Long-term follow-up on HIV infected and non-infected women with cervical cancer from Tanzania: staging, access to cancer-directed therapies and associated survival in a real-life remote setting.

BACKGROUND: Worldwide 85% of cervical cancer (CC) related deaths occur in low- and middle-income countries. Sub-Saharan Africa is burdend by an overlapping high incidence of CC as well as HIV infection, a risk factor for HPV associated disease progression. Recent upscaling of CC screening activities increased the number of CC diagnoses in a previous unscreened population. The aim of the 2H study was to follow up on women with CC in the context of available health care services in Tanzania in relation to their HIV infection status. METHODS: This longitudinal observational cohort study included women with histological confirmed CC from Mbeya, Tanzania, between 2013-2019. All women were referred for CC staging and cancer-directed therapies (CDT), including surgery and/or radio-chemotherapy, or palliative care. Annual follow-up focused on successful linkage to CDT, interventions and survival. We assessed factors on compliance, used Kaplan-Meier-Survivor functions to evaluate survival time and poisson regression models to calculate incidence rate ratios on mortality (IRR) two years after diagnosis. RESULTS: Overall, 270 women with CC (123 HIV infected) were included. Staging information, available in 185 cases, showed 84.9% presented with advanced stage disease (FIGO ≥ IIB), no difference was seen in respect to HIV status. HIV-infected women were 12 years younger at the time of cancer diagnosis (median age 44.8 versus 56.4 years, p < 0.001). Median follow up period was 11.9 months (range 0.2-67.2). Survival information, available in 231 cases, demonstrated for women diagnosed in early-stage disease a median survival time of 38.3 months, in advanced-stage 16.0 months and late-stage disease 6.5 months after diagnosis. Of all women, 42% received CDT or palliative support. HIV co-infection and education were associated with higher health care compliance. CDT was significantly associated with lower 2-year mortality rates (IRR 0.62, p = 0.004). HIV coinfection did not impact mortality rates after diagnosis. CONCLUSION: High numbers of advanced and late staged CC were diagnosed, compliance to CDT was low. A beneficial impact of CDT on CC mortality could be demonstrated for local health care services. This study indicates challenges for successful linkage and supports an effective scale up of cancer care and treatment facilities.

Where and how do young people like to get their sexual and reproductive health (SRH) information? Experiences from students in higher learning institutions in Mbeya, Tanzania: a cross-sectional study.

BACKGROUND: Sexual and reproductive health (SRH) among young adults in low- and middle-income countries (LMIC) is still a major public health challenge. Early school-based sexuality education programs and sexual health information sharing between teachers, parents and young people have been considered protective against the sexual health risks to which young people are exposed. There is, however, limited information on the preferred choices of "where", "how" and "from whom" young people would like to receive SRH information. We aimed to describe the experience and preferences of young people regarding their SRH education and learning and in particular communication with their parents/guardians. METHODS: We conducted a cross-sectional study among randomly selected students aged 18-24y attending Higher Learning Institutions (HLIs) in Mbeya, Tanzania. We used a self-administered questionnaire to collect information on SRH education received, ability to discuss SRH matters with a parent/guardian and SRH information gaps encountered during their early sexual experience. RESULTS: We enrolled 504 students from 5 HLIs, of whom 446 (88.5%) reported to be sexually active, with mean age at sexual debut of 18.4y (SD 2.2). About 61% (307/504) of the participants found it difficult to discuss or did not discuss SRH matters with their parent/guardian while growing up. Learning about SRH matters was reported from peers (30.2%) and teacher-led school curriculum (22.7%). There was a strong gender-biased preference on SRH matters' discussions, female and male participants preferred discussions with adults of their respective sex. Peers (18.2%), media (16.2%) and schools (14.2%) were described as the preferred sources of SRH information. On recalling their first sexual experience, sexually-initiated participants felt they needed to know more about sexual feelings, emotions and relationships (28.8%), safer sex (13.5%), how to be able to say 'No' (10.7%) and how to use a condom correctly (10.2%). CONCLUSION: Young people have a gender preference when it comes to learning about SRH matters from their parents; however, such conversations seldom occur. Community health education should focus on building skills of parents on parent-child communication on SRH matters so as to empower them to confidently initiate and convey accurate SRH information. Comprehensive SRH education and skills building need to be strengthened in the current school SRH curriculum in order to meet the demand and needs of students and increase the competence of teachers.

High-risk human papillomavirus genotype distribution among women living with and at risk for HIV in Africa.

OBJECTIVE: Cervical cancer is a common preventable cancer among African women living with HIV (WLWH). Molecular diagnostics for high-risk human papillomavirus (HR-HPV) genotypes are standard components of cervical cancer screening in resource-rich countries but not in resource-limited settings. We evaluated HR-HPV genotypes among women with and without HIV in four African countries to inform cervical cancer preventive strategies. METHODS: The African Cohort Study (AFRICOS) enrolled participants with and without HIV at 12 clinics in Tanzania, Kenya, Uganda, and Nigeria. Cervical cytobrush specimens from women were genotyped for 14 HR-HPV types using the multiplex Seegene Anyplex real-time PCR assay. Robust Poisson regression was used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for factors associated with HR-HPV in WLWH. RESULTS: From January 2015 to March 2020, 868 WLWH and 134 women living without HIV (WLWoH) were tested for HR-HPV with prevalence of 50.9 and 38.1%, respectively ( P  = 0.007). Among WLWH, 844 (97.4%) were antiretroviral therapy (ART)-experienced and 772 (89.7%) virally suppressed 1000 copies/ml or less. The most frequent HR-HPV types among WLWH were HPV-16 (13.5%), HPV-52 (9.5%), and HPV-35 (9.3%). HR-HPV infection was more common among Tanzanian WLWH (adjusted RR: 1.23, 95% CI 1.05-1.44, P  = 0.012). Also, WLWH with CD4 + T cells of less than 200 cell/µl had 1.51-fold increased risk of having HR-HPV (95% CI 1.23-1.86, P  < 0.001). CONCLUSION: HR-HPV was common in WLWH in four African countries, particularly among women with low CD4 + cell count. Scale up of HPV vaccines and development of vaccines with broader activity against less common HR-HPV types may improve cervical cancer prevention in Africa.

HIV testing and linkage to care-A case of a mobile diagnostic and counseling service in Mbeya, Tanzania; A quantitative study.

HIV-care programmes are faced with significant challenges in getting newly diagnosed People Living with Human Immunodeficiency Virus (PLHIV) linked to care despite massive investment in HIV prevention, treatment and care. This study assessed the performance of mobile HIV Testing and Counseling service (mHTC) in provision of HIV-testing and linkage to care of newly diagnosed PLHIV from Key and Vulnerable Populations (KVPs). A retrospective review of the records of 25,248 clients was extracted from the mHTC database from October-2016 to September-2018. Of 25,248 clients, 51.71% were in 25-45 years age group, 55.4% were males, 60.5% were married and 62.1% had primary level of education. The median age of clients was 31 (IQR: 23-42) years. Out of the clients tested, 800 (3.17%) were diagnosed HIV-positive. Positivity was high among females 450 (4%), age group 25-45 years 538 (4.12%), divorced 202 (7.41%) and clients with primary level of education 504 (3.21%). An association between HIV status and sex, age group, relationship status and level of education was observed (P<0001). Out of the 800 HIV-positive clients, 418 (52.30%) were successfully linked to care. Among the positive clients, 5/6 (83.33%) children below 15 years old, 238/450 (52.89%) females and 39/64 (60.94%) widows were successfully linked to care. In the multivariable log binomial regression model age of the clients was associated with successful linkage to care. The mHTC was able to reach KVP clients; overall linkage for both sexes was 52.30% below the recommended UNAIDS 90-90-90 target. Raising the need to address the challenges associated with linkage and specific care for KVPs as a subset of the general population. The mHTC has shown that it is feasible to improve the reach of KVP clients; however, further research is required to examine the quality of this service at the community level.

Prevalence of and risk factors associated with HIV, Herpes Simplex Virus-type 2, Chlamydia trachomatis and Neisseria gonorrhoeae infections among 18-24 year old students attending Higher Learning Institutions in Mbeya-Tanzania.

BACKGROUND: Sexually transmitted infections (STIs) are common among young people in low- and middle-income countries and are associated with negative reproductive and pregnancy outcomes. Most of the studies have assessed HIV among adolescents and young adults, with limited information on occurrence of other STIs in this population. This study aimed to describe the prevalence of and risk factors associated with Herpes Simplex Virus-type 2 (HSV-2), Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Syphilis and HIV infection among young adults attending Higher Learning Institutions (HLIs) in Mbeya, Tanzania. METHODS: We conducted a cross-sectional study among students aged 18-24years attending HLIs in Mbeya-Tanzania, randomly selected using a computerized random number. Participants were tested for HSV-2, CT, NG, Syphilis and HIV infection. We used a self-administered questionnaire to collect information on sexual activity and risk factors to the tested STIs. RESULTS: We enrolled 504 students from 5 HLIs, with mean age of 21.5 years (SD 1.7). 17% of the students had at least one STI; prevalence was higher among females than males (21.1% versus 14.1%). CT (11%) and HSV-2 (6.1%) were the most common STIs, while NG (1.1%) and HIV (0.7%) infection had the least occurrence. None of the participants was diagnosed with Syphilis. In univariate analysis, predictors for STIs were Sex, inconsistent condom use in the past 4weeks, report of oral sex, sexual orientation (bisexual/homosexual) and having a sexual partner with an age-difference of at least 5years (either older or younger); while in the multivariate analysis, Sex, inconsistent condom use in the past 4weeks and sexual orientation (bisexual/homosexual) remained significant. CONCLUSION: STIs such as Chlamydia and HSV-2 which are commonly asymptomatic are of concern among young adults attending HLIs. The latter is an important group that needs attention and recognition that is pivotal in transmission of STIs considering their risk. Information, Education and Communication (IEC) campaigns targeting young adults, especially those at HLIs, need to focus on exposure-risk minimization. Funding institutions that have invested heavily on HIV prevention campaigns should consider giving similar recognition to other STIs for a streamlined outcome.

Depletion of Human Papilloma Virus E6- and E7-Oncoprotein-Specific T-Cell Responses in Women Living With HIV.

Background: Cervical cancer - caused by persistent High Risk Human Papilloma Virus (HR HPV) infections - is the second most common cancer affecting women globally. HIV infection increases the risk for HPV persistence, associated disease progression and malignant cell transformation. We therefore hypothesized that this risk increase is directly linked to HIV infection associated dysfunction or depletion of HPV-oncoprotein-specific T-cell responses. Methods: The 2H study specifically included HIV+ and HIV- women with and without cervical lesions and cancer to analyze HPV oncogene-specific T cell responses in relation to HPV infection, cervical lesion status and HIV status. Oncoprotein E6 and E7 specific T-cell responses were quantified for the most relevant types HPV16, 18 and 45 and control antigens (CMV-pp65) and M.tb-PPD in 373 women, using fresh peripheral blood mononuclear cells in an IFN-γ release ELISpot assay. Results: Overall, systemic E6- and E7-oncoprotein-specific T-cell responses were infrequent and of low magnitude, when compared to CMV-pp65 and M.tb-PPD (p < 0.001 for all HR HPV types). Within HIV negative women infected with either HPV16, 18 or 45, HPV16 infected women had lowest frequency of autologous-type-E6/E7-specific T-cell responses (33%, 16/49), as compared to HPV18 (46% (6/13), p = 0.516) and HPV45 (69% (9/13), p = 0.026) infected women. Prevalent HPV18 and 45, but not HPV16 infections were linked to detectable oncoprotein-specific T-cell responses, and for these infections, HIV infection significantly diminished T-cell responses targeting the autologous infecting genotype. Within women living with HIV, low CD4 T-cell counts, detectable HIV viremia as well as cancerous and precancerous lesions were significantly associated with depletion of HPV oncoprotein-specific T-cell responses. Discussion: Depletion of HPV-oncoprotein-specific T-cell responses likely contributes to the increased risk for HR HPV persistence and associated cancerogenesis in women living with HIV. The low inherent immunogenicity of HPV16 oncoproteins may contribute to the exceptional potential for cancerogenesis associated with HPV16 infections.

HPV Type Distribution in HIV Positive and Negative Women With or Without Cervical Dysplasia or Cancer in East Africa.

BACKGROUND: Women living with HIV in sub-Saharan Africa are at increased risk to develop cervical cancer (CC), which is caused by persistent infection with 13 oncogenic human papilloma viruses (HR-HPVs). It is important to accurately identify and target HIV-positive women at highest risk to develop CC for early therapeutic intervention. METHODS: A total of 2,134 HIV+ and HIV- women from South-West Tanzania were prospectively screened for cervical cancer and precancerous lesions. Women with cervical cancer (n=236), high- and low-grade squamous intraepithelial lesions (HSIL: n=68, LSIL: n=74), and without lesion (n=426) underwent high-resolution HPV genotyping. RESULTS: Eighty percent of women who were diagnosed with HSIL or LSIL were living with HIV. Any lesion, young age, HIV status, and depleted CD4 T cell counts were independent risk factors for HPV infections, which were predominantly caused by HR-HPV types. While multiple HR-HPV type infections were predominant in HIV+ women with HSIL, single-type infections predominated in HIV+ CC cases (p=0.0006). HPV16, 18, and 45 accounted for 85% (68/80) and 75% (82/110) of HIV+ and HIV- CC cases, respectively. Of note, HPV35, the most frequent HPV type in HSIL-positive women living with HIV, was rarely detected as a single-type infection in HSIL and cancer cases. CONCLUSION: HPV16, 18, and 45 should receive special attention for molecular diagnostic algorithms during CC prevention programs for HIV+ women from sub-Saharan Africa. HPV35 may have a high potential to induce HSIL in women living with HIV, but less potential to cause cervical cancer in single-type infections.

Risky sexual behaviours among young adults attending Higher Learning Institutions in Mbeya, Tanzania: implications for STIs and HIV preventive programs.

Background High-risk sexual behaviors(HRSBs) among young adults are key risk for Sexually Transmitted Infections(STIs), HIV and unplanned pregnancies. WHO has identified the 15-24years age-group as high-risk for STIs. Students at Higher Learning Institutions(HLIs) may be at higher risk because they are free of immediate parental-supervision, are a transient migratory population, probably at peak-years of sexual activity.  In Tanzania, information is limited on sexual and preventive behaviours among young adults in HLIs. We describe risky sexual behaviours and preventive practices among young adults attending HLIs in Mbeya-Tanzania. Methods We conducted a cross-sectional study from March2019 to January2020 among randomly selected students aged 18-24years enrolled in HLIs within Mbeya.  Probability proportional to size was used to determine total student number from each HLI. We used a self-administered questionnaire to collect information on sexual health education, activity, behaviour and STI knowledge. Results Total of 504students were enrolled with mean age of 21.5(SD 1.74)years. Total of 446(88.5%) students reported ever having had sex. Mean-age at first sex was 18.4years and 9.9% reported sexual debut <15years. A higher proportion of male students(57%) reported sexual debut with non-steady partners than females(37.9%). Lack of condom use at sexual debut was reported by 52% of the participants. Consistent condom use during past 4-weeks was reported at 33% and 16.5% among males and females, respectively. About 1 in 10 students reported forced sex by someone they were dating. Sex under the influence of alcohol was reported by 24% of the students.  Nearly 8 in 10 (78.7%) students have heard of STIs, but only 16% were aware STIs can be asymptomatic.  Conclusion STI prevention programs need to recognize young adults in HLIs as at-risk population; and advocate targeted messages to minimize risk to acquiring STIs, counseling and support for those experiencing sexual violence, promote condom use and safer-sex negotiation skills.

Depletion and activation of mucosal CD4 T cells in HIV infected women with HPV-associated lesions of the cervix uteri.

BACKGROUND: The burden of HPV-associated premalignant and malignant cervical lesions remains high in HIV+ women even under ART treatment. In order to identify possible underlying pathophysiologic mechanisms, we studied activation and HIV co-receptor expression in cervical T-cell populations in relation to HIV, HPV and cervical lesion status. METHODS: Cervical cytobrush (n = 468: 253 HIV- and 215 HIV+; 71% on ART) and blood (in a subset of 39 women) was collected from women in Mbeya, Tanzania. Clinical data on HIV and HPV infection, as well as ART status was collected. T cell populations were characterized using multiparametric flow cytometry-based on their expression of markers for cellular activation (HLA-DR), and memory (CD45RO), as well as HIV co-receptors (CCR5, α4ß7). RESULTS: Cervical and blood T cells differed significantly, with higher frequencies of T cells expressing CD45RO, as well as the HIV co-receptors CCR5 and α4ß7 in the cervical mucosa. The skewed CD4/CD8 T cell ratio in blood of HIV+ women was mirrored in the cervical mucosa and HPV co-infection was linked to lower levels of mucosal CD4 T cells in HIV+ women (%median: 22 vs 32; p = 0.04). In addition, HIV and HPV infection, and especially HPV-associated cervical lesions were linked to significantly higher frequencies of HLA-DR+ CD4 and CD8 T cells (p-values < 0.05). Interestingly, HPV infection did not significantly alter frequencies of CCR5+ or α4ß7+ CD4 T cells. CONCLUSION: The increased proportion of activated cervical T cells associated with HPV and HIV infection, as well as HPV-associated lesions, together with the HIV-induced depletion of cervical CD4 T cells, may increase the risk for HPV infection, associated premalignant lesions and cancer in HIV+ women. Further, high levels of activated CD4 T cells associated with HPV and HPV-associated lesions could contribute to a higher susceptibility to HIV in HPV infected women.