Mukendi Kayembe

High-Resolution Microendoscopy for the Detection of Cervical Neoplasia in Low-Resource Settings

Cervical cancer is the second leading cause of cancer death among women in developing countries. Developing countries often lack infrastructure, cytotechnologists, and pathologists necessary to implement current screening tools. Due to their low cost and ease of interpretation at the point-of-care, optical imaging technologies may serve as an appropriate solution for cervical cancer screening in low resource settings. We have developed a high-resolution optical imaging system, the High Resolution Microendoscope (HRME), which can be used to interrogate clinically suspicious areas with subcellular spatial resolution, revealing changes in nuclear to cytoplasmic area ratio. In this pilot study carried out at the womens clinic of Princess Marina Hospital in Botswana, 52 unique sites were imaged in 26 patients, and the results were compared to histopathology as a reference standard. Quantitative high resolution imaging achieved a sensitivity and specificity of 86% and 87%, respectively, in differentiating neoplastic (≥CIN 2) tissue from non-neoplastic tissue. These results suggest the potential promise of HRME to assist in the detection of cervical neoplasia in low-resource settings.

Addressing the growing cancer burden in the wake of the AIDS epidemic in Botswana: The BOTSOGO collaborative partnership.

Botswana has experienced a dramatic increase in HIV-related malignancies over the past decade. The BOTSOGO collaboration sought to establish a sustainable partnership with the Botswana oncology community to improve cancer care. This collaboration is anchored by regular tumor boards and on-site visits that have resulted in the introduction of new approaches to treatment and perceived improvements in care, providing a model for partnership between academic oncology centers and high-burden countries with limited resources.

Cancer Incidence following Expansion of HIV Treatment in Botswana.

Background The expansion of combination antiretroviral treatment (ART) in southern Africa has dramatically reduced mortality due to AIDS-related infections, but the impact of ART on cancer incidence in the region is unknown. We sought to describe trends in cancer incidence in Botswana during implementation of the first public ART program in Africa. Methods We included 8479 incident cases from the Botswana National Cancer Registry during a period of significant ART expansion in Botswana, 2003–2008, when ART coverage increased from 7.3% to 82.3%. We fit Poisson models of age-adjusted cancer incidence and counts in the total population, and in an inverse probability weighted population with known HIV status, over time and estimated ART coverage. Findings During this period 61.6% of cancers were diagnosed in HIV-infected individuals and 45.4% of all cancers in men and 36.4% of all cancers in women were attributable to HIV. Age-adjusted cancer incidence decreased in the HIV infected population by 8.3% per year (95% CI -14.1 to -2.1%). However, with a progressively larger and older HIV population the annual number of cancers diagnosed remained constant (0.0% annually, 95% CI -4.3 to +4.6%). In the overall population, incidence of Kaposi’s sarcoma decreased (4.6% annually, 95% CI -6.9 to -2.2), but incidence of non-Hodgkin lymphoma (+11.5% annually, 95% CI +6.3 to +17.0%) and HPV-associated cancers increased (+3.9% annually, 95% CI +1.4 to +6.5%). Age-adjusted cancer incidence among individuals without HIV increased 7.5% per year (95% CI +1.4 to +15.2%). Interpretation Expansion of ART in Botswana was associated with decreased age-specific cancer risk. However, an expanding and aging population contributed to continued high numbers of incident cancers in the HIV population. Increased capacity for early detection and treatment of HIV-associated cancer needs to be a new priority for programs in Africa.

Prevalence of human papillomavirus genotypes and associated cervical squamous intraepithelial lesions in HIV-infected women in Botswana

Human papillomaviruses (HPV) constitute one of the most prevalent sexually transmitted infections and are the etiological agents for invasive cervical cancer, the predominant cancer among women in Botswana. However, the prevalence of HPV genotypes in Botswana has yet to be reported.

High Prevalence of Hypertension and Placental Insufficiency, but No In Utero HIV Transmission, among Women on HAART with Stillbirths in Botswana

Background Increased stillbirth rates occur among HIV-infected women, but no studies have evaluated the pathological basis for this increase, or whether highly active antiretroviral therapy (HAART) influences the etiology of stillbirths. It is also unknown whether HIV infection of the fetus is associated with stillbirth. Methods HIV-infected women and a comparator group of HIV-uninfected women who delivered stillbirths were enrolled at the largest referral hospital in Botswana between January and November 2010. Obstetrical records, including antiretroviral use in pregnancy, were extracted at enrollment. Verbal autopsies; maternal HIV, CD4 and HIV RNA testing; stillbirth HIV PCR testing; and placental pathology (blinded to HIV and treatment status) were performed. Results Ninety-nine stillbirths were evaluated, including 62 from HIV-infected women (34% on HAART from conception, 8% on HAART started in pregnancy, 23% on zidovudine started in pregnancy, and 35% on no antiretrovirals) and 37 from a comparator group of HIV-uninfected women. Only 2 (3.7%) of 53 tested stillbirths from HIV-infected women were HIV PCR positive, and both were born to women not receiving HAART. Placental insufficiency associated with hypertension accounted for most stillbirths. Placental findings consistent with chronic hypertension were common among HIV-infected women who received HAART and among HIV-uninfected women (65% vs. 54%, p = 0.37), but less common among HIV-infected women not receiving HAART (28%, p = 0.003 vs. women on HAART). Conclusions In utero HIV infection was rarely associated with stillbirths, and did not occur among women receiving HAART. Hypertension and placental insufficiency were associated with most stillbirths in this tertiary care setting.

HIV Infection and Survival Among Women With Cervical Cancer

Purpose Cervical cancer is the leading cause of cancer death among the 20 million women with HIV worldwide. We sought to determine whether HIV infection affected survival in women with invasive cervical cancer. Patients and Methods We enrolled sequential patients with cervical cancer in Botswana from 2010 to 2015. Standard treatment included external beam radiation and brachytherapy with concurrent cisplatin chemotherapy. The effect of HIV on survival was estimated by using an inverse probability weighted marginal Cox model. Results A total of 348 women with cervical cancer were enrolled, including 231 (66.4%) with HIV and 96 (27.6%) without HIV. The majority (189 [81.8%]) of women with HIV received antiretroviral therapy before cancer diagnosis. The median CD4 cell count for women with HIV was 397 (interquartile range, 264 to 555). After a median follow-up of 19.7 months, 117 (50.7%) women with HIV and 40 (41.7%) without HIV died. One death was attributed to HIV and the remaining to cancer. Three-year survival for the women with HIV was 35% (95% CI, 27% to 44%) and 48% (95% CI, 35% to 60%) for those without HIV. In an adjusted analysis, HIV infection significantly increased the risk for death among all women (hazard ratio, 1.95; 95% CI, 1.20 to 3.17) and in the subset that received guideline-concordant curative treatment (hazard ratio, 2.63; 95% CI, 1.05 to 6.55). The adverse effect of HIV on survival was greater for women with a more-limited stage cancer ( P = .035), those treated with curative intent ( P = .003), and those with a lower CD4 cell count ( P = .036). Advanced stage and poor treatment completion contributed to high mortality overall. Conclusion In the context of good access to and use of antiretroviral treatment in Botswana, HIV infection significantly decreases cervical cancer survival.

Cervical Cancer in Botswana: Current State and Future Steps for Screening and Treatment Programs.

Botswana has a high burden of cervical cancer due to a limited screening program and high HIV prevalence. About 60% of the cervical cancer patients are HIV positive; most present with advanced cervical disease. Through initiatives by the Botswana Ministry of Health and various strategic partnerships, strides have been made in treatment of pre-invasive and invasive cancer. The See and Treat program for cervical cancer is expanding throughout the country. Starting in 2015, school-going girls will be vaccinated against HPV. In regards to treatment of invasive cancer, a multidisciplinary clinic has been initiated at the main oncology hospital to streamline care. However, challenges remain such as delays in treatment, lack of trained human personnel, limited follow-up care, and little patient education. Despite improvements in the care of pre-invasive and invasive cervical cancer patients, for declines in cervical cancer-related morbidity and mortality to be achieved, Botswana needs to continue to invest in decreasing the burden of disease and improving patient outcomes of patients with cervical cancer.

Predictors of Timely Access of Oncology Services and Advanced-Stage Cancer in an HIV-Endemic Setting

This study explored predictors of timely oncology care and whether being engaged in the medical system for HIV care improved time to access. According to records and interviews of cancer patients in Botswana, the median time from first symptom to specialized oncology care was 13 months. HIV status did not affect time to oncology care; however, advanced cancer stage and use of traditional medicine/healers was associated with earlier oncology access.

Oncogenic viral prevalence in invasive vulvar cancer specimens from human immunodeficiency virus-positive and -negative women in Botswana.

Objective The primary aim of this study was to describe the prevalence of select oncogenic viruses within vulvar squamous cell carcinoma (VSCC) and their association with human immunodeficiency virus (HIV) status in women in Botswana, where the national HIV prevalence is the third highest in the world. Methods A cross-sectional study of biopsy-confirmed VSCC specimens and corresponding clinical data was conducted in Gaborone, Botswana. Polymerase chain reaction (PCR) and immunohistochemistry (IHC) viral testing were done for Epstein-Barr virus, human papillomavirus (HPV) strains, and Kaposi sarcoma herpesvirus, and PCR viral testing alone was done for John Cunningham virus. Results Human papillomavirus prevalence by PCR was 100% (35/35) among tested samples. Human papillomavirus type 16 was the most prevalent HPV strain (82.9% by PCR, 94.7% by either PCR or IHC). Kaposi sarcoma herpesvirus prevalence by PCR had a significant association with HIV status (P = 0.013), but not by IHC (P = 0.650). Conclusions The high burden of HPV, specifically HPV16, in vulvar squamous cell cancer in Botswana suggests a distinct HPV profile that differs from other studied populations, which provides increased motivation for HPV vaccination efforts. Oncogenic viruses Kaposi sarcoma herpesvirus and Epstein-Barr virus were also more prevalent in our study population, although their potential role in vulvar squamous cell cancer pathology is unclear.

Oncogenic viruses associated with vulva cancer in HIV-1 patients in Botswana.

BackgroundOncoviruses such as HPV, KSHV, and EBV have been reported in patients with HIV infection and AIDS. How oncovirus-associated cancers rise in AIDS patients has not been fully established. The purpose of our study was to identify the viral agents in vulvar cancer and to assess their contribution to pathogenesis.MethodWe retrospectively identified a total of 13 vulva tissue samples from HIV-1 positive and 9 vulvar samples from HIV-1 negative patients from the Botswana National Health Laboratory in Gaborone, Botswana, a Southern African Country with a high incidence of HIV. We utilized PCR and IHC to identify HPV, EBV, KSHV, and JC virus in FFPE preserved tissue samples.ResultsUsing the GP5+/GP6+ primer set we detected several HPV types in tissue samples. EBV was detected in all of the positive cases (100%) and in most of the negative cases (89%). KSHV was detected in 39% of the HIV-1 positive samples and in 11% of the negative samples, and no JC virus was detected in any of the samples.Using IHC we demonstrated that LANA was expressed in 61% of the positive samples and in 44% of the negative samples. The ubiquitous EBV was more consistently expressed in negative cases (100%) than in positive cases (69%). Interestingly, the HPV-16 E6 transcript was detected in 56% of the negative samples compared to 31% of the positive samples. However, the cell cycle protein P21 used as a surrogate marker for HPV was detected in 77% of the positive samples and in 44% of the negative samples, while VEGF signals were similar in both positive (92%) and negative samples (89%).ConclusionOur study, suggests that in Botswana, vulvar squamous cell carcinoma (VSCC) is associated with oncogenic viruses present in the niche but the contribution and progression may be regulated by HPV and other immunosuppressive infections that include HIV-1.