10 1111@tbed 13621

Accepted Article
DR. EKRAM WASSIM ABD EL-WAHAB (Orcid ID : 0000-0003-4220-5859)
Article type : Review
Attributes of HIV infection over decades (1982-2018): A systematic review and meta-analysis
Ahmed F. Kabapy 1, 2, Hanan Z. Shatat 3, Ekram W. Abd El-Wahab 3^
1 Fellow of Tropical Health Department, High Institute of Public Health, Alexandria University, Egypt
2 Department of Endemic and Infectious Diseases, Alexandria Fever Hospital, Egypt
3 Department of Tropical Health, High Institute of Public Health, Alexandria University, Egypt
^To whom correspondence should be addressed:

Ekram W. Abd El-Wahab
Address: Tropical Health Department, High Institute of Public Health
165 El Horreya Road, 21561 Alexandria, Egypt
Email: [email protected]
Tel: +201110456072
Running title: Meta-analysis of HIV risk factors
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/tbed.13621
This article is protected by copyright. All rights reserved
Accepted Article
Abstract
Understanding the risk factors for HIV infection is the foundation of successful preventive strategies, which
must bundle sociocultural, behavioural and biomedical interventions to halt disease transmission. We aimed in
this study to provide a pooled estimation of HIV risk factors and trace changes across decades in order to drive
consensus and accurate assessment of disease transmission risk.
We comprehensively searched PubMed, ISI Web of Knowledge, Medline, EMBASE, ScienceDirect, Ovid,
EBSCO, Google Scholar and the Egyptian Universities Library Consortium from October-December 2018.
Two independent reviewers extracted data from eligible studies. Funnel plots were inspected to identify
publication bias. Heterogeneity across studies was checked using the Q and I2 statistics. The results were
reported based on the pooled odds ratio (pOR) with 95% CI using a random-effects model. Meta-analysis of
HIV risk factors revealed a superior role for risky sexual practices (unprotected vaginal/anal sex), injecting
drug use (IDU), sharing needles, sexually transmitted infections (STIs), child sexual abuse, and vertical
transmissions. Trends across decades (1982 – 1999 and 2000 – 2018 respectively) showed rising evidence for
prostitution [pOR (95% CI)= 2.3 (1.12 – 4.68) vs 2.69 (1.67 – 4.32)] and men who have sex with men (MSM)
[pOR (95% CI)= 2.28 (1.64 – 3.17) vs 3.67 (1.88 – 7.17)], while transmission through IDU [pOR (95% CI)=
3.42 (2.28 – 5.12) vs 2.16 (1.74 – 2.70)], alcoholism [pOR (95% CI)= 2.35 (0.73 – 7.59) vs 1.71(1.08 – 2.72)],
and sharing syringes [pOR (95% CI)= 6.10 (2.57 – 14.5) vs 2.70 (2.01 – 6.35)] showed notable decline. Harm
reduction programs and condom use have been recognized as chief HIV prevention strategies, while male
circumcision contributed a partial role. Collectively, sexual risk factors continue to be a key driver of the global
HIV epidemic. Persistent and emerging risk factors identified in our analysis should constitute the primary
targets of HIV prevention programmes to accelerate efforts towards HIV elimination.
Keywords: Meta-analysis; HIV; Risk factors; Dynamics; Transmission

Accepted Article
Summary box
What is already known on this subject:
1. Sexual contact, IDUs and vertical transmission are established major risk factors
2. Negligible role of blood transfusion, organ transplantation and medical procedures
3. None is specific about Egypt
What does this study add:
1. The pace of HIV transmission is refolding, but major risks are continuing
2. Sociocultural factors are driving the HIV epidemic and sexual promiscuity has become the
cornerstones of HIV transmission
3. Condom use and harm reduction are key pillars of HIV prevention
Policy Implications Box
This study combined data across epidemiological studies to drive consensus and accurate assessment of
HIV transmission risk. Attention must be paid for behavioral and sociocultural determinants of disease
transmission. New intervention programs must be implemented to halt the transmission of HIV based on
the evidence‐based emerging risk factors that started to take considerable roles over the recent years.

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Introduction
Human immunodeficiency virus (HIV) infection is one of the world’s most serious public health
challenges, having claimed more than 35 million lives [31.1 million–43.9 million], with 1.8 million [1.4
million–2.4 million] new infections and approximately 1 million HIV-related deaths occurring per year (Bain,
Nkoke, & Noubiap, 2017; UNAIDS, 2018).
The risk of HIV transmission differs according to the location, customs and culture of the population
and according to couples’ biological and behavioural factors. Important biological factors include the viral
load, other sexually transmitted infections (STIs), and placental inflammation (Antonovics et al., 2017).
Behaviours and conditions that put individuals at greater risk of contracting HIV include having unprotected
anal or vaginal sex; prostitution; sharing contaminated needles, syringes or drug solutions when injecting
drugs; and medical procedures that involve unsterile cutting or piercing (Baral et al., 2015; Bourne, Reid,
Hickson, Torres-Rueda, & Weatherburn, 2015; Kelley et al., 2017; Patel et al., 2014). Oral sex and kissing
were associated with low transmission risk (T. R. Glynn, Operario, Montgomery, Almonte, & Chan, 2017), and
condom use was found to be protective (Smith, Herbst, Zhang, & Rose, 2015).
Key populations are groups who are at increased risk of HIV regardless of epidemic type or local
context. These groups include men who have sex with men (MSM), injecting drug users (IUDs), prisoners,
street children, sex workers and their clients, and transgender people particularly transgender women. Key
populations are often affected by legal and social challenges related to their behaviours which increase their
vulnerability to HIV and reduce access to testing and treatment programmes. In 2017, an estimated 47% of new
infections occurred among key populations and their partners (UNAIDS, 2018).
Multiple strategies are being adopted to halt the spread of HIV, such as abstinence, limiting the number
of sexual partners, safe injection sites and needle exchange programmes, correct and consistent condom use,
pre-exposure prophylaxis (PrEP) for high-risk groups, and post-exposure prophylaxis (PEP) (Cohen et al.,
2016; Fisher et al., 2018; Luba et al., 2017).
To implement effective HIV programmes, data that reflect current HIV epidemiology are required.
Combining data across epidemiological studies will substantially drive consensus and accurate assessment of
HIV transmission risk in a way that takes into account multiple co-factors and their variation over time. This
approach will help target preventive efforts and improve the application of such risk-reduction strategies. This
meta-analysis aimed to provide a pooled estimation of HIV risk factors across decades.
Methods

Formulation and registration
Accepted Article PRISMA checklist was used in the formulation of the systematic review and meta-analysis context
(File S1) (Moher et al., 2015). The systematic review was registered on the PROSPERO prospective register of
systematic reviews after piloting of the study selection process (registration number PROSPERO 2019:
CRD42020144838)
Data sources and search strategy
A detailed literature review for all available literature on HIV transmission (published or Epub Ahead
of Print between 1982 - 2018 was carried out. The following sources were searched for original research
studies and review articles: Medline, ISI Web of Knowledge, and the Cochrane Database of Systematic
Reviews. Identification of robust studies published in the English language and quantifying the extent to which
a particular factor had increased or decreased HIV transmission were included in the analysis.
The searches were done using the appropriate keywords of human immunodeficiency virus, HIV,
acquired immunodeficiency syndrome, AIDS, risk factors, determinants, predictors, transmission,
epidemiology, vertical transmission, mother-to-child transmission (MTCT), breastfeeding, STIs, hepatitis B
virus (HBV), hepatitis C virus (HCV), MSM, homosexual, female sex workers (FSWs), commercial sex,
transgender, oral sex, injecting/intravenous drug use (IVDU), male circumcision, incarceration/imprisonment,
along with all possible word combinations. Search string was developed using “AND” and “OR” Boolean
operators. Example of search strategy used is describes in File S2. Additional manual searches were performed
using reference lists of relevant articles to find further papers which may be missed in the electronic searching
process. Gray literature search included reviewing unpublished thesis and conference materials, the databases
of the Central Library of Alexandria University and the Egyptian universities libraries’ online repository.
While grey literature was searched, no studies included in the grey literature met the eligibility criteria of the
current review.
Quality assessment and criteria for selection
The relevance of the studies was checked based on their aims and methodology. Articles were selected
for full review if they were relevant to this study question and met the predefined inclusion criteria: i) HIV
acquisition is the outcome analyzed using odds ratios (OR) or relative risk (RR), ii) ascertainment of HIV
status by a reliable test of unknown sensitivity and specificity. The quality of each article was evaluated on the
basis of correct sampling, valid and reliable measurement of exposure, similarity of groups; similarity of
exposure measurement; standard assessment of outcome; appropriateness of statistical analysis, clear ethical
statement. Possible risk of bias (selection, recall, confounding bias, assessment bias) was assessed using the

Risk of Bias Assessment tool for observational studies and RCTs (Clarity group, McMaster University). Each
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domain was allocated one of three possible outcomes: “low risk,” “probable/unclear” and “high risk” (File S3).
Data extraction
All retrieved studies were exported to the EndNote X8 (Thomson Reuters, London) reference manager,
and duplicated studies were carefully removed. Two investigators (AFK & EWAW) independently screened
the titles and abstracts and then performed a full-text review to determine the eligibility of each study. Data
extraction was completed using a standardized form with clear selection criteria. A checklist of necessary
information was provided for all the studies. For each study, we recorded the name of the first author, year of
publication, country of origin, study context (setting, design, period and scope), special group of study
population, comparison groups, sample size, a variety of risk factors, HIV/AIDS prevalence rate, and adjusted
OR/RR with 95% CI. Provisional reports were circulated to all investigators for consensus review. Extracted
data were cross-checked to ensure consistency. Comments and discrepancies were resolved by discussion
between the authors and repeating the procedure or by consulting the third author.
At this stage, 48386 (including 230 hits in Egypt) potentially relevant articles on HIV/AIDS prevalence
and its associated risk factors were entered into the initial list. A total of 4182 articles were omitted after being
identified as duplicates (n=3581), their full text was found to be inaccessible (383), or they were found to be
meta-analyses and review articles rather than original publications (n=218). Studies focused on the assessment
of knowledge, attitude, and practice without the outcome of interest; programme evaluation studies; studies
with only abstracts; case studies; qualitative studies; studies with inadequate information; non-English
language published articles; and citations without full text were considered irrelevant. If an article was deemed
eligible for inclusion, the abstract was reviewed if the full text could not be obtained. Relevant studies
comprised 1387 articles from which 1156 were excluded as they were found to be frequency descriptive
research studies. Finally, 231 research articles were selected as the most relevant and of sufficiently high
quality to be eligible for inclusion in this meta-analysis (Figure 1). Due to the limited number of data points
about the situation in Egypt, we could not separate Egyptian data into a separate group.
The selected articles were separated into 3 groups; the first group studied the prevalence of the risk
factors in each of the exposed and unexposed groups, allowing us to estimate the risk in the study population
via crude OR calculation. The second group estimated the risk using adjusted OR/RR, with a confidence limit
of 95.0%, allowing us to directly use it or the estimated risk in a multivariate regression adjusted for a specific
subgroup when applicable. The third group did not have any data that could be used to estimate risk; this group
was excluded from the study.

A total of 124 risk factors were identified in the different articles and condensed down to 46 factors by
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grouping synonymous variables (File S4). Risk factors with fewer than 2 data points could not be statistically
analysed.
Stratification by time
Data points of the selected risk factors were grouped under two time strata: 1982-1999 and 2000-2018.
The crude pooled odds ratio (pOR) was calculated for each variable in each time period. The basis for time
stratification is the transition between the two time periods, which is based on the following: i) era of highly
active antiretroviral therapy (HAART), ii) setting of the Millennium Development Goals (MDGs) by the
United Nations, with strong commitments to halting the spread of HIV/AIDS and ensuring universal access to
ART for all people in need by 2010 (Prendergast, Essajee, & Penazzato, 2015; Travis et al., 2004), iii)
paradigm shift in perception and awareness of HIV/AIDS.
Assessment of heterogeneity and publication bias
Egger’s linear regression test and funnel plots were used to check the presence of publication bias
across studies (Peters, Sutton, Jones, Abrams, & Rushton, 2006). The studies were sorted from the most precise
to the least precise (according to standard error). Heterogeneity was checked using the Q and I2 statistic which
describes the percentage of observed total variation across studies that is due to heterogeneity rather than to
chance. It is calculated as I2 = 100% × (Q - df)/Q, where Q is Cochran's heterogeneity statistic and df the
degrees of freedom. Negative values of I2 are put equal to zero so that I2 lies between 0% and 100%. A value of
0% indicates no observed heterogeneity. The values of 25-50%, 50-75%, and 75-100% represented low,
moderate and substantial heterogeneity respectively (Higgins, Thompson, Deeks, & Altman, 2003). A funnel
plot was generated when a variable had more than 10 data points (File S5).
Quantitative analysis
The comprehensive Meta-Analysis software (Version 3, USA 2019) and MedCalc software (Version
19.0.5, USA) were used to analyse and graph the data. A meta-analysis using a weighted inverse variance
random-effects model (DerSimonian & Kacker, 2007; Lee, Cook, Lee, & Han, 2016) was constructed. Crude
pOR with the corresponding 95% CIs were calculated for all variables with more than 2 data points. A forest
plot was generated when a variable had more than 2 data points (File S6).
Results
1- Risk factors of HIV infection
Tables 1–4 summarize the key factors influencing HIV transmission based on the eligible
epidemiological studies.

Regarding patient demographics, females were almost as likely as males to report HIV infection
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[pOR= 3.73 vs 3.63, respectively]. Primary or secondary education was associated with a > 1.5 higher risk of
HIV infection relative to no education. Among biologic variables, risk was increased in individuals with low
baseline T4–lymphocyte count [<1,000/cmm] [pOR= 8.5, 95% CI:2.94–24.6], STI [pOR= 2.68, 95% CI: 2.21–
3.27], genital ulcers [pOR= 3.13, 95% CI:2.38–4.13] and HBV infection [pOR= 3.14, 95% CI: 2.07–4.77]. The
cumulative risk revealed for blood transfusion was equivocal [pOR= 1.00, 95% CI: 1.00–1.00] (Table 1).
Community–acquired risky behaviours, including cigarette smoking, alcoholism, IVDU, sharing
syringes and having a partner who is an injecting drug user, were associated with 2–3 times higher odds of
being HIV positive. Harm reduction in terms of safe injection programmes and drug treatment programmes
significantly reduced the risk of acquiring HIV infection [pOR= 0.60, 95% CI: 0.43–0.82] (Table 2).
The odds of having HIV infection increased in relation to history of early sexual intercourse among
adolescent females [pOR= 1.74, 95% CI: 1.36–2.22], incarceration [pOR= 1.61, 95% CI: 1.31–1.97], migration
[pOR= 2.02, 95% CI: 1.52–2.68)], rape [pOR= 1.94, 95% CI: 1.33–2.84], child sexual abuse [pOR= 1.71, 95%
CI: 1.47–1.98)], and having mental illness or depression [pOR= 1.97, 95% CI: 1.43–2.70]. Likewise, higher
risks were linked to prostitution [pOR= 2.5, 95% CI: 1.74–3.60], bisexual partners [pOR= 2.52, 95% CI: 1.31–
5.05], multiple sex partners [pOR= 2.34, 95% CI: 1.91–2.88] and homosexual men [pOR= 3.1, 95% CI: 1.84–
5.22)]. Nevertheless, the risk of HIV acquisition through heterosexual contact [pOR= 1.18, 95% CI: 0.85–1.63]
or having sex with a sex worker [pOR= 1.69, 95% CI: 0.84–3.39] was not statistically significant.
Regarding the sexual promiscuity, receptive anal sex [pOR= 2.58, 95% CI:1.75–3.81] was a significant
determinant of HIV infection compared to insertive anal sex [pOR= 1.4, 95% CI: 0.99–1.98] and oral sex
[pOR= 1.28, 95% CI: 0.72–2.29]. Non–use of condoms and lack of MC increased the likelihood of HIV
infection by >3.5 times, whereas practising MC was an important protective factor [pOR= 0.43, 95% CI: 0.30–
0.61]. Although vaginal douching did not significantly increase the risk of HIV infection, the pooled 95% CI
indicates that any protection that might exist is likely to be very small [pOR= 1.08, 95% CI: 0.60–1.69] (Table
3).
Vertical transmission (VT) appeared to be a strong predictor of HIV acquisition among children [pOR=
3.83, 95% CI: 1.74–8.44]. Maternal–to–child transmission of HIV was seriously enhanced by maternal
smoking [pOR= 1.45, 95% CI: 1.07–1.96], high maternal viral RNA levels (>43,000 copies/mL) [pOR= 3.23,
95% CI: 2.39–4.35], low maternal CD4+ lymphocyte count [pOR= 3.19, 95% CI: 2.30–4.41], placental
membrane inflammation [pOR= 6.15, 95% CI: 2.05–18.4], and very low birth weight <1500 g [pOR= 2.80,
95% CI: 1.39–5.65]. Elective caesarean section (CS) did not seem to protect children against materno-foetal

transmission [pOR= 0.45, 95% CI: 0.17–1.20]. HIV transmission from mother to infant through breastfeeding
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was not statistically significant [pOR= 1.77, 95% CI: 0.85–3.71] (Table 4).
2- Changing dynamics of HIV transmission over decades

There were slight variations towards an increase between early and late time periods (1982 – 1999 and
2000 – 2018 respectively) in the strength of the association between certain risky sexual exposures and HIV
infection. These exposures included prostitution [pOR (95% CI)= 2.3 (1.12–4.68) vs 2.69 (1.67–4.32)] and
MSM [pOR (95% CI)= 2.28 (1.64–3.17) vs 3.67 (1.88–7.17)]. On the other hand, receptive anal sex [pOR
(95% CI)= 2.47 (1.84–3.31) vs 2.63(1.58–4.39)], presence of STIs [pOR (95% CI)= 2.57 (1.91–3.47) vs
2.82(2.17–3.66)], presence of genital ulcers [pOR (95% CI)= 3.15 (2.25–4.41) vs 2.92(1.46–5.85)], child
sexual abuse [pOR (95% CI)= 1.78 (1.19–2.67) vs 1.70 (1.43–2.01)], and vertical transmission [pOR (95%
CI)= 2.89 (1.78–4.69) vs 2.56(1.28–5.14)] remained almost unchanged across the two-time strata. Several
behavioural factors showed notable declines over time, such as IDUs [pOR (95% CI)= 3.42 (2.28–5.12) vs 2.16
(1.74–2.70)], having multiple sex partners [pOR (95% CI)= 2.54 (1.93–3.35) vs 2.27(1.72–3.00)], alcoholism
[pOR (95% CI)= 2.35 (0.73–7.59) vs 1.71(1.08–2.72)], sharing syringes [pOR (95% CI)= 6.10 (2.57–14.5) vs
2.70 (2.01–6.35)], and lack of condom use [pOR= 6.79 vs 2.52] [pOR (95% CI)= 6.79 (6.48–7.12) vs
2.52(1.66–3.85)].
Obviously, harm reduction programs and condom use were chief protective factors against HIV across
early and late time periods. Nevertheless, MC has emerged in the late time periods as a contributing factor in
HIV prevention [pOR= 0.43, 95% CI: 0.30–0.61] (Table 5).
Discussion
Influence of sociodemographic determinates and risky behaviours

Looking carefully at the impact of sex on the risk of HIV infection, the present meta-analysis revealed that
males and females were equally affected. While men accounted for 76% of all adults and adolescents living
with HIV infection, women represent one of the fastest-growing populations infected with HIV, particularly in
rural and smaller communities with high rates of poverty, unstable housing, domestic violence, substance abuse
and poor access to healthcare (Haley & Justman, 2013). Nevertheless, social and behavioural factors could not
fully explain the discrepancy in HIV prevalence between men and women (J. R. Glynn et al., 2001). In fact,
biological sex remains an important factor influencing the risk of HIV infection and viral pathogenesis (Jarrin
et al., 2008). Women tend to have lower viral loads than men with the same or similar CD4+ cell counts during
the early stages of infection, although this had no effect on disease progression or AIDS-related mortality,

probably due to delayed initiation of HAART (Prins, Meyer, & Hessol, 2005). Female sex hormones,
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particularly progesterone, downregulate the number of CCR5 receptors, a crucial cell surface protein for viral
entry (Jarrin et al., 2008; Jiang et al., 2015).
Males were found to have a higher probability of HIV seroconversion (Steffanie A. Strathdee et al.,
2001) as well as late presentation and advanced HIV disease (Jiang et al., 2015) compared with females.
Moreover, HIV risk factors differed markedly by sex. Whereas drug-related risk behaviours and homosexual
activity were commonly associated with acquiring HIV among men, factors consistent with high-risk
heterosexual activities were the main predictors among women (Sabri et al., 2017; Steffanie A. Strathdee et al.,
2001; Steffanie A Strathdee et al., 1998). It is important to note that gender is socially defined and thus can
affect women's access to care and their opportunity to benefit from therapy.
On the other hand, in HIV endemic regions, women are infected at a much younger age than men
(Bekker & Hosek, 2015). Female adolescents are a key population in the HIV epidemic. They were found to be
8 times more likely to be HIV-infected than male adolescents (Dellar, Dlamini, & Karim, 2015), probably due
to biological differences in mucosal immunology at the site of genital HIV exposure, which enhances HIV
susceptibility. More particularly, a pro-inflammatory immune environment and a proportionate increase in
single-cell, columnar genital epithelium may increase susceptibility (Yi, Shannon, Prodger, McKinnon, &
Kaul, 2013). Furthermore, young women are infected by having sex with older experienced men, who might be
infected (Muula, 2008). This observation supports the present findings in which early sexual intercourse among
female adolescents was associated with a 3-fold increased risk of acquiring HIV compared to adults.
It is plausible that HIV infection will shadow the typical pattern of other infectious diseases, largely
affecting deprived and uneducated communities (Michelo, Sandøy, & Fylkesnes, 2006). To gain a better
understanding of the socio-ecological factors that place particular populations at risk for HIV, we found – in
agreement with previous reports – that high literacy was associated with a greater risk of HIV infection (Caraël
& Holmes, 2001; J. R. Glynn et al., 2001; Michelo et al., 2006; Mmbaga, Hussain, et al., 2007). Educational
attainment is linked to higher wealth status, having premarital sex, and increased mobility and travel to urban
areas where HIV prevalence is high and paid sex is more available, although this may vary substantially across
countries (Fortson, 2008). On the other hand, a number of studies suggested that education may play a social
vaccine role that reduces the lifetime risk of acquiring HIV (Alsan & Cutler, 2013; Legarth et al., 2014; Leon,
Baker, Salinas, & Henck, 2017). Notably, education increases access to the awareness messages diffused by
media and HIV-specific health promotion campaigns (Hargreaves & Glynn, 2002; Mmbaga, Leyna, Mnyika,
Hussain, & Klepp, 2007). In fact, educated individuals are expected to understand and take up information
about HIV risk and prevention. They are more likely to accept changing their behaviours, particularly those

that contradict traditional cultural practices (Coombe & Kelly, 2001; Hargreaves & Glynn, 2002; Mmbaga,
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Leyna, et al., 2007). Although we could not analyse the temporal changes in education in relation to the risk of
HIV acquisition, we may witness a shift in HIV infection risk from educated to uneducated groups. Variations
in study design and time periods can strengthen or weaken different effects of formal education on HIV risk.
Further research is warranted to develop a more nuanced understanding of mechanisms linking education and
health.
The results of this analysis did not reveal a risk associated with blood transfusion. Since the early
1980s, tremendous progress has been made in understanding, as well as decreasing, the risk of HIV
transmission from blood transfusion. The introduction of antibody testing and careful donor selection criteria
have reduced the risk of HIV transmission to blood recipients by a substantial margin. The rate of HIV
seropositivity in the blood donor population has been shown to be approximately 0.3 per 10,000 donations, a
value much lower than the rate of 3.5 per 10,000 donations shortly after the introduction of routine HIV
antibody screening (Dodd et al., 2016; Zou et al., 2010). However, HIV transmission may still occur during the
window period [preantibody phase] of infection or in cases of infection with variant strains of HIV that may
escape detection by current screening assays (Kleinman, Lelie, & Busch, 2009; Phelps et al., 2004). This risk
emphasizes the importance of self-selection by potential donors to eliminate those who have engaged in high-
risk behaviours. Because HIV can be readily inactivated in plasma derivatives, considerable effort has been
directed towards inactivating HIV and other pathogens (photoactivation with ultraviolet light (UV-A) that
alters nucleic acids) in blood components after they have serologically tested negative for HIV Ab and for viral
RNA. The value of adding such technology is to eliminate the residual risk from window-period donations, the
theoretical risk from genetic variants, or test performance error (Yonemura et al., 2017).
Although the rate of new STIs is globally on the rise (Newman et al., 2015), our data demonstrated that
the role of STIs or genital ulcers in HIV transmission remained almost unchanged across the two-time strata.
Having STIs or genital ulcers appear to be important determinants of HIV infection, although the link between
STIs and the sexual spread of HIV is unclear. A growing amount of scientific evidence reinforces the role of
genital ulcer diseases and other STIs in facilitating the sexual transmission of HIV, probably through boosting
HIV shedding in the genital tract, which amplifies HIV infectiousness. The presence of STIs increases
susceptibility to HIV by recruiting HIV-receptive inflammatory cells to the genital tract as well as by
disrupting mucosal barriers to infection, thus facilitating blood-to-blood contact (Piot & Laga, 1989; Ward &
Ronn, 2010). Consistent with the present meta-analysis, pooled estimates for the odds of HIV detection in the
genital tract increased by 2-3-fold in the presence of urethritis, cervicitis, gonorrhoea, chlamydia, syphilis,
trichamoniasis and vulvovaginal candidiasis (Johnson & Lewis, 2008). A recent review of 37 studies found

that, on average, 16.3% of people living with HIV were co-infected with another STI, particularly genital
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herpes and syphilis (Kalichman, Pellowski, & Turner, 2011).
Likewise, HBV seropositivity was associated with 3-fold increased chance of being HIV positive. In
most epidemiologic studies, HIV patients have evidence of past or active infection with HBV (Alter, 2006;
Hoffmann & Thio, 2007; Thio, 2003). In fact, HBV infection maybe just the co-infection with HIV because
HIV and HBV share common routes of transmission, but they differ in their prevalence by geographic region
and the efficiency by which certain types of exposures transmit them. The prevalence of HBV among HIV-
infected individuals is as high as 20-30%, a rate 10 times higher than that for the general population. HIV-
infected patients exposed to HBV are less likely to spontaneously clear HBV compared to immunocompetent
adults (Alter, 2006; Hoffmann & Thio, 2007). In a multicenter AIDS cohort study that included 4,498
homosexual participants, HBV infection at baseline increased the chance of HIV-1 seroconversion by 1.5
times, implying that past or current HBV infection probably facilitates HIV-1 infection by "priming" T-
lymphocytes for penetration or viral replication (Solomon et al., 1990).
In the present analysis, smoking, alcoholism and substance abuse were significant predictors of HIV
infection and increased the odds of transmission by almost 2-fold. Tobacco smoking is common in people
living with HIV. Smoking alters immune and virological responses, leading to increased vulnerability to
infection and tuberculosis as well as low adherence to ART (Ande, McArthur, Kumar, & Kumar, 2013).
Cigarette smoking remains among the most detrimental health concerns facing people with HIV today because
it reduces the effectiveness of HIV treatment and doubles their risk of death from serious illnesses, including
heart disease, respiratory illnesses, and cancers (Kariuki et al., 2016). HIV-positive people who smoke are
more likely to get HIV-related infections such as thrush or pneumonia (Dharma N. Bhatta, Subedi, & Sharma,
2018; Rahmanian et al., 2011). Moreover, smoking causes an increase in the MTCT of HIV (Westreich et al.,
2017). Likewise, alcohol is the most commonly abused substance in HIV patients and correlates with illicit
drug use (Galvan et al., 2002). Considerable new scientific evidence supports a causal role of alcohol in HIV
incidence by enhancing viral transmission and replication, altering host immunity, and reducing treatment
efficacy (Baliunas, Rehm, Irving, & Shuper, 2010; Pandrea, Happel, Amedee, Bagby, & Nelson, 2010; Pithey
& Parry, 2009; Rehm, Probst, Shield, & Shuper, 2017; Scott-Sheldon et al., 2013; Woolf & Maisto,
2009). Impulsive and risky sexual behaviour such as engagement in condomless sex and sex with multiple
partners were linked to drinking alcohol, which increased the risk of HIV transmission (Dharma Nand Bhatta,
2014). Alcohol was found to increase the risk of HIV from oral sex by enhancing the infection efficiency of
HIV in primary oral epithelial cells (Bagby, 2005). A large new study that analysed trends in alcohol intake in
189 countries from 1990–2017 and estimated the rates through 2030 found that individual alcohol consumption

has soared to a warding rate (Manthey et al., 2019). Our temporal trend analysis mapped a reduction in the role
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of alcohol in HIV transmission. This could be attributed to the low number of studies published before 2000
and included in the analysis.
Although the number of people newly infected with HIV continues to fall, with a 20% reduction in
HIV acquisition between 2001 and 2011(UNAIDS, 2019), IDU is fuelling HIV epidemics across the globe
(Des Jarlais, Kerr, Carrieri, Feelemyer, & Arasteh, 2016). It is estimated that people who inject drugs are 22
times more likely to acquire HIV than the general population. Outside of sub-Saharan Africa, IDU is a major
concern in industrialized nations and accounts for 30-50% of new HIV infections. Moreover, injection and
non-injection drug use have affected HIV risks and HIV incidence among key sub-populations, including
FSWs, MSM and young IUDs (Des Jarlais et al., 2016; Mathers et al., 2008). Although our analysis did not
show an appreciable reduction in the risk of HIV transmission among IDUs over the last decades, the risk
through sharing needles was dramatically reduced. This reduction may reflect the increased access to HIV
combination prevention (behavioural and biomedical) and supports the effectiveness of specific interventions
for persons who inject drugs, including needle/syringe exchange programmes, medication-assisted treatment
(with methadone or buprenorphine) and antiretroviral therapy (ART) (Aspinall et al., 2014; Platt et al., 2018).
Across eight countries in Eastern Europe and central Asia, a tripling of needle exchange programme coverage
between 2005 and 2010 was associated with reduced injecting risk behaviour and reduced new HIV and HCV
infections. After ten years of needle exchange programmes in Australia, the number of new HIV infections was
reduced by up to 70%. These efforts effectively ended the local HIV epidemic among persons who inject drugs
in many locations. However, notable outbreak storms of HIV among persons who inject drugs have recently
occurred in several countries, including Greece, Israel, and Ireland; these outbreaks were attributed to
economic crises that led to homelessness, lack of preventive services and access to harm reduction equipment,
and quick changes in local patterns of drug use with the introduction of the new psychoactive substance “snow
blow” (Des Jarlais et al., 2016).
The exact risk of HIV transmission with sexual exposure is incompletely defined, but it is plausible
that the risk is widely impacted by the type of sexual behaviour (Baggaley, White, & Boily, 2010; Boily et al.,
2009). Our findings point to a continually increasing role of risky sexual practices in HIV transmission,
particularly receptive anal sex, MSM, and prostitution. Approximately 80% of all newly diagnosed HIV/AIDS
cases among adolescents and adults in the USA were in males, primarily MSM (Kwan, Rose, Brooks, Marks,
& Sionean, 2016). Although the global incidence of HIV is declining, the incidence among MSM and
transgender women is alarmingly high. It is estimated that MSM are 27 times more likely to acquire HIV than
the general population (Control & Prevention, 2018). Biological factors are the key reasons for high

vulnerability to HIV among this group. In fact, unprotected anal sex carries a higher risk of transmission than
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vaginal sex due to thinner and more easily torn anal mucosa, thus creating an entry point for HIV into the
bloodstream and submucosal lymphocytes. High rates of STIs and having multiple sexual partners are common
among MSM who consistently engage in casual condomless sex (Chow, Grulich, & Fairley, 2019). These
circumstances ultimately facilitate HIV transmission. However, many young MSM may underestimate their
personal risk for HIV. Moreover, same-sex activities are criminalized and highly stigmatized in the Arab world
and most sub-Saharan African countries. Despite the great risk of HIV infection, the rate of HIV testing and
sexual health counselling remains relatively low among this group. Stigma, homophobia, fearful
discrimination, lack of insurance and concerns about confidentiality breaches in healthcare settings are barriers
that deter MSM from seeking HIV prevention services and limit their access to testing, care, and ART,
consequently placing them at a higher risk of HIV (Schwartz et al., 2015).
On the other hand, heterosexual transmission is appraised as the main contributor to the HIV epidemic
in sub-Saharan Africa [accounts for 75% of new HIV diagnoses versus 24% worldwide]. In a systematic
review and meta-analysis of observational studies of the risk of HIV-1 transmission through heterosexual
contact, pooled female-to-male and male-to-female transmission estimates indicated a low risk of infection in
the absence of antiretrovirals unless there was receptive anal intercourse or other cofactors such STIs, although
male-to-female HIV transmission was more efficient than female-to-male transmission (Boily et al., 2009).
Together, these findings agree with the present analysis, where heterosexual contact and having sex with a sex
worker appeared insignificant in increasing HIV infectivity.
The present study traced an increasingly high risk of HIV infection associated with prostitution or
FSWs over time. It is assumed that FSWs could act as a core group in HIV/AIDS transmission and propagation
within societies due to engagement in daily sexual relationships with different partners, infrequent condom use
and high frequency of IVDU and STIs. These findings are consistent with Eilami et al., who showed that the
overall risk of HIV/AIDS among FSWs between 2010 and 2017 was 2.17 (95% CI: 1.37–3.14)(Eilami, Nazari,
Dousti, Sayehmiri, & Ghasemi, 2019), although we believe that the magnitude may be higher than that reported
in the present study and in other studies. Because many issues related to HIV/AIDS are taboo, a limited number
of studies have been developed on this subject. As we noted earlier, due to the criminal nature of sex work, no
special services are provided for this risk group. This gap underpins the need to implement comprehensive and
global interventional programmes to reduce the prevalence of HIV/AIDS among FSW and to halt HIV
propagation in societies.
Prison environments are ideal breeding grounds that facilitate the spread of HIV due to clustering and
persistent risk factors, such as sharing needles for drug use, unavailability of condoms and high-risk sex and

rape being commonplace. Overcrowding, stress, malnutrition, drugs and violence weaken the immune system,
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making prisoners more vulnerable to infection. Moreover, prisons lack HIV prevention and harm reduction
programmes (Moazen et al., 2018). A recent systematic review of evidence found that incarceration is
associated with an 81% increase in HIV risk (Stone et al., 2018). The proportion of people in prison has grown
by 20% since 2000 (18% for males and 50% for females). Approximately 3.8% of the global prison population
is living with HIV, and the percentage reaches 10% in low-income and middle-income countries. Consistent
with our findings, UNAIDS estimates that people in prison are on average five times more likely to be living
with HIV compared with adults who are not incarcerated (UNAIDS, 2017b).
Sexual violence or forced sex can increase the risk of transmitting HIV. In the present analysis, rape
and child sexual abuse (CSA) were significant predictors of HIV infection. The role of CSA in HIV
transmission has been increasingly recognized and has persisted over decades. This finding highlights a gap in
access to post-rape care that connects survivors to PEP and routine follow-up to minimize the risk of HIV
seroconversion (Ajema et al., 2018). When unprotected forced vaginal or anal penetration occurs, abrasions
and cuts commonly occur, thus facilitating the entry of the virus into the bloodstream. The immature vaginal
mucous membrane of adolescent girls does not provide the effective barrier that develops later in adulthood.
Anal rape, particularly in children, is associated with a multiplied risk of infection because anal tissues can be
easily damaged (Murray, Nguyen, & Cohen, 2014). Victims of sexual violence during childhood are more
likely to engage in an array of behaviours later in life that put them at greater risk of HIV acquisition, including
substance abuse, homosexuality, having multiple partners, and participating in sex work (Miltz et al., 2019; M.
J. Mimiaga et al., 2009; Shamu et al., 2019). Furthermore, sexual coercion among adolescents and adults is
associated with low self-esteem and depression, factors that perpetuate many of the risk behaviours for HIV
infection (Richter et al., 2014).
Syndemics research has linked psychological health problems to HIV/AIDS, particularly among MSM,
who face a unique constellation of stressors that may contribute to negative psychosocial functioning and risky
sexual behaviour (Miltz et al., 2019; Matthew J Mimiaga et al., 2013; Mustanski, Garofalo, Herrick, &
Donenberg, 2007). Having a major depressive episode increased the odds of sexual risk-taking (Thomas et al.,
2009) and the rate of non-adherence to HIV treatment (Willie, Overstreet, Sullivan, Sikkema, & Hansen,
2016). This finding supports the present analysis in which mental illness and depression emerged as significant
risk factors in HIV transmission. Further exploration of this association is warranted, particularly in diverse
regions of the world where cultural customs and social attitudes may differ.
Although casual contact with saliva, such as through sharing eating utensils or toothbrushes, remains
insignificant in mediating HIV transmission, oral sexual contact is speculated to contribute to HIV infection. In

agreement with earlier studies, there is little risk of getting or transmitting HIV from oral sex (Rothenberg,
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Scarlett, del Rio, Reznik, & O'daniels, 1998). The chance of HIV-negative person contracting HIV from oral
sex with an HIV-positive partner is extremely low unless there are genital/mouth sores or bleeding gums.
However, the exact risk is difficult to estimate because people who have oral sex usually engage in vaginal
and/or anal sex. Unprotected and frequent oral sex was shown to carry a risk for the transmission of HIV,
possibly leading to 6–8% of new HIV infections (Hawkins, 2001).
The present analysis comprehensively examined the role of vertical transmission of HIV, which
appeared significant and persistent over early and late time points. In sub-Saharan Africa, 20-40% of pregnant
women are HIV-positive compared to 1% worldwide, and one-third of their babies become infected (UNAIDS,
2019). Approximately 400,000 infants contract HIV from their mothers every year, which is approximately
15% of the total global HIV incidence. The rate of paediatric HIV infections in sub-Saharan Africa remains
unacceptably high, with over 1,000 newborns infected with HIV per day (Hampanda, 2013; UNAIDS, 2017a).
The transmission rate of HIV from an HIV-positive mother to her child in utero, at birth, or during
breastfeeding is 50% (Endalamaw, Demsie, Eshetie, & Habtewold, 2018; John-Stewart et al., 2004). This rate
can be reduced to less than 1% with an effective set of interventions, referred to as prevention of mother-to-
child transmission (PMTCT), that primarily involve ART, measures to minimize HIV acquisition in the
pregnant woman and appropriate breastfeeding practices. Approximately 1.4 million HIV infections among
children were prevented between 2010 and 2018 due to the implementation of PMTCT services. The number
of pregnant women living with HIV and receiving ART was increased to 80% in 2017 compared with 2010
levels, although receiving ART is still far from universal in this population. The MTCT of HIV has been
eliminated in the United States and Europe but continues to be largely uncontrolled in several African countries
(Taylor, Newman, & Ishikawa, 2017). Underutilization and poor adherence to PMTCT, extensive home
delivery, less availability and accessibility of PMTCT interventions in remote areas, deprived infrastructures,
low literacy, poor knowledge of MTCT of HIV and a high proportion of mothers unaware of their HIV status
are behind the higher rate of MTCT of HIV in sub-Saharan Africa (Abajobir & Zeleke, 2013; Abtew, Awoke,
& Asrat, 2016; Hampanda, 2013; Luba et al., 2017; Sahlu, Howe, Clark, & Marshall, 2014). It is important to
note that a significant number of children newly infected with HIV were infected during breastfeeding due to
the difficulties of providing consistent care and effective ART to HIV-positive women throughout the
breastfeeding period (UNAIDS, 2017a). To eliminate the MTCT of HIV, the sociocultural context regarding
adherence to PMTCT needs to be better explored and addressed.
Tools for HIV risk reduction

Drug use continues to be a major factor fueling the global epidemic of HIV infection (Metzger,
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Woody, & O'Brien, 2010). Harm reduction through drug treatment/opioid substitution therapy (OST) and safe
injection programs (the provision of access to sterile injection equipment) are essential components of
HIV/AIDS prevention strategies to reduce HIV transmission among injection and non-injection drug users. The
WHO/UNAIDS strongly advocates harm reduction as an approach to HIV prevention (Harm Reduction
International, 2018). The benefits of harm reduction have been proven in the current meta-analysis. The effect
remained consistent over time and became clearer in late time decades reflecting the wider uptake and adoption
of more innovative harm reduction interventions. This finding is also supported by the obvious decline in
needle sharing in late 2000s as we mentioned earlier. Beyond the reduced frequency of drug use, OST
improved access and adherence to ART and reduced risk behaviors and infections (Metzger et al., 2010;
Vlahov, Robertson, & Strathdee, 2010; Wodak & Maher, 2010).
Early implementers of harm reduction programmes such as Switzerland, the UK and Australia have
reduced the number of new HIV infections among IDUs to practically zero (Harm Reduction International,
2018). Despite the overwhelming effectiveness of harm reduction for preventing the spread of HIV and
reducing other harms associated with drug use, global harm reduction service coverage remains insufficient
due to lack of sustained political and financial support (Metzger et al., 2010)
Latex and polyurethane condoms are impenetrable by HIV viral particles (Van de Perre, Jacobs, &
Sprecher-Goldberger, 1987). Based on several longitudinal studies amid female-to-male and male-to-female
serodiscordant couples and in agreement with our findings, consistent and proper condom use effectively
curtails the risk of sexual HIV transmission and acquisition by up to 80%, particularly in areas of high
prevalence (Holmes, Levine, & Weaver, 2004; Mindel & Sawleshwarkar, 2008). In a meta-analysis of 12
observational studies of heterosexual HIV-serodiscordant couples, HIV infection rates were much higher in
those who never used condoms versus those who always did (6.7 versus 0.9 infections per 100 person/years)
(Pinkerton & Abramson, 1997). Additionally, in a trial of ART to reduce HIV transmission within
serodiscordant couples, a self-report of "100% use" of condoms compared with "less than 100% use" was
associated with decreased HIV transmission (HR 0.35; 0.14-0.88) (Cohen et al., 2011). Female condoms are
equally impervious to viruses, including HIV, although this was not systematically evaluated and more studies
are needed to prove their efficacy (Drew, Blair, Miner, & Conant, 1990). In the late time period of the current
analysis, the role of condomless sex was obviously reduced. This declining trend may be linked to ongoing
interventional efforts and the implementation of community-based HIV prevention programmes.
Previous research has suggested that physical, chemical, or biological factors associated with
intravaginal practices can damage the vaginal epithelial barrier and increase the risk of infection (Martino &

Vermund, 2002). Frequent vaginal douching alters the normal vaginal pH and modifies vaginal flora, thus
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creating an environment suitable for bacterial vaginosis, a probable risk factor for HIV (Alcaide, Rodriguez,
Fischl, Jones, & Weiss, 2017; Fonck et al., 2001), although this appeared insignificant in the present analysis.
Gresenguet et al. suggest that vaginal cleansing with non-commercial preparations irritates vaginal mucosa and
enhances HIV transmission, whereas douching with commercial antiseptic preparations that have antifungal
and bacteriostatic properties reduces the inoculum of HIV through a flushing mechanism or reduces the
frequency of sexually transmitted diseases that serve as co-factors for HIV infection (Gresenguet, Kreiss,
Chapko, Hillier, & Weiss, 1997).
Admittedly, MC has been widely cited as a key pillar of HIV prevention that can significantly reduce
new HIV infections in a population (Siegfried et al., 2005) and a plausible biological mechanism for reduced
risk of infection has been suggested (Donoval et al., 2006; McCoombe & Short, 2006). We found lower odds
of HIV infection among circumcised men. The paradigm shift in adopting MC as an HIV- and AIDS-
preventive strategy highlights that the prevention benefits of this intervention will continue to play an
important role in addressing the HIV epidemic. However, a number of ethical challenges are surrounding its
implementation or even translation of research findings into policy and practice (Rennie, Muula, & Westreich,
2007; Sawires et al., 2007).
Medicalized MC is generally safe and reduces the risk of heterosexual men becoming infected with
HIV. The efficacy of MC in protecting males against HIV infection has been established by several
randomized controlled trials of circumcision conducted in Africa, which showed a 50-70% reduction in female-
to-male sexual transmission of HIV over two years and after five years (Auvert et al., 2005; Bailey et al., 2007;
Galbraith et al., 2014; R. Gray et al., 2012; R. H. Gray et al., 2007). Nevertheless, early trial termination can
lead to an overestimate of clinical effects. Moreover, MC did not avert HIV acquisition among female sexual
partners of HIV-infected men because HIV is likely concentrated in genital secretions (Wawer et al., 2009).
Likewise, MC was suggested to have a possible but uncertain protective effect for HIV infection in MSM
probably because some engage in both insertive and receptive anal intercourse. A meta-analysis of 15
observational studies among 53,567 MSM showed a lower but insignificant odds of being HIV-infected among
the circumcised men (Millett, Flores, Marks, Reed, & Herbst, 2008). A voluntary medicalized MC programme
has been implemented as a national strategy in some HIV-endemic countries since 2007. The coverage showed
substantial increases from 85.0% in 2007 to 91.2% in 2012 in priority countries, although it is still beyond the
national target in traditionally noncircumcising communities (Davis et al., 2018). Fear of pain, bleeding,
perception of low HIV risk, lack of social support, presence of female providers on the circumcision team and a
preference for traditional ‘rite of passage’ circumcision are important barriers to the uptake and scaling-up of

this intervention (Masese, Chimango, & Mbirimtengerenji, 2017). Health authorities should collaborate with
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traditional circumcisers and local leaders to provide safer, gender-and-culture-sensitive medical male
circumcision services.
Ultimately, the pooled effect in this meta-analysis should not be concluded such certain and the effect
of MC cannot be equivalent to the use of correct and consistent condom use, because many scholars denied this
way to prevent HIV. Since MC provides only partial protection, it should therefore be only one element of a
comprehensive HIV prevention package. Moreover, the success of MC as an HIV prevention strategy on a
population level depends on significant uptake of circumcision services among men and boys in traditionally
noncircumcising communities (Rennie et al., 2007). According to the WHO/UNAIDS MC is considered an
efficacious intervention for HIV prevention in countries and regions with heterosexual epidemics, high HIV
and low MC prevalence (WHO, 2020). Indeed, substantial ethical, socioeconomic, religious and ethnic
challenges are facing this approach and there remain unanswered questions and room for reasonable doubt.
Therefore, the ethics of MC promotion will have to be continuously revisited in the future. Furthermore, MC
may be overshadowed by stronger commitments and investing in forthcoming interventions with relatively less
gear such as microbicides, pre-exposure prophylaxis, vaccines or behavioral education (Rennie et al., 2007).
Conclusions and Recommendations
The epidemic of HIV is refolding, and concerns about casual contact, needle sharing and blood
transfusion have been abated while other determinants, including MSM, FSWs, and anal sex have become the
cornerstones of HIV transmission. Despite continuing concerns about major risks, the overall moderating pace
of HIV transmission offers an opportunity to reconsider several features whose magnitude may be alleviated by
tailored bundling interventions that may have a synergistic impact on HIV risk-reduction. Current prevention
strategies do not adequately address these changing patterns of HIV transmission. The development of new
interventions or modifications of existing interventions must take into consideration this heterogeneity and
dynamism in HIV magnitude among different population groups and according to different transmission
determinants. Hence, information on the drivers of the epidemic is of paramount importance in guiding
prevention efforts.
Limitations of the study
The results of this analysis should be carefully interpreted in light of the following potential
limitations: i) the findings are based on the data extracted from observational studies that are associated with
inherent biases, ii) the included studies were limited to the English language only, which may result in missing
studies that could have studies that could have been published in other languages. In addition, some relevant
articles were not accessible for the investigators as full text so it was difficult to show the pooled effect size for

all published papers reporting predictors of HIV infection, iii) the studies included in the analysis reported
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behavioural data, which are susceptible to desirability bias, iv) the different study designs would provide
different strength of evidence, some publication bias were inescapable, some factors were just studied in two
articles or three which is not enough to get a robust evidence. Despite these limitations, we conducted a
comprehensive search of databases to include all relevant studies, and sub-group analyses were conducted to
determine whether any specific study level factor explained the results.
Conflict of Interest
All authors declare no conflict of interest.
Data availability
All data are fully available without restriction by the corresponding author at [email protected]
and through the public data repository “Harvard Dataverse” at https://dataverse.harvard.edu/dataverse/
Ethical considerations
Funding
No financial support or fund was received.
Conflicts of interest: None to declare
Ethical approval
The study was approved by the institutional review board and the Ethics Committee of the High Institute of
Public Health-Alexandria University [no. 358-2019]. The IRB waived the need for the informed consent. The
research was conducted in accordance with the ethical guidelines of Helsinki’s Declaration (2013). Data sheets
were coded with numbers to maintain the anonymity and confidentiality of patient’s data.
This article does not contain any studies with animals performed by any of the authors.
Informed consent: N/A
Author contributions
AFK: Conducted the database search, data extraction, data curation, statistical analysis and interpretation of
data, contributed to writing of the manuscript, revised and approved final version of the manuscript

HZS: Supervised the study implementation and data collection, revised and approved final version of the
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manuscript.
EWAW: Conceptualization, developed the theoretical framework and study design, conducted the data base
search, data extraction, took the lead for overall direction and planning, supervised the study implementation,
data curation, analysis and interpretation of data, major contribution to writing, revised and approved final
version of the manuscript
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men. AIDS Behavior, 13(4), 757-782. doi:10.1007/s10461-007-9354-0
Yi, T. J., Shannon, B., Prodger, J., McKinnon, L., & Kaul, R. (2013). Genital immunology and HIV
susceptibility in young women. American Journal of Reproductive Immunology, 69, 74-79.
Yonemura, S., Doane, S., Keil, S., Goodrich, R., Pidcoke, H., & Cardoso, M. (2017). Improving the safety of
whole blood-derived transfusion products with a riboflavin-based pathogen reduction technology.
Blood Transfusion, 15(4), 357-364. doi:10.2450/2017.0320-16
Zou, S., Dorsey, K. A., Notari, E. P., Foster, G. A., Krysztof, D. E., Musavi, F., . . . Stramer, S. L. (2010).
Prevalence, incidence, and residual risk of human immunodeficiency virus and hepatitis C virus
infections among United States blood donors since the introduction of nucleic acid testing.
Transfusion, 50(7), 1495-1504. doi:10.1111/j.1537-2995.2010.02622.x
Figure Legend
Figure 1: Prisma flow diagram illustrating the search strategy and the process of study selection and sorting for
inclusion in the meta-analysis articles.
Footnote of Figure 1
* Articles were omitted due to the inaccessibility of their full text.

Accepted Article
Tables
Table 1: Patient demographics and medical history
Total studies
Risk factor Pooled 95% C.I. No. Studies~
OR LL UL (I2)
Male sex 3.63 1.88 6.99 9/6 (87.5)
Female sex 3.73 1.23 11.3 7/5 (97.6)
Primary education 1.55 1.19 2.02 5/3 (0.0)
Secondary education 1.68 1.27 2.22 6/5 (25.0)
Blood transfusion 1.00 1.00 1.00 2/1 (0.0)
T4-lymphocyte count <1,000/cmm 8.50 2.94 24.6 2/1 (0.0)
STIs 2.68 2.21 3.27 28/27 (65.6)
Genital ulcers 3.13 2.38 4.13 17/10 (0.0)
HBV positive 3.14 2.07 4.77 3/3 (47.9)
~ number of included studies (in bold) versus the total number of eligible studies
I2= The percentage of variation across studies that is due to heterogeneity
Table 2: Smoking, alcoholism and drug use
Total studies
OR LL UL (I2)
Cigarette smokers 1.94 1.36 2.75 5/4 (36.8)
Alcoholism 1.77 1.20 2.62 10/9 (75.6)
Injectable drug users 2.60 2.05 3.31 45/33 (88.2)
Syringe sharing 2.95 2.22 3.91 11/7 (0.0)
Partner is injecting drug user 2.48 1.24 4.98 3/2 (84.4)
Harm reduction^ 0.60 0.43 0.82 11/10 (84.5)
^ includes drug treatment programs and Safe injection programs

Accepted Article
Table 3: Sexual behavior
Total studies
OR LL UL (I2)
Young sexual intercourse (adolescent females) 1.74 1.36 2.22 3/3 (0.0)
Imprisonment 1.61 1.31 1.97 6/4 (3.2)
Migration 2.02 1.52 2.68 2/1 (0.0)
Mental illness and depression 1.97 1.43 2.70 7/5 (47.1)
Rape 1.94 1.33 2.84 2/2 (0.0)
Child sexual abuse 1.71 1.47 1.98 8/8 (31.5)
Prostitution 2.50 1.74 3.60 15/12 (65.7)
Sex with a sex worker 1.69 0.84 3.39 5/3 (76.8)
Heterosexual intercourse 1.18 0.85 1.63 7/3 (0.0)
Bisexual partner 2.57 1.31 5.05 3/2 (51.8)
Multiple sex partners 2.34 1.91 2.88 19/12 (67.2)
Homosexual men 3.10 1.84 5.22 13/11 (91.7)
Oral sex 1.28 0.72 2.29 4/4 (78.5)
Receptive anal sex 2.58 1.75 3.81 17/15 (89.6)
Insertive anal sex 1.40 0.99 1.98 4/3 (29.2)
Having condomless sex 3.59 1.98 6.53 13/8 (90.7)
Vaginal douching 1.08 0.60 1.96 3/3 (83.3)
Male circumcision 0.43 0.30 0.61 11/7 (33.4)
Lack of male circumcision 3.70 1.51 9.06 5/1 (0.0)
Table 4: Mother-to-child transmission (Vertical transmission)
Total studies
OR LL UL (I2)
Vertical transmission (VT) 3.83 1.74 8.44 3/2 (70.6)
(VT): Breast feeding 1.77 0.85 3.71 5/3 (72.6)
(VT): smoking 1.45 1.07 1.96 2/1 (0.0)
(VT): maternal viral RNA levels >43,000 copies/mL 3.23 2.39 4.35 2/2 (0.0)
(VT): elective caesarean section 0.45 0.17 1.20 2/1 (0.0)
(VT): maternal low CD4+ lymphocyte count 3.19 2.30 4.41 6/4 (5.3)
(VT): placental membrane inflammation 6.15 2.05 18.4 2/2 (13.6)
(VT): maternal p24 antigenemia 9.61 0.52 176.6 3/2 (74.3)
(VT): very low birth weight <1500 g 2.80 1.39 5.65 3/1 (0.0)
(VT): chemokine receptor CCR5(Δ32ccr5) heterozygotes gene 1.06 0.85 1.32 2/2 (4.1)

Accepted Article
Table 5: HIV risk factors over decades
1982-1999 2000-2018 Total studies

Risk factor Pooled 95% C.I. No. Studies~ Pooled 95% C.I. No. Studies~ Pooled 95% C.I. No. Studies~
2 2 2
OR LL UL (I ) OR LL UL (I ) OR LL UL (I )
Prostitution 2.30 1.12 4.68 4/3 (73.0) 2.69 1.67 4.32 11/9 (67.5) 2.50 1.74 3.60 15/12 (65.7)
Injectable drug users 3.42 2.28 5.12 19/12 (84.3) 2.16 1.74 2.70 26/21 (74.4) 2.60 2.05 3.31 45/33 (88.2)
Male circumcision - - - - 0.43 0.30 0.61 11/7 (33.4) 0.43 0.30 0.61 11/7 (33.4)
Harm reduction^ 0.44 0.23 0.85 3/3 (37.1) 0.65 0.46 0.91 8/7 (86.9) 0.60 0.43 0.82 11/10 (84.5)
Receptive anal sex 2.47 1.84 3.31 6/6 (0.0) 2.63 1.58 4.39 11/9 (93.3) 2.58 1.75 3.81 17/15 (89.6)
Multiple sex partners 2.54 1.93 3.35 5/4 (32.6) 2.27 1.72 3.00 14/8 (74.3) 2.34 1.91 2.88 19/12 (67.2)
Homosexual men [MSM] 2.28 1.64 3.17 5/5 (0.0) 3.67 1.88 7.17 8/6 (93.4) 3.10 1.84 5.22 13/11 (91.7)
STIs 2.57 1.91 3.47 15/14 (66.3) 2.82 2.17 3.66 13/13 (59.6) 2.68 2.21 3.27 28/27 (65.6)
Alcoholism 2.35 0.73 7.59 2/2 (65.7) 1.71 1.08 2.72 8/7 (78.5) 1.77 1.20 2.62 10/9 (75.6)
Genital ulcers 3.15 2.25 4.41 11/7 (0.0) 2.92 1.46 5.85 6/3 (48.5) 3.13 2.38 4.13 17/10 (0.0)
Syringe sharing 6.10 2.57 14.5 1/1 (0.0) 2.70 2.01 3.65 10/6 (0.0) 2.95 2.22 3.91 11/7 (0.0)
Having condomless sex 6.79 6.48 7.12 3/3 (0.0) 2.52 1.66 3.85 10/5 (46.8) 3.59 1.98 6.53 13/8 (90.7)
Vertical transmission 2.89 1.78 4.69 16 /12 (70.1) 2.56 1.28 5.14 9/5 (94.9) 2.76 1.88 4.06 25/17 (87.3)
Child sexual abuse 1.78 1.19 2.67 3/3 (38.6) 1.70 1.43 2.01 5/5 (41.7) 1.71 1.47 1.98 8/8 (31.5)
2
I = The percentage of variation across studies that is due to heterogeneity
^ includes drug treatment programs and Safe injection programs

Accepted Article
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Accepted Article

DR. EKRAM WASSIM ABD EL-WAHAB (Orcid ID : 0000-0003-4220-5859)

Article type : Review

Ahmed F. Kabapy 1, 2, Hanan Z. Shatat 3, Ekram W. Abd El-Wahab 3^

^To whom correspondence should be addressed:

Running title: Meta-analysis of HIV risk factors

Keywords: Meta-analysis; HIV; Risk factors; Dynamics; Transmission

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What is already known on this subject:

2. Negligible role of blood transfusion, organ transplantation and medical procedures

3. None is specific about Egypt

What does this study add:

cornerstones of HIV transmission

Policy Implications Box

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2- Changing dynamics of HIV transmission over decades

Influence of sociodemographic determinates and risky behaviours

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Conflicts of interest: None to declare

Informed consent: N/A

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Table 1: Patient demographics and medical history

Table 2: Smoking, alcoholism and drug use

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Table 4: Mother-to-child transmission (Vertical transmission)

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1982-1999 2000-2018 Total studies

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