Building communities of practice through case-based e-learning to prevent and manage TB among people living with HIV-India.

BACKGROUND: Co-management of HIV-TB coinfection remains a challenge globally. Addressing TB among people living with HIV (PLHIV) is a key priority for the Government of India (GoI). In 2016, GoI implemented single-window services to prevent and manage TB in PLHIV. To strengthen HIV-TB service delivery, case-based e-learning was introduced to health care providers at Antiretroviral Therapy centres (ARTc). METHODS: We implemented a hub and spoke model to deliver biweekly, virtual, case-based e-learning at select ARTc (n = 115), from four states of India-Delhi, Uttar Pradesh, Andhra Pradesh and Tamil Nadu. We evaluated feasibility and acceptability of case-based e-learning and its impact on professional satisfaction, self-efficacy, knowledge retention using baseline and completion surveys, session feedback, pre-and post-session assessments. We reviewed routine programmatic data and patient outcomes to assess practices among participating ARTc. RESULTS: Between May 2018 and September 2020, 59 sessions were conducted with mean participation of 55 spokes and 152 participants. For 95% and 88% of sessions ≥ 80% of respondents agreed that topics were clear and relevant to practice, and duration of session was appropriate, respectively. Session participants significantly improved in perceived knowledge, skills and competencies (+ 8.6%; p = 0.025), and technical knowledge (+ 18.3%; p = 0.04) from baseline. Participating ARTc increased TB screening (+ 4.2%, p < 0.0001), TB diagnosis (+ 2.7%, p < 0.0001), ART initiation (+ 4.3%, p < 0.0001) and TB preventive treatment completion (+ 5.2%, p < 0.0001). CONCLUSION: Case-based e-learning is an acceptable and effective modus of capacity building and developing communities of practice to strengthen integrated care. E-learning could address demand for accessible and sustainable continuing professional education to manage complex diseases, and thereby enhance health equity. We recommend expansion of this initiative across the country for management of co-morbidities as well as other communicable and non-communicable diseases to augment the existing capacity building interventions by provide continued learning and routine mentorship through communities of practice.

Clinicodemographic profile and outcome of tuberculosis treatment in TB-HIV co-infected patients receiving daily ATT under a single window TB/HIV services delivery initiative.

The risk of death in HIV-TB coinfected individuals is far greater than in HIV-only patients. It is critical to provide timely and appropriate therapy in HIV-TB coinfected patients in order to reduce morbidity and mortality. The purpose of this study was to evaluate the clinical presentation and outcome of TB treatment in HIV-TB co-infected patients receiving daily anti-tubercular therapy (ATT) and concurrent antiretroviral therapy (ART) at a tertiary respiratory care centre in New Delhi, India. The research was cross-sectional, observational, and hospital-based A. From September 2018 to August 2019, a total of 53 patients with HIV-TB coinfection were enrolled at the Institute's ART centre. Patients were evaluated with a structured proforma. Data were evaluated using SPSS version 23.0 and p-value of less than 0.05 was considered statistically significant. Among the patients enrolled, the mean age was 35.98 years. Among the patients enrolled, 56.6% patients had EPTB, 32% had PTB and 11.3% had both PTB and EPTB. The majority of the enrolled patients (n=46, 86.7%) had favourable TB treatment outcomes, while 13.3% (n=7) had unfavourable outcome [including death (n=5) and loss to follow up (n=2)]. During the study and follow-up period, no patients transferred out or relapsed. In univariate analysis, low SES, bedridden functional status, low BMI, anaemia, hypoalbuminemia, and a low CD-4 cell count (<100 cells/mm3 were significantly associated with an unfavourable outcome. Bedridden functional status (p=0.002), anaemia (p=0.040), and low BMI (p<0.001) were independently associated with a poor outcome. Adequate disease knowledge and health education can be very beneficial in reducing morbidity and mortality. Early ART in combination with ATT can reduce mortality in TB-HIV co-infected patients.

Effectiveness of isoniazid preventive therapy on incidence of tuberculosis among HIV-infected adults in programme setting.

BACKGROUND & OBJECTIVES: As India and other developing countries are scaling up isoniazid preventive therapy (IPT) for people living with HIV (PLHIV) in their national programmes, we studied the feasibility and performance of IPT in terms of treatment adherence, outcome and post-treatment effect when given under programmatic settings. METHODS: A multicentre, prospective pilot study was initiated among adults living with HIV on isoniazid 300 mg with pyridoxine 50 mg after ruling out active tuberculosis (TB). Symptom review and counselling were done monthly during IPT and for six-month post-IPT. The TB incidence rate was calculated and risk factors were identified. RESULTS: Among 4528 adults living with HIV who initiated IPT, 4015 (89%) successfully completed IPT. IPT was terminated in 121 adults (3%) due to grade 2 or above adverse events. Twenty five PLHIVs developed TB while on IPT. The incidence of TB while on IPT was 1.17/100 person-years (p-y) [95% confidence interval (CI) 0.8-1.73] as compared to TB incidence of 2.42/100 p-y (95% CI 1.90-3.10) during the pre-IPT period at these centres (P=0.017). The incidence of TB post-IPT was 0.64/100 p-y (95% CI 0.04-1.12). No single factor was significantly associated with the development of TB. INTERPRETATION & CONCLUSIONS: Under programmatic settings, completion of IPT treatment was high, adverse events minimal with good post-treatment protection. After ruling out TB, IPT should be offered to all PLHIVs, irrespective of their antiretroviral therapy (ART) status. Scaling-up of IPT services including active case finding, periodic counselling on adherence and re-training of ART staff should be prioritized to reduce the TB burden in this community.

Role of routine abdominal ultrasonography in intensified tuberculosis case finding algorithms at HIV clinics in high TB burden settings.

BACKGROUND: High proportion of TB in people living with HIV (PLHIV) is undiagnosed. Due to this active TB case finding is recommended for HIV clinics in high TB burden countries. Presently sputum examination and chest radiography are frontline tests recommended for HIV infected TB presumptives. Abdominal TB which occurs frequently in PLHIV may be missed even by existing programmatic intensified case finding protocols. This study evaluated the routine use of ultrasonography (USG) for active case finding of abdominal TB in HIV clinics. METHODS: Retrospective analysis of eight years' data from an HIV Clinic in a TB hospital in India. Patients underwent chest x-ray, sputum examination, USG abdomen and routine blood tests at entry to HIV care. Case forms were scrutinized for diagnosis of TB, USG findings and CD4 cell counts. Abdominal TB was classified as probable or possible TB. Probable TB was based on presence of two major USG (abdomen) findings suggestive of active TB, or one major USG finding with at least two minor USG findings or at least two symptoms, or any USG finding with microbiologically confirmed active TB at another site. Possible TB was based on the presence of one major USG finding, or the presence of two minor USG findings with at least two symptoms. Bacteriological confirmation was not obtained. RESULTS: Eight hundred and eighty-nine people PLHIV underwent a baseline USG abdomen. One hundred and thirteen of 340 cases already diagnosed with TB and 87 of the 91 newly diagnosed with TB at time of HIV clinic registration had abdominal TB. Non-abdominal symptoms like weight loss, fever and cough were seen in 53% and 22% cases had no symptoms at all. Enlarged abdominal lymph nodes with central caseation, ascitis, splenic microabsesses, bowel thickening and hepatosplenomegaly were the USG findings in these cases. CONCLUSIONS: Abdominal TB is a frequent TB site in PLHIV presenting with non-abdominal symptoms. It can be easily detected on basis of features seen on a simple abdominal ultrasound. Abdominal USG should be essential part of intensified TB case finding algorithms for HIV infected people living in high TB burden settings.

The relationships between perceived organizational support, affective commitment, psychological contract breach, organizational citizenship behaviour and work engagement.

AIM: This study examines the factors that mediate and moderate the relationships of perceived organizational support with work engagement and organization citizenship behaviour. Specifically, affective commitment is posited to mediate and psychological contract breach to moderate the above relationships. BACKGROUND: Nurses play a critical role in delivering exemplary health care. For nurses to perform at their best, they need to experience high engagement, which can be achieved by providing them necessary organizational support and proper working environment. DESIGN: Data were collected via a self-reported survey instrument. METHODS: A questionnaire was administered to a random sample of 750 nurses in nine large hospitals in India during 2013-2014. Four hundred and seventy-five nurses (63%) responded to the survey. Hierarchical multiple regression was used for statistical analysis of the moderated-mediation model. RESULTS: Affective commitment was found to mediate the positive relationships between perceived organizational support and work outcomes (work engagement, organizational citizenship behaviour). The perception of unfulfilled expectations (psychological contract breach) was found to moderate the perceived organizational support-work outcome relationships adversely. CONCLUSION: The results of this study indicate that perceived organizational support exerts its influence on work-related outcomes and highlight the importance of taking organizational context, such as perceptions of psychological contract breach, into consideration when making sense of the influence of perceived organizational support on affective commitment, work engagement and citizenship behaviours of nurses.

Effectiveness of symptom screening and incidence of tuberculosis among adults and children living with HIV infection in India.

BACKGROUND: WHO recommends the use of a simplified symptom-based algorithm for screening for tuberculosis (TB) among people living with HIV (PLHIV). We assessed the feasibility and effectiveness of this algorithm and determined the prevalence and incidence of TB among PLHIV attending antiretroviral treatment (ART) centres in India. METHODS: We did a prospective multicentric implementation research study in four states of India. To rule out TB, we administered the WHO symptom-screen algorithm to all PLHIV every month for 6 months. If they were found to be symptomatic any time during this period, they were referred for investigations for TB. A case of TB diagnosed during the first month of screening was taken as a prevalent case while those detected TB in the subsequent 5 months were considered cases of incident TB. We calculated the incidence rate using the person-years method. Results . Between May 2012 and October 2013, a total of 6099 adults and 1662 children living with HIV were screened for TB at the ART centres of four states. Of the 6099 adult PLHIV, 1815 (30%) had at least one symptom suggestive of TB, of whom only 634 (35%) were referred for investigations of TB. Of those referred, 97 (15%) PLHIV were diagnosed with TB. Overall, the prevalence of undiagnosed TB was 0.84 person-years and in the subsequent period, the incidence of TB was 2.4/100 person-years (95% CI 1.90-3.10). Among 1662 children, 434 (26%) had at least one symptom suggestive of TB. But only 57 (13%) children were referred for investigations of TB and 13 (23%) of them were diagnosed with TB. The prevalence of TB among children was 0.5% and its incidence among them was 2.7/100 person-years (95% CI 1.60-4.30). CONCLUSION: Prevalence and incidence of TB is high among PLHIV attending ART centres. This emphasizes the need to strengthen regular screening for symptoms of TB and further referral of those symptomatic for diagnosis of TB.

Tuberculosis associated immune reconstitution inflammatory syndrome in patients infected with HIV: meningitis a potentially life threatening manifestation.

BACKGROUND: Tuberculosis (TB) is the most common co infection in HIV-infected persons in India, requiring concomitant administration of anti TB and antiretroviral therapies. Paradoxical worsening of tuberculosis after anti-retroviral therapy (ART) initiation is frequently seen. OBJECTIVE: To study the frequency, clinical presentation and outcome of paradoxical tuberculosis associated immune reconstitution inflammatory syndrome (TB-IRIS) in HIV infected patients in a TB hospital in North India. DESIGN: A retrospective chart review of HIV-infected TB patients on anti-tubercular treatment (ATT) at time of ART initiation over a 3 year period. Medical records were reviewed for clinical manifestations and outcome in patients who developed TB-IRIS. RESULTS: 514 HIV-infected patients were enrolled between January 2006 and December 2008. Thirteen (12.6%) of 103 patients who had received ART and ATT simultaneously developed paradoxical TB-IRIS. Clinical presentations of paradoxical TB-IRIS included new lymphadenopathy (n = 3), increase in size of existing lymphadenopathy (n = 3), worsening of existing pulmonary lesions (n = 2), appearance of new pleural effusion (n = 1) and prolonged high grade fever (n = 2). Four patients developed new tubercular meningitis as manifestation of TB-IRIS. Our cases developed TB-IRIS a median of 15 days after starting ART (IQR 15-36). TB-IRIS patients were older (> 35 years) than those with no IRIS (P = 0.03), but were not distinguishable by CD4 T-cell count, duration of ATT before ART or the outcome of TB treatment. Eight (62%) patients had a complete recovery while 5 (38%) patients with TB-IRIS died, of which majority (n = 3) had meningitis. CONCLUSIONS: Paradoxical TB-IRIS is a frequent problem during concomitant ATT and ART in HIV-TB co infected patients in north India. Meningitis is a potentially life threatening manifestation of TB-IRIS.

Immune restoration diseases reflect diverse immunopathological mechanisms.

Up to one in four patients infected with human immunodeficiency virus type 1 and given antiretroviral therapy (ART) experiences inflammatory or cellular proliferative disease associated with a preexisting opportunistic infection, which may be subclinical. These immune restoration diseases (IRD) appear to result from the restoration of immunocompetence. IRD associated with intracellular pathogens are characterized by cellular immune responses and/or granulomatous inflammation. Mycobacterial and cryptococcal IRD are attributed to a pathological overproduction of Th1 cytokines. Clinicopathological characteristics of IRD associated with viral infections suggest different pathogenic mechanisms. For example, IRD associated with varicella-zoster virus or JC polyomavirus infection correlate with a CD8 T-cell response in the central nervous system. Exacerbations or de novo presentations of hepatitis associated with hepatitis C virus (HCV) infection following ART may also reflect restoration of pathogen-specific immune responses as titers of HCV-reactive antibodies rise in parallel with liver enzymes and plasma markers of T-cell activation. Correlations between immunological parameters assessed in longitudinal sample sets and clinical presentations are required to illuminate the diverse immunological scenarios described collectively as IRD. Here we present salient clinical features and review progress toward understanding their pathogeneses.

"99DOTS"techno-supervision for tuberculosis treatment - A boon or a bane? Exploring challenges in its implementation at a tertiary centre in Delhi, India.

BACKGROUND: In India, daily regimen with fixed-dose combination along with 99DOTS adherence tool and one-stop service at Anti-Retroviral Treatment (ART) centres for HIV infected Tuberculosis (TB) patients was launched in 2017. No systematic evaluation of its implementation has been done so far in a tertiary care setting in urban India. METHODS: A mixed-methods study was conducted at National Institute of Tuberculosis and Respiratory Diseases, Delhi in 2018-19. Missed doses, average adherence and treatment outcomes were compared across 99DOTS dashboard and TB treatment card. In-depth interviews of patients and health care providers were conducted to explore the implementation challenges and benefits. RESULTS: Median of missed doses recorded during intensive and continuation phase were 56 and 68 respectively in 99DOTS as compared to 0 in the TB Treatment card (p<0.0001). Average adherence was observed to be 27% in 99DOTS versus 99% in the TB treatment card (p<0.0001). Technical issues like software malfunction, logistic difficulties such as missing custom envelops and patient's inability to give call were reported. Role clarity among ART and TB program staff was ambiguous, which contributed to poor information flow between them. Patient benefits such as reduced stigma, less travel costs and reduced work absenteeism were reported. CONCLUSION: Success of 99DOTS program under programmatic condition needs webtool stability, uninterrupted logistic supplies (envelops), training of staff and better coordination between TB and HIV program personnel. Despite the challenges in its implementation, the benefit of this tool in terms of greater convenience and reduced stigma for patients is encouraging.

Profile of HIV associated tuberculosis at a tertiary institute in setting of free anti-retroviral therapy.

SETTING: With the rollout of the national program, free of cost antiretroviral therapy is available to the Indian population since 2004, resulting in sea change in outcome of HIV associated tuberculosis. OBJECTIVE: To assess the presentation and outcome in patients being treated for concurrent TB and HIV. DESIGN: Retrospective analysis of data from standardized patient records. RESULTS: Seventy-three (29.1%) of the 251 HIV infected patients, who reported to the ART centre at LRS Institute of TB and Respiratory Diseases, New Delhi, between January 2006 and June 2007, were diagnosed with concurrent active tuberculosis. The mean CD4 count at presentation was 108.2 cells/microl and 87.6% patients had CD4 counts less than 200 cells/microl. 38.4% patients had purely pulmonary tuberculosis, 39.7% had purely extra-pulmonary tuberculosis and 21.9% had both. Sputum positivity in those with pulmonary involvement was 34.1%. Immune reconstitution inflammatory syndrome was seen in 20.5% patients. 67.2% patients had a favorable outcome (cure and treatment completed). 17.8% case fatality was observed in the study period. CONCLUSION: Despite severe immune suppression, treatment with ATT and ART leads to an improved outcome in patients with concurrent HIV and TB.

A gastric resident drug delivery system for prolonged gram-level dosing of tuberculosis treatment.

Multigram drug depot systems for extended drug release could transform our capacity to effectively treat patients across a myriad of diseases. For example, tuberculosis (TB) requires multimonth courses of daily multigram doses for treatment. To address the challenge of prolonged dosing for regimens requiring multigram drug dosing, we developed a gastric resident system delivered through the nasogastric route that was capable of safely encapsulating and releasing grams of antibiotics over a period of weeks. Initial preclinical safety and drug release were demonstrated in a swine model with a panel of TB antibiotics. We anticipate multiple applications in the field of infectious diseases, as well as for other indications where multigram depots could impart meaningful benefits to patients, helping maximize adherence to their medication.

Clinical profile and diagnosis of extrapulmonary tb in HIV infected patients: routine abdominal ultrasonography increases detection of abdominal tuberculosis.

OBJECTIVE: To study the clinical profile and assess the utility of the procedures performed for the diagnosis of extrapulmonary TB (EPTB) in HIV patients. DESIGN: Prospective observational study of HIV patients suspected to have EPTB. RESULTS: Two hundred and thirty HIV-infected patients were enrolled over 18 months. Of them, 87 cases had active TB, 60 (69%) of whom were of EPTB. Major presenting symptoms were fever (93.3%), weight loss (80%) and cough (61.6%). The most common site of active EPTB was the abdomen (70%), which could be detected due to routine use of abdominal ultrasonography, followed by CT scans in inconclusive cases. Peripheral lymph node (22%), pleura (15%), CNS involvement (3%) and one case each of psoas abscess and mediastinal lymphadeopathy were the other extra-pulmonary sites seen. Diagnosis of peripheral lymph node and pleural TB was based on cytological and mycobacterial examinations. Direct smear examinations were positive for AFB in 11 of 24 samples and mycobacterial cultures were positive in five of 18 samples. The median CD4 cell count in our HIV-EIPTB cases was 126 cells/micro1 (IQR=79.5-205.75). There was no statistical difference in the baseline CD4 cell counts in patients with PTB vs EPTB (p=0.70), single vs multiple extra-pulmonary site involvement (p=0.57), and AFB positive vs AFB negative EPTB cases (p=0.51). CONCLUSIONS: EPTB is the most common form of TB in HIV patients with low CD4 cell counts. Fever, weight loss and cough are common presenting symptoms of EPTB. Routine abdominal ultrasonography followed by an abdominal CT scan in inconclusive cases can significantly increase the detection of abdominal TB.

The search for a genetic factor associating with immune restoration disease in HIV patients co-infected with Mycobacterium tuberculosis.

BACKGROUND: Up to 43% of HIV-infected patients co-infected with Mycobacterium tuberculosis experience exacerbations of tuberculosis (TB) after commencing antiretroviral therapy (ART). These are termed immune restoration disease (IRD). It is unclear why individual susceptibility varies. OBJECTIVE: We investigate if single nucleotide polymorphisms (SNP) in genes encoding cytokines, chemokines and their receptors associate with development of an IRD event in patients of two different ethnicities. METHODS: DNA samples were available from small well-characterised groups of HIV patients treated in Cambodia (TB-IRD, n=17; HIV(+)TB(+) controls, n=55) and India (TB-IRD, n=19; HIV(+)TB(+) controls, n= 43). HIV patients with a TB diagnosis but no evidence of IRD were included to control for susceptibility to TB per se. Sixteen SNP implicated in inflammation or mycobacterial disease were genotyped. RESULTS: Susceptibility to TB-IRD associated with carriage of TNFA-1031*T (rs1799964; P=0.05) and SLC11A1 D543N*G (rs17235409; P=0.04) in Cambodian patients and carriage of IL18-607*G (rs1946518; P=0.02) and VDR FokI (F/f)*T (rs10735810; P=0.05) in Indian patients. CONCLUSIONS: Associations between polymorphisms in immune-related genes and TB-IRD were found, but none were common across two ethnicities.

Short communication: Plasma levels of vitamin D in HIV patients initiating antiretroviral therapy do not predict immune restoration disease associated with Mycobacterium tuberculosis.

Immune restoration disease associated with Mycobacterium tuberculosis (TB IRD) is clinically important among HIV patients commencing antiretroviral therapy in countries where tuberculosis is endemic. Vitamin D affects dendritic cell and T cell function and the antimicrobial activity of monocytes. Plasma levels of vitamin D and polymorphisms in the vitamin D receptor may affect tuberculosis, and HIV infection associates with vitamin D deficiency. Here we assess whether plasma vitamin D levels may predict TB IRD. Samples were available from prospective studies of TB IRD in Cambodia (26 cases), India (19 cases), and South Africa (29 cases). IRD cases and controls from each site were similar in age and baseline CD4(+) T cell count. Plasma samples were assessed using 25(OH) vitamin D immunoassay plates. DNA samples were available from a subset of patients and were genotyped for the VDR FokI (F/f) [C/T, rs10735810] SNP. When data from each cohort were pooled to assess ethnic/geographic differences, 25(OH)D levels were higher in Cambodian than Indian or South African patients (p<0.0001) and higher in South African than Indian patients (p<0.0001). TB IRD was not associated with differences in levels of 25(OH)D in any cohort (p=0.36-0.82), irrespective of the patients' prior TB diagnoses/treatment. Carriage of the minor allele of VDR FokI (F/f) was marginally associated with TB IRD in Indian patients (p=0.06) with no association in Cambodians. Neither plasma levels of vitamin D nor the vitamin D allele will usefully predict TB IRD in diverse populations from TB endemic regions.

HIV-TB: the 'cursed duet'.

Tuberculosis is the most common infection among HIV-infected patients in India. More deaths were reported due to tuberculosis in AIDS patients in pre-antiretroviral therapy era. HIV is the strongest of all known, risk factors for the development of TB. Tuberculosis can develop at any stage of the HIV disease. Extrapulmonary tuberculosis is more common and constitues half of the cases in HIV-infected individual with TB. Hilar lymphadenopathy is frequently observed. TB in HIV frequently poses a diagnostic challenge. Acid-fast bacillus demonstration on sputum smear microscopy is the main-stay laboratory investigation for TB. In addition to antituberculous therapy, antiretroviral therapy must be initiated in HIV-infected individual with TB. Early referrals to the RNTCP and ART programmes are the best option for management.

Mycobacterial antibody levels and immune restoration disease in HIV patients treated in South East Asia.

AIM: Immune restoration disease (IRD) associated with Mycobacterium tuberculosis parallels the reconstitution of a pathogen-specific Th1 response. However, it is not clear whether humoral responses to M. tuberculosis antigens also rise, or whether antibody levels predict IRD. Here, humoral immunity to M. tuberculosis antigens was investigated in four Asian cohorts. METHODS: Plasma samples were obtained from longitudinal prospective studies of HIV patients beginning antiretroviral therapy (ART) in New Delhi (India), Kuala Lumpur (Malaysia), Jakarta (Indonesia) and Phnom Penh (Cambodia). IgG antibodies to purified protein derivative, lipoarabinomannan and 38-kDa antigens of M. tuberculosis were quantitated using in-house ELISAs. IRD was defined as exacerbated symptoms of tuberculosis in patients on anti-tuberculosis therapy or a novel presentation of tuberculosis on ART. RESULTS: Pre-ART IgG levels to purified protein derivative, lipoarabinomannan and 38-kDa antigen were similar in the IRD and control groups from each site. Compared with non-IRD controls, a higher proportion of IRD patients had elevated IgG levels to lipoarabinomannan (defined as a greater than twofold increase) over 12 weeks of ART. However, this trend was not significant for the other antigens and longitudinal analyses did not reveal clear rises in antibody levels at the time of IRD. CONCLUSION: Levels of antibody to mycobacterial antigens do not predict IRD, but levels of antibody reactive with lipoarabinomannan rise during an IRD in some patients.