Prevalence and Risk Factors of Infection with High Risk Human Papilloma Viruses among HIV-Positive Women with Clinical Manifestations of Tuberculosis in a Middle-Income Country

Abstract

Women living with HIV-1 are at high risk of infection with human papillomavirus of high carcinogenic risk (HR HPVs). M. tuberculosis (TB) promotes HPV infection and increases the risk to develop HPV-associated cancer. Our knowledge of persisting HR HPVs genotypes, and of the factors promoting HR HPV infection in people living with HIV-1 with clinical TB manifestations is sparse. Here, we analyzed 58 women living with HIV-1 with clinical TB manifestations (WLWH with TB) followed up in specialized centers in Russia, a middle income country endemic for HIV-1 and TB, for the presence in cervical smears of DNA of twelve HR HPV genotypes. DNA encoding HPV16 E5, E6/E7 was sequenced. Sociodemographic data of patients was collected by questionnaire. All women were at C2-C3 stages of HIV-infection (by CDC). The majority were over 30 years old, had secondary education, were unemployed, had sexual partners, experienced 2-3 pregnancies and at least one abortion, and were smokers. The most prevalent was HPV16 detected in the cervical smears of 38% of study participants. Altogether 34.5% of study participants were positive for HR HPV types other than HPV16; however, but none of these types was seen in more than 7% of tested samples. Altogether, 20.7% of study participants were positive for several HR HPV types. Infections with HPVs other than HPV16 were common among WLWH with generalized TB receiving combined ART/TB-therapy, and associated with their ability to work, indirectly reflecting both their health and lifestyle. The overall prevalence of HR HPVs was associated with sexual activity of women reflected by the number of pregnancies, and of HPV 16, with young age; none was associated to CD4+-counts, route of HIV-infection, duration of life with HIV, forms of TB-infection, or duration of ART, characterizing the immune status. Thus, WLWH with TB-especially young-were predisposed to infection with HPV16, advancing it as a basis for a therapeutic HPV vaccine. Phylogenetic analysis of HPV16 E5, E6/E7 DNA revealed no common ancestry; sequences were similar to those of the European and American HPV16 strains, indicating that HPV vaccine for WLWH could be the same as HPV16 vaccines developed for the general population. Sociodemographic and health correlates of HR HPV prevalence in WLWH deserve further analysis to develop criteria/recommendations for prophylactic catch-up and therapeutic HPV vaccination of this highly susceptible and vulnerable population group.

Keywords: AIDS; ART and TB treatment; M. tuberculosis; clinical TB manifestations; prevalence of high risk HPVs; sequence of HPV 16 E6 and E7; sociodemographic characteristics; therapeutic HPV vaccine; women living with HIV-1.

Figure 1

Determinants of the severity of clinical TB manifestations in women living with HIV-1 co-infected with M. tuberculosis. Severity of clinical TB manifestations increased with the decrease of CD4+ T cell counts (A), with the lowest CD4+ counts observed in patients with severe clinical manifestations of TB (p < 0.05) (B); CD4+ T cell counts (y-axis) and the severity of clinical manifestations of TB, scored as generalized = 1, disseminated = 2, infiltrative = 3, lymph nodes and other = 4, pleural = 5, cirrhotic = 6, and focal = 7 (x-axis), were correlated (C); The severity of clinical manifestations of TB was not dependent on the on the patient’s age (D). Statistical analysis was done using Kruskall–Wallis, Mann–Whitney tests, and Spearman ranking test, and graphically represented using Statistica 11 software; p values < 0.05 were considered significant.

Figure 1

Determinants of the severity of clinical TB manifestations in women living with HIV-1 co-infected with M. tuberculosis. Severity of clinical TB manifestations increased with the decrease of CD4+ T cell counts (A), with the lowest CD4+ counts observed in patients with severe clinical manifestations of TB (p < 0.05) (B); CD4+ T cell counts (y-axis) and the severity of clinical manifestations of TB, scored as generalized = 1, disseminated = 2, infiltrative = 3, lymph nodes and other = 4, pleural = 5, cirrhotic = 6, and focal = 7 (x-axis), were correlated (C); The severity of clinical manifestations of TB was not dependent on the on the patient’s age (D). Statistical analysis was done using Kruskall–Wallis, Mann–Whitney tests, and Spearman ranking test, and graphically represented using Statistica 11 software; p values < 0.05 were considered significant.

Figure 2

Parameters of sexual activity in WLWH with TB naive to antiretroviral treatment (ART; n = 23) and receiving ART by the time of the survey (n = 35), including proportion of WLWH self-reporting as sexually active, the average number of reported sexual partners during six months preceding the survey, and the average reported number of life-time pregnancies. Statistical analysis was done by F-test (Statistica 11).

Figure 3

Prevalence of HR HPVs in the cervical smears of women living with HIV-1. TB -negative WLWH (n = 50) and WLWH with TB (n = 58). * p = 0.03, ** p = 0.014, *** p = 0.0035, two-sided difference test (Statistica Axa 11).

Figure 4

Prevalence of infection with HR HPVs among WLWH with different clinical forms of tuberculosis (n = 58).

Figure 5

Representation of HR HPV genotypes in HR HPV positive cervical smears. WLWH positive for any of HR HPVs represented by WLWH without TB on ART (n = 35), WLWH with TB naïve to ART or ART treated <3 month (treatment started in the hospital; n = 19) and WLWH with TB receiving ART for >3 month (on treatment before hospitalization; n = 15) were compared in prevalence (%) of HPV 16 and of any HR HPV other than HPV 16 (A), and of individual HR HPV genotypes (B). * p < 0.05, WLWH with TB compared to WLWH without TB for those ART-treated for >3 month; ** p < 0.05 WLWH without TB on ART compared to both subgroups of WLWH with TB; two- sided difference test (Statistica 11).