Human immunodeficiency virus is a driven factor of human papilloma virus among women: evidence from a cross-sectional analysis in Yaoundé, Cameroon

Human papilloma viruses (HPV) are non-enveloped DNA viruses that represent the most widespread sexually transmitted infection worldwide, with more than 200 species. HPV genotypes are responsible for 95% of the occurrence of cervical cancer in women [1]. Notably, HPV causes benign and malignant tumours in humans and viral genotypes that are oncogenic are classified as high-risk (HR-HPV) or low-risk oncogenic HPV (LR-HPV) [2]. Although all HR-HPV genotypes have oncogenic potential, some are more frequently involved in cancers than others. Thus, HPV 16 and 18 represent approximately 70% of all cervical cancers worldwide, followed by HPV 31, 33, 45, 52, 58 and 68 which are among the ten most commonly isolated HR-HPV genotypes from cervical tumor biopsies [3, 4].

Indeed, cervical cancer is known to be a viro-induced neoplasm and that HPV is the causal agent in 99% of cases [4]. According to the World Health Organization (WHO), cervical cancer will kill more than 443,000 people worldwide each year by 2030, and 98% of these deaths will occur in developing countries, particularly in sub-Saharan Africa (SSA) where the HIV epidemic and other risk factors further increase the burden of this cancer [5, 6]. In SSA, HPV and HIV co-infection is commonly found and contributes to a rapid disease progression toward cervical cancer [4]. Importantly, HIV-positive women, especially those who are severely immunocompromised, are 5 times more likely to develop the cervical cancer than their HIV-negative peers.

Even though little is known on HPV genotypes circulating among HIV-infected women in SSA countries, recommendations for HPV vaccination in the population of people living with HIV (PLHIV) are still unclear [7]. Of note, Generally 66% of infections are cleared at 12 months and this increases to 90% at 24 months [8]. For 10% of HPV-infected individuals, there is viral persistence that remains at latency. In this frame, immunodeficiency may be the cause of viral persistence and reactivation subsequently [7, 9].

Factors that contribute to HPV infections include: early sexual activity, multiple sexual partners, smoking, prolonged oral contraception and immuno-compromission (due to HIV essentially) [9]. HIV infection also promotes HPV infection at molecular and cellular levels during different phases of HPV replication cycle such as, penetration into the target cell, HPV multiplication and HPV immune evasion from the host’s defences. Direct consequences are clinical manifestations of HPV-associated dysplasia, which has been recognized in early HIV epidemics [10]. As reported by Kevin A. Ault in 2006, High-risk, oncogenic HPV types (including HPV 16 and HPV 18) are associated with 99.7% of all cervical cancers [11]. A recent study conducted in Chad during the year 2018 showed that 11 genotypes of HR-HPV were detected in nearly 70% of the study population, and HR-HPV 58 genotype was the most prevalent (22.9%) [12]. In Cameroon, out of 14,000 new cases of cancer reported in 2016, cervical cancer occupied the second leading position of cancers among women (23.2%) [12, 13]. These observations are very concerning and suggest a high burden of HPV in these settings where HIV is also highly prevalent [14, 15]. We therefore hypothesised that HPV-infection is significantly higher among Cameroonian HIV-seropositive women as compared to their seronegative peers. Thus, in the light of evidence generated from countries with similar programmatic challenges [14, 16], understanding the burden of HPV among women, its circulating genotypes and the effect of HIV-infection on HPV-positivity, might help in shaping HPV preventive measures according to local realities in Cameroon.

Our study objective was to compare the rate of HPV-positivity according to HIV-serostatus, and to determine other predictors of HPV-positivity.

The purpose of our study was to compare the rate of HPV positivity among HIV-positive women with that of HIV-negative women, and to determine predictors of HPV-infection. Though all women participating in this study were living in the centre region of Cameroon, the population living in this region is very cosmoplite, as they come from all regions of the country. Therefore, evidence from this geographical setting could mitigate the national representativeness.

Out of a sample of 278 women enrolled, the mean age (37 years) mainly represents the most sexually active population and therefore having chronic exposure to sexually transmitted infections, including HPV. These results are similar to those obtained in Cameroon with Kabayene et al. (mean age of 38.5 years) and in Chad (mean age of 35 years) [12, 17, 18].

According to marital status, single women were the most represented (58%), a rate above the national proportion published in 2005 by the Central Bureau of Censuses and Population Studies in Cameroon where single women had a percentage of 41.46% [14]. the difference could be explained by changing overtime, as the social realities in the population could justify the increasing rate of single women [15].

The median CD4 count was lower in the frame of HIV-infection (354 versus 414 cells/mm³] in HIV-negative women. Median CD4 obtained in HIV-free population was surprising; however, this could be justified by the fact that these women attending the health facility (likely due to illed-health for some of them) [14, 15, 19]. Furthermore, it was previously reported that CD4 levels could vary with different conditions, including but not limited to stress, smoking, menstrual cycle, contraceptive pill, physical activity, etc. [20]

The HR-HPV positivity rate was 38.48%, with very low rate of genotypes 16 and 18. 3% for mono-infection with HPV genotype 16 and 4% for mono-infection with HPV genotype 18. This suggests that other genotypes are drivers of HPV-infection in the Cameroonian context and need to be depict among cervical cancer cases, especially in the frame of HIV-infection [14, 20]. Our findings are comparable to those found in Central Africa Republic [21], which suggest a predominance of non-vaccine HR-HPV different from those found in Western Europe and North America [22, 23]. Interestingly, in a systematic review conducted by Doh et al., the prevalence of pure HPV 16 and 18 was 6.25 and 3.28% respectively, a finding very similar to our report showing evidence of 3% HPV 16 and 4% HPV 18 within the same country [24]. This thererfore stresses the fact that a bivalent vaccine would have very little predictive effectiveness within the population of Cameroonin women. Co-infection with HIV infection is a factor facilitating carcinogenesis associated with HR-HPV infections. Prospective studies have reported a higher incidence of HPV among HIV-positive women compared to HIV-negative women [1, 14, 16]. Co-infections of several HR-HPV genotypes was also been recorded, similar to previous reports [25]. Multi-infections are often associated with viral persistence, especially if co-present with HPV 16.

HIV is confirmed as a contributing factor to HPV-infection (p < 0.019), also confirmed by multi-variate analysis. As expected, women infected with HIV have a weaker immune status [26], which henceforth increases risk of acquiring HPV [27, 28]. This calls for the need to regularly test people with HPV infection for HIV [27].

Younger age are at higher risk of acquiring HPV-infection, likely due to sexual habits [29]. Regarding marital status, divorced women stand at high risk of acquiring HR-HPV. The lack of statiscal power limits the interpretation of this finding. Nonetheless, divorced women might be prone to multiple sexual partners, leading to HPV-infection [3, 30, 31]. The lack of synergistic effect between the HIV viral load and HPV-infection simply confirmed that HIV-infection interfers with HPV through immunodeficiency induced by HIV, and not via a direct viral-viral interaction [32, 33].

After adjusting the different variables based on a multi-variate analysis, HIV status remains the independent factor associated with the risk of infection with this high-risk oncogenic HPV (12 times higher risk), as previously demonstrated [34, 35]. Similar to our findings, the study by Tartaglia E. et al. also supports HIV-status as the main independent factor associated with risk of HPV infection among women, likely due to immunodeficiency. In other words, following multivariate analysis, none of the other parameters (except CD4 which is strongly related to the HIV condition) were found to be significantly associated with HPV infection [36].

Our study has some limitations. For instance, the low CD4-count in uninfected women was surpoirsing. This could simply be due to the consecutive sampling strategy that might lead to a certain degree of selection bias. Of note, the number of HIV-uninfected women was low; the presence of other comorbidities or infections such as hepatitis B, hepatitis C, and tuberculosis, could also affect the immune status. Unfortunately, diagnosis of these clinical conditions was not covered within the frame of the study. Further studies could therefore considered these aspects. Also, we have enrolled our patients only in the city of Yaounde and the reference molecular technique used for HPV detection made it possible to identify only genotypes 16 and 18. Given the high rate of other genotypes, it becomes essential to characterize this group. This therefore calls for sequencing for a better molecular characterization toward a rational selection of HPV vaccine candidate for the country.

In this sub-population of Cameroonian women, HPV burden appears to be very high, with higher rates of genotypes other than the commonly known 16 and 18. Interestingly, in the event of HIV infection, the risk of HPV-infection becomes higher, favoured essentially by immunodeficiency. Further HPV gentopic studies, coupled to vaccine trials, would are needed to ensure effective prevention of cervical cancer among HIV-infected women.