduction counselling of study participants which took place at every study visit in all studies [23], or increased desirability bias (which may have been influenced by regular counselling and may result in misclassification bias). Interestingly, the decline in RAI contrasts with the reported use of condoms during RVI and RAI during VOICE, which slightly declined over time and may have been partly influenced by beliefs of product efficacy among participants, despite counselling and condom distribution (Figure S9), whilst the participants’ reported number of partners (over the past 3 months) remained stable over time (Figure S12). Our analysis also showed that, although few individuals continued practicing RAI throughout the studies, a non-negligible number (around 8%) reported initiation of RAI at the first follow-up visit (Fig. 2b), despite HIV/STI risk reduction counselling. When available (VOICE, HVTN 907), RAI fraction appeared to remain stable over time at substantial levels among women practicing RAI, and higher in VOICE (at risk women) than in HVTN 907 (FSW), which could explain why the estimated risk of acquiring HIV due to RAI among women consistently practicing RAI over time was high.
In VOICE, the only study which provided sufficient information to conduct all adjusted statistical analysis, the estimates of the magnitude of association were larger for exposure definitions that measured more precise (time-varying) and more consistent RAI exposures, as hypothesized, albeit not necessarily statistically significant. The opposite was found for RV 217 where, contrary to our hypothesis, reporting RAI at baseline was more strongly associated with HIV incidence than when using follow-up data to define RAI exposure. Our estimates are in line with pooled African estimates from the Stannah at al. review, where the crude and adjusted measures of association were 1.2 (0.9 − 1.5) and 2.3 (0.8 − 6.4), respectively, based on 13 studies [16]. In the review, more precise definitions of RAI exposure were also not associated with higher increase in HIV incidence. The lower magnitude of the association during VOICE compared to RV 217 and HVTN may be partly due to the higher incidence of HIV during the study (when risky behaviors are not needed to lead to HIV infection because of higher prevalence among partners or other risk factors among women, their association with HIV incidence is diminished), as well as less precise HIV testing algorithm compared to RV 217.
Limitations to our analysis are primarily due to the low HIV incidence during the RV 217 and HVTN 907 observational incidence studies and limitations on the RAI data and condom use during RAI and RVI. Only 12 incident infections occurred during the HVTN 907 study, and if 34 infections occurred in the Ugandan and Tanzanian RV 217 study sites, only 22 of them occurred among individuals reporting data during follow-up, which reduced our ability to assess the effect of RAI practice since RV 217 and HVTN 907 data could not be combined due to large differences in behavior and HIV measurements. The reliability of the estimated dates of HIV infection depended on the frequency and type of HIV tests used, which were rapid tests used monthly and every 6 months in the case of VOICE and HVTN, respectively, whereas RV 217 used RNA tests twice a week, minimizing the risk of misclassification bias.
Despite efforts and improvements in the methods of data collection, RAI may still be not accurately reported by participants [17]. This might be especially true here since the meaning of RAI is particularly ambiguous in several Southern Africa local languages [17, 32]. The VOICE and RV 217 studies relied on ACASI techniques that may yield higher RAI prevalence estimates, for example due to reduced social desirability biases [3, 33], but this technique does not allow the interviewer to ensure respondents have understood the question well. However, in our sensitivity analysis, more accurate translation of RAI practice questions in local languages on the ACASI questionnaire [23] and reduced possibility of misclassification biases did not result in higher estimates of the RAI prevalence and magnitude of HIV association. The reported fraction of acts that were RAI was not associated with HIV incidence during VOICE, which could be partly due to the inconsistency in the recall periods used to measure RAI and RVI; the number of RVI was reported over only one week compared to 3 months for RAI, leading to significant number of women not reporting RVI but reporting RAI, potentially overestimating the RAI fraction. Misclassification bias was more likely in the RV 217 analysis since the recall period for the question on RAI practice was shorter (3 months) than the time period (6 months) between two behavioral assessments. Finally, condom use during RAI was asked at last sex during surveys, which did not allow us to fully control for it in our statistical models.
Our study has several strengths. Our analysis benefitted from longitudinal data from different studies and contexts, rarely fully described in the literature [19]. Although our analysis improves on estimates of association from cross sectional studies, which are more likely to lead to reverse causation (past HIV infection could explain changes in behaviors), it also highlighted persistent challenges in estimating RAI and its associated HIV risk. Our analyses of the HIV incidence were adjusted on several important cofactors such as number of partners or condom use, and other higher risk practices such as sex work and injecting drugs, leading to more reliable estimates of association. Condom use was available at last sex (or RVI), but also at last RAI specifically for VOICE and RV 217. In VOICE, the levels of condom use at last RVI and last RAI were similar (Figure S9), whilst during RV 217 condom use (reported at last intercourse) was less frequent among RAI + women compared to RVI-only women (which was accounted for by our statistical models), but condom use by RAI + women during RAI was similar to during RVI (Table S1). However, available data did not allow control for the HIV status of the participants’ male partners which was not known. It is possible that the lack of association between RAI and HIV incidence could be due to residual confounding due to unmeasured demographic characteristics and HIV status (including viral load suppression) of the clients of the study participants being able to afford paying for RAI (in one study with African sex workers, charges for RAI were greater than for RVI [12]). Importantly, none of the studies recorded where ejaculation occurred during RAI and RVI, a factor influencing HIV acquisition risk. Estimates suggest that per-act HIV acquisition risk is ~ 3-fold higher when ejaculation occurs in the rectum or vagina, compared to withdrawal [34, 35]). Overall, the modest magnitude of associations estimated during our study was slightly lower than hypothesized based on the large differences in pooled estimates of per-act HIV acquisition probabilities between RAI and RVI from meta-analytic reviews, when also considering the fractions of sex acts which are RAI among VOICE and HVTN 907 participants. For example, assuming that 25% of sex acts of women practicing RAI are anal (i.e. 75% of acts are RVI), and that the per-act HIV acquisition probability is 5-fold higher during RAI than RVI, would lead to a 1.9-fold increase in HIV incidence rate among women practicing RAI compared to women only practicing RVI. This suggest that more data is still needed to better measure these HIV per-act acquisition probabilities and risks, especially within the context of recent scale-up of HIV prevention and treatment tools which can have different efficacies during RAI and RVI.
In conclusion, RAI was prevalent in the three cohorts analyzed for this study and its practice and frequency should be more systematically and more precisely recorded and reported by studies looking at sexual behaviors and HIV seroconversions, using standardized measures, culturally adapted study instruments and confidential interview methods. In particular, more data on the fraction of sex acts, or condomless sex acts, which are RAI (instead of the sole history of RAI practice) could help better understand RAI magnitude, its individual and contextual determinants, as well as its contribution to incident HIV as a public health problem [19].
Data Availability
The data and material analyzed can be obtained following specific procedures.
Code Availability
The code used for the presented analysis is available for review upon request.
References
McBride KR, Fortenberry JD. Heterosexual anal sexuality and anal sex behaviors: a review. J Sex Res Mar. 2010;47(2):123–36.
Voeller B. AIDS and heterosexual anal intercourse. Arch Sex Behav Jun. 1991;20(3):233–76.
Owen BN, Elmes J, Silhol R, et al. How common and frequent is heterosexual anal intercourse among South Africans? A systematic review and meta-analysis. J Int Aids Soc Jan. 2017;11(1):1–14.
Baggaley RF, White RG, Boily MC. HIV transmission risk through anal intercourse: systematic review, meta-analysis and implications for HIV prevention. Int J Epidemiol Aug. 2010;39(4):1048–63.
Halperin DT. Heterosexual anal intercourse: prevalence, cultural factors, and HIV infection and other health risks, part I. AIDS patient care and STDs Dec. 1999;13(12):717–30.
Owen BN, Brock PM, Butler AR, et al. Prevalence and frequency of heterosexual anal intercourse among Young People: a systematic review and Meta-analysis. Aids Behav Jul. 2015;19(7):1338–60.
Baggaley RF, Dimitrov D, Owen BN, et al. Heterosexual anal intercourse: a neglected risk factor for HIV? Am J Reprod Immunol Feb. 2013;69(Suppl 1):95–105.
Morhason-Bello IO, Kabakama S, Baisley K, Francis SC, Watson-Jones D. Reported oral and anal sex among adolescents and adults reporting heterosexual sex in sub-saharan Africa: a systematic review. Reprod Health May. 2019;6(1):48.
Reynolds GL, Fisher DG, Rogala B. Why women engage in anal intercourse: results from a qualitative study. Arch Sex Behav May. 2015;44(4):983–95.
Baggaley RF, Owen BN, Silhol R et al. Does per-act HIV-1 transmission risk through anal sex vary by gender? An updated systematic review and meta-analysis. Am J Reproductive Immunol Nov 2018;80(5).
Boily MC, Baggaley RF, Wang L, et al. Heterosexual risk of HIV-1 infection per sexual act: systematic review and meta-analysis of observational studies. Lancet Infect Dis Feb. 2009;9(2):118–29.
Maheu-Giroux M, Baral S, Vesga JF, et al. Anal intercourse among female sex workers in Côte d’Ivoire: prevalence, determinants, and model-based estimates of the Population-Level Impact on HIV Transmission. Am J Epidemiol. 2017;187(2):287–97.
McGowan I, Taylor DJ. Heterosexual anal intercourse has the potential to cause a significant loss of power in Vaginal Microbicide Effectiveness Studies. Sex Transm Dis Jun. 2010;37(6):361–4.
Masse BR, Boily MC, Dimitrov D, Desai K. Efficacy dilution in randomized placebo-controlled vaginal microbicide trials. Emerg themes Epidemiol. 2009;6:5.
Boily MC, Dimitrov D, Karim SSA, Masse B. The future role of rectal and vaginal microbicides to prevent HIV infection in heterosexual populations: implications for product development and prevention. Sex Transm Infect Dec. 2011;87(7):646–53.
Stannah J, Silhol R, Elmes J et al. Increases in HIV Incidence following receptive anal intercourse among women: a systematic review and Meta-analysis. Aids Behav Sep 4 2019.
Duby Z, Hartmann M, Mahaka I, et al. Lost in translation: Language, Terminology, and understanding of Penile-Anal Intercourse in an HIV Prevention Trial in South Africa, Uganda, and Zimbabwe. J Sex Res Nov. 2015;13:1–11.
Peebles K, van der Straten A, Palanee-Phillips T, et al. Brief report: anal intercourse, HIV-1 risk, and efficacy in a trial of a Dapivirine Vaginal Ring for HIV-1 Prevention. J Acquir Immune Defic Syndr. 2020;83(3):197–201.
Owen BN, Baggaley RF, Maheu-Giroux M, et al. Patterns and trajectories of Anal Intercourse Practice over the Life Course among US women at risk of HIV. J Sex Med Sep. 2020;17(9):1629–42.
Owen BN, Baggaley RF, Maheu-Giroux M et al. Longitudinal determinants of anal intercourse among women with, and without HIV in the United States. Bmc Womens Health Jul 14 2022;22(1).
Robb ML, Eller LA, Kibuuka H, et al. Prospective study of Acute HIV-1 infection in adults in East Africa and Thailand. New Engl J Med Jun. 2016;2(22):2120–30.
Palanee-Phillips T, Schwartz K, Brown ER et al. Characteristics of women enrolled into a Randomized Clinical Trial of Dapivirine Vaginal Ring for HIV-1 Prevention. Plos One Jun 10 2015;10(6).
Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-Based Preexposure Prophylaxis for HIV infection among african women. New Engl J Med Feb. 2015;5(6):509–18.
Montgomery ET, Mensch B, Musara P, et al. Misreporting of product adherence in the MTN-003/VOICE Trial for HIV Prevention in Africa: participants’ explanations for dishonesty. Aids Behav Feb. 2017;21(2):481–91.
Deschamps MM, Metch B, Morgan CA, et al. Feasibility of identifying a female sex worker cohort at high risk of HIV infection in the Caribbean for HIV Vaccine efficacy trials: longitudinal results of HVTN 907. Jaids-J Acq Imm Def Jan. 2016;1(1):70–7.
Cox DR. Regression models and life-tables. J R Stat Soc B. 1972;34(2):187–.
Fisher LD, Lin DY. Time-dependent covariates in the Cox proportional-hazards regression model. Annu Rev Public Health. 1999;20:145–57.
R Core Team. R: A Language and Environment for Statistical Computing. 2013; http://www.R-project.org.
Owen BN, Baggaley RF, Elmes J, et al. What proportion of female sex workers practise anal intercourse and how frequently? A systematic review and Meta-analysis. Aids Behav Mar. 2020;24(3):697–713.
Elmes J, Silhol R, Hess KL, et al. Receptive anal sex contributes substantially to heterosexually acquired HIV infections among at-risk women in twenty US cities: results from a modelling analysis. Am J Reprod Immunol Aug. 2020;84(2):e13263.
Barnett AG, van der Pols JC, Dobson AJ. Regression to the mean: what it is and how to deal with it. Int J Epidemiol. 2004;34(1):215–20.
Gorbach PM, Mensch BS, Husnik M, et al. Effect of computer-assisted interviewing on self-reported sexual Behavior Data in a Microbicide Clinical Trial. Aids Behav Feb. 2013;17(2):790–800.
Phillips AE, Gomez GB, Boily MC, Garnett GP. A systematic review and meta-analysis of quantitative interviewing tools to investigate self-reported HIV and STI associated behaviours in low- and middle-income countries. Int J Epidemiol Dec. 2010;39(6):1541–55.
Jin F, Jansson J, Law M, et al. Per-contact probability of HIV transmission in homosexual men in Sydney in the era of HAART. Aids Mar. 2010;27(6):907–13.
Devincenzi I. Longitudinal-study of human-immunodeficiency-virus transmission by Heterosexual Partners. New Engl J Med Aug. 1994;11(6):341–6.
Acknowledgements
The authors would like to express heartfelt appreciation to Dr Peter Anton from the University of California, Los Angeles and Dr Edith Swann from the US national institute of health for their support and comments on the project. We would also like to thank Dr Mike Chirenje from the University of Zimbabwe and Dr Barbra Richardson from the University of Washington for providing insight on the VOICE trial.
Funding
This work was partly supported by the HPTN Modelling Centre, which is funded by the U.S. National Institutes of Health (NIH UM1 AI068617) through HPTN. RS and MCB acknowledge funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 programme supported by the European Union.
MTN 003 (VOICE): funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615, UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health.
RV 217: This work was supported by a cooperative agreement (W81XWH-18-2-0040) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DOD). This research was funded, in part, by the U.S. National Institute of Allergy and Infectious Diseases. Material has been reviewed by the Walter Reed Army Institute of Research. The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army, the Department of Defense, or HJF. The investigators have adhered to the policies for protection of human subjects as prescribed in AR 70 − 25.
HVTN 907: This research was supported by the HIV Vaccine Trials Network, which is funded through a cooperative agreement with the Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health, grants UO1AI068614, UO1AI068635, UO1AI068618, U01AI069415, 5U01AI069421, and 5U01AI069486.
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health Award [Grant Numbers R01AI057020 and UM1AI068619]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Centers for Disease Control and Prevention.
For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising.
Author information
Authors and Affiliations
Contributions
The study was conceptualized and designed by RSi, JE, and MCB. Data analysis was performed by RSi, AN, and RSt. RSi, JE, MCB, MMG and DD contributed to data interpretation. The first draft of the manuscript was written by RSi, AN, and JE and commented and edited by MCB, MMG, and DD. All authors commented on the following versions of the manuscript, data interpretation, and overall message. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflicts of Interest
The authors have no conflicts of interest to disclose. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Ethics Approval
Ethics Approval was obtained for VOICE, for RV 217, and for HVTN 907. Further ethics approval was obtained from Imperial College London (approval # 16IC3667).
Consent to Participate
Written informed consent was obtained from all participants in the study.
Consent for Publication
Not applicable.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Silhol, R., Nordsletten, A., Maheu-Giroux, M. et al. The Association Between Heterosexual anal Intercourse and HIV Acquisition in Three Prospective Cohorts of Women. AIDS Behav 27, 4010–4021 (2023). https://doi.org/10.1007/s10461-023-04115-y
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10461-023-04115-y