Zizipho Z. A. Mbulawa

Impact of Human Immunodeficiency Virus on the Natural History of Human Papillomavirus Genital Infection in South African Men and Women

BACKGROUND This study investigated genital human papillomavirus (HPV) incidence and clearance in 278 human immunodeficiency virus (HIV)-seropositive (HIV-positive) women, 208 HIV-negative women, 161 HIV-positive men, and 325 HIV-negative men, followed at 6-month intervals for up to 24 months. METHODS HPV types were determined by the Roche Reverse Linear Array HPV genotyping assay. RESULTS The rate of new HPV detection at the cervix and penis were 33.83 events/1000 person-months (95% confidence interval [CI], 26.39-43.46) and 55.68 events/1000 person-months (95% CI, 43.59-69.19), respectively. HIV infection was associated with increased risk of new HPV detection in women (relative risk [RR], 2.98; 95% CI, 2.07-4.29) and men (RR, 2.00; 95% CI, 1.49-2.69). The risk of new HPV detection increased in women (RR, 5.25; 95% CI, 3.52-7.81) and men (RR, 8.71; 95% CI, 6.19-12.24) when the sexual partner was infected with the same HPV type. The rate of clearing any HPV infection was 95.1 events/1000 person-months (95% CI, 83.3-108.1) in men and 66.9 events/1000 person-months (95% CI, 57.0-78.5) in women. HIV infection reduced the rate of HPV clearance in women (RR, 0.46; 95% CI, .34-.62) and men (RR, 0.71; 95% CI, .55-.93). CONCLUSIONS HIV infection increases the risk of new HPV detection and decreases the rate of HPV clearance in both women and men.

Influence of human immunodeficiency virus and CD4 count on the prevalence of human papillomavirus in heterosexual couples

This study investigated the impact of human immunodeficiency virus (HIV) infection on genital human papillomavirus (HPV) in heterosexual couples. More HIV-positive men and women had genital HPV compared with HIV-negative men (77 vs 49%; P<0.001) and women (74 vs 36%; P<0.001). More men and women with partners who were HPV positive had HPV genital infection compared with those with HPV-negative partners (for men, 72% compared with 40%; P<0.001). Men with HIV-positive female partners were at greater risk of high-risk HPV and low-risk HPV (LR HPV) infection compared with men with HIV-negative female partners. This risk increased with decreasing CD4 count { ≥ 350 ml⁻¹: odds ratio [OR ], 2.37 [95% confidence interval (CI), 1.47-3.83]; < 350 ml⁻¹: OR, 3.02 [95 % CI, 1.86-4.9]}. Conversely, the risk of HPV of any type was not found to differ between women with an HIV-positive or HIV-negative male partner. In men, HIV infection and female partner HIV-positive status were both associated with a higher risk of type-specific HPV concordance with their sexual partner, though the associations were not significant for LR HPV. In women, HIV infection and low CD4 count were significantly associated with increased risk of type-specific HPV concordance, but male partner HIV-positive status was not significantly associated with this concordance. In conclusion, male genital HPV prevalence and type-specific sharing were influenced by their own HIV-positive status and that of their female partner. In contrast, female genital HPV prevalence and HPV type-specific sharing were determined by their own HIV-positive status and not by that of their male partner.

Comprehensive profiling of the vaginal microbiome in HIV positive women using massive parallel semiconductor sequencing

Infections by HIV increase the risk of acquiring secondary viral and bacterial infections and methods are needed to determine the spectrum of co-infections for proper treatment. We used rolling circle amplification (RCA) and Ion Proton sequencing to investigate the vaginal microbiome of 20 HIV positive women from South Africa. A total of 46 different human papillomavirus (HPV) types were found, many of which are not detected by existing genotyping assays. Moreover, the complete genomes of two novel HPV types were determined. Abundance of HPV infections was highly correlated with real-time PCR estimates, indicating that the RCA-Proton method can be used for quantification of individual pathogens. We also identified a large number of other viral, bacterial and parasitic co-infections and the spectrum of these co-infections varied widely between individuals. Our method provides rapid detection of a broad range of pathogens and the ability to reconstruct complete genomes of novel infectious agents.

High burden of human papillomavirus (HPV) infection among young women in KwaZulu-Natal, South Africa.

Objectives HPV infection causes cervical cancer, yet information on prevalence and risk factors for HPV in Africa remain sparse. This study describes the prevalence of HPV genotypes and risk factors associated with HPV among young women ≤ 30 years of age in KwaZulu-Natal (KZN), South Africa. Methods Cervicovaginal lavage samples were tested for HPV genotypes in 224 women enrolled in a prospective cohort study. Clinical, behavioural and demographic data were collected. We measured prevalence of HPV genotypes and using logistic regression, examined for factors associated with HPV. Results Median age of participants was 21 years [interquartile range (IQR):18–23]. The overall prevalence of HPV was 76.3% (171/224) with multiple and single genotypes prevalent in 56.3% and 20.1% of women respectively. Proportion of women with high-risk genotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56 and 58) was 54.5%. Women not living with their partner [adjusted odds ratio (aOR)] = 3.42 95% CI1.22–9.60; p = 0.019), was significantly associated with HPV infection and high-risk HPV genotype infection. Conclusion The high burden of HPV and associated risk behaviours highlight the need to intensify behavioural interventions to prevent HPV acquisition in young women. The large scale delivery of HPV vaccine should be prioritised to prevent HPV acquisition and reduce HPV-related morbidity.

Increased alpha-9 human papillomavirus species viral load in human immunodeficiency virus positive women

BackgroundPersistent high-risk (HR) human papillomavirus (HPV) infection and increased HR-HPV viral load are associated with the development of cancer. This study investigated the effect of human immunodeficiency virus (HIV) co-infection, HIV viral load and CD4 count on the HR-HPV viral load; and also investigated the predictors of cervical abnormalities.MethodsParticipants were 292 HIV-negative and 258 HIV-positive women. HR-HPV viral loads in cervical cells were determined by the real-time polymerase chain reaction.ResultsHIV-positive women had a significantly higher viral load for combined alpha-9 HPV species compared to HIV-negative women (median 3.9 copies per cell compared to 0.63 copies per cell, P = 0.022). This was not observed for individual HPV types. HIV-positive women with CD4 counts >350/μl had significantly lower viral loads for alpha-7 HPV species (median 0.12 copies per cell) than HIV-positive women with CD4 ≤350/μl (median 1.52 copies per cell, P = 0.008), but low CD4 count was not significantly associated with increased viral load for other HPV species. High viral loads for alpha-6, alpha-7 and alpha-9 HPV species were significant predictors of abnormal cytology in women.ConclusionHIV co-infection significantly increased the combined alpha-9 HPV viral load in women but not viral loads for individual HPV types. High HR-HPV viral load was associated with cervical abnormal cytology.

Association of serum and mucosal neutralizing antibodies to human papillomavirus type 16 (HPV-16) with HPV-16 infection and cervical disease

We investigated neutralizing antibodies to human papillomavirus type 16 (HPV-16) in serum and cervical washes from 84 women with normal cytology or cervical disease. Serum neutralizing antibodies were detected in 78 % of women infected at the cervix with HPV-16, compared with 35 % (P=0.002) of women infected with HPV-16-related types (alpha9 HPV types), 14 % (P<0.0001) of women infected with HPV-16 non-related types and none of HPV-uninfected women. A significant correlation between HPV-16 infection and serum HPV-16-neutralizing antibodies was observed (r(s)=0.97; P=0.032). Cervical neutralizing antibodies were detected in 38 % of women with HPV-16 infection and in 17 % of women infected with the HPV-16-related type HPV-31. Cervical neutralizing antibodies correlated with HPV-16 infection (r(s)=0.95; P=0.08), but not with cervical disease. Serum and cervical HPV-16 antibody responses were not affected significantly by human immunodeficiency virus type 1 infection. In conclusion, serum and cervical HPV-16-neutralizing antibodies were found to correlate with HPV-16 infection, but not with cervical disease.

Female genital tract inflammation, HIV co-infection and persistent mucosal Human Papillomavirus (HPV) infections

BACKGROUND Persistent genital infections with high-risk HPV types increase risk of cervical disease and cancer. Since genital inflammation increases HIV acquisition risk and cancer progression, we evaluated whether HPV infection induces cytokine expression in the reproductive tract. METHODS Genital cytokines concentrations were measured in 93 HIV-infected and 72 uninfected women. HPV typing was done by Roche Linear array. Persistence and clearance of HPV were evaluated using longitudinal data. RESULTS Infection with HPV did not influence genital cytokine concentrations. In contrast, HIV-infected women had higher IL-1α, IL-6, IL-8, IP-10, MCP-1 and G-CSF concentrations compared to HIV-uninfected women, and HPV-infections that were more prevalent, persistent and multi-type. CONCLUSION HPV did not influence inflammatory cytokine levels in the genital tract, although immune suppression may favor persistence.

Xpert human papillomavirus test is a promising cervical cancer screening test for HIV-seropositive women

This study investigated the performance of Cepheid Xpert human papillomavirus (HPV) assay in South African human immunodeficiency virus (HIV)-infected women and compared its performance with that of hybrid capture-2 (hc2). Methods: Stored cervical specimens from HIV-infected women that had previously been tested using hc2 were tested using Xpert. Results: The overall HR-HPV prevalence was found to be 62.0% (720/1161) by Xpert and 61.2% (711/1161) by hc2. 13.6% (158/1161) were HPV16 positive, 18.8% (218/1161) were HPV18/45, 37.3% (434/1161) were HPV31/33/35/52/58, 12.7% (147/1161) were HPV51/59 and 23.3% (270/1161) were HPV39/68/56/66. Overall agreement with hc2 was 90%; Cohen’s kappa was 0.78 (95% CI 0.74–0.82) indicating substantial agreement. Detection of HPV16, HPV18/45, and HPV31/33/35/52/58 were independently associated with cervical intraepithelial neoplasia (CIN)−2+ (P<0.0001 for each); while HPV51/59 and HPV39/68/56/66 were not. Women infected with HPV16, HPV18/45 or HPV31/33/35/52/58 were found to have significantly higher amounts of HPV DNA detected for those with CIN2+ compared to those without CIN2+, P<0.0001 for each. Xpert and hc2 were similarly sensitive (88.3% and 91.5%, respectively) and specific (48.4% and 51.0%) for CIN2+ and CIN3 (sensitivity: 95.8% and 97.9%; specificity: 41.4% and 42.8%). Conclusions: Xpert is a promising screening test in HIV-infected women that performs similarly to hc2.

High human papillomavirus (HPV) prevalence in South African adolescents and young women encourages expanded HPV vaccination campaigns

The objectives of the study were to investigate prevalence of cervical human papillomavirus (HPV) genotypes to inform HPV vaccination strategy in South Africa and to study factors associated with HPV prevalence. Sexually active, HIV-negative women, aged 16–22 years recruited from Soweto (n = 143) and Cape Town (n = 148) were tested for cervical HPV and other genital infections. Overall HPV prevalence was 66.7% (194/291) in young women. Cape Town women were more likely to have multiple HPV infections than the Soweto women (48.0%, 71/148 versus 35.0%, 50/143 respectively, p = 0.033) and probable HR-HPV types (34.5%, 51/148 versus 21.7%, 31/143 respectively, p = 0.022). The most frequently detected HPV types were HPV-16 (11.7%), HPV-58 (10.3%), HPV-51 (8.9%), HPV-66 (8.6%), HPV-18 and HPV-81 (7.6% each). HPV types targeted by the bivalent HPV vaccine (HPV-16/18) were detected in 18.6% (54/291) of women, while those in the quadrivalent vaccine (HPV-6/11/16/18) were detected in 24.7% (72/291) of women; and those in the nonavalent vaccine (HPV-6/11/16/18/31/33/45/52/58) were detected in 38.5% (112/291) of women. In a multivariable analysis, bacterial vaginosis remained significantly associated with HPV infection (OR: 4.0, 95% CI: 1.4–12.6). Women were more likely to be HPV positive if they had received treatment for STI during the past 6-months (OR: 3.4, 95% CI: 1.1–12.4) or if they had ever been pregnant (OR: 2.3, 95% CI: 1.1–5.5). Compared to women who reported only one sexual partner, those with increased number of lifetime sex partners were more likely to have HPV (4–10 partners: OR: 2.9, 95% CI: 1.1–8.0). The high prevalence of HPV types targeted by the nonavalent HPV vaccine encourages the introduction of this vaccine and catch-up HPV vaccination campaigns in South Africa. The high burden of BV and concurrent STIs also highlights the need to improve the prevention and appropriate management of sexually-acquired and other genital tract infections in South African youth.

Converging epidemics of sexually transmitted infections and bacterial vaginosis in southern African female adolescents at risk of HIV

Adolescents in Africa are at high risk for HIV infection, other sexually transmitted infections (STIs) and bacterial vaginosis (BV). Since behavior and burden of STIs/BV may influence HIV risk, behavioral risk factors and prevalence of STIs/BV were compared in HIV-seronegative adolescent females (n = 298; 16–22 years) from two South African communities (Soweto and Cape Town). STIs (Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Mycoplasma genitalium, herpes simplex virus (HSV)-1, HSV-2, Treponema pallidum, and Haemophilus ducreyi) were detected by multiplex polymerase chain reaction, human papillomavirus (HPV) by Roche Linear Array, and BV by Nugent scoring. Rates of BV (Nugent ≥7; 46.6%) and HPV (66.8%) were high in both communities. Prevalence of C. trachomatis and N. gonorrhoeae were >2-fold higher in Cape Town than Soweto (Chlamydia: 42% [62/149] versus 18% [26/148], p < 0.0001; gonorrhoea 11% [17/149] versus 5% [7/148], p = 0.05). Only 24% of adolescents with vaginal discharge-causing STIs or BV were symptomatic. In South African adolescents, clinical symptoms compatible with vaginal discharge syndrome had a sensitivity of 23% and specificity of 85% for the diagnosis of discharge-causing STI or BV. In a region with high HIV prevalence and incidence, >70% of young women with treatable conditions that could enhance HIV risk would have been missed because they lacked symptoms associated with syndromic management.