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Prevalence of high-risk HPV genotypes in sub-Saharan Africa according to HIV status: a 20-year systematic review

OBJECTIVES This review assessed the rate of high-risk human papillomavirus (HPV) infection among women living in sub-Saharan Africa. It also determined the prevalence of high-risk HPV (hrHPV) among human immunodeficiency virus (HIV) seropositive (HIV+) and seronegative (HIV-) women in sub-Saharan Africa, pre-2010 and post-2010. METHODS In this systematic review, Google Scholar, PubMed Central, and Embase were searched to identify cohort and case-control studies that investigated the relationship between HIV and HPV infection. The database searches yielded 17 studies published between 1999 and 2018. RESULTS In the general population, the prevalence of any HPV/multiple HPV infections was higher among HIV+ (53.6/22.6%) than among HIV- women (26.5/7.3%) with odds ratios of 3.22 and 3.71, respectively (95% confidence interval, 3.00 to 3.42 and 2.39 to 5.75, p<0.001). The prevalent HPV genotypes among HIV+ and HIV- women diagnosed with invasive cervical cancer (ICC) were HPV-16/18 and HPV-45. The prevalence of HPV-16, HPV-18, and HPV-45 was lower in 1999-2010 (3.8, 1.7, and 0.8%, respectively) than in 2011-2018 (19.1, 6.0, and 3.6%, respectively). Among women diagnosed with ICC, HIV+ women had a higher prevalence of HPV-56, HPV-31, and HPV-51 (7.3, 5.3, and 3.3%, respectively) than HIV- women (1.3, 2.2, and 0.4%, p<0.001, p=0.050, and p=0.013, respectively). CONCLUSIONS The prevalence of HPV infection, multiple HPV infections, and non-vaccine HPV types were higher among HIV+ women than among HIV- women in sub-Saharan Africa. Although HIV infection influences the distribution of HPV types, this study suggests that cervical cancer incidence in sub-Saharan Africa is primarily driven by the prevalence of vaccine hrHPVs, especially HPV-16 and HPV-18.

INTRODUCTION miologic association and potential risk of cervical cancer [18][19][20][21]. Of note, individuals infected with multiple hrHPV genotypes are more likely to develop large tumors and have a poor treatment response [22], owing to a high propensity of co-existing with other hrHPVs than low-risk HPVs [23]. The co-existence of the nonvaccine hrHPV reduces the efficacy of vaccines in preventing cervical cancer. According to Yar et al. [23], the involvement of nonvaccine hrHPV in hrHPV co-infections among African women was higher for HPV-35 (19.6%), followed by HPV-53 (15.0%), HPV-56 (7.5%), HPV-59/66 (6.5%), and HPV-82 (5.6%). Since the introduction of HPV vaccination into the national immunization program, to the best of our knowledge, no study has assessed the prevalence of HPV types, especially among HIV+ and HIV seronegative (HIV-) women, in sub-Saharan Africa between years up to 2010 and in 2011 and later; hence, the present review was conducted to address this gap in the research. This review suggests that a high prevalence of non-vaccine hrHPV and multiple HPV infections could be associated with the high ASIR of cervical cancer in sub-Saharan Africa.

MATERIALS AND METHODS
This systematic review was carried out (up to September 16, 2020) in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [24,25].

Search strategy
Studies that investigated the relationship between HIV status and HPV infection or acquisition were searched for in Google Scholar, Scopus, PubMed Central, and Embase databases and selected using the PRISMA guidelines ( Figure 1). We screened the titles of cohort and case-controlled studies published between 1999 and 2018 using the following keywords and Medical Subject Headings (MeSH) terms: ('HPV' and 'human papillomavirus') AND ('HIV' and 'human immunodeficiency virus') AND ('ICC' and 'invasive cervical cancer') AND ('prevalence' OR 'incidence' OR 'distribution' OR 'genotype'), AND ('sub-Saharan Africa'). We also searched for unpublished studies (gray literature) by evaluating ClinicalTrials.gov (National Institutes of Health, NIH) and the International Clinical Trial Registry Platform (World Health Organization, WHO).

Study quality assessment and study selection
The quality of the included studies was assessed using an adapted version of the NIH's Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies [26]. Three authors assessed the risk of bias (as good, unclear, or poor) in non-randomized observational studies across 5 criteria: study population, imprecision, inconsistency, bias in study design, and disclosure of conflict of interest [27,28]. The exclusion criteria were articles not written in English, abstracts, non-full-length articles, articles without specific frequency of HPV types, articles not involving Africa, and articles not dealing with cervical cancer. The inclusion criteria were studies that tested for hrHPV DNA, studies with specific frequency of hrHPV infection, and full-length articles involving sub-Saharan Africa.
Only studies that used polymerase chain reaction, which is the gold standard for HPV testing, were included in this study (Tables  1-3). The overall prevalence of an HPV type (for example HPV-16) was dependent on the study size of studies that tested participants for the specific virus. In Figure 2A and B, the study of Menon et al. [19], which was carried out between 2009 and 2015, was excluded because its data cut across the 2 time periods (up to 2010 and in 2011 and later). The studies carried out by Diop-Ndiaye et al. [29], Dols et al. [30] and Denny et al. [31] were excluded from the calculations of the prevalence of multiple HPV infections due to lack of data ( Table 4). The mean age of HIV+ and HIV-women did not include data from Mpunga et al. [32], Mudini et al. [20], Marembo et al. [33], Maranga et al. [34], and Banura et al. [35] because they did not specify the mean age and age range of the 2 groups. The data presented in Table 5 were only extracted from the studies carried out by Mpunga et al. [32], Mudini et al. [20], and Maranga et al. [34] due to the fact that their papers reported the prevalence of HPV types for both HIV+ and HIV-women diagnosed with cancer.

Data extraction
The essential information extracted for analysis included participant characteristics such as sample size, cases of HIV+ and HIV-women, the prevalence of any HPV infection and multiple HPV infections, HPV types (16,18,31,33,35,39,45,51,52,53,56,58,59,66,68, and 82), mean age, recruitment method, period of data collection, and study location and region (according to the WHO classification). We investigated the frequency of HPV infections in women living with HIV using HIV-women as the comparison group. When calculating the prevalence of any HPV infection (women who tested positive for any HPV type), an individual may have acquired multiple types (e.g., HPV-35 and -45) but it would only count as 1 event. The range of high-risk HPVs investigated in the selected studies varied; thus when calculating the prevalence of an HPV type, only studies or cases that investigated that particular HPV type were considered. To assess the impact of the time period on the prevalence of HPV infection, data points were categorized into a group until 2010 (inclusive) and a post-2010 group.

Statistical analysis
The ORs between HIV+ and HIV-women were also calculated in order to determine the risk of HPV acquisition and development of cervical cancer. Chi-square analysis was used to calculate the difference in HPV infection between HIV+ and HIV-women in Africa (GraphPad Prism version 6.0; GraphPad, San Diego, CA, USA), and the level of statistical significance was set at p-value ≤ 0.05.

Ethics statement
This review is exempt from ethical review and approval, since the secondary data used for pooled analysis were extracted from journal-related publications.

Selected studies and sample size
Based on the inclusion criteria, 11 cross-sectional studies and 6 cohort studies were analyzed. Overall, this review included 16,237 participants (N) from 17 full-length articles ( Figure 1 and Table 1). The number of HIV+ and HIV-women were 5,341 and 10,896, respectively. Southern Africa had the highest number of participants (10,285; n = 3 studies), followed by West Africa (3,553; n = 9 studies), and East Africa (2,399; n = 5 studies), and Southern Africa (10,285; n = 3 studies). The mean age of HIV-women was insignificantly higher than that of HIV+ women (38.1 vs. 36.2 years, p = 0.59). The prevalence of HPV infection and multiple hrHPV infections in the cohort studies (which involved HIV+ women only) were twice the prevalence in the cross-sectional studies (which included both HIV+ and HIV-women). No cohort studies involving only HIV-women were identified. The 3 most prevalent HPV types in the cohort studies were HPV-52, HPV-16, and HPV-35, while those in the cross-sectional studies were   (Table 2). Table 3 shows the summary of the findings from each study.

Human papillomavirus infection and study timing
Between 1999-2010 and 2011-2018, the prevalence of HPV-16, HPV-18, and HPV-45 among HIV-and HIV+ women increased by 19.1%p versus 3.8%p, 6.0%p versus 1.7%p, and 3.6%p versus 0.8%p, respectively ( Figure 2). Furthermore, the prevalence of HPV-53, HPV-66, HPV-59, HPV-58, and HPV-68 decreased by 12.6%p, 6.7%p, 2.4%p, 2.2%p, and 1.7%p among HIV+ women, respectively. Overall, the prevalence of HPV and multiple HPV infections increased in sub-Sahara Africa within the study period ( Figure 2). As shown in Figure 2A, in sub-Saharan Africa, the prevalence of HPV types among HIV-women up to 2010 was higher than in 2011 and later, except for HPV-16, HPV-18, and HPV-45. Furthermore, the prevalence of HPV types among HIV+ women up to 2010 was lower than in 2011 and later, except for HPV-58, HPV-68, HPV-66, HPV-53, and HPV-59. A higher prevalence of HPV infection was observed in 2011 and later than up to 2010 both in HIV+ and HIV-women ( Figure 2B). The difference in the prevalence of HPV infection, the difference between 2011 and later and up to 2010 was higher among HIV-women than in HIV+ women (26.8 vs. 7.2%). Among HIV-women, the prevalence of HPV infection doubled between 2010 and 2018, unlike HPV prevalence in HIV+ women, which increased by 5.4%p ( Figure 2B). Furthermore, a higher prevalence of multiple HPV infections was observed in 2011 and later than up to 2010 both in HIV+ women (p< 0.05) and HIV-women (p> 0.05). In Figure 2C, a higher prevalence of vaccine and non-vaccine HPV types were observed among HIV+ women when compared with their HIV-counterparts (18.5 vs. 14.7%, and 3.0 vs. 1.3%, respectively at p<0.001). However, a higher frequency of vaccine HPV types was observed among HIV-women than among HIV+ women (91.9 vs. 86.0%), whereas a higher frequency of non-vaccine HPV types was observed among HIV+ women than among HIV-women (14.0 vs. 8.1%) at p<0.001.

Prevalence of multiple infections and human papillomavirus types among women with cervical cancer
Among women diagnosed with ICC, the prevalence of multiple HPV infections was higher in HIV+ women than in HIV-women (28.9 vs. 13.1%, respectively; p < 0.001). In descending order, the most prevalent hrHPV types among HIV+ and HIV-women diagnosed with ICC were HPV-16 (51.9 vs. 58.2%), HPV-18 (24.6 vs. 18.5%), and HPV-45 (12.8 vs. 12.6%, respectively). Significant differences between HIV+ and HIV-women diagnosed with ICC were only observed for the prevalence of HPV-56 (7.3 vs. 1.3%), HPV-31 (5.3 vs. 2.2%), and HPV-51 (3.3 vs. 0.4%, respectively) at p < 0.001, p = 0.050, and p = 0.013, respectively. HIV+ women in sub-Saharan Africa who were positive for HPV-56/51 and HPV-68 were 6 times and 5 times more likely to develop cervical cancer than their HIV-counterparts (p< 0.001/p= 0.013 and p= 0.125, respectively). Figure 2 also shows that HIV+ women with multiple HPV infections and HPV-31/-39/-58 were approximately 3 times more likely to develop cervical cancer than HIV-women. Furthermore, HIV+ women with HPV-16 and HPV-35 were 23% and 51% less likely to develop cervical cancer than their HIV-counterparts ( Table 5). As shown in Table 5, the prevalence of all HPV types, including multiple HPV types, was higher among HIV+ women than among HIV-women, except HPV-16 and HPV-35.

DISCUSSION
This study assessed the prevalence of HPV types among HIV+ and HIV-women in regions of sub-Saharan Africa and between 2 time intervals: up to 2010 and 2011 and later. The prevalence of HPV and multiple HPV infections was higher among HIV+ women than among HIV-women living in sub-Saharan Africa. Between 2013 and 2016, this pattern of infection was also observed among HIV+ and HIV-women in North Africa (65.7 vs. 13.3% and 38.5 vs. 7.6% respectively) [10,13]. The lower ASIR of cervical cancer in North Africa could be attributed to higher HPV vaccine coverage than in sub-Saharan Africa [16]. Conversely, the reason(s) for the differences between HIV+ and HIV-women are not wellunderstood. However, previous studies [11,42] opined that HIV+ women initiate sex at a younger age, and therefore have a higher number of lifetime sexual partners, in turn increasing their risk of acquisition and persistence of HPV infections relative to their HIV-counterparts. As of 2016, the review carried out by Clifford  [18] Nigeria HIV+ women with a low CD4+ T count were at a higher risk of cervical precancerous lesions Ndizeye et al. [36] Burundi There was a high burden of hrHPV and phrHPV infections among women with HIV; The nonavalent vaccine covered most of the hrHPV infections irrespective of residential area and HIV status Mudini et al. [20] 1 Zimbabwe HIV may influence the distribution of some HPV genotypes given the significant increase in prevalence of HPV-18 among HIV+ women; The proportion of women with multiple genotypes was high and almost equal in both HIV+ and HIV-women Obiri-Yeboah et al. [37] Ghana HIV-1 infected women bore a significant burden of HPV infection and related disease; The nonavalent HPV vaccine is likely the best means of cervical cancer prevention in Ghana Marembo et al. [33] Zimbabwe There was an increased risk of hrHPV infection as well as multiple hrHPV genotypes in HIV+ women Menon et al. [19] 2 Kenya Co-infection with phrHPV and hrHPV genotypes was more strongly associated with abnormal cytology than any single hrHPV; There was a high prevalence of multiple hrHPV genotypes in FSW, especially in HIV+ women Ezechi et al. [38] Nigeria HPV-16, -35, -58, and -31 were the most common hrHPV infections in the population and HIV+ women awere at higher risk of acquiring HPV infection; Current HPV vaccines prevented genotypes 16 and 18, which accounted for only a minority of hrHPV infection (21.7%) with no significant difference been HIV+ and HIV-women Akarolo-Anthony et al. [21] Nigeria There was a high prevalence of non-16 and -18 hrHPV among HIV+ women in Nigeria and other African countries Kelly et al. [39] SA/Burkina Faso hrHPV infections and cervical lesions were very common among HIV+ women in Africa; Bivalent or quadrivalent vaccines could prevent up to 45% of treatable precursor lesions, and the nonavalent vaccine could prevent up to 90% of cases in HIV+ women Diop-Ndiaye et al. [29] 3 Senegal HPV-16 and -35 were the most prevalent HPV types among HIV-infected FSW Dols et al. [30] Tanzania/SA More than one-third (42%) of women with normal cytology tested positive for hrHPV Guthrie et al. [40] Kenya hrHPV prevalence was high in HIV+ women; Screening for hrHPV genotypes would identify a large majority of women who have high-grade cervical lesions or more severe cytology Maranga et al. [34] Kenya HIV infection appeared to alter the spectrum of HPV types found in both cervical smears and invasive cervical carcinomas; HPV infections were associated with a reduced level of immunity McDonald et al. [41] SA HPV-16 and -35 were the prevalent HPV types among HIV+ and HIV-women with or without cervical disease Banura et al. [35] Uganda There was an elevated prevalence of HPV infection in HIV+ and HIV-young women Denny et al. [ et al. [8] shows that HPV-16 (46.6%), HPV-18 (24.4%), and HPV-45 (15.5%) were the prevalent HPV types in HIV+ women diagnosed with ICC in Africa. Our findings further show that HPV-16, HPV-18, and HPV-45 were the prevalent HPV types not only among HIV+ women, but also among HIV-women in sub-Saharan Africa. The prevalence of HPV-16 and HPV-18 among HIV+ women in this review were higher than that of Clifford et al. [8], possibly due to differences in study timelines and regions involved [11]. The differences observed between HIV+ and HIV-women suggest that the prevalence of HIV in a population increases the risk of acquiring HPV and multiple infections [20,29,34]. These factors, in turn, predict a disproportionate ASIR of cervical cancer among HIV+ and HIV-women in sub-regions of Africa [19]. Additionally, in sub-Saharan Africa, the prevalence of HPV-16 and HPV-35 infections was higher in HIV-women diagnosed with ICC than in their HIV+ counterparts. The reason for this is un- known.
Studies have shown that HPV-infected women, especially those infected with hrHPV types, are approximately at a 2-fold higher risk of acquiring HIV than HPV-uninfected women [43,44]. A follow-up investigation carried out among HIV-uninfected women showed that 28.4% of HPV-infected women seroconverted af-