A portable thermal ablation device for cervical cancer prevention in a screen-and-treat setting: a randomized, noninferiority trial.

Implementing standard-of-care cryotherapy or electrosurgical excision to treat cervical precancers is challenging in resource-limited settings. An affordable technological alternative that is as effective as standard-of-care techniques would greatly improve access to treatment. This randomized controlled trial aims to demonstrate the noninferiority efficacy of a portable, battery-driven thermal ablation (TA) device compared to cryotherapy and electrosurgical excision (large loop excision of transformation zone (LLETZ)) to treat cervical precancer in a screen-and-treat program in Zambia. A total of 3,124 women positive on visual inspection with acetic acid and eligible for ablative therapy were randomized to one of the treatment arms. Human papillomavirus (HPV) testing was performed at baseline and at the follow-up. The primary outcome was treatment success, defined as either type-specific HPV clearance at the follow-up in participants positive for HPV at baseline, or a negative visual inspection with acetic acid test for those who had a negative HPV test at baseline. After a median follow-up of 12 months, treatment success rates were 74.0%, 71.1% and 71.4% for the TA, cryotherapy and LLETZ arms, respectively, thus demonstrating noninferiority (P = 0.83). TA was a safe and well-accepted procedure. Only 3.6% of those randomized to TA reported moderate-to-severe pain, compared to 6.5% and 1.9% for the cryotherapy and LLETZ arms, respectively. Thus, our randomized controlled trial demonstrates the safety and efficacy of TA, which is not inferior to cryotherapy or surgical excision.ClinicalTrials.gov registration: NCT02956239 .

Internal validation of Automated Visual Evaluation (AVE) on smartphone images for cervical cancer screening in a prospective study in Zambia.

OBJECTIVES: Visual inspection with acetic acid (VIA) is a low-cost approach for cervical cancer screening used in most low- and middle-income countries (LMICs) but, similar to other visual tests, is subjective and requires sustained training and quality assurance. We developed, trained, and validated an artificial-intelligence-based "Automated Visual Evaluation" (AVE) tool that can be adapted to run on smartphones to assess smartphone-captured images of the cervix and identify precancerous lesions, helping augment VIA performance. DESIGN: Prospective study. SETTING: Eight public health facilities in Zambia. PARTICIPANTS: A total of 8204 women aged 25-55. INTERVENTIONS: Cervical images captured on commonly used low-cost smartphone models were matched with key clinical information including human immunodeficiency virus (HIV) and human papillomavirus (HPV) status, plus histopathology analysis (where applicable), to develop and train an AVE algorithm and evaluate its performance for use as a primary screen and triage test for women who are HPV positive. MAIN OUTCOME MEASURES: Area under the receiver operating curve (AUC); sensitivity; specificity. RESULTS: As a general population screening tool for cervical precancerous lesions, AVE identified cases of cervical precancerous and cancerous (CIN2+) lesions with high performance (AUC = 0.91, 95% confidence interval [CI] = 0.89-0.93), which translates to a sensitivity of 85% (95% CI = 81%-90%) and specificity of 86% (95% CI = 84%-88%) based on maximizing the Youden's index. This represents a considerable improvement over naked eye VIA, which as per a meta-analysis by the World Health Organization (WHO) has a sensitivity of 66% and specificity of 87%. For women living with HIV, the AUC of AVE was 0.91 (95% CI = 0.88-0.93), and among those testing positive for high-risk HPV types, the AUC was 0.87 (95% CI = 0.83-0.91). CONCLUSIONS: These results demonstrate the feasibility of utilizing AVE on images captured using a commonly available smartphone by nurses in a screening program, and support our ongoing efforts for moving to more broadly evaluate AVE for its clinical sensitivity, specificity, feasibility, and acceptability across a wider range of settings. Limitations of this study include potential inflation of performance estimates due to verification bias (as biopsies were only obtained from participants with visible aceto-white cervical lesions) and due to this being an internal validation (the test data, while independent from that used to develop the algorithm was drawn from the same study).

Comparison of HIV prevalence, incidence, and viral load suppression in Zambia population-based HIV impact assessments from 2016 and 2021.

BACKGROUND: The Zambian government has implemented a public health response to control the HIV epidemic in the country. Zambia conducted a population-based HIV impact assessment (ZAMPHIA) survey in 2021 to assess the status of the HIV epidemic to guide its public health programs. METHODS: ZAMPHIA 2021 was a cross-sectional two-stage cluster sample household survey among persons aged ≥15 years conducted in Zambia across all 10 provinces. Consenting participants were administered a standardized questionnaire and whole blood was tested for HIV according to national guidelines. HIV-1 viral load (VL), recent HIV infection, and antiretroviral medications were tested for in HIV-seropositive samples. Viral load suppression (VLS) was defined as <1000 copies/ml. ZAMPHIA 2021 results were compared to ZAMPHIA 2016 for persons aged 15-59 years (i.e., the overlapping age ranges). All estimates were weighted to account for nonresponse and survey design. RESULTS: During ZAMPHIA 2021, of 25 483 eligible persons aged ≥15 years, 18 804 (73.8%) were interviewed and tested for HIV. HIV prevalence was 11.0% and VLS prevalence was 86.2% overall, but was <80% among people living with HIV aged 15-24 years and in certain provinces. Among persons aged 15-59 years, from 2016 to 2021, HIV incidence declined from 0.6% to 0.3% ( P -value: 0.07) and VLS prevalence increased from 59.2% to 85.7% ( P -value: <0.01). DISCUSSION: Zambia has made substantial progress toward controlling the HIV epidemic from 2016 to 2021. Continued implementation of a test-and-treat strategy, with attention to groups with lower VLS in the ZAMPHIA 2021, could support reductions in HIV incidence and improve overall VLS in Zambia.

Internal Validation of Automated Visual Evaluation (AVE) on Smartphone Images for Cervical Cancer Screening in a Prospective Study in Zambia.

Objectives: Visual inspection with acetic acid (VIA) is a low-cost approach for cervical cancer screening used in most low- and middle-income countries (LMICs) but, similar to other visual tests like histopathology, is subjective and requires sustained training and quality assurance. We developed, trained, and validated an artificial-intelligence-based "Automated Visual Evaluation" (AVE) tool that can be adapted to run on smartphones to assess smartphone-captured images of the cervix and identify precancerous lesions, helping augment performance of VIA. Design: Prospective study. Setting: Eight public health facilities in Zambia. Participants: 8,204 women aged 25-55. Interventions: Cervical images captured on commonly used low-cost smartphone models were matched with key clinical information including human immunodeficiency virus (HIV) and human papillomavirus (HPV) status, plus histopathology analysis (where applicable), to develop and train an AVE algorithm and evaluate its performance for use as a primary screen and triage test for women who are HPV positive. Main outcome measures: Area under the receiver operating curve (AUC); sensitivity; specificity. Results: As a general population screening for cervical precancerous lesions, AVE identified cases of cervical precancerous and cancerous (CIN2+) lesions with high performance (AUC = 0.91, 95% confidence interval [CI] = 0.89 to 0.93), which translates to a sensitivity of 85% (95% CI = 81% to 90%) and specificity of 86% (95% CI = 84% to 88%) based on maximizing the Youden's index. This represents a considerable improvement over VIA, which a meta-analysis by the World Health Organization (WHO) estimates to have sensitivity of 66% and specificity of 87%. For women living with HIV, the AUC of AVE was 0.91 (95% CI = 0.88 to 0.93), and among those testing positive for high-risk HPV types, the AUC was 0.87 (95% CI = 0.83 to 0.91). Conclusions: These results demonstrate the feasibility of utilizing AVE on images captured using a commonly available smartphone by screening nurses and support our transition to clinical evaluation of AVE's sensitivity, specificity, feasibility, and acceptability across a broader range of settings. The performance of the algorithm as reported may be inflated, as biopsies were obtained only from study participants with visible aceto-white cervical lesions, which can lead to verification bias; and the images and data sets used for testing of the model, although "unseen" by the algorithm during training, were acquired from the same set of patients and devices, limiting the study to that of an internal validation of the AVE algorithm.

Validation in Zambia of a cervical screening strategy including HPV genotyping and artificial intelligence (AI)-based automated visual evaluation.

BACKGROUND: WHO has recommended HPV testing for cervical screening where it is practical and affordable. If used, it is important to both clarify and implement the clinical management of positive results. We estimated the performance in Lusaka, Zambia of a novel screening/triage approach combining HPV typing with visual assessment assisted by a deep-learning approach called automated visual evaluation (AVE). METHODS: In this well-established cervical cancer screening program nested inside public sector primary care health facilities, experienced nurses examined women with high-quality digital cameras; the magnified illuminated images permit inspection of the surface morphology of the cervix and expert telemedicine quality assurance. Emphasizing sensitive criteria to avoid missing precancer/cancer, ~ 25% of women screen positive, reflecting partly the high HIV prevalence. Visual screen-positive women are treated in the same visit by trained nurses using either ablation (~ 60%) or LLETZ excision, or referred for LLETZ or more extensive surgery as needed. We added research elements (which did not influence clinical care) including collection of HPV specimens for testing and typing with BD Onclarity™ with a five channel output (HPV16, HPV18/45, HPV31/33/52/58, HPV35/39/51/56/59/66/68, human DNA control), and collection of triplicate cervical images with a Samsung Galaxy J8 smartphone camera™ that were analyzed using AVE, an AI-based algorithm pre-trained on a large NCI cervical image archive. The four HPV groups and three AVE classes were crossed to create a 12-level risk scale, ranking participants in order of predicted risk of precancer. We evaluated the risk scale and assessed how well it predicted the observed diagnosis of precancer/cancer. RESULTS: HPV type, AVE classification, and the 12-level risk scale all were strongly associated with degree of histologic outcome. The AVE classification showed good reproducibility between replicates, and added finer predictive accuracy to each HPV type group. Women living with HIV had higher prevalence of precancer/cancer; the HPV-AVE risk categories strongly predicted diagnostic findings in these women as well. CONCLUSIONS: These results support the theoretical efficacy of HPV-AVE-based risk estimation for cervical screening. If HPV testing can be made affordable, cost-effective and point of care, this risk-based approach could be one management option for HPV-positive women.

A Randomized Trial of Point-of-Care Early Infant Human Immunodeficiency Virus (HIV) Diagnosis in Zambia.

BACKGROUND: Point-of-care (POC) early infant diagnosis (EID) provides same-day results and the potential for immediate initiation of antiretroviral therapy (ART). METHODS: We conducted a pragmatic trial at 6 public clinics in Zambia. HIV-exposed infants were individually randomized to either (1) POC EID (onsite testing with the Alere q HIV-1/2 Detect) or (2) enhanced standard of care (SOC) EID (off-site testing at a public laboratory). Infants with HIV were referred for ART and followed for 12 months. Our primary outcome was defined as alive, in care, and virally suppressed at 12 months. RESULTS: Between March 2016 and November 2018, we randomized 4000 HIV-exposed infants to POC (n=1989) or SOC (n=2011). All but 2 infants in the POC group received same-day results, while the median time to result in the SOC group was 27 (interquartile range: 22-30) days. Eighty-one (2%; 95% confidence interval [CI]: 1.6-2.5%) infants were diagnosed with HIV. Although ART initiation was high, there were 15 (19%) deaths, 15 (19%) follow-up losses, and 31 (38%) virologic failures. By 12 months, only 20 of 81 (25%; 95% CI: 15-34%) infants with HIV were alive, in care, and virally suppressed: 13 (30%; 16-43%) infants in the POC group vs 7 (19%; 6-32%) in the SOC group (RR: 1.56; .7-3.50). CONCLUSIONS: POC EID eliminated diagnostic delays and accelerated ART initiation but did not translate into definitive improvement in 12-month outcomes. In settings where centralized EID is well functioning, POC EID is unlikely to improve pediatric HIV outcomes. CLINICAL TRIALS REGISTRATION: This trial is registered at https://clinicaltrials.gov (NCT02682810).

Serum antibodies to selected Helicobacter pylori antigens are associated with active gastritis in patients seen at the University Teaching Hospital in Lusaka, Zambia.

Introduction: Little is known about specific bacterial characteristics of Helicobacter pylori (H. pylori) infection influencing gastric carcinogenesis in Zambia. The aim of this study was to evaluate the associations between pre-selected H. pylori antibodies with gastric cancer, premalignant lesions and active gastritis. Methods: This was cross-sectional study with multiple comparisons of patients with gastric cancer (GC), gastric premalignant (GP) lesions and active or chronic gastritis. A fluorescent bead-based antibody multiplex serology assay was used to quantify antibodies to thirteen immunogenic H. pylori antigens. Logistic regression models were used to examine the associations. Results: Included were 295 patients with: 59 GC, 27 GP lesions, 48 active and 161 chronic gastritis. Overall, 257/295 (87%) were H. pylori positive. H. pylori seropositivity was not associated with sex, age, body mass index, socio-economic status, HIV infection, alcohol consumption or cigarette smoking (p-values all above 0.05). When compared to the patients with chronic gastritis, the presence of catalase and cinnamyl alcohol dehydrogenase (Cad) antibodies was positively associated with GP lesions (OR 3.53; 95% CI 1.52-8.17 and OR 2.47; 95% CI 1.08-5.67 respectively). However, seropositivity to Cad antibodies was significantly lower in GC patients (OR 0.28; 95% CI 0.09-0.83). Compared to chronic, active gastritis was significantly associated with (p<0.05) H. pylori sero-positivity (OR 9.46; 95% CI 1.25-71.52) and specific antibodies including cytotoxin-associated gene A, vacuolating cytotoxin A, Helicobacter cysteine-rich protein C, hypothetical protein HP0305 and outer membrane protein HP1564. Conclusions: Among Zambian patients seen at a single center, antibodies to H. pylori (CagA, VacA, Omp, HcpC, HP0305 and HpaA) were associated with active gastritis.

Minimizing Delays in the Breast Cancer Pathway by Integrating Breast Specialty Care Services at the Primary Health Care Level in Zambia.

PURPOSE: In Zambia, more than two-thirds of female patients with breast cancer present with late-stage disease, leading to high mortality rates. Most of the underlying causes are associated with delays in symptom recognition and diagnosis. By implementing breast care specialty services at the primary health care level, we hypothesized that some of the delays could be minimized. METHODS: In March 2018, we established a breast care specialty clinic for women with symptomatic disease within 1 of the 5 district hospitals in Lusaka. The clinic offers breast self-awareness education, clinical breast examination, breast ultrasound, ultrasound-guided breast biopsy, surgery, referral for chemoradiation, follow-up care, and electronic medical records. RESULTS: Between March 2018 and April 2019, of 1,790 symptomatic women who presented to the clinic, 176 (10%) had clinical and/or ultrasound indications for histologic evaluation. Biopsy specimens were obtained using ultrasound-guided core-needle procedures, all of which were performed on the same day as the initial visit. Of the 176 women who underwent biopsy, 112 (64%) had pathologic findings compatible with a primary breast cancer, and of these, 42 (37%) were early-stage (stage I/II) disease. Surgery for early-stage cancers was performed at the district hospital within 2 weeks of the time of definitive pathologic diagnosis. Patients with advanced disease were referred to the national cancer center for multimodality therapy, within a similar time frame. CONCLUSION: Breast care specialty services for symptomatic women were established in a district-level hospital in a resource-constrained setting in Africa. As a result, the following time intervals were minimized: initial presentation and performance of clinical diagnostics; receipt of a definitive pathologic diagnosis and initiation of surgery; receipt of a definitive pathologic diagnosis and referral.

Biomass Smoke Exposure Is Associated With Gastric Cancer and Probably Mediated Via Oxidative Stress and DNA Damage: A Case-Control Study.

PURPOSE: We investigated the association between gastric cancer and environmental and dietary exposures. In addition, we explored probable mechanistic pathways for the influence of biomass smoke on gastric carcinogenesis. PATIENTS AND METHODS: The study was conducted in Lusaka, Zambia. Questionnaires were used to collect data on risk factors, whereas enzyme-linked immunosorbent assays and high-performance liquid chromatography were used to measure biologic exposures. Study data were analyzed using contingency tables and logistic regression. RESULTS: We enrolled 72 patients with gastric adenocarcinoma and 244 controls. Gastric cancer was positively associated with rural residence (odds ratio [OR], 2.9; 95% CI, 1.5 to 5.3), poverty (OR, 4.2; 95% CI, 1.9 to 9.1), and daily consumption of processed meat (OR, 6.4; 95% CI, 1.3 to 32) and negatively associated with consumption of green vegetables (OR, 0.2; 95% CI, 0.1 to 0.5). Gastric cancer was also associated with biomass smoke exposure (OR, 3.5; 95% CI, 1.9 to 6.2; P < .0001), an association that was stronger for intestinal-type cancers (OR, 3.6; 95% CI, 1.5 to 9.1; P = .003). Exposure to biomass smoke in controls was associated with higher urinary levels of 8-isoprostane (P < .0001), 8-hydroxydeoxyguanosine (P = .029), and 1-hydroxypyrene (P = .041). Gastric cancer was not associated with biochemical measures of current exposure to aflatoxins or ochratoxins. CONCLUSION: In Zambia, exposure to biomass smoke, daily consumption of processed meat, and poverty are risk factors for gastric cancer, whereas daily consumption of green vegetables is protective against gastric cancer. Exposure to biomass smoke was associated with evidence of oxidative stress and DNA damage, suggesting mechanistic plausibility for the observed association, and the association was restricted to intestinal-type gastric cancer.

Leverage of an Existing Cervical Cancer Prevention Service Platform to Initiate Breast Cancer Control Services in Zambia: Experiences and Early Outcomes.

PURPOSE: In 2005, the Cervical Cancer Prevention Program in Zambia (CCPPZ) was implemented and has since provided cervical cancer screen-and-treat services to more than 500,000 women. By leveraging the successes and experiences of the CCPPZ, we intended to build capacity for the early detection and surgical treatment of breast cancer. METHODS: Our initiative sought to build capacity for breast cancer care through the (1) formation of a breast cancer advocacy alliance to raise awareness, (2) creation of resource-appropriate breast cancer care training curricula for mid- and high-level providers, and (3) implementation of early detection and treatment capacity within two major health care facilities. RESULTS: Six months after the completion of the initiative, the following outcomes were documented: Breast health education and clinical breast examination (CBE) services were successfully integrated into the service platforms of four CCPPZ clinics. Two new breast diagnostic centers were opened, which provided access to breast ultrasound, ultrasound-guided core needle biopsy, and needle aspiration. Breast health education and CBE were provided to 1,955 clients, 167 of whom were evaluated at the two diagnostic centers; 55 of those evaluated underwent core-needle biopsy, of which 17 were diagnosed with invasive cancer. Newly trained surgeons performed six sentinel lymph node mappings, eight sentinel lymph node dissections, and 10 breast conservation surgeries (lumpectomies). CONCLUSION: This initiative successfully established clinical services in Zambia that are critical for the early detection and surgical management of breast cancer.

Demonstration of an algorithm to overcome health system-related barriers to timely diagnosis of breast diseases in rural Zambia.

BACKGROUND: Long delays to diagnosis is a major cause of late presentation of breast diseases in sub-Saharan Africa. AIMS: We designed and implemented a single-visit breast care algorithm that overcomes health system-related barriers to timely diagnosis of breast diseases. METHODS: A multidisciplinary team of Zambian healthcare experts trained a team of mid- and high-level Zambian healthcare practitioners how to evaluate women for breast diseases, and train trainers to do likewise. Working collaboratively, the two teams then designed a clinical platform that provides multiple breast care services within a single visit. The service platform was implemented using a breast outreach camp format, during which breast self-awareness, psychosocial counseling, clinical breast examination, breast ultrasound, ultrasound-guided biopsy, imprint cytology of biopsy specimens and surgical treatment or referral, were offered within a single visit. RESULTS: Eleven hundred and twenty-nine (1129) women attended the camps for breast care. Mean age was 35.9 years. The majority were multiparous (79.4%), breast-fed (76.0%), and reported hormone use (50.4%). Abnormalities were detected on clinical breast examination in 122 (10.8%) women, 114 of whom required ultrasound. Of the 114 who underwent ultrasound, 48 had identifiable lesions and were evaluated with ultrasound-guided core needle biopsy (39) or fine-needle aspiration (9). The concordance between imprint cytology and histopathology was 100%, when breast specimens were classified as either benign or malignant. However, when specimens were classified by histopathologic subtype, the concordance between imprint cytology and histology was 85.7% for benign and 100% for malignant lesions. Six (6) women were diagnosed with invasive cancer. Eighteen (18) women with symptomatic breast lesions had next-day surgery. SIGNIFICANCE: Similar to its impact on cervical cancer prevention services, a single visit breast care algorithm has the potential to overcome health system-related barriers to timely diagnosis of breast diseases, including cancer, in rural African settings.

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

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

HIV related hypochlorhydria does not appear to respond to anti-retroviral therapy in Zambian adults: a case control study.

INTRODUCTION: Human Immunodeficiency Virus (HIV) infection is associated with hypochlorhydria but the mechanism is unknown. The objective of this study was to determine effects of anti-retroviral therapy (ART) on gastric physiology as measured by validated markers. METHODS: We studied HIV infected individuals who were either ART-naïve or on treatment with undetectable viral loads. We measured H.pylori IgG antibodies, pepsinogen (PG) 1 and 2 levels and fasting gastrin-17 using Biohit GastroPanel®. Gastric antral biopsies and juice were obtained for histology and pH respectively. Also included were historical data from HIV negative participants (n = 72) in a previous study, for reference. RESULTS: We enrolled 84 HIV positive individuals with a median age 42 years (IQR 37-40 years). 55(66%) were female, 32(38%) were ART naïve, and 52(62%) were on ART. Hypochlorhydria (pH>4) was present in 48(57%) of the HIV positive and 18(25%) of the HIV negative individuals (OR 4: 95% CI 1.9-8.5, P<0.001) with no significant effect of ART (OR 0.9: 95% CI 0.3-2.3, P = 0.82). Hypochlorhydria was not associated with the serological detection of corpus atrophy using low PG 1:2 ratio (OR 2.1: 95% CI 0.5-10.2, P = 0.37) or GastroPanel® algorithm, (OR 0.7: 95% CI 0.01-60.1, P = 1.0). ART reduced the frequency of low PG 1:2 ratio (P = 0.001), but not the histological detection in the antrum of atrophy or non-atrophic gastritis. CONCLUSION: ART use is associated with reduced serological evidence of corpus atrophy but has no effect on fasting pH, supporting earlier data that suggest that the mechanism of HIV-associated hypochlorhydria is multifactorial.

High prevalence of gastric intestinal metaplasia detected by confocal laser endomicroscopy in Zambian adults.

BACKGROUND: Confocal laser endomicroscopy (CLE) may increase the detection of gastric premalignant lesions, and facilitate targeted biopsies for histology. The study aim was to analyse premalignant lesions in Zambian adults using CLE. METHODS: Using CLE and histology we analysed the antral mucosa for gastric premalignant lesions in asymptomatic adults living with HIV and in HIV seronegative adults. Fasting gastric pH and the presence of Helicobacter pylori (H. pylori) were also evaluated. RESULTS: We enrolled 84 HIV seropositive participants (median age 43 years; 55 (65%) female), of whom 32 (38%) were anti-retroviral therapy (ART)-naïve. Also enrolled were 22 HIV seronegative controls (median age 39 years, 12 (55%) females). Hypochlorhydria was found in 48 (57%) HIV positive and 8 (38%) HIV negative controls (P = 0.14). Detection of gastric intestinal metaplasia (GIM) was higher (P = 0.007) using CLE (49, 54%) than histology (9, 9%) and, using CLE, GIM was similar between HIV positive (41, 60%) and negative groups (8, 36%; P = 0.08). Gastric luminal fluorescein leakage was significantly associated with the presence of GIM [OR 8.2; 95% CI 2.5-31, P<0.001]. CONCLUSION: CLE is useful for the detection of GIM, and luminal fluorescein leakage may represent a novel CLE marker for GIM. GIM is common in Zambian adults, and is highly prevalent irrespective of HIV infection or use of ART.

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.

Population-level scale-up of cervical cancer prevention services in a low-resource setting: development, implementation, and evaluation of the cervical cancer prevention program in Zambia.

BACKGROUND: Very few efforts have been undertaken to scale-up low-cost approaches to cervical cancer prevention in low-resource countries. METHODS: In a public sector cervical cancer prevention program in Zambia, nurses provided visual-inspection with acetic acid (VIA) and cryotherapy in clinics co-housed with HIV/AIDS programs, and referred women with complex lesions for histopathologic evaluation. Low-cost technological adaptations were deployed for improving VIA detection, facilitating expert physician opinion, and ensuring quality assurance. Key process and outcome indicators were derived by analyzing electronic medical records to evaluate program expansion efforts. FINDINGS: Between 2006-2013, screening services were expanded from 2 to 12 clinics in Lusaka, the most-populous province in Zambia, through which 102,942 women were screened. The majority (71.7%) were in the target age-range of 25-49 years; 28% were HIV-positive. Out of 101,867 with evaluable data, 20,419 (20%) were VIA positive, of whom 11,508 (56.4%) were treated with cryotherapy, and 8,911 (43.6%) were referred for histopathologic evaluation. Most women (87%, 86,301 of 98,961 evaluable) received same-day services (including 5% undergoing same-visit cryotherapy and 82% screening VIA-negative). The proportion of women with cervical intraepithelial neoplasia grade 2 and worse (CIN2+) among those referred for histopathologic evaluation was 44.1% (1,735/3,938 with histopathology results). Detection rates for CIN2+ and invasive cervical cancer were 17 and 7 per 1,000 women screened, respectively. Women with HIV were more likely to screen positive, to be referred for histopathologic evaluation, and to have cervical precancer and cancer than HIV-negative women. INTERPRETATION: We creatively disrupted the 'no screening' status quo prevailing in Zambia and addressed the heavy burden of cervical disease among previously unscreened women by establishing and scaling-up public-sector screening and treatment services at a population level. Key determinants for successful expansion included leveraging HIV/AIDS program investments, and context-specific information technology applications for quality assurance and filling human resource gaps.

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.

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

BACKGROUND: The 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. FINDINGS: We 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. CONCLUSIONS: To 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.

Observed and expected incidence of cervical cancer in lusaka and the southern and Western provinces of Zambia, 2007 to 2012.

OBJECTIVES: Cervical cancer is increasing but underestimated in developing countries. We calculated the observed and expected incidence of cervical cancer in Lusaka and Southern and Western provinces of Zambia. METHODS/MATERIALS: Data for 2007 to 2012 were obtained for the 3 provinces. Data included age, residence, year of diagnosis, marital status, occupation, human immunodeficiency virus (HIV), stage, radiotherapy, and chemotherapy. Expected incidence in Southern and Western provinces was calculated based on observed incidence for Lusaka province, adjusting for HIV. RESULTS: Crude and age-standardized incidence rates (ASRs) in Lusaka were 2 to 4 times higher than incidence in the other 2 provinces. Lusaka had a rate of 54.1 per 10(5) and ASR of 82.1 per 10(5) in the age group of 15 to 49 years. The Southern province had a rate of 17.1 per 10(5) and ASR of 25.5 per 10(5); the Western province had a rate of 12.3 per 10(5) and ASR rate of 17.2 per 10(5). The observed cervical cancer incidence rates in the Southern and Western provinces were lower than the rate in Lusaka, possibly because of the uncertainty of underreporting/underdiagnosis or actual lower risk for reasons yet unclear. The HIV seroprevalence rates in patients from the 3 provinces were 46% to 93% higher than seroprevalence in the respective general populations. CONCLUSIONS: Cervical cancer is significantly underestimated in Zambia, and HIV has a significant role in pathogenesis. Future studies should establish methods for case ascertainment and better utilization of hospital- and population-based registries in Zambia and other similar developing countries.