Aaron Shibemba

Tuberculosis and Tuberculosis/HIV/AIDS–Associated Mortality in Africa: The Urgent Need to Expand and Invest in Routine and Research Autopsies

Frequently quoted statistics that tuberculosis and human immunodeficiency virus (HIV)/AIDS are the most important infectious causes of death in high-burden countries are based on clinical records, death certificates, and verbal autopsy studies. Causes of death ascertained through these methods are known to be grossly inaccurate. Most data from Africa on mortality and causes of death currently used by international agencies have come from verbal autopsy studies, which only provide inaccurate estimates of causes of death. Autopsy rates in most sub-Saharan African countries have declined over the years, and actual causes of deaths in the community and in hospitals in most sub-Saharan African countries remain unknown. The quality of cause-specific mortality statistics remains poor. The effect of various interventions to reduce mortality rates can only be evaluated accurately if cause-specific mortality data are available. Autopsy studies could have particular relevance to direct public health interventions, such as vaccination programs or preventive therapy, and could also allow for study of background levels of subclinical tuberculosis disease, Mycobacterium tuberculosis-HIV coinfection, and other infectious and noncommunicable diseases not yet clinically manifest. Autopsies performed soon after death may represent a unique opportunity to understand the pathogenesis of M. tuberculosis and the pathogenesis of early deaths after initiation of antiretroviral therapy. The few autopsies performed so far for research purposes have yielded invaluable information and insights into tuberculosis, HIV/AIDS, and other opportunistic infections. Accurate cause-specific mortality data are essential for prioritization of governmental and donor investments into health services to reduce morbidity and mortality from deadly infectious diseases such as tuberculosis and HIV/AIDS. There is an urgent need for reviving routine and research autopsies in sub-Saharan African countries.

Burden of tuberculosis at post mortem in inpatients at a tertiary referral centre in sub-Saharan Africa: a prospective descriptive autopsy study

BACKGROUND Patients with subclinical tuberculosis, smear-negative tuberculosis, extrapulmonary tuberculosis, multidrug-resistant tuberculosis, and asymptomatic tuberculosis are difficult to diagnose and may be missed at all points of health care. We did an autopsy study to ascertain the burden of tuberculosis at post mortem in medical inpatients at a tertiary care hospital in Lusaka, Zambia. METHODS Between April 5, 2012, and May 22, 2013, we did whole-body autopsies on inpatients aged at least 16 years who died in the adult inpatient wards at University Teaching Hospital, Lusaka, Zambia. We did gross pathological and histopathological analysis and processed lung tissues from patients with tuberculosis through the GeneXpert MTB/RIF assay to identify patients with multidrug-resistant tuberculosis. The primary outcome measure was specific disease or diseases stratified by HIV status. Secondary outcomes were missed tuberculosis, multidrug-resistant tuberculosis, and comorbidities with tuberculosis. Data were analysed using Pearson χ(2), the Mann-Whitney U test, and binary logistic regression. FINDINGS The median age of the 125 included patients was 35 years (IQR 29-43), 80 (64%) were men, and 101 (81%) were HIV positive. 78 (62%) patients had tuberculosis, of whom 66 (85%) were infected with HIV. 35 (45%) of these 78 patients had extrapulmonary tuberculosis. The risk of extrapulmonary tuberculosis was higher among HIV-infected patients than among uninfected patients (adjusted odds ratio 5·14, 95% CI 1·04-24·5; p=0·045). 20 (26%) of 78 patients with tuberculosis were not diagnosed during their life and 13 (17%) had undiagnosed multidrug-resistant tuberculosis. Common comorbidities with tuberculosis were pyogenic pneumonia in 26 patients (33%) and anaemia in 15 (19%). INTERPRETATION Increased clinical awareness and more proactive screening for tuberculosis and multidrug-resistant tuberculosis in inpatient settings is needed. Further autopsy studies are needed to ascertain the generalisability of the findings. FUNDING UBS Optimus Foundation, EuropeAID, and European Developing Countries Clinical Trials Partnership (EDCTP).

HIV infection and domestic smoke exposure, but not human papillomavirus, are risk factors for esophageal squamous cell carcinoma in Zambia: a case–control study

There is emerging evidence that esophageal cancer occurs in younger adults in sub‐Saharan Africa than in Europe or North America. The burden of human immunodeficiency virus (HIV) is also high in this region. We postulated that HIV and human papillomavirus (HPV) infections might contribute to esophageal squamous cell carcinoma (OSCC) risk. This was a case–control study based at the University Teaching Hospital in Lusaka, Zambia. Cases were patients with confirmed OSCC and controls had completely normal upper endoscopic evaluations. A total of 222 patients were included to analyze the influence of HIV infection; of these, 100 patients were used to analyze the influence of HPV infection, alcohol, smoking, and exposure to wood smoke. The presence of HIV infection was determined using antibody kits, and HPV infection was detected by polymerase chain reaction. HIV infection on its own conferred increased risk of developing OSCC (odds ratio [OR] 2.3; 95% confidence interval [CI] 1.0–5.1; P = 0.03). The OR was stronger when only people under 60 years were included (OR 4.3; 95% CI 1.5–13.2; P = 0.003). Cooking with charcoal or firewood, and cigarette smoking, both increased the odds of developing OSCC ([OR 3.5; 95% CI 1.4–9.3; P = 0.004] and [OR 9.1; 95% CI 3.0–30.4; P < 0.001], respectively). There was no significant difference in HPV detection or alcohol intake between cases and controls. We conclude that HIV infection and exposure to domestic and cigarette smoke are risk factors for OSCC, and HPV immunization unlikely to reduce OSCC incidence in Zambia.

The Prevalence of Tuberculosis in Zambia: Results from the First National TB Prevalence Survey, 2013-2014.

Background Tuberculosis in Zambia is a major public health problem, however the country does not have reliable baseline data on the TB prevalence for impact measurement; therefore it was among the priority countries identified by the World Health Organization to conduct a national TB prevalence survey Objective To estimate the prevalence of tuberculosis among the adult Zambian population aged 15 years and above, in 2013–2014. Methods A cross-sectional population-based survey was conducted in 66 clusters across all the 10 provinces of Zambia. Eligible participants aged 15 years and above were screened for TB symptoms, had a chest x-ray (CXR) performed and were offered an HIV test. Participants with TB symptoms and/or CXR abnormality underwent an in-depth interview and submitted one spot- and one morning sputum sample for smear microscopy and liquid culture. Digital data collection methods were used throughout the process. Results Of the 98,458 individuals who were enumerated, 54,830 (55.7%) were eligible to participate, and 46,099 (84.1%) participated. Of those who participated, 45,633/46,099 (99%) were screened by both symptom assessment and chest x-ray, while 466/46,099 (1.01%) were screened by interview only. 6,708 (14.6%) were eligible to submit sputum and 6,154/6,708 (91.7%) of them submitted at least one specimen for examination. MTB cases identified were 265/6,123 (4.3%). The estimated national adult prevalence of smear, culture and bacteriologically confirmed TB was 319/100,000 (232-406/100,000); 568/100,000 (440-697/100,000); and 638/100,000 (502-774/100,000) population, respectively. The risk of having TB was five times higher in the HIV positive than HIV negative individuals. The TB prevalence for all forms was estimated to be 455 /100,000 population for all age groups. Conclusion The prevalence of tuberculosis in Zambia was higher than previously estimated. Innovative approaches are required to accelerate the control of TB.

Clinical Performance Validation of 4 Point-of-Care Cervical Cancer Screening Tests in HIV-Infected Women in Zambia.

Objectives We sought to determine the clinical performance of visual inspection with acetic acid (VIA), digital cervicography (DC), Xpert human papillomavirus (HPV), and OncoE6 for cervical cancer screening in an HIV-infected population. Materials and Methods HIV-infected women 18 years or older were included in this cross-sectional validation study conducted in Lusaka, Zambia. The screening tests were compared against a histological gold standard. We calculated sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and odds ratios using cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) and grade 3 or worse (CIN 3+) thresholds. Results Between January and June 2015, a total of 200 women were enrolled. Fifteen percent were screen positive by VIA, 20% by DC, 47% by Xpert HPV, and 6% by OncoE6. Using a CIN 2+ threshold, the sensitivity and specificity of VIA were 48% (95% CI = 30%–67%) and 92% (95% CI = 86%–95%), respectively. Similarly, the sensitivity and specificity of DC were 59% (95% CI = 41%–76%) and 88% (95% CI = 82%–93%), respectively. The sensitivity and specificity of Xpert HPV were 88% (95% CI = 71%–97%) and 60% (95% CI = 52%–68%), respectively. Finally, the sensitivity and specificity of OncoE6 were 31% (95% CI = 16%–50%) and 99% (95% CI = 97%–100%), respectively. Conclusions VIA and DC displayed moderate sensitivity and high specificity. Xpert HPV performed equivalently to currently approved HPV DNA tests, with high sensitivity and moderate specificity. OncoE6 displayed excellent specificity but low sensitivity. These results confirm an important role for VIA, DC, and Xpert HPV in screen-and-treat cervical cancer prevention in low- and middle-income countries, such as Zambia.

Clinical performance of digital cervicography and cytology for cervical cancer screening in HIV-infected women in Lusaka Zambia.

Abstract:Although there is a growing literature on the clinical performance of visual inspection with acetic acid in HIV-infected women, to the best of our knowledge, none have studied visual inspection with acetic acid enhanced by digital cervicography. We estimated clinical performance of cervicography and cytology to detect cervical intraepithelial neoplasia grade 2 or worse. Sensitivity and specificity of cervicography were 84% [95% confidence interval (CI): 72 to 91) and 58% (95% CI: 52 to 64). At the high-grade squamous intraepithelial lesion or worse cutoff for cytology, sensitivity and specificity were 61% (95% CI: 48 to 72) and 58% (95% CI: 52 to 64). In our study, cervicography seems to be as good as cytology in HIV-infected women.

Identification of human papillomaviruses from formalin-fixed, paraffin-embedded pre-cancer and invasive cervical cancer specimens in Zambia: a cross-sectional study

BackgroundThe most common human papillomavirus (HPV) genotypes isolated from cervical cancer in select African countries are HPV-16, HPV-18, HPV-35, and HPV-45, but the most common genotypes in Zambia are unknown. The overall objective of this study was to assess the potential impact of current HPV vaccines in preventing cervical cancer in Zambia, by determining the combined prevalence of HPV-16 and/or HPV-18 in invasive cervical cancer (ICC) and high-grade pre-cancer [cervical intraepithelial neoplasia 2 or 3 (CIN2/3)] cases.FindingsWe compared DNA extraction techniques to determine which assay performs well in the Zambian context, where unbuffered formalin is used to fix specimens. We then tested specimens with the Abbott RealTime High-Risk HPV test to estimate the prevalence of HPV-16/18 in formalin-fixed, paraffin-embedded ICC and CIN2/3 specimens. DNA extraction using heat (without xylene) was more successful than xylene-based extraction. Over 80% of specimens tested using heat extraction and the Abbott RealTime HPV test were positive for HPV. HPV-16 and/or HPV-18 were identified in 65/93 (69.9%) ICC specimens positive for HPV and in 38/65 (58.5%) CIN2/3 specimens positive for HPV.ConclusionsTo our knowledge this is the first report to identify HPV genotypes in cervical cancers in Zambia. A combined HPV-16/18 prevalence of 69.9% in ICC specimens suggests that current vaccines will be highly protective against cervical cancer in Zambia.

Drivers of advanced stage at breast cancer diagnosis in the multicountry African breast cancer - disparities in outcomes (ABC-DO) study: Drivers of advanced stage at breast cancer diagnosis

Breast cancer (BC) survival rates in sub‐Saharan Africa (SSA) are low in part due to advanced stage at diagnosis. As one component of a study of the entire journey of SSA women with BC, we aimed to identify shared and setting‐specific drivers of advanced stage BC. Women newly diagnosed in the multicountry African Breast Cancer–Disparities in Outcomes (ABC‐DO) study completed a baseline interview and their stage information was extracted from medical records. Ordinal logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for advanced stage (I, II, III, IV) in relation to individual woman‐level, referral and biological factors. A total of 1795 women were included from Nigeria, Uganda, Zambia, and the multiracial populations of Namibia and South Africa, 1091 of whom (61%) were stage III/IV. Stage was lower in women with greater BC knowledge (OR 0.77 (95% CI: 0.70, 0.85) per point on a 6 point scale). More advanced stage was associated with being black (4.00 (2.79, 5.74)), having attended

Performance of the Xpert MTB/RIF assay in the diagnosis of tuberculosis in formalin-fixed, paraffin-embedded tissues

Objective/Background: Extrapulmonary tuberculosis (EPTB), which accounts for 10%–40% of the global burden of TB, with the highest incidence in Sub-Saharan Africa, is strongly associated with human immunodeficiency virus infection. Diagnosing EPTB is challenging, and recently, there has been a concerted effort to evaluate the latest molecular diagnostics for diagnosing TB in a range of specimen types. The Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA) is one such technology, which simultaneously detects Mycobacterium tuberculosis and rifampicin resistance. Our objective was to evaluate the accuracy of the Xpert MTB/RIF assay for the diagnosis of EPTB and detection of rifampicin resistance in routinely processed formalin-fixed, paraffin-embedded (FFPE) tissues, compared with histological detection of TB as the gold standard. Methods: A convenience set of 100 biobanked FFPE tissues, including lymph nodes (n = 64), male genital tract tissue (n = 10), abdominal tissue (n = 8), female genital tissue (n = 5), breast tissue (n = 5), synovial tissue (n = 4), skin (n = 2), tongue tissue (n = 1), and thyroid (n = 1), from routine cases of clinically suspected EPTB admitted to the University Teaching Hospital, Lusaka, Zambia, were analyzed using the Xpert MTB/RIF assay and in-house polymerase chain reaction (PCR) assay targeting IS6110, in parallel with Ziehl–Neelsen (ZN) staining, against histology as the gold standard. Results: Some 66% of specimens had histological evidence of TB infection. ZN staining was positive for TB in 8% of cases, and Xpert MTB/RIF was positive for TB in 25% of cases. Taking histology as the gold standard, the sensitivity and specificity were as follows: In lymph tissue the accuracy of the Xpert MTB/RIF assay was 41% (95%CI 27-57), not significantly better than ZN or the in-house PCR assay. In non-lymph tissue the sensitivity of the in-house PCR assay was 82% (95%CI: 56%-95%), significantly higher than the Xpert MTB/RIF assay (P = 0.004). The Xpert MTB/RIF assay indicated rifampicin resistance in just three cases. Conclusion: The Xpert MTB/RIF assay is potentially a useful tool for the diagnosis of TB in routine FFPE tissues.

New global estimates of malaria deaths

India figures prominently as the largest contributor of malaria deaths outside Africa in new global estimates by Christopher Murray and colleagues.1 However, India is often the greatest source of uncertainty in such estimates because of its sheer scale. With 85% of the 1·2 billion population at risk of malaria from both major parasite species, across varied transmission settings, and via six primary vectors, representative empirical data are hard to produce.