Gaps in TB preventive therapy for persons initiating antiretroviral therapy in Uganda: an explanatory sequential cascade analysis.

BACKGROUND: The WHO recommends TB symptom screening and TB preventive therapy (TPT) for latent TB infection (LTBI) in persons living with HIV (PLWH). However, TPT uptake remains limited. We aimed to characterize and contextualize gaps in the TPT care cascade among persons enrolling for antiretroviral therapy (ART).SETTING: Four PEPFAR-supported facilities in Uganda.METHODS: We studied a proportionate stratified random sample of persons registering for ART when TPT was available. Patient-level data on eligibility, initiation, and completion were obtained from registers to determine proportion of eligible patients completing each cascade step. We interviewed providers and administrators and used content analysis to identify barriers to guideline-concordant TPT practices.RESULTS: Of 399 study persons, 309 (77%) were women. Median age was 29 (IQR 25-34), CD4 count 405 cells/µL (IQR 222-573), and body mass 23 kg/m² (IQR 21-25). Of 390 (98%) screened, 372 (93%) were TPT-eligible. Only 62 (17%) eligible PLWH initiated and 36 (58%) of 62 completed TPT. Providers reported hesitating to prescribe TPT because they lacked confidence excluding TB by symptom screening alone and feared promoting drug resistance. Although isoniazid was available, past experience of irregular supply discouraged TPT initiation. Providers pointed to insufficient TB-dedicated staff, speculated that patients discounted TB risk, and worried TPT pill burden and side effects depressed ART adherence.CONCLUSIONS: While screening was nearly universal, most eligible PLWH did not initiate TPT. Only about half of those who initiated completed treatment. Providers feared promoting drug resistance, harbored uncertainty about continued availability, and worried TPT could antagonize ART adherence. Our findings suggest urgent need for stakeholder engagement in TPT provision.

Hyperglycaemia and pharmacokinetics of rifampicin/isoniazid among TB-HIV co-infected patients in Kampala, Uganda.

OBJECTIVE: 1) To determine the prevalence of diabetes mellitus and impaired fasting glucose (IFG) in patients with TB and HIV co-infection, and 2) to investigate the effect of fasting plasma glucose (FPG) on rifampicin (RIF) and isoniazid (INH) serum concentrations.DESIGN: Retrospective data analysis of a cohort of HIV-infected adults with newly diagnosed pulmonary TB. Plasma glucose and TB drug levels were obtained at Week 0, 2, 8 and 24 of TB treatment.RESULTS: A total of 107 patients were included in this analysis. Random plasma glucose ≥200 mg/dL was found in 1/53 (2%) participant at Week 0. The prevalence of FPG ≥ 126 mg/dL decreased from 8/41 (20%) at Week 2 to 3/89 (3%) at Week 24. IFG (100-125 mg/dL) was observed in 23/41 (56%) participants at Week 2, and 39/89 (44%) at Week 24. FPG was inversely correlated with lower area under the curve (AUC0-24h) for RIF (c = -0.52; 95%CI -0.84 to -0.21; P = 0.001). FPG was not associated with lower INH AUC0-24h.CONCLUSION: We found a high prevalence of FPG ≥ 126 mg/dL, which decreased significantly during treatment, and a high proportion of IFG at the end of TB treatment. Higher FPG was associated with lower AUC for RIF.

Detection of tuberculosis patterns in digital photographs of chest X-ray images using Deep Learning: feasibility study.

OBJECTIVE: To evaluate the feasibility of Deep Learning-based detection and classification of pathological patterns in a set of digital photographs of chest X-ray (CXR) images of tuberculosis (TB) patients. MATERIALS AND METHODS: In this prospective, observational study, patients with previously diagnosed TB were enrolled. Photographs of their CXRs were taken using a consumer-grade digital still camera. The images were stratified by pathological patterns into classes: cavity, consolidation, effusion, interstitial changes, miliary pattern or normal examination. Image analysis was performed with commercially available Deep Learning software in two steps. Pathological areas were first localised; detected areas were then classified. Detection was assessed using receiver operating characteristics (ROC) analysis, and classification using a confusion matrix. RESULTS: The study cohort was 138 patients with human immunodeficiency virus (HIV) and TB co-infection (median age 34 years, IQR 28-40); 54 patients were female. Localisation of pathological areas was excellent (area under the ROC curve 0.82). The software could perfectly distinguish pleural effusions from intraparenchymal changes. The most frequent misclassifications were consolidations as cavitations, and miliary patterns as interstitial patterns (and vice versa). CONCLUSION: Deep Learning analysis of CXR photographs is a promising tool. Further efforts are needed to build larger, high-quality data sets to achieve better diagnostic performance.

Tuberculosis treatment success among rural and urban Ugandans living with HIV: a retrospective study.

Setting: Government health centres and hospitals (six urban and 20 rural) providing tuberculosis (TB) treatment for people living with the human immunodeficiency virus (PLHIV) in central and western Uganda. Objective: To identify and quantify modifiable factors that limit TB treatment success among PLHIV in rural Uganda. Design: A retrospective cross-sectional review of routine Uganda National Tuberculosis and Leprosy Programme clinic registers and patient files of HIV-positive patients who received anti-tuberculosis treatment in 2014. Results: Of 191 rural patients, 66.7% achieved treatment success compared to 81.1% of 213 urban patients. Adjusted analysis revealed higher average treatment success in urban patients than in rural patients (OR 3.95, 95%CI 2.70-5.78, P < 0.01, generalised estimating equation model). Loss to follow-up was higher and follow-up sputum smear results were less frequently recorded in TB clinic registers among rural patients. Patients receiving treatment at higher-level facilities in rural settings had greater odds of treatment success, while patients receiving treatment at facilities where drug stock-outs had occurred had lower odds of treatment success. Conclusion: Lower reported treatment success in rural settings is mainly attributed to clinic-centred factors such as treatment monitoring procedures. We recommend strengthening treatment monitoring and delivery.

Contexte: L'étude a été réalisée dans des centres de santé et des hôpitaux publics, six urbains et 20 ruraux, fournissant un traitement de la tuberculose (TB) aux personnes vivant avec le VIH (PVVIH) dans le centre et l'ouest de l'Ouganda.Objectif: Identifier et quantifier les facteurs modifiables qui limitent le succès du traitement de la TB parmi les PVVIH dans l'Ouganda rural.Schéma: Une revue rétrospective transversale des registres cliniques et des dossiers de patients du Programme national tuberculose et lèpre d'Ouganda pour les patients VIH positifs qui ont reçu un traitement de TB en 2014.Résultats: Parmi 191 patients ruraux, 66,7% ont eu un bon résultat de leur traitement, tandis que parmi 213 patients urbains, 81,1% ont eu un bon résultat. Une analyse ajustée a révélé un succès thérapeutique moyen plus élevé chez les patients urbains comparés aux patients ruraux (OR 3,95 ; IC95% 2,70­5,78 ; P < 0,01 ; modèle d'équation d'estimation généralisée). Les pertes de vue ont été plus élevées et les résultats de frottis de crachats de suivi ont été moins souvent enregistrés dans les registres des centres TB pour les patients ruraux. Les patients recevant un traitement dans des structures de plus haut niveau, toujours en zone rurale, avaient plus de chances d'avoir un succès thérapeutique. Les patients recevant leur traitement dans des structures où étaient survenues des ruptures de stock de médicaments avaient moins de chances de succès thérapeutique.Conclusion: Les taux plus faibles de succès du traitement rapportés en zone rurale sont en majorité attribués à des facteurs liés aux centres de santé, comme les procédures de suivi du traitement. Nous recommandons le renforcement de la fourniture et du suivi du traitement.

Marco de referencia: El estudio se llevó a cabo en centros de salud y hospitales del sector público, seis en entornos urbanos y 20 en medio rural y consistió en suministrar el tratamiento antituberculoso a las personas positivas frente al virus de la inmunodeficiencia humana (VIH) en la región central y occidental de Uganda.Objetivo: Determinar y cuantificar los factores modificables que limitan la eficacia del tratamiento antituberculoso en las personas positivas frente al VIH en las zonas rurales de Uganda.Método: Fue este un estudio transversal retrospectivo de análisis de los registros corrientes y las historias clínicas de los pacientes positivos frente al VIH, en los consultorios del Programa Nacional contra la Tuberculosis y la Lepra de Uganda en el 2014.Resultados: De los 191 pacientes de entornos rurales, el 66,7% logró un tratamiento eficaz y en los 213 pacientes en medio urbano esta proporción fue 81,1%. Un análisis ajustado reveló un promedio de éxito terapéutico más alto en los pacientes urbanos en comparación con los pacientes rurales (OR 3,95; IC95% de 2,70 a 5,78; P < 0,01, según un modelo de ecuaciones de estimación generalizadas). En medio rural, se observó una mayor pérdida durante el seguimiento y se consignaban con menor frecuencia los resultados de las baciloscopias de seguimiento en los registros de tuberculosis de los consultorios. Los pacientes que recibían tratamiento en los establecimientos de nivel de atención más alto en medio rural tenían mayores posibilidades de éxito terapéutico. Los pacientes que recibían tratamiento en centros que presentaban desabastecimientos de medicamentos tuvieron menos probabilidades de lograr un tratamiento eficaz.Conclusión: La menor proporción de éxito terapéutico notificada en los entornos rurales se debe en su mayor parte a factores que dependen del consultorio, como los procedimientos de supervisión del tratamiento. Se recomienda reforzar la supervisión y el suministro del tratamiento antituberculoso.

Anti-TB drug concentrations and drug-associated toxicities among TB/HIV-coinfected patients.

Background: Toxicities due to anti-TB treatment frequently occur among TB/HIV-coinfected patients. Objectives: To determine the association between anti-TB drug concentrations and the occurrence of hepatotoxicity and peripheral neuropathy among TB/HIV-coinfected patients. Methods: TB/HIV-coinfected patients were started on standard dose anti-TB treatment according to WHO guidelines. Anti-TB drug concentrations were measured using HPLC 1, 2 and 4 h after drug intake at 2, 8 and 24 weeks following initiation of TB treatment. Participants were assessed for hepatotoxicity using Division of AIDS toxicity tables and for peripheral neuropathy using clinical assessment of tendon reflexes, vibration sensation or symptoms. Cox regression was used to determine the association between toxicities and drug concentrations. Results: Of the 268 patients enrolled, 58% were male with a median age of 34 years. Participants with no hepatotoxicity or mild, moderate and severe hepatotoxicity had a median C max of 6.57 (IQR 4.83-9.41) µg/mL, 7.39 (IQR 5.10-10.20) µg/mL, 7.00 (IQR 6.05-10.95) µg/mL and 3.86 (IQR 2.81-14.24) µg/mL, respectively. There was no difference in the median C max of rifampicin among those who had hepatotoxicity and those who did not ( P = 0.322). There was no difference in the isoniazid median C max among those who had peripheral neuropathy 2.34 (1.52-3.23) µg/mL and those who did not 2.21 (1.45-3.11) µg/mL ( P = 0.49). Conclusions: There was no association between rifampicin concentrations and hepatotoxicity or isoniazid concentrations and peripheral neuropathy among TB/HIV-coinfected patients.

Challenges in achieving a target international normalized ratio for deep vein thrombosis among HIV-infected patients with tuberculosis: a case series.

BACKGROUND: Tuberculosis (TB) and HIV are among the risk factors for deep vein thrombosis (DVT). There are several challenges in the management of DVT patients with TB-HIV co-infection including drug-drug interactions and non-adherence due to pill burden. METHODS: HIV infected patients starting treatment for TB were identified and followed up two weekly. Cases of DVT were diagnosed with Doppler ultrasound and patients were initiated on oral anticoagulation with warfarin and followed up with repeated INR measurements and warfarin dose adjustment. RESULTS: We describe 7 cases of TB and HIV-infected patients in Uganda diagnosed with DVT and started on anticoagulation therapy. Their median age was 30 (IQR: 27-39) years and 86 % were male. All patients had co-medication with cotrimoxazole, tenofovir, lamivudine and efavirenz and some were on fluconazole. The therapeutic range of the International Normalization Ratio (INR) was difficult to attain and unpredictable with some patients being under-anticoagulated and others over-anticoagulated. The mean Time in Therapeutic Range (TTR) for patients who had all scheduled INR measurements in the first 12 weeks was 33.3 %. Only one patient among those with all the scheduled INR measurements had achieved a therapeutic INR by 2 weeks. Four out of seven (57 %) of the patients had at least one INR above the therapeutic range which required treatment interruption. None of the patients had major bleeding. CONCLUSION: We recommend more frequent monitoring and timely dose adjustment of the INR, as well as studies on alternative strategies for the treatment of DVT in TB-HIV co-infected patients.

Cryptococcal disease and the burden of other fungal diseases in Uganda; Where are the knowledge gaps and how can we fill them?

The HIV epidemic in Uganda has highlighted Cryptococcus and Candida infections as important opportunistic fungal infections. However, the burden of other fungal diseases is not well described. We aimed to estimate the burden of fungal infections in Uganda. All epidemiological papers of fungal diseases in Uganda were reviewed. Where there is no Ugandan data, global or East African data were used. Recurrent vaginal candidiasis is estimated to occur in 375 540 Uganda women per year; Candida in pregnant women affects up to 651,600 women per year. There are around 45,000 HIV-related oral and oesophageal candidosis cases per year. There are up to 3000 cases per year of post-TB chronic pulmonary aspergillosis. There are an estimated 40,392 people with asthma-related fungal conditions. An estimated 1,300,000 cases of tinea capitis occur in school children yearly in Uganda. There are approximately 800 HIV-positive adults with Pneumocystis jirovecii pneumonia (PJP) annually and up to 42 000 children with PJP per year. There are an estimated 4000 cryptococcal cases annually. There are an estimated 2.5 million fungal infections per year in Uganda. Cryptococcus and PJP cause around 28,000 deaths in adults and children per year. We propose replicating the model of research around cryptococcal disease to investigate and development management strategies for other fungal diseases in Uganda.

'If at first you don't succeed, try again'. Looking beyond the initial results of a failed tuberculosis diagnosis.

We report the outcome of investigations conducted in 73 human immunodeficiency virus (HIV) infected Ugandan adults presumed to have pulmonary tuberculosis (PTB). Following initial investigations, 32 of 73 patients were diagnosed with PTB. Of the remaining 41 patients initially classified as 'non-PTB', six had a delayed PTB diagnosis after a median of 6 weeks. Of the six patients lost to follow-up, four (66%) were reported to have died. Active tracking and close monitoring of HIV-infected patients presumed to have PTB independently of initial investigation results may reduce morbidity and mortality among this vulnerable patient group.

Nous rapportons le résultat d'investigations réalisées chez 73 adultes Ougandais positifs au virus de l'immunodéficience humaine (VIH) et présumés d'avoir une tuberculose pulmonaire (TBP). Après les investigations initiales, 32 de 73 patients ont eu un diagnostic de TBP. Sur les 41 patients restants initialement classés comme « pas de TBP ¼, six ont eu un diagnostic de TBP retardé après un délai médian de 6 semaines. Sur les six patients perdus de vue, quatre (66%) sont décédés. Une recherche active et un suivi rapproché des patients VIH positifs présumés d'avoir une TBP indépendamment des résultats des investigations initiales pourrait réduire la morbidité et la mortalité dans ce groupe de patients vulnérables.

En el presente artículo se comunican los resultados de las investigaciones realizadas en 73 adultos ugandeses aquejados de infección por el virus de la inmunodeficiencia humana (VIH), en quienes existía la presunción clínica de tuberculosis pulmonar (TBP). Tras los exámenes iniciales se emitió el diagnóstico de TBP en 32 de los 73 pacientes. De los 41 pacientes restantes, clasificados inicialmente 'sin TBP', este diagnóstico se estableció de manera tardía en seis de ellos y la mediana del plazo hasta el diagnóstico fue 6 semanas. Se notificó la defunción de cuatro de los seis pacientes perdidos de vista durante el seguimiento (66%). La localización activa y el seguimiento estrecho de los pacientes con infección por el VIH y presunción clínica de TBP, sea cual fuere el resultado de las investigaciones iniciales, disminuirían la morbilidad y mortalidad en este grupo de pacientes vulnerables.

Factors before enrolment are associated with being removed from a Pharmacy-only Refill Programme at a large urban HIV/AIDS clinic, Uganda.

A Pharmacy-only Refill Programme (PRP) a type of task shifting in which stable HIV-positive patients are managed through pharmacy-only visits instead of physician visits. We performed a study to identify factors for being removed from the PRP in order to establish better referral criteria. The study was performed at the Infectious Disease Clinic (IDC) in Kampala, Uganda. We selected a random sample of 588 patients from 2431 patients on antiretroviral therapy referred to the PRP at least 12 months before commencement of the PRP evaluation. We compared the characteristics of patients who during 12 months of follow-up were removed from the PRP with those who continued to be followed up. Data were abstracted from the IDC data base, the pharmacy register and the patient clinical notes. Of 588 patients, 106 (18%) were removed from the PRP. In multivariate analysis, less than 100% self-reported adherence to antiretroviral therapy, missing at least one scheduled appointment in the six months before referral to the PRP and being on a lopinavir/ritonavir-containing regimen were independently associated with being removed from the PRP. Criteria for referring patients to a PRP should focus on antiretroviral therapy adherence and appointment keeping. Patients on a lopinavir/ritonavir-containing regimen should not be targeted for a PRP. On the other hand a PRP is an efficient strategy that targets stable adherent patients in clinics with high patient load.

Using a clinic based creativity initiative to reduce HIV related stigma at the Infectious Diseases Institute, Mulago National Referral Hospital, Uganda.

BACKGROUND: Stigma has been associated with chronic health conditions such as HIV/AIDS, leprosy, tuberculosis, Mental illness and Epilepsy. Different forms of stigma have been identified: enacted stigma, perceived stigma, and self stigma. Stigma is increasingly regarded as a key driver of the HIV/AIDS epidemic and has a major impact on public health interventions. OBJECTIVES: The initiative was to provide activities in the clinic while patients waited to be seen by healthcare professionals. It was envisaged this would contribute to reduction of clinic based stigma felt by clients. METHODS: This was a repeated cross-sectional survey (October-November 2005 and March-April 2007) that was conducted at the Infectious Diseases Institute clinic (IDC) at Mulago, the national referral hospital in Uganda. We utilized quantitative (survey) and qualitative (key informants, focus group discussions) methods to collect the data. Data were collected on stigma before the creativity initiative intervention was implemented, and a second phase survey was conducted to assess effectiveness of the interventions. RESULTS: Clients who attended the IDC before the creativity intervention were about twice as likely to fear catching an infection as those who came after the intervention. The proportion that had fears to be seen by a friend or relative at the clinic decreased. Thus during the implementation of the Creativity intervention, HIV related stigma was reduced in this clinic setting. CONCLUSIONS: The creativity intervention helped to build self esteem and improved communication among those attending the clinic; there was observed ambiance at the clinic and clients became empowered, with creative, communication and networking skills. Improved knowledge and communication are key in addressing self stigma among HIV positive individuals.

Earlier initiation of antiretroviral therapy, increased tuberculosis case finding and reduced mortality in a setting of improved HIV care: a retrospective cohort study.

OBJECTIVES: High early mortality after antiretroviral therapy (ART) initiation in resource-limited settings is associated with low baseline CD4 cell counts and a high burden of opportunistic infections. Our large urban HIV clinic in Uganda has made concerted efforts to initiate ART at higher CD4 cell counts and to improve diagnosis and care of patients coinfected with tuberculosis (TB). We sought to determine associated treatment outcomes. METHODS: Routinely collected data for all patients who initiated ART from 2005 to 2009 were analysed. Median baseline CD4 cell counts by year of ART initiation were compared using the Cuzick test for trend. Mortality and TB incidence rates in the first year of ART were computed. Hazard ratios (HRs) were calculated using multivariable Cox proportional hazards models. RESULTS: First-line ART was initiated in 7659 patients; 64% were women, and the mean age was 37 years (standard deviation 9 years). Median baseline CD4 counts increased from 2005 to 2009 [82 cells/µL (interquartile range (IQR) 24, 153) to 148 cells/µL (IQR 61, 197), respectively; P<0.001]. The mortality rate fell from 6.5/100 person-years at risk (PYAR) [95% confidence interval (CI) 5.5-7.6 PYAR] to 3.6/100 PYAR (95% CI 2.2-5.8 PYAR). TB incidence rates increased from 8.2/100 PYAR (95% CI 7.1-9.5 PYAR) to 15.6/100 PYAR (95% CI 12.4-19.7 PYAR). A later year of ART initiation was independently associated with decreased mortality (HR 0.91; 95% CI 0.83-1.00; P=0.04). CONCLUSIONS: Baseline CD4 cell counts have increased over time and are associated with decreased mortality. Additional reductions in mortality might be a result of a better standard of care and increased TB case finding. Further efforts to initiate ART earlier should be prioritized even in a setting of capped or reduced funding for ART programmes.

Improvement of the patient flow in a large urban clinic with high HIV seroprevalence in Kampala, Uganda.

Antiretroviral treatment roll-out programmes in Africa often have difficulties to cope with the increasing number of clients. Based on the findings of a survey carried out in 2005 that showed long waiting times, innovative organizational changes (nurse visits and pharmacy-only refill visits) were introduced in our clinic. In August 2007, the survey was repeated to evaluate the impact of these changes. During both surveys we used the same standardized questionnaire. In 2007, 400 patients visited the clinic on the study day compared to 250 in 2005. The median time spent at the clinic decreased from 157 minutes in 2005 (range 22-426) to 124 minutes (15-314). All the waiting times for different services decreased except the time between the visit to the triage nurse and the doctors' visit. A similar methodology could be used by other health services to evaluate and compare different models of care.

A Case report: Herpes zooster IRIS in pregnancy.

Pregnant women are increasingly being initiated on antiretroviral therapy either as part of prevention of mother to child transmission of HIV or as purely highly active antiretroviral therapy.In this case report, we describe a 26 year old woman who was 28 weeks pregnant and who presented after 4 weeks of initiation of antiretroviral therapy with a herpes zoster eruption and how the case was managed at the Infectious Diseases Institute, Kampala, Uganda.

The Spectrum of Liver Diseases in HIV Infected Individuals at an HIV Treatment Clinic in Kampala; Uganda

Background: Liver diseases are common in patients with HIV due to viral hepatitis B and C co-infections; opportunistic infections or malignancies; antiretroviral drugs and drugs for opportunistic infections. Objective: To describe the spectrum of liver diseases in HIV-infected patients attending an HIV clinic in Kampala; Uganda. Method: Consecutive patients presenting with jaundice; right upper quadrant pain with fever or malaise; ascites and/or tender hepatomegaly were recruited and underwent investigations to evaluate the cause of their liver disease. Results: Seventy-seven consecutive patients were recruited over an eleven month period. Of these; 23 (30) had increased transaminases because of nevirapine (NVP) and/or isoniazid (INH) hepatotoxicity. Although 14 (61) patients with drug-induced liver disease presented with jaundice; all recovered with drug discontinuation. Hepatitis B surface antigen was positive in 11 (15) patients while anti-hepatitis C antibody was reactive in only 2 (3). Probable granulomatous hepatitis due to tuberculosis was diagnosed in 7 (9) patients and all responded to anti-TB therapy. Other diagnoses included alcoholic liver disease; AIDS cholangiopathy; hepatocellular carcinoma; schistosomiasis; haemangioma and hepatic adenoma. Twelve (16) patients died during follow-up of which 7 (9) died because of liver disease. Conclusion: Drug history; liver enzyme studies; ultrasound; and hepatitis B and C investigations identified the probable etiology in 60 (78) of 77 patients with HIV infection presenting with symptoms and/or signs of liver disease

Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources.

Mycobacterium tuberculosis infection accounts for probably one third of human immunodeficiency virus (HIV) related immune reconstitution inflammatory syndrome (IRIS) events, particularly in developing countries where HIV and tuberculosis (TB) co-infection is very common. Small cohort studies of HIV-positive patients with active TB treated with antiretroviral therapy (ART) suggest an incidence of TB IRIS varying between 11% and 45%. Risk factors for TB IRIS that have been suggested in certain studies but not in others include: starting ART within 6 weeks of starting TB treatment; extra-pulmonary or disseminated disease; a low CD4+ lymphocyte count and a high viral load at the start of ART; and a good immunological and virological response during highly active antiretroviral therapy (HAART). It is important to agree on a clinical case definition of TB IRIS that could be used in resource-limited settings. Such a case definition could be used to determine the exact incidence and consequences of TB IRIS and would be valuable worldwide in clinical trials that are needed to answer questions on how this phenomenon could be prevented and treated.