Tuberculosis and Hepatic Steatosis Are Prevalent Liver Pathology Findings among HIV-Infected Patients in South Africa

Liver disease epidemiology in sub-Saharan Africa has shifted as a result of HIV and the increased use of antiretroviral therapy leading to a need for updated data on common causes of liver disease. We retrospectively reviewed records from all hospitalized patients who had liver biopsy at a single hospital in South Africa from 2001 to 2009 and compared diagnosis by HIV status. During the period of study 262 patients had liver biopsy, 108 (41%) were HIV-infected, 25 (10%) were HIV-sero-negative, and 129 (49%) had unknown or unrecorded HIV status. Overall 81% of biopsies provided additional diagnostic data. Malignancy was the most common finding reported on 56 (21%) biopsies followed by granuloma or TB, hepatic steatosis, and fibrosis or cirrhosis. HIV-infected patients were more likely to have granulomas and steatosis. Half of patients with granulomas were already on TB treatment, suggesting paradoxical reactions or drug induced liver injury may have been important causes of liver inflammation among these patients. We note that TB, paradoxical reactions during TB treatment, possible drug induced liver injury, and hepatic steatosis are important causes of liver pathology among HIV-infected hospitalized patients with unclear etiology of liver disease after initial assessment. Among HIV sero-negative patients, malignancy was the major cause of liver disease. Our findings re-enforce the importance of TB as a diagnosis among HIV-infected individuals.\ud \u

Causes of Death on Antiretroviral Therapy: A Post-Mortem Study from South Africa

Background: Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients. Methods: HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death. Results: Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7–90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non-infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death. Conclusions: Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge

Prospective One Year follow up of HIV infected women screened for cervical cancer using visual inspection with acetic acid, cytology and human papillomavirus testing in Johannesburg, South Africa

BACKGROUND: Cervical cancer is the most common cancer in Sub-Saharan Africa. There are little of HIV-infected women one-year after screening using visual inspection with acetic acid (VIA), HPV or cytology in sub-Saharan Africa. METHODS: HIV-infected women in Johannesburg South Africa were screened one year later by Pap smear, VIA and human papillomavirus (HPV) testing. Women qualified for the 12 month follow-up visit if they had a negative or cervical intra-epithelial neoplasia (CIN) 1 results at the baseline visit. Modified Poisson regression was used to analyse associations between patient baseline characteristics and progression. RESULTS: A total of 688 of 1,202 enrolled at baseline study who were CIN-2+ negative and qualified for a 12 month follow-up visit. Progression to CIN-2+ was higher in women with positive VIA results (12.6%; 24/191) than those VIA-negative (4.4%; 19/432). HPV-positive women at baseline were more likely to progress to CIN-2+ (12.3%; 36/293) than those HPV-negative (2.1%; 7/329). Cytology-positive women at baseline were more likely to progress to CIN-2+ (9.6%; 37/384) than cytology-negative women (2.5%; 6/237). Approximately 10% (10.4%; 39/376) of women with CIN 1 at baseline progressed to CIN 2+. Women who were VIA or HPV positive at baseline were more likely to progress aIRR 1.85, CI 95% (1.46 to 2.36), aIRR 1.41 CI 95% (1.14 to 1.75) respectively. CONCLUSION: Progression to CIN-2+ in HIV-infected women is significant when measured by baseline positive VIA, HPV or Pap and yearly screening by any method should be considered in this population if possible

Diagnostic value of human papillomavirus (HPV) 16 and HPV18 viral loads for the detection of high-grade cervical intraepithelial neoplasia (CIN2+) in a cohort of African women living with HIV.

BACKGROUND: African women living with HIV (WLHIV) are at high risk of cervical cancer but rarely adequately screened. Better strategies enabling identification of WLHIV with high-grade cervical intraepithelial lesions (CIN2+) are required. OBJECTIVES: To investigate the diagnostic value of HPV16 and HPV18 viral loads in a cohort of African WLHIV. DESIGN: HPV16 and HPV18 viral loads were determined by quantitation of the E6 gene DNA by real-time PCR in cervical specimens collected at baseline and endline (16 months) from 245 African WLHIV positive for HPV16 or/and HPV18. Cervical biopsies were graded using the histopathological CIN classification. RESULTS: Women with CIN2+ had higher viral load for HPV16 (p < 0.0001) or HPV18 (p = 0.03) than those without CIN2+. HPV16 viral load ≥3.59 log copies/1000 cells detected CIN2+ with sensitivity and specificity of 93.5% (95%CI: 81.7-98.3%) and 74.1% (95%CI: 66.3-80.6%), respectively, whereas HPV18 viral load ≥1.63 log copies/1000 cells detected CIN2+ with sensitivity and specificity of 59.1% (95%CI: 38.7-76.7%) and 66.9% (95%CI: 58.8-74.1%), respectively. A high baseline HPV16 viral load was significantly associated with persistence of, or progression to CIN2+ at endline; these findings were not observed for HPV18. CONCLUSIONS: HPV16 viral load is a powerful marker of CIN2+ in African WLHIV. HPV18 viral load is of lower diagnostic value in this population

Diagnostic accuracy of cervical cancer screening and screening–triage strategies among women living with HIV-1 in Burkina Faso and South Africa: A cohort study

Background: Cervical cancer screening strategies using visual inspection or cytology may have suboptimal diagnostic accuracy for detection of precancer in women living with HIV (WLHIV). The optimal screen and screen-triage strategy, age to initiate, and frequency of screening for WLHIV remain unclear. This study evaluated the sensitivity, specificity, and positive predictive value of different cervical cancer strategies in WLHIV in Africa. Methods and findings: WLHIV aged 25-50 years attending HIV treatment centres in Burkina Faso (BF) and South Africa (SA) from 5 December 2011 to 30 October 2012 were enrolled in a prospective evaluation study of visual inspection using acetic acid (VIA) or visual inspection using Lugol's iodine (VILI), high-risk human papillomavirus DNA test (Hybrid Capture 2 [HC2] or careHPV), and cytology for histology-verified high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) at baseline and endline, a median 16 months later. Among 1,238 women (BF: 615; SA: 623), median age was 36 and 34 years (p < 0.001), 28.6% and 49.6% ever had prior cervical cancer screening (p < 0.001), and 69.9% and 64.2% were taking ART at enrolment (p = 0.045) in BF and SA, respectively. CIN2+ prevalence was 5.8% and 22.4% in BF and SA (p < 0.001), respectively. VIA had low sensitivity for CIN2+ (44.7%, 95% confidence interval [CI] 36.9%-52.7%) and CIN3+ (56.1%, 95% CI 43.3%-68.3%) in both countries, with specificity for ≤CIN1 of 78.7% (95% CI 76.0%-81.3%). HC2 had sensitivity of 88.8% (95% CI 82.9%-93.2%) for CIN2+ and 86.4% (95% CI 75.7%-93.6%) for CIN3+. Specificity for ≤CIN1 was 55.4% (95% CI 52.2%-58.6%), and screen positivity was 51.3%. Specificity was higher with a restricted genotype (HPV16/18/31/33/35/45/52/58) approach (73.5%, 95% CI 70.6%-76.2%), with lower screen positivity (33.7%), although there was lower sensitivity for CIN3+ (77.3%, 95% CI 65.3%-86.7%). In BF, HC2 was more sensitive for CIN2+/CIN3+ compared to VIA/VILI (relative sensitivity for CIN2+ = 1.72, 95% CI 1.28-2.32; CIN3+: 1.18, 95% CI 0.94-1.49). Triage of HC2-positive women with VIA/VILI reduced the number of colposcopy referrals, but with loss in sensitivity for CIN2+ (58.1%) but not for CIN3+ (84.6%). In SA, cytology high-grade squamous intraepithelial lesion or greater (HSIL+) had best combination of sensitivity (CIN2+: 70.1%, 95% CI 61.3%-77.9%; CIN3+: 80.8%, 95% CI 67.5%-90.4%) and specificity (81.6%, 95% CI 77.6%-85.1%). HC2 had similar sensitivity for CIN3+ (83.0%, 95% CI 70.2%-91.9%) but lower specificity compared to HSIL+ (42.7%, 95% CI 38.4%-47.1%; relative specificity = 0.57, 95% CI 0.52-0.63), resulting in almost twice as many referrals. Compared to HC2, triage of HC2-positive women with HSIL+ resulted in a 40% reduction in colposcopy referrals but was associated with some loss in sensitivity. CIN2+ incidence over a median 16 months was highest among VIA baseline screen-negative women (2.2%, 95% CI 1.3%-3.7%) and women who were baseline double-negative with HC2 and VIA (2.1%, 95% CI 1.3%-3.5%) and lowest among HC2 baseline screen-negative women (0.5%, 95% CI 0.1%-1.8%). Limitations of our study are that WLHIV included in the study may not reflect a contemporary cohort of WLHIV initiating ART in the universal ART era and that we did not evaluate HPV tests available in study settings today. Conclusions: In this cohort study among WLHIV in Africa, a human papillomavirus (HPV) test targeting 14 high-risk (HR) types had higher sensitivity to detect CIN2+ compared to visual inspection but had low specificity, although a restricted genotype approach targeting 8 HR types decreased the number of unnecessary colposcopy referrals. Cytology HSIL+ had optimal performance for CIN2+/CIN3+ detection in SA. Triage of HPV-positive women with HSIL+ maintained high specificity but with some loss in sensitivity compared to HC2 alone

Associations of Human Papillomavirus (HPV) genotypes with high-grade cervical neoplasia (CIN2+) in a cohort of women living with HIV in Burkina Faso and South Africa.

OBJECTIVE: To describe associations of high-risk human papillomavirus (HR-HPV) with high-grade cervical intraepithelial neoplasia (CIN2+) in women living with HIV (WLHIV) in Burkina Faso (BF) and South Africa (SA). METHODS: Prospective cohort of WLHIV attending HIV outpatient clinics and treatment centres. Recruitment was stratified by ART status. Cervical HPV genotyping using INNO-LiPA and histological assessment of 4-quadrant cervical biopsies at enrolment and 16 months later. RESULTS: Among women with CIN2+ at baseline, the prevalence of any HR-HPV genotypes included in the bi/quadrivalent (HPV16/18) or nonavalent (HPV16/18/31/35/45/52/58) HPV vaccines ranged from 37% to 90%. HPV58 was most strongly associated with CIN2+ (aOR = 5.40, 95%CI: 2.77-10.53). At 16-months follow-up, persistence of any HR-HPV was strongly associated with incident CIN2+ (aOR = 7.90, 95%CI: 3.11-20.07), as was persistence of HPV16/18 (aOR = 5.25, 95%CI: 2.14-12.91) and the additional HR types in the nonavalent vaccine (aOR = 3.23, 95%CI: 1.23-8.54). CONCLUSION: HR-HPV persistence is very common among African WLHIV and is linked to incident CIN2+. HPV vaccines could prevent between 37-90% of CIN2+ among African WLHIV

Validation of cervical cancer screening methods in HIV positive women from Johannesburg South Africa

BACKGROUND: HIV-infected women are at increased risk for developing cervical cancer. Women living in resource-limited countries are especially at risk due to poor access to cervical cancer screening and treatment. We evaluated three cervical cancer screening methods to detect cervical intraepithelial neoplasia grade 2 and above (CIN 2+) in HIV-infected women in South Africa; Pap smear, visual inspection with 5% acetic acid (VIA) and human papillomavirus detection (HPV). METHODS: HIV-infected women aged 18-65 were recruited in Johannesburg. A cross-sectional study evaluating three screening methods for the detection of the histologically-defined gold standard CIN-2 + was performed. Women were screened for cervical abnormalities with the Digene HC2 assay (HPV), Pap smear and VIA. VIA was performed by clinic nurses, digital photographs taken and then later reviewed by specialist physicians. The sensitivity, specificity and predictive valves for CIN-2 + were calculated using maximum likelihood estimators. RESULTS: 1,202 HIV-infected women participated, with a median age of 38 years and CD4 counts of 394 cells/mm 3 . One third of women had a high grade lesion on cytology. VIA and HPV were positive in 45% and 61% of women respectively. Estimated sensitivity/specificity for HPV, Pap smear and VIA for CIN 2+ was 92%/51.4%, 75.8%/83.4% and 65.4/68.5% (nurse reading), respectively. Sensitivities were similar, and specificities appeared significantly lower for the HPV test, cytology and VIA among women with CD4 counts ≤200 cells/mm 3 as compared to CD4 counts >350 cells/mm 3 . CONCLUSIONS: Although HPV was the most sensitive screening method for detecting CIN 2+, it was less specific than conventional cytology and VIA with digital imaging review. Screening programs may need to be individualized in context of the resources and capacity in each area

High Cryptococcal Antigen Titers in Blood Are Predictive of Subclinical Cryptococcal Meningitis Among Human Immunodeficiency Virus-Infected Patients

Background High mortality rates among asymptomatic cryptococcal antigen (CrAg)–positive patients identified through CrAg screening, despite preemptive fluconazole treatment, may be due to undiagnosed cryptococcal meningitis. Methods Symptoms were reviewed in CrAg-positive patients identified by screening 19233 individuals with human immunodeficiency virus infection and CD4 cell counts <100/µL at 17 clinics and 3 hospitals in Johannesburg from September 2012 until September 2015, and at 2 hospitals until June 2016. Cerebrospinal fluid samples from 90 of 254 asymptomatic patients (35%) and 78 of 173 (45%) with headache only were analyzed for cryptococcal meningitis, considered present if Cryptococcus was identified by means of India ink microscopy, culture, or CrAg test. CrAg titers were determined with stored blood samples from 62 of these patients. The associations between blood CrAg titer, concurrent cryptococcal meningitis, and mortality rate were assessed. Results Cryptococcal meningitis was confirmed in 34% (95% confidence interval, 25%–43%; 31 of 90) of asymptomatic CrAg-positive patients and 90% (81%–96%; 70 of 78) with headache only. Blood CrAg titer was significantly associated with concurrent cryptococcal meningitis in asymptomatic patients (P 160 (sensitivity, 88.2%; specificity, 82.1%); the odds ratio for concurrent cryptococcal meningitis was 34.5 (95% confidence interval, 8.3–143.1; P < .001). Conclusions About a third of asymptomatic CrAg-positive patients have concurrent cryptococcal meningitis. More effective clinical assessment strategies and antifungal regimens are required for CrAg-positive patients, including investigation for cryptococcal meningitis irrespective of symptoms. Where it is not possible to perform lumbar punctures in all CrAg-positive patients, blood CrAg titers should be used to target those most at risk of cryptococcal meningitis

Autopsy Prevalence of Tuberculosis and Other Potentially Treatable Infections among Adults with Advanced HIV Enrolled in Out-Patient Care in South Africa: Lesedi Kamoso study data

Early mortality among HIV-positive adults starting antiretroviral therapy (ART) remains high in resource-limited settings, with tuberculosis (TB) the leading cause of death. However, current methods to estimate TB-related deaths are inadequate and most autopsy studies do not adequately represent those attending primary health clinics (PHCs). The TB Fast Track study aimed to determine the autopsy prevalence of TB and other infections in adults enrolled at South African PHCs in the context of a pragmatic trial of empiric TB treatment. This dataset contains basic demographic information and lab investigation results of 34 HIV-positive individuals who died after study enrolment. This includes MGIT culture and Xpert MTB/RIF; aerobic and fungal cultures; and histological finding

Undiagnosed TB in adults dying at home from natural causes in a high TB burden setting: a post mortem study

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfillment of the requirement for the degree of Master of Medicine in the branch Anatomical Pathology Johannesburg, 2016Background: A high proportion of deaths in Africa occur at home where cause of death (CoD) is often unknown. We ascertained undiagnosed pulmonary TB in adults dying at home in whom there was no apparent CoD by doing limited autopsies. Methods: Mortuaries in Matlosana, South Africa identified eligible adults without an ante-mortem diagnosis and/or no recent hospital admission. A questionnaire was administered to next-of-kin. Bilateral lung core biopsies, and modified broncho-alveolar lavages (BAL) were performed. Biopsies were examined histologically and submitted with BAL aspirates for mycobacterial culture and Xpert® MTB/RIF. HIV testing was not performed. Results: 162 families were approached to participate. 28 Refused; 49 were not eligible for the study and included 29 deceased who were on, or had recently stopped TB treatment; 85 were included. All were Black and 53% were men. The median age was 57 years (IQR: 44-66), and median symptom duration 63 days (IQR: 14-112). Laboratory evidence of TB was found in 27(31.8%); 21 were Xpert positive, 23 were MGIT positive, and 14 had histological evidence consistent with TB. Conclusion: In this high HIV prevalence setting, almost one third of home deaths had evidence of undiagnosed TB, suggesting TB-related mortality is underascertained and under-reported, with grave implications for TB control in high TB burden settings.MT201