Venous thromboembolic disease in adults admitted to hospital in a setting with a high burden of HIV and TB.

BACKGROUND: HIV and tuberculosis (TB) independently cause an increased risk for venous thromboembolic disease (VTE): deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Data from high HIV and TB burden settings describing VTE are scarce. The Wells' DVT and PE scores are widely used but their utility in these settings has not been reported on extensively. OBJECTIVES: To evaluate new onset VTE, compare clinical characteristics by HIV status, and the presence or absence of TB disease in our setting. We also calculate the Wells' score for all patients. METHODS: A prospective cohort of adult in-patients with radiologically confirmed VTE were recruited into the study between September 2015 and May 2016. Demographics, presence of TB, HIV status, duration of treatment, CD4 count, viral load, VTE risk factors, and parameters to calculate the Wells' score were collected. RESULTS: We recruited 100 patients. Most of the patients were HIV-infected (n=59), 39 had TB disease and 32 were HIV/TB co-infected. Most of the patients had DVT only (n=83); 11 had PE, and 6 had both DVT and PE. More than a third of patients on antiretroviral treatment (ART) (43%; n=18/42) were on treatment for <6 months. Half of the patients (51%; n=20/39) were on TB treatment for <1 month. The median (interquartile range (IQR)) DVT and PE Wells' score in all sub-groups was 3.0 (1.0 - 4.0) and 3.0 (2.5 - 4.5), respectively. CONCLUSION: HIV/TB co-infection appears to confer a risk for VTE, especially early after initiation of ART and/or TB treatment, and therefore requires careful monitoring for VTE and early initiation of thrombo-prophylaxis.

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Choice architecture-based prescribing tool for TB preventive therapy: a pilot study in South Africa.

BACKGROUND: All people with HIV who screen negative for active tuberculosis (TB) should receive isoniazid preventive therapy (IPT). IPT implementation remains substantially below the 90% WHO target. This study sought to further understanding of IPT prescription by piloting a simplified prescribing approach. SETTING: Primary care clinics in Matlosana, South Africa. DESIGN: This was a mixed-methods implementation study. METHODS: Nine providers were recruited and underwent training on 2018 WHO guidelines. A simplified prescribing tool containing antiretroviral therapy (ART) and IPT prescriptions was introduced into the workflow for 2 weeks. Prescription data were collected from file review. Interviews were conducted with prescribers. RESULTS: During the study period, 41 patients were evaluated for ART initiation; 34 (83%) files used the simplified prescribing tool. Thirty-seven (90%) patients were eligible for same-day ART and IPT initiation, of whom 36 (97%) received IPT prescription. Qualitative interviews identified the following barriers to IPT prescription: cognitive burden, extensive documentation, limited management support, paucity of training, stock-outs, and patient-related factors. Provider acceptability of the tool was favorable, with unanimous recommendation to colleagues on the basis of streamlining documentation and reminding to prescribe. CONCLUSIONS: This simplified prescribing device for IPT was feasible to implement. Streamlining documentation and reminding providers to prescribe can reduce work-flow barriers to IPT provision.

HIV-1 antiretroviral drug resistance patterns in patients failing NNRTI-based treatment: results from a national survey in South Africa.

BACKGROUND: Routine HIV-1 antiretroviral drug resistance testing for patients failing NNRTI-based regimens is not recommended in resource-limited settings. Therefore, surveys are required to monitor resistance profiles in patients failing ART. METHODS: A cross-sectional survey was conducted amongst patients failing NNRTI-based regimens in the public sector throughout South Africa. Virological failure was defined as two consecutive HIV-1 viral load results >1000 RNA copies/mL. Pol sequences were obtained using RT-PCR and Sanger sequencing and submitted to Stanford HIVdb v7.0.1. RESULTS: A total of 788 sequences were available for analysis. Most patients failed a tenofovir-based NRTI backbone (74.4%) in combination with efavirenz (82.1%) after median treatment duration of 36 months. K103N (48.9%) and V106M (34.9%) were the most common NNRTI mutations. Only one-third of patients retained full susceptibility to second-generation NNRTIs such as etravirine (36.5%) and rilpivirine (27.3%). After M184V/I (82.7%), K65R was the most common NRTI mutation (45.8%). The prevalence of K65R increased to 57.5% in patients failing a tenofovir regimen without prior stavudine exposure. Cross-resistance to NRTIs was often observed, but did not seem to affect the predicted activity of zidovudine as 82.9% of patients remained fully susceptible to this drug. CONCLUSIONS: The introduction of tenofovir-based first-line regimens has dramatically increased the prevalence of K65R mutations in the HIV-1-infected South African population. However, most patients failing tenofovir-based regimens remained fully susceptible to zidovudine. Based on these data, there is currently no need to change either the recommended first- or second-line ART regimens in South Africa.

Latent tuberculous infection in schoolchildren and contact tracing in Matlosana, North West Province, South Africa.

This is a cross-sectional study to estimate the prevalence of latent tuberculous infection (LTBI) and the annual risk of tuberculous infection (ARTI) among a sample of children aged 5 and 7 years in Matlosana, South Africa. LTBI prevalence was significantly higher in children aged 7 years (n = 704) (19.7%, 95%CI 16.75-22.65) than in those aged 5 years (212/1401, 15.1%, 95%CI 13.23-16.97) (P = 0.0075). The ARI was 2.9% (95%CI 2.2-3.6).

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

BACKGROUND: A high proportion of deaths in Africa occur at home, where cause of death (CoD) is often unknown. We ascertained undiagnosed pulmonary tuberculosis (TB) by performing limited autopsies in adults dying at home in whom there was no apparent CoD. METHODS: Mortuaries in Matlosana, South Africa, identified potentially eligible adults with no ante-mortem diagnosis and/or no recent hospital admission. A questionnaire was administered to family members. Bilateral lung core biopsies and modified bronchoalveolar lavage (BAL) were performed. The biopsies were examined histologically and submitted with BAL aspirates for mycobacterial culture (MGIT(TM)) and Xpert(®) MTB/RIF testing. Human immunodeficiency virus (HIV) testing was not performed. RESULTS: Of 162 families approached, 28 refused and 29 of the deceased were on or had recently stopped anti-tuberculosis treatment; 85 were included. All were Black and 53% were men. The median age was 57 years (interquartile range [IQR] 44-66) and median symptom duration (mainly cough) was 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 active TB. CONCLUSION: In this high HIV prevalence setting, a quarter of the home deaths had evidence of undiagnosed, likely infectious TB, suggesting that TB-related mortality is under-ascertained and under-reported, with serious implications for TB control in high TB burden settings.

Treatment of drug-resistant tuberculosis with bedaquiline in a high HIV prevalence setting: an interim cohort analysis.

BACKGROUND: South Africa has a large burden of extensively drug-resistant tuberculosis (XDR-TB); only 15% of XDR-TB patients have successful outcomes. OBJECTIVE: To describe the safety and effectiveness of bedaquiline (BDQ) in the South African BDQ Clinical Access Programme. DESIGN: An interim cohort analysis. RESULTS: Of the first 91 patients enrolled between March 2013 and July 2014 (with follow-up until August 2014), 54 (59%) were human immunodeficiency virus (HIV) infected. The median CD4 count was 239 cells/µl, and all patients were on antiretroviral therapy (ART) at initiation of BDQ; 33 had XDR-TB, 41 were pre-XDR-TB with fluoroquinolone resistance and 17 were pre-XDR-TB with resistance to an injectable. Of the 91 patients, 58 (64%) had completed 24 weeks of BDQ, 28 were still on BDQ, 3 were lost to follow-up, 1 had died and 1 had BDQ withdrawn following atrial fibrillation. Of the 63 patients with 6 months follow-up, 48 (76%) had either culture-converted or remained culture-negative after initiation of BDQ. QTcF was monitored monthly and exceeded 500 ms in three participants; this resolved in all three. CONCLUSION: Interim safety and culture conversion outcomes for patients accessing BDQ in South Africa, including HIV-infected patients on ART and patients with pre-XDR- and XDR-TB, suggest that BDQ may be both efficacious and safe.

Predictors of delay in the diagnosis and treatment of suspected tuberculosis in HIV co-infected patients in South Africa.

SETTING: In South Africa, the majority of tuberculosis (TB) patients are co-infected with the human immunodeficiency virus (HIV), and delays in diagnosis and treatment likely exacerbate morbidity and mortality. OBJECTIVE: To determine predictors of delays in the diagnosis and treatment of hospitalised suspected pulmonary TB patients co-infected with HIV. DESIGN: Post-analysis of data collected in a three-centre prospective cohort of in-patients clinically diagnosed with active TB in three hospitals in South Africa between 2006 and 2009 during the first 24 h of admission. Delay was assessed by asking time of first symptoms and any prior health-seeking behaviour for this episode of illness. RESULTS: Data from a total of 891 participants with a median age of 36 years and a CD4 count of 67 cells/mm(3) were analysed. Median patient, system and total delays were respectively 28, 1 and 28 days. Unemployment, treatment at Tshepong Hospital, alcohol consumption, crowding index, seeking prior treatment, cotrimoxazole treatment and WHO Stage 4 disease predicted prolonged total delay. CONCLUSION: Patient delay in seeking care for TB in this high HIV prevalence setting is substantial. Factors identified with delay could be used to develop interventions to improve care seeking and earlier diagnosis of TB.

Tuberculosis among adults starting antiretroviral therapy in South Africa: the need for routine case finding.

OBJECTIVE: To investigate the prevalence of and evaluate screening modalities for undiagnosed tuberculosis (TB) in antiretroviral therapy (ART) eligible adults in South Africa. METHODS: Individuals were screened for TB using symptoms, chest radiograph (CXR) and two sputum specimens for microscopy and culture, and were then followed for <6 months to determine TB diagnoses. RESULTS: Among 361 participants (67% female, median age 38 years, median CD4 count 120 cells/mm(3)), 64 (18%) were sputum culture-positive; 114 (32%) fulfilled any TB case definition (culture- and/or smear-positive, or improvement on specific treatment). Symptom screening comprising any of cough, appetite loss or night sweats > 2 weeks had a sensitivity and specificity of respectively 74.5% and 50.8%. Sensitivity was increased by CXR (to 96.1%), but not by smear microscopy. The World Health Organization symptom screen had a sensitivity and specificity of respectively 96.1% and 5.2% in our study population; the addition of CXR increased sensitivity to 100%. Median time to TB treatment was 8 days for diagnoses based on CXR (n = 72) vs. 37 days for diagnoses based only on sputum culture (n = 14). CONCLUSIONS: The very high prevalence of undiagnosed TB among patients presenting for ART mandates their routine investigation. CXR improved sensitivity substantially, allowed rapid treatment initiation and should be routine, where available, pending better point-of-care diagnostics.