Dianne J. Marais

Genital Human Papillomavirus Prevalence and Human Papillomavirus Concordance in Heterosexual Couples Are Positively Associated with Human Immunodeficiency Virus Coinfection

This study examined the concordance of genital human papillomavirus (HPV) infection in 254 heterosexually active couples and the impact of HIV coinfection. Genital HPV detection was significantly more common among HIV-infected women than among HIV-seronegative women (99 [68%] of 145 women vs. 33 [31%] of 107 women; P < .001); similarly, HPV detection was significantly more common among HIV-infected men than among HIV-seronegative men (67 [72%] of 93 and 65 [43%] of 150 men, respectively; P < .001). HIV-seronegative male partners of HIV-infected women had a significantly greater prevalence of HPV infection than did HIV-seronegative male partners of HIV-seronegative women (38 [58%] of 65 men vs. 27 [32%] of 85 men; P = .001), indicating that HIV coinfection in one partner has a significant impact on the prevalence of HPV genital infection in the other partner. HPV concordance between couples was associated with HIV infection status (P < .001, by Pearsons chi2 test) and was significantly higher among HIV-infected couples than among HIV-seronegative couples. Type-specific sharing of HPV was associated with HIV concordance status (P = .024). HIV-seronegative couples were more likely to share 1 HPV type and were unlikely to share >1 type, whereas HIV-infected or HIV-discordant couples were more likely to share >1 HPV type. Women with a high HPV load frequently shared HPV types with their male partners, suggesting that a high HPV load may play a role in HPV transmission between partners. In conclusion, HIV coinfection in one or both sexually active partners increased HPV prevalence and HPV type-specific concordance.

Age distribution of antibodies to human papillomavirus in children, women with cervical intraepithelial neoplasia and blood donors from South Africa

Sera from 95 women with cervical intraepithelial neoplasia (CIN), 95 age‐matched female blood donors, and 155 children aged between 1 and 12 years were tested by enzyme‐linked immunosorbent assay (ELISA) for levels of serum IgG to three human papillomavirus (HPV) peptides (HPV‐16 E2 [E2‐16], HPV‐18 E2 (E2‐18], HPV‐16 L1 [L1‐16]), as well as HPV‐16 virus‐like particles (VLP‐16) and bovine papillomavirus type 1 virus‐like particles (BPV‐VLP). In the adult group antibodies to E2‐16 and VLP‐16 were significantly associated with CIN when compared to the blood donor controls (P = .039 and P = .002, respectively). In women with CIN there was an increase in seropositivity to E2‐16 and a decrease in seropositivity to VLP‐16 with age. Antibodies to HPV‐16 E2 could therefore be an important marker of CIN in women over 40 years of age, whereas antibodies to VLP‐16 could be a marker for CIN in younger women. There was no correlation with CIN and antibodies to E2‐18, L1‐16, and BPV‐VLP. In the childrens sera antibodies were detected to E2‐16 (44.5%), E2‐18 (18.7%), L1‐16 (20%), VLP‐16 (4.5%), · and BPV‐VLP (5.1%). Between the ages of 3 and 12 years the prevalence of antibodies to E2‐16 decreased with age. The presence of antibodies to HPV‐16 in young children indicated infection with either HPV‐16 or a related virus. HPV DNA isolation from children could help resolve this question. J Med Virol 51:126–131, 1997.

Cervical and oral human papillomavirus types in HIV-1 positive and negative women with cervical disease in South Africa.

This study tested cervical and oral human papillomavirus (HPV) infection in HIV‐1 seropositive (HIV+) and seronegative (HIV−) women to determine any association between infections at both sites and the difference in prevalence of the HPV types infecting these women. Participants were 115 women referred to a colposcopy clinic after diagnosis of abnormal cervical cytology. The women showed low grade cervical intraepithelial neoplasia (CIN1) or high grade disease (CIN2/3) or no CIN based on colposcopy and histology. Typing of HPV in cervical and oral cells was by Roche linear array and included direct sequencing on selected oral samples. Cervical HPV prevalence was 86.5% and 97.1% in HIV− and HIV+ women respectively. With the exception of HPV‐45, prominent in HIV+ women, the hierarchy of predominant types were similar in HIV− and HIV+ women. HPV‐16 was most prevalent in both HIV+ (41.7%) and HIV− women (38.5%) with CIN2/3. Significantly more HIV+ women had multiple cervical (>1) infections than HIV− women (36.1% vs. 88.2%, P < 0.001) and more oral HPV infections (45.5% and 25% respectively; P = 0.04). The most prevalent oral HPV types were HPV‐33, ‐11, and ‐72. The majority of women did not have concordant oral and cervical HPV types, reflecting possible independence of infection at the two sites. HIV immune suppression did not impact significantly on the predominant types of cervical HPV infection (except for HPV‐45). HIV+ women had more multiple HPV infections and those with severe cervical disease a similar prevalence of HIV‐16 but a lower HPV‐18 prevalence than HIV− women. J. Med. Virol. 80:953–959, 2008.

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.

The effectiveness of Carraguard, a vaginal microbicide, in protecting women against high-risk human papillomavirus infection.

BACKGROUND A randomised, double-blind, placebo-controlled trial found the vaginal microbicide Carraguard unable to prevent HIV infection. A substudy assessed the association of genital high-risk human papillomavirus (HR-HPV) in women at study end with Carraguard use. METHODS Participants received Carraguard gel or placebo plus condoms, and were instructed to use gel plus condoms during each act of vaginal intercourse. HR-HPV detection on cervical samples from 1,723 women was by Digene Hybrid Capture 2 analysis. Poisson regression analysis assessed the prevalence of genital HR-HPV for individuals receiving Carraguard relative to individuals receiving placebo. RESULTS In the Carraguard arm (n=875) the end trial unadjusted HR-HPV prevalence was 23.5% (95% CI 20.8-26.3) and 23.0% (95% CI 20.2-25.8) in placebo arm (n=843). Significant risk factors for HR-HPV infection were younger age, being single, an abnormal pap smear, multiple sexual partners and promiscuous behaviour without the use of a condom. There were 348 compliant women (174 Carraguard, 174 placebo users), with relatively high adherence to gel use, who inserted 80% of their opened, returned applicators of test product with the proportion of applicator insertions to sex acts >30%. After adjusting for risk factors, these compliant Carraguard users were 0.62 as likely to be classified HR-HPV positive (95% CI 0.41-0.94) as compliant placebo users. CONCLUSIONS The prevalence of HR-HPV infection was lower in compliant Carraguard users than compliant placebo users. To our knowledge, this is the first report showing a negative association of HPV infection with a vaginal microbicide.

Seroresponses to human papillomavirus types 16, 18, 31, 33, and 45 virus-like particles in South African women with cervical cancer and cervical intraepithelial neoplasia.

The aim of the study was to determine the prevalence of antibodies to human papillomavirus (HPV) types 16, 18, 31, 33, and 45 in woman in Cape Town with cervical intraepithelial neoplasia (CIN) (n = 95), cervical cancer (n = 40), female blood donors (n = 95) and children (n = 110). The enzyme‐linked immunosorbent assay (ELISA) made use of baculovirus synthesised HPV virus like particles (VLPs) as antigen. Antibodies to at least one HPV type were detected in sera from 75% of cancer patients, 71.6% of CIN patients, 44.2% of blood donors and 27.3% of children. Sera from 95 women with CIN were compared with age‐matched female blood donors. There was a significant association of seropositivity to VLP‐16 (P = 0.006) and VLP‐45 (P = 0.008) with CIN compared with the blood donors. There was also a significant difference in the seropositivity of women with CIN to any of the five virus‐like particle (VLP) types compared to the blood donors (P = 0.0002: OR = 3.2). Thirty‐nine of sixty‐nine (56.5%) women with CIN were found to be HPV‐16 DNA positive. The average age of women in this group that were VLP‐16 seropositive was 34 years and those found to be VLP‐16 seronegative was 52 years of age. Antibodies to all five VLP types were detected in these populations, thus an ideal vaccine should induce protection from infection by a wide range of HPV types. J. Med. Virol. 60:403–410, 2000.

A recombinant human papillomavirus (HPV) type 16 L1–vaccinia virus murine challenge model demonstrates cell-mediated immunity against HPV virus-like particles

Human papillomavirus (HPV) virus-like particles (VLP) are emerging as the immunogen of choice for prophylactic vaccines. The inability to infect animals with HPV has prevented the testing of potential vaccines such as these in animal systems. This study describes the development of a recombinant vaccinia virus (VV)-HPV type 16 (HPV-16) VLP challenge model to evaluate the efficacy of the cell-mediated immune response following HPV-16 VLP immunization in mice. Inoculation of BALB/c and C57 BL/6 mice with HPV-16 VLP resulted in HPV VLP-specific T cell proliferative responses characterized by the production of both Th1 and Th2 cytokines, and afforded protection against virus challenge from recombinant VV expressing HPV-16 L1 (VVL1R-16). Protection was demonstrated by a 4.6 log10 reduction in ovarian titres of VVL1R-16 in vaccinated BALB/c mice and a 2.3 log10 reduction in vaccinated C57 BL/6 mice, compared with unvaccinated mice.

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.

Cervical Human Papillomavirus (HPV) Infection and HPV Type 16 Antibodies in South African Women

ABSTRACT There is a high incidence of cervical cancer in South African women. No large studies to assess human papillomavirus virus (HPV) infection or HPV type 16 (HPV-16) exposure have occurred in the region, a requirement for policy making with regards to HPV screening and the introduction of vaccines. Control women (n = 1,003) enrolled in a case control study of hormonal contraceptives and cervical cancer were tested for 27 cervical HPV types by reverse line blot analysis. The seroprevalence of HPV-16 immunoglobulin G (IgG) and IgA antibodies was assessed by a virus-like particle-based enzyme-linked immunoassay of 908 and 904 control women, respectively, and of 474 women with cervical cancer. The cervical HPV prevalence was 26.1%. The HPV-16 IgG seroprevalence was 44.4% and the HPV-16 IgA seroprevalence was 28.7% in control women, and these levels were significantly higher (61.8% and 52.7%, respectively) for women with cervical cancer (odds ratio [OR], 2.1 and 2.8, respectively). The cervical HPV prevalence showed an association with cervical disease, and the HPV-16 IgG prevalence decreased while the HPV-16 IgA prevalence increased with increasing age (P < 0.05). The prevalence of oncogenic HPV types (including HPV-16) decreased with age, whereas nononcogenic HPV types showed limited association with age. Multivariate analysis revealed cervical HPV infection to be associated with herpes simplex virus type 2 infection (OR, 1.7) and increasing years of education (OR, 1.9). HPV-16 IgG antibodies were inversely associated with current smoking status (OR, 0.6), and the presence of HPV-16 IgA antibodies was inversely associated with the use of alcohol (OR, 2.1) and inversely associated with the use of oral contraceptives (OR, 0.6). High levels of exposure to HPV, and particularly HPV-16, were evident in this population. The apparent increase of serum HPV-16 IgA with increasing age requires further investigation.

Cervical Human Papillomavirus (HPV) Infection in South African Women: Implications for HPV Screening and Vaccine Strategies

ABSTRACT The prevalence of cervical human papillomavirus (HPV) in South African women (n = 1,073) increased from 20.4% (173/848) in women with normal cytology to 41.7% (48/115) in women with atypical squamous cells of undetermined significance, 70.2% (40/57) in women with low-grade squamous intraepithelial lesions, and 83% (44/53) in women with high-grade squamous intraepithelial lesions (HSILs). HPV types 16 and 35 were the dominant types in women with HSILs but not in women in the other categories.