Mucosal Human papillomaviruses (HPVs) are the etiologic agents for genital warts and cervical cancer and are recognized as the most common STD worldwide. Among the large number of high risk (HR) and low risk (LR) HPV genotypes, at least 15 genetically distinct HR-HPVs cause oral and anogenital cancers, including approximately 95% of cervical cancers. The HPV genotype distribution is an important consideration in developing effective screening, clinical interventions and vaccine strategies. This is especially true in low and middle-income countries (LMIC) like Tanzania.
Fig 1: We are collecting pap smears and cervical DNA swabs from women in the urban areas, the Ocean Road Cancer Institute (ORCI) in Dar es Salaam, and rural areas, Bagamoyo and Chalinze, Tanzania.
We are investigating the effect of HIV and HPV genotype on cervical pathogenesis. We are investigating the role of HIV in promoting HR-HPV infection and progression of dysplasia among rural and urban Tanzanian women. We are also investigating the role of HPV multiplicity in cervical pathogenesis. We have implemented a low-cost HPV genotyping method to assess the contributions of HPVs to the burden of cervical cancer in Tanzania.
Tanzania has an overall HIV rate of approximately 5.1%. However, patients who seek care at regional clinics are more likely to do so because they are HIV positive. Our cervical cancer screening study is targeted at one urban site: ORCI in Dar es Salam, and two rural sites at Bagamoyo and Chalinze. As expected, at our cervical screening sites, we found HIV rates higher than the national average (Fig 2. Not surprisingly, areas with higher rates of HIV are expected to have higher rates of HR-HPVs and cervical pathogenesis.
Fig2: HIV rates among recruits at ORCI was 12.5%, 16% in Bagamoyo and 25% in Chalinze. Currently, we have screened 1046 patients across the cohort.
Within this cohort, we compared the efficiency of visual inspection of the cervix with acetic acid (VIA) versus the standard pap smear. We specifically found that VIA efficiency was variably in comparison to the pap smear. For example, we found that VIA results were variable across the cohort. The VIA failed to reliably detect high-grade lesions in younger women (aged 18-24) in ORCI. Among VIA negative patients recruited from Chalinze, we found 30.5% had HSIL, again indicating that the VIA was not always reliable. Overall, the results indicate that younger HIV positive patients who are particularly at risk for cervical dysplasia are missed by the VIA screening, most likely because lesions are microscopic.
Fig 3: The percent of abnormal cytology among VIA negative patients across each of the cervical screening sites.
An important goal of our study is to ascertain the influence of demographic factors (such as age, occupation, income, smoking, drinking, other STI coinfections and sexual history) upon HPV-dependent pathogenesis. Working closely with our Tanzanian cervical cancer screening clinic colleagues, we have succeeded in identifying eligible study participants and documenting socio-demographic and health history information using a structured and pre-validated questionnaire.
We developed very exciting side project utilizing cervical swab DNA to assess the correlation between particularly cervical bacterial microbiota and the severity of HPV-related dysplasias. We have currently submitted 144 cervical DNA samples for 16S bacterial DNA sequencing. This is an extraordinary opportunity to expand the impact of our cohort studies and offers the opportunity for future collaborative funding with our colleagues with at the ORCI.
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS). KS is one of the most prevalent HIV/AIDS-associated malignancies in sub-Saharan African countries, including Tanzania. The endemic form of KS (HIV-1 negative) accounts for 4.5% of all tumors in Tanzania, but the ongoing HIV-1 epidemic in Africa has resulted in AIDS-associated KS becoming the leading malignancy in HIV-infected patients. The incidence of KS in developed countries has reduced dramatically through administration of anti-retroviral therapy (ART), but KS remains a common HIV-associated malignancy in sub-Saharan Africa where ART has only recently become widely available. Therefore, incomplete coverage, uptake and adherence to ART, and lack of information about HIV drug resistance in ART treated patients makes it imperative to investigate the feasibility of other strategies to control and treat HIV-associated malignancies. Our team is widely recognized for elucidating mechanisms of KSHV transmission in Lusaka, Zambia. We have found that approximately 40% of Zambian children are infected with KSHV by age four; HIV infection is a major risk factor for transmission, and the transmission route is likely through saliva. Taken together, these results underscore the need to develop new strategies to prevent KSHV infection.
The objective of the KS project is to recruit a cohort of epidemic and endemic KS patients at the Ocean Road Cancer Institute (ORCI), Tanzania to longitudinally characterize the KSHV nAb response and its correlation to KSHV viral load and to HIV-1 or KS treatment. We hypothesize that the presence of nAb correlates with development of KS due to high KSHV viral load but differs between the two types of KS due to HIV infection. If KSHV nAb responses require antigen to be maintained, ART reconstitution of immune response in HIV+ KS patients suppressing KSHV could result in reduced nAb. We believe this will differ in the endemic KS patients in the absence of HIV and immunosuppression. This project is of considerable significance because outcomes will lead to a better understanding of the role of immune reconstitution and treatment. The knowledge gained will lead to strategies to prevent KSHV infection, including the development of a prophylactic vaccine and hence prevent the development of KS in endemic areas. Our prior experience with large longitudinal cohort studies in Zambia and our prior investigation of humoral responses in KSHV infected patients has ideally positioned our group to conduct the proposed study, the first of its magnitude in the African setting.