A meta-analysis of the efficacy of HAART on HIV transmission and its impact on sexual risk behaviours among men who have sex with men

Evidence showed preventive impacts of the highly active antiretroviral therapy (HAART) on the Human Immunodeficiency Virus (HIV) transmission amomg heterosexual population, however, that is of deficit among men who have sex with men (MSM). The aim was to systematically examine the efficacy of HAART on HIV transmission and the association between the HAART initiation and unprotected anal intercourse (UAI) in MSM population. Three electronic databases were fully searched for articles published in peer-reviewed journals between 1996 and 2017. Of 1616 identified articles, fifteen articles were eligible for meta-analyses. The summary incidence rate (IR) of HIV was 6.63/100 person-year (95%CI 2.06–11.20/100 person-year)(p = 0.004). The pooled per-contact rate (PCR) of HIV was 0.42% (95% CI 0.21–0.63%)(p < 0.05). The HAART initiation (vs non-HAART) was not associated with engaging in UAI, with odds ratio (OR) 1.09 (95% CI 0.90–1.34)(p > 0.05). In the stratified analysis, participants with no less than 6 months recall period was slightly more likely to engage in UAI (OR 1.32; 95% CI 1.01–1.74)(p < 0.05). It indicated that HAART has potential efficacy on reducing infectivity of HIV positive individuals in anal intercourses. The relationship between the HAART initiation and UAI was not significant and may be influenced by some social-demographic factors. Consistent condom use and education on safe sex among MSM are crucial.

MSM population is uncertain and may be influenced by many factors. For instance, some researchers pointed that the unstable and weak relationship between MSM may avert the preventive effect of the HAART 7 . In addition, the viral load remained at high level in rectal tissues, even though it has been suppressed at an undetectable level in plasma 13,14 . Hence, behavioural factors like condomless anal intercourses may induce negative impact on the TasP 15 . In contrast, a prospective cohort study illustrated none HIV negative participants were linked-infected by their HIV positive partners via unsafe sex 16 .
It is imperative to fill the gap with specific evidences of the efficacy of TasP on HIV transmission in MSM. Detecting the association between UAI and HAART and potential influential factors for UAI would help researchers and policy-makers tailored their public health projects for this sub-group population. In this meta-analysis, the term HIV is represented the HIV-1 type infection.
The aim of this systematic review and meta-analysis was twofold: 1) to examine the efficacy of HAART on the risk of HIV transmission among MSM, 2) to examine the likelihood of engaging in sexual risk behaviours which measured as UAI among MSM while HAART initiation.

Results
Characteristics of studies. Eighteen studies published between 2001 and 2006 were initially involved in the meta-analysis. Excluding 3 qualitative researches, 7 cross-sectional studies and 8 cohort studies were finally rolled in further analysis, contributing to an overall study population of 26040. Data were collected at clinical sites or gay communities via self-administrated questionnaires and medical records. Over half of the studies (8/15) adopted the 6-month recall period. Three articles [17][18][19] from the same prospective national cohort were also included due to different study periods and samples ( Table 1). The median of sample size (n = 14) was 714.5 (IQR 1410), ranging from 155 to 12573. Researches mainly conducted in developed countries (i.e. UK, Australia and USA, n = 12). The majority of the participants (91.83%) were HIV positive status. The median age of MSM (n = 12) ranged from 28 to 45, with mean age 35.7 ± 4.44 y. Ten studies reported ethnicities of participants, mainly consisting of white (80%, n = 16150), the others were Asians, African Americans and Latino/Hispanic. Nearly half of the participants   www.nature.com/scientificreports www.nature.com/scientificreports/ (Fig. 3). The heterogeneity test showed wide heterogeneous across studies (p < 0.05, I 2 = 85.82), thus, the random-effects model was used. The overall effect size was not influenced by removing single effect sizes when running the sensitivity analysis. There was no evidence of publication bias investigated by the Egger's regression intercept (p > 0.05).
By previous literature review, we stratified data into sub-analyses (Table 4). On HAART group (vs non-HAART) with the recall period over 6 months had more slightly likelihood of engaging in UAI (OR 1.32; 95% CI 1.01-1.74, p < 0.047). While the other factors (i.e. study setting, Data collection method) remained none association between two variables (HAART and UAI).

Discussion
Effects of HAART on HIV infectiousness. Few international studies examined the IR among MSM before HAART therapy adopted. Therefore, comparable groups' data (non-HAART) in most researches were absent.
In general, the pooled IR (6.63/100 person-year, p < 0.05)) in our meta-analysis was within the range of the incidence rate of HIV (1.2 to 14.4/100 person-year) in MSM population reported by WHO 24 . The overall weighted IR was highly influenced by the number contributed from Brazil 25 . This extreme data indicated that the risk of HIV transmission among MSM may be different within distinct regions. However, the assumption, whether the diversity of IR came from different samples or it was only an extreme case, needs further proof.
A prospective cohort study among four effect sizes demonstrated that the HAART had a preventive effect on HIV transmission via condomless anal intercourse at the individual-level 16 . It moderated the infectivity of HIV positive individuals 17 . However, at the population level, studies calculated the HIV IR in the era of pre-HAART and post-HAART seperately showed an increasing trend during 1991 and 2001 in Netherland 26 . This contradicted phenomenon revealed that there might be some environmental factors around MSM influence the preventive impact of HAART, even averted the preventive efficacy at this population.
The PCR refers to the probability of one person be infected by their sexual partners while exposed at a certain sexual pattern, measured as infectivity (β) of HIV 7 . Porco and colleagues (2004) calculated 60% decrease of the PCR of per-partnership in the post-HAART era compared with that in the pre-HAART era 27 . An across-country prospective cohort study (Opposites Attract study) investigated that the HAART had a positive impact on diminishing the infectivity of HIV viral hosts by suppressing the viral load in the plasma under 200 copies/ml (0 linked-infection, unpublished data), which is similar with that found by Rodger. AJ et al. 16 . Those optimistic findings were only shown between steady sexual relationships. However, evidences displayed that homosexual males were more prone to be involved in polygamous and vulnerable relationships 4 , which may contribute part of reasons for the uncertain efficacy of HAART on MSM. In addition, this research showed that the overall β of UAI is not zero even the HAART initiated. Thus, keep encouraging condom use among MSM is indispensable to prevent the HIV transmission. Researches have been proved that the preventive impact of condom use on HIV/STI transmission was effective if a person practices sexual activities with condoms all the time 28 . Consistently expanding HAART on MSM could be one approach to control the epidemic of HIV, which potentially decreases the average infectivity of the total population. Monitoring and guaranteeing the adherence of HAART intake should be a supplementary approach to maximise the impact of HAART.
Association between HAART and UAI. The pooled effect size of the third meta-analysis showed the HAART would not influence the people's choice on condom use during sexual activities. However, in the stratified analysis, participants had sexual experience no less than previous 6 months were more likely to engage in UAI (p = 0.047) compared with that within past 3 months, which implies that the frequency of sexual intercourses may influence the association between UAI and HAART. On the other hand, there may be a recall bias, since participants with longer recall period had higher chance to be vague on the memory of past sexual experiences. The reduction of self-reported reliability of sexual behaviours was also reported in the study of Napper (2009), which mentioned this reduction could be detected if the recall period beyond 6 months 29 . However, Napper pointed out that this finding needs further proof on anal intercourses 29 .
Confounders in the third meta-analysis were probably multiple and probably involve both socio-demographic and individual sides. The age, income and educational level, alcohol and drug abuse have been found to be significantly associated with engaging in UAI, indicating that people are at both young and old age, with lower education, successive alcohol drinking and substance (i.e. "popper") use before or during sex were more likely to engage in UAI 18,[20][21][22]30,31 . The high income was found to be the risk factor for engaging UAI 21 . However, the lower income group held optimistic beliefs on the preventive impact of HAART 20 . Some researchers believed that people held positive beliefs on the HAART was more likely to engaging in UAI 17,20 . This psychological construction also found in the research of Huebner. DM and Gerend. MA. (2001), pointing out that the HIV infected MSM who believed HAART has the preventive capability were more prone to take UAI, especially with casual sexual partners 32 . Therefore, consistent providing knowledge about safe sex, such as the limitation of TasP strategies and the importance of condom use in anal sex, is essential in the post-HAART era. However, the "condom fatigue", referring to people get tired of health education on condom use and lag to change sexual risk behaviours, was mentioned in both Cox. J. (2004) and Brennan. DJ. (2010) researches, which may decrease the efficacy of safe sex education in the long-term run 20,21 .

Conclusion
Even though the information of HAART on MSM is limited and HAART preventive efficacy on HIV transmission among MSM was hardly draw a robust conclusion at this stage, this meta-analysis was the first aggregated quantitative research focused on the HIV transmission among MSM and provided specific information of this public health issue. Individual epidemiological findings have illustrated an optimistic opportunity for TasP to (2020) 10:1075 | https://doi.org/10.1038/s41598-019-56530-8 www.nature.com/scientificreports www.nature.com/scientificreports/ control the epidemic of HIV in community. However, since related information was scarce, further researches could emphases on its efficacy on population-level and detect potential influential factors. Also, data were mainly contributed from open societies like the USA and Europe, researchers and public health policy-makers from other regions should interpret those findings carefully in local contexts. In our meta-analysis, we reviewed social and individual factors that may confound the relationship between HAART and UAI. However, the impact of characteristics of HAART was not mentioned, including the adverse effect and drug resistance. Therefore, we encourage future studies could be designed more comprehensively to explore the relationship between HAART and UAI in MSM.

Limitations
There are some limitations in this meta-analysis. First, this meta-analysis did not include unpublished articles due to limited accessible literature resources. Also, we excluded non-full articles because we did not access original data. Second, there are wide heterogeneities. We did not perform a stratified analysis for the meta-analysis of the HAART efficacy since the total number of effect sizes was too few to conduct the sub-group analysis. However, we conducted a stratified analysis for the third meta-analysis to examine the influential factors. Third, participants included in the meta-analysis were skewed on western countries and open societies. In  www.nature.com/scientificreports www.nature.com/scientificreports/ eastern countries, cultures and social structures would be different. For instance, in some countries in Africa and Asia, admitting self-identities as gay are still illegal 2 . Hence, findings of this meta-analysis need carefully and cautiously to generalize into different contexts. In addition, due to few HIV data of MSM collected in Asian and African countries, we encourage further researches to turn eyes on investigating reasons behind this phenomenon, help policy-makers in those countries formulate public health policies on HIV interventions and devote to changing this social issue. Fourth, we reviewed the social and individual factors that may confound the relationship between HAART and UAI, however, the impact of characteristics of HAART was not mentioned, including the adverse effect and drug resistance. Fifth, there are a few biases in the meta-analysis. Data were collected from self-reports, which would introduce a recall bias. Participants recruited from clinics  www.nature.com/scientificreports www.nature.com/scientificreports/ may introduce the selection bias, since people who attended to clinics may be more care about their health and this self-awareness may overestimate the efficacy of HAART on the HIV incidence and sexual behaviours in the overall MSM population.

Materials and Methods
Screening and inclusion criteria. The following criteria were carried out for literature research: 1. Participants were over 18 years old (including 18) or defined as adults according to National Laws. 2. Participants were homosexual males, self-identified as gay or engaging in male-to-male sexual behaviours regardless of original sexual orientation. 3. HAART were exposed on HIV positive rather than negative participants. 4. Studies performed to examine 1) the risk of HIV transmission, and/or 2) any types of UAI (i.e. receptive or insertive). 5. Studies published as journal articles in English with peer reviewed. 6. Full text articles are available online. Screening. 2327 articles were found and 1616 articles were remained for further examination after removing duplications. Titles or abstracts were excluded if relating to: (1) irrelative study purposes: psychological and mental health,virology, health economics and policy, other STIs and AIDS-related diseases, drug resistance, belief or attitudes towards safe sex rather than behavioural changes, characters of participant, HAART scaling-up strategies. (2) irrelative exposures (HAART) or study groups: PrEP or PEP, alternative interventions (i.e. behaviours, partner notification, testing and counselling),heterosexual or women participants only. (3) irrelative study design: molecular epidemiology, qualitative researches, grey articles, news and reviews.
As a result, 75 articles were left for eligibility assessment via full text reviewed. The following principles were used to guide the full text article screening of this meta-analysis: 1. Studies performed to examine the efficacy of HAART on HIV transmission and/or the relationship of HAART and the UAI irrespective types of sexual patterns and partners. 2. Studies were focused on the change of actual sexual behaviours rather than the change of attitudes towards sexual behaviours. 3. If participants were made up of mixed subgroups (i.e. homosexual, heterosexual and bisexual), the subgroup of homosexual males or male couples would be included in this meta-analysis. 4. If the database overlapped between articles, with similar research purposes, the one contained the widest range of data would be included. 5. Outcomes were measured for HIV incidence or the likelihood of engaging UAI. 6. The ecological studies would not be included, because exposures were multiple and aggregated, potential confounders and the ecological fallacy may contribute great heterogeneity to the pooled analysis 33 .
57 articles were excluded via full text screening with following reasons listed in the Fig. 4. Finally, eighteen articles were included in this quantitative analysis. However, data presented in three articles were not eligible for meta-analyses 27,34,35 . Two studies measured by the incidence per year, which was not comparable with other studies 34 . The other study measured the association between HAART and HIV transmission risk by rate ratio (RR) was hardly fitted into the third meta-analysis 35 . Thus, there were fifteen full text articles enrolled in the final data analysis. This systematic review was carried out according to guidelines by PRISMA checklist 36 . The PRISMA flaw chat for the data selection procedure has been followed and presented in Fig. 4 If both adjusted and unadjusted effect sizes were reported by independent studies, the unadjusted one would be included for the meta-analysis. Additionally, if the effect size was stratified by regions or types of sexual patterns, the sub-level number would be added into the meta-analysis. The extracted items listed in standard forms (Tables 1, 2, 3 and 5) were tested by three different pilot studies 21,22,37 . Data analysis. Three independent meta-analysis were performed. The pooled risk of HIV transmission was measured separately by the IR (the number of new infections divided by at risk population over specific time) and the PCR (estimation based on Bernoulli model or boost rapping algorithm likelihood function) with 95% CI. The pooled OR with 95% CI was used to estimate the association between HAART and UAI, representing the probability of engaging UAI between the on-HAART group (index group) and the non-HAART group (reference group). The baseline data in cohort studies were included in meta-analysis. If OR is over 1, it represented that the index group is more likely to engage in UAI than the reference group. Otherwise, the index group is less likely to engage in UAI (OR < 1). If OR = 1, it means there is no association between both variables.

PRISMA 2009 Flow Diagram
Records idenƟfied through database searching (n = 2327) 1540 arƟcles were found in PubMed 198 arƟcles were found in ScienceDirect 589 arƟcles were found in Google Scholar    Table 5. Characteristics of studies tested the association between HAART and UAI.