Mapping the tuberculosis scientific landscape among BRICS countries: a bibliometric and network analysis

BACKGROUND The five BRICS (Brazil, Russian, Indian, China, and South Africa) countries bear 49% of the world's tuberculosis (TB) burden and they are committed to ending tuberculosis. OBJECTIVES The aim of this paper is to map the scientific landscape related to TB research in BRICS countries. METHODS Were combined bibliometrics and social network analysis techniques to map the scientific publications related to TB produced by the BRICS. Was made a descriptive statistical data covering the full period of analysis (1993-2016) and the research networks were made for 2007-2016 (8,366 records). The bubble charts were generated by VantagePoint and the networks by the Gephi 0.9.1 software (Gephi Consortium 2010) from co-occurrence matrices produced in VantagePoint. The Fruchterman-Reingold algorithm provided the networks' layout. FINDINGS During the period 1993-2016, there were 38,315 peer-reviewed, among them, there were 11,018 (28.7%) articles related by one or more authors in a BRICS: India 38.7%; China 23.8%; South Africa 21.1%; Brazil 13.0%; and Russia 4.5% (The total was greater than 100% because our criterion was all papers with at least one author in a BRICS). Among the BRICS, there was greater interaction between India and South Africa and organisations in India and China had the highest productivity; however, South African organisations had more interaction with countries outside the BRICS. Publications by and about BRICS generally covered all research areas, especially those in India and China covered all research areas, although Brazil and South Africa prioritised infectious diseases, microbiology, and the respiratory system. MAIN CONCLUSIONS An overview of BRICS scientific publications and interactions highlighted the necessity to develop a BRICS TB research plan to increase efforts and funding to ensure that basic science research successfully translates into products and policies to help end the TB epidemic.

National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, 2017: A commentary

The Indian Council of Medical Research (ICMR) has been at the forefront in setting up the ethical guidance for the conduct of biomedical and health research in India. The latest version of National Guidelines for Biomedical and Health Research Involving Human Participants, 2017 was planned in order to provide a more detailed guidance to the existing topics in view of emerging ethical concerns and to add a number of newer areas in which guidance was lacking. The scope of the guidelines has been expanded to include socio-behavioural research related to health and research involving biological material and datasets. The guidelines have 12 sections which cover a wide range of topics and areas of research. The first six sections are more generic, applying to all types of biomedical and health research, while the next six sections are more subject specific. The guidelines have been revised in consultation with a large number of experts and stakeholders and went through an exhaustive process stretching over a period of two years in its drafting, review, consultation and finalisation. This commentary seeks to explain the process and key components of the Guidelines.

Undernutrition & tuberculosis in India: Situation analysis & the way forward.

Undernutrition and tuberculosis (TB) are linked and have a bidirectional relationship. Undernutrition increases the risk of TB which in turn, can lead to malnutrition. Undernutrition not only is a risk factor for progression of latent TB infection to active disease, but also increases the risk of drug toxicity, relapse and death once TB develops. The dietary intake of TB patients in the country is inadequate. Nutritional supplementation in patients with TB is associated with faster sputum conversion, higher cure and treatment completion rates, significant gain in body weight and body composition as well as better performance status. The Government of India has various social support schemes (including nutrition supplementation schemes) and policies, at the Centre as well as State levels. Here we discuss some successful examples and suggest a few solutions to address this gap; like considering TB patients as a vulnerable group for “Targeted Public Distribution System” and providing extra rations for the duration of treatment. Recommendations for the research community, civil societies, government organizations, non-governmental and corporate sector on the actions needed to achieve the goals of the End TB Strategy are also provided. Ultimately, reduction of TB burden in India and its elimination will require improving the nutritional status of the community as a whole.

Drug resistance among extrapulmonary TB patients: Six years experience from a supranational reference laboratory.

Background & objectives: There is limited information available about the drug resistance patterns in extrapulmonary tuberculosis (EPTB), especially from high burden countries. This may be due to difficulty in obtaining extrapulmonary specimens and limited facilities for drug susceptibility testing. This study was undertaken to review and report the first and second-line anti-TB drug susceptibility patterns in extrapulmonary specimens received at the National Institute for Research in Tuberculosis (NIRT), Chennai, India, between 2005 and 2012. Methods: Extrapulmonary specimens received from referring hospitals were decontaminated and cultured using standard procedures. Drug susceptibility testing (DST) for Mycobacterium tuberculosis was done by absolute concentration or resistance ratio methods for the first and the second line anti-TB drugs. Results: Between 2005 and 2012, of the 1295 extrapulmonary specimens, 189 grew M. tuberculosis, 37 (19%) cases were multidrug resistant (MDR) while one was extensively drug resistant (XDR). Specimen-wise MDR prevalence was found to be: CSF-10 per cent, urine-6 per cent, fluids and aspirates-27 per cent, pus-23 per cent, lymph nodes-19 per cent. Resistance to isoniazid and ethionamide was found to be high (31 and 38%, respectively). Interpretation & conclusions: Drug resistance including MDR-TB was observed in a significant proportion of extrapulmonary specimens referred for DST. Access to culture and DST for extrapulmonary specimens should be expanded. Guidelines for MDR-TB management should have explicit sections on extra-pulmonary tuberculosis and training on laboratory techniques is urgently required.

Outcome of Prevention of Parent-to-Child Transmission of HIV in an Urban Population in Southern India.

Objective: To analyze the outcomes of Prevention of Parent to Child Transmission (PPTCT) of HIV program in an urban Southern Indian setting. Design: Observational study. Setting: Anti-retroviral Therapy (ART) Centers/ Integrated Counseling and Testing Centers (ICTC) at four government Obstetrics Institutes in an urban area. Participants: 100 HIV-positive pregnant women and their infants delivered in the study centers. Methods: Triple drug ART to HIV-positive pregnant women was started for maternal indications only. Rest of the pregnant women were given single dose Nevirapine (200 mg) at the onset of labor. All infants were given single dose Nevirapine (2 mg/kg) prophylaxis, according to National AIDS Control Organization guidelines. Mothers were counseled regarding breastfeeding and artificial feeding, and the choice was left to them. Whole blood HIV 1 DNA PCR was done for all infants at 6 weeks of life. A second PCR was done at 6 months or 6 weeks after stopping breastfeeds. PCR-positive infants were started on ART, and were followed-up till18 months of life. Results: Four infants were PCR-positive for HIV. All of them were breastfed. They were born to mothers of HIV stage 1 or 2 who were not on ART as CD4 counts were >350 cells/mm3. Among the mothers in Stage 3 or 4 or CD4 count <200 cells/mm3 and on ART, none of the infants was HIV-positive. The cumulative HIV-free survival at 18 months was 94%. Conclusion: Parent-to-child transmission rate in HIV was low with the currently used strategies . Triple drug ART to mother reduces mother-to-child transmission despite advanced maternal stage or low CD4 counts.

Pulmonary tuberculosis among tribals in India: A systematic review & meta-analysis.

Background & objectives: There has been limited investigation on the prevalence of tuberculosis (TB) in tribal communities in India, a vulnerable section of Indian society. The lack of a population-based estimate prompted us to conduct a meta-analysis of existing studies to provide a single, population-based estimate of the TB prevalence for tribals. Methods: Literature search was conducted in PubMed using the keywords - “tuberculosis”, “tribals”, “India”, “prevalence”, and “survey”. References cited in the articles retrieved were also reviewed, and those found relevant were selected. TB prevalence rates estimated by the studies were used for our calculation of a pooled-estimate. Results: The pooled estimate, based on the random effects model, was 703 per 100,000 population with a 95 % CI of 386-1011. The associated heterogeneity measures in terms of Cochran’s Q was significant (p=0.08 <0.1) and I2 was moderate at 48 per cent. Interpretation & conclusions: The meta-analysis demonstrated a large variability in pulmonary TB prevalence estimates among the different studies with poor representation of the various tribal groups. The moderate level of heterogeneity found across the studies suggests that the pooled-estimate needs to be treated with caution. Our findings also highlight the need to assess the pulmonary TB burden in India.

Challenges in the Early Diagnosis of HIV Infection in Infants: Experience from Tamil Nadu, India.

Objective: To analyze critical steps in the testing algorithm of the National Early Infant Diagnosis (EID) program in India. Methods: A retrospective analysis of data on cases enrolled in the EID program during 2010-2012 from Tamil Nadu was undertaken. Results: 2745 dried blood spots were tested; 9% of these tested positive. Median age of infants at the time of testing was 4 months. Second specimen for confirmation was received from 67% of cases with a turn-around time of 10-270 days. Conclusions: Even with high levels of uptake into the program, huge delays and loss-to-follow-up observed between the first and second sampling, suggests need for revision of the current testing algorithm.

Lack of association between plasma levels of non-nucleoside reverse transcriptase inhibitors & virological outcomes during rifampicin co-administration in HIV-infected TB patients.

Background & objectives: Among patients with HIV-associated tuberculosis (TB), reduced plasma non-nucleoside reverse transcriptase inhibitors (NNRTI) concentrations during rifampicin (RMP) co-administration could lead to HIV treatment failure. This study was undertaken to examine the association between plasma nevirapine (NVP) and efavirenz (EFV) concentrations and virological outcomes in patients infected with HIV-1 and TB. Methods: This was a nested study undertaken in a clinical trial of patients with HIV-1 and TB, randomized to two different once-daily antiretroviral treatment (ART) regimens along with anti-TB treatment (ATT). Trough concentrations of plasma NVP and EFV were estimated at months 1 (during ATT and ART) and 6 months (ART only) by HPLC. Plasma HIV-1 RNA level >400 copies/ml or death within 6 months of ART were considered as unfavourable outcomes. Genotyping of CYP2B6 516G>T polymorphism was performed. Results: Twenty nine per cent of patients in NVP arm had an unfavourable outcome at 6 months compared to 9 per cent in EFV arm (P<0.08). The mean NVP and EFV levels estimated at 1 and 6 months did not significantly differ between favourable and unfavourable responders. Logistic regression analysis showed CYP2B6 516G>T polymorphism significantly associated with virologic outcome in patients receiving EFV–based regimen. Interpretation & conclusions: Trough plasma concentrations of NVP and EFV did not show any association with response to ART in patients on ATT and once-daily ART. CYP2B6 516G>T polymorphism was associated with virologic outcome among patients on EFV.

Serum Nevirapine and Efavirenz Concentrations and Effect of Concomitant Rifampicin in HIV Infected Children on Antiretroviral Therapy.

Objective: To determine factors affecting serum levels of Efavirenz and Nevirapine and analyze the effect of Rifampicin on Nevirapine drug levels. Methods: A cross-sectional study was conducted on 30 HIV infected children on Antiretroviral therapy (ART) with Nevirapine or Efavirenz. Patients on simultaneous Rifampicin and Nevirapine were given higher doses of Nevirapine with regular monitoring of liver function tests. Trough levels (before morning dose of Nevirapine) and levels after 2 hours of administration of Nevirapine and levels of Efavirenz were assessed using HPLC and were checked to see if they fall within the therapeutic range. Results: Thirty patients (14 males) were enrolled in the study with 20 on Nevirapine and 10 (33.3%) on Efavirenz. Seven (23.3%) patients were simultaneously taking rifampicin. The mean Nevirapine dose given to the patients was 350.9±59.8mg/m2/day (on simultaneous rifampicin) and 309.2±54.6mg/m2/day (not on concurrent rifampicin). Thirteen (81.3%) of the 16 patients with trough Nevirapine had values in the normal range, 1 (6.3%) had low Nevirapine trough levels and 2 (12.5%) had high Nevirapine trough levels. Of the post 2 hours Nevirapine levels, 1 (5%) had low levels and 3 (15%) had high Nevirapine blood levels. Factors like age (P=0.4, P=0.4087), nourishment (P=0.2679, P=0.4132), ART combination (P=0.4199, P=0.4132), form of the drug (tablet/syrup) (P=0.1964, P=0.4696) or if it was being given as single or in a fixed dose combination (P=0.4179, P=0.4696) and even concurrent rifampicin administration (P=0.284, P=0.472) did not significantly affect the trough and post 2 hours Nevirapine values, respectively. All the five patients being given concurrent rifampicin had normal trough and post 2 hours levels of Nevirapine. The Efavirenz drug levels were 1.9±1.1 g/mL. Of the 10 patients on Efavirenz, 2 (20%) had high and 1 (10%) had low blood levels. Conclusion: Concurrent Rifampicin administration does not alter blood levels of Nevirapine; provided the dose of Nevirapine is increased by 20-30%. Formulation of drugs does not alter the blood levels provided drug administered is in the recommended dose.

HIV in Indian MSM: Reasons for a concentrated epidemic & strategies for prevention.

Men who have sex with men (MSM) in India are disproportionately likely to be HIV-infected, and face distinct psychosocial challenges. Understanding the unique socio-cultural issues of MSM in India and how they relate to HIV risk could maximize the utility of future prevention efforts. This review discusses: (i) the importance of addressing co-occurring mental health issues, such as depression, which may interfere with MSM’s ability to benefit from traditional risk reduction counselling, (ii) reducing HIV-related stigma among health providers, policymakers and the lay public, and (iii) the role for nongovernmental organizations that work with the community to play in providing culturally relevant HIV prevention programmes for MSM.

Diagnosis & treatment of tuberculosis in HIV co-infected patients.

Human immunodeficiency virus (HIV) associated tuberculosis (TB) remains a major global public health challenge, with an estimated 1.4 million patients worldwide. Co-infection with HIV leads to challenges in both the diagnosis and treatment of tuberculosis. Further, there has been an increase in rates of drug resistant tuberculosis, including multi-drug (MDR-TB) and extensively drug resistant TB (XDRTB), which are difficult to treat and contribute to increased mortality. Because of the poor performance of sputum smear microscopy in HIV-infected patients, newer diagnostic tests are urgently required that are not only sensitive and specific but easy to use in remote and resource-constrained settings. The treatment of co-infected patients requires antituberculosis and antiretroviral drugs to be administered concomitantly; challenges include pill burden and patient compliance, drug interactions, overlapping toxic effects, and immune reconstitution inflammatory syndrome. Also important questions about the duration and schedule of anti-TB drug regimens and timing of antiretroviral therapy remain unanswered. From a programmatic point of view, screening of all HIV-infected persons for TB and viceversa requires good co-ordination and communication between the TB and AIDS control programmes. Linkage of co-infected patients to antiretroviral treatment centres is critical if early mortality is to be prevented. We present here an overview of existing diagnostic strategies, new tests in the pipeline and recommendations for treatment of patients with HIV-TB dual infection.

Persistence of Stunting After Highly Active Antiretroviral Therapy in HIV-Infected Children in South India.

After one year of antiretroviral treatment in 49 HIV-infected children compared to 53 children without, weight for age improved significantly and was highly correlated with baseline immune status and CD4% increase but height for age did not change. Stunting is a common feature of pediatric HIV, both on and off HAART.

Emergence of drug resistant mutations after single dose nevirapine exposure in HIV-1 infected pregnant women in south India.

Background & objectives: Resistance to nevirapine (NVP) has been described with single dose preventive regimens in other populations. Our aim was to study the pattern and prevalence of HIV drug resistance (DR) at baseline (during pregnancy) and after delivery among antenatal women exposed to single dose NVP for prevention of parent to child transmission (PPTCT). Methods: HIV-infected, ART-naive primigravidae between 18-25 years of age, attending government antenatal clinics in Chennai, Vellore or Madurai were recruited. Drug resistance testing was carried out during pregnancy and after Sd-NVP treatment (one month after delivery) by Viroseq sequencing. HIV-1 testing by DNA PCR was done in newborns at 30 days. Results: Thirty one women were enrolled but only twenty six plasma specimens were analyzable (24 paired and two postnatal only). No major mutations were observed in any drug class at baseline though many polymorphisms were observed in both the reverse transcriptase and protease genes. Mutations to non-nucleoside reverse transcriptase inhibitors (NNRTI) were observed post-delivery in 33 per cent of women who were treated with Sd-NVP. None of the infants were HIV-positive. Interpretation & conclusions: Among pregnant ART-naïve women, baseline HIV drug resistance was not observed. A high rate of development of NNRTI class resistance among women treated with single-dose NVP was observed. Our results emphasize the need to implement more effective PPTCT regimens, minimizing emergence of drug resistance and thereby preserving long-term treatment options for HIV-infected women in India.

Plasma Efavirenz in HIV-Infected Children Treated with Generic Antiretroviral Drugs in India.

We measured plasma concentration of efavirenz (EFV) in 16 HIV-infected Indian children receiving antiretroviral treatment at Government ART centres. The mean 12-hour concentration was 2.39 μg/mL (range: 0.72- 7.82 μg/mL). The majority of children treated with generic EFV at currently recommended doses had blood levels within the therapeutic range.

Comparison of HPLC & spectrophotometric methods for estimation of antiretroviral drug content in pharmaceutical products.

Background & objectives: Simple and reliable methods to estimate drugs in pharmaceutical products are needed. In most cases, antiretroviral drug estimations are performed using a HPLC method, requiring expensive equipment and trained technicians. A relatively simple and accurate method to estimate antiretroviral drugs in pharmaceutical preparations is by spectrophotometric method, which is cheap and simple to use as compared to HPLC. We undertook this study to standardise methods for estimation of nevirapine (NVP), lamivudine (3TC) and stavudine (d4T) in single tablets/capsules by HPLC and spectrophotometry and to compare the content of these drugs determined by both these methods. Methods: Twenty tablets/capsules of NVP, 3TC and d4T each were analysed for their drug content by HPLC and spectrophotometric methods. Suitably diluted drug solutions were run on HPLC fitted with a C18 column using UV detection at ambient temperature. The absorbance of the diluted drug solutions were read in a spectrophotometer at 300, 285 and 270 nm for NVP, 3TC and d4T respectively. Pure powders of the drugs were used to prepare calibration standards of known drug concentrations, which was set up with each assay. Results: The inter-day variation (%) of standards for NVP, 3TC and d4T ranged from 2.5 to 6.7, 2.1 to 7.7 and 6.2 to 7.7, respectively by HPLC. The corresponding values by spectrophotometric method were 2.7 to 4.7, 4.2 to 7.2 and 3.8 to 6.0. The per cent variation between the HPLC and spectrophotometric methods ranged from 0.45 to 4.49 per cent, 0 to 4.98 per cent and 0.35 to 8.73 per cent for NVP, 3TC and d4T, respectively. Conclusions: The contents of NVP, 3TC and d4T in the tablets estimated by HPLC and spectrophotometric methods were similar, and the variation in the amount of these drugs estimated by HPLC and spectrophotometric methods was below 10 per cent. This suggests that the spectrophotometric method is as accurate as the HPLC method for estimation of NVP, 3TC and d4T in tablet/capsule. Hence laboratories that do not have HPLC equipment can also undertake these drug estimations using spectrophotometer.

Pharmacokinetics of lamivudine & stavudine in generic fixed-dose combinations in HIV-1 infected adults in India.

Background & objectives: Antiretroviral drug concentrations are important determinants of clinical response to a drug accounting for both toxicity and efficacy. Several factors such as age, ethnicity, body weight and patients’ immune status may influence antiretroviral drug concentrations. The aim of the study was to determine the influence of immunological status, sex and body mass index on the steady state pharmacokinetics of lamivudine (3TC) and stavudine (d4T) in HIV-infected adults, who were undergoing treatment with generic fixed dose combinations (FDC) of these drugs in India. Methods: Twenty seven HIV-1 infected patients receiving antiretroviral treatment (ART) for at least two weeks at the Government ART clinic at Tambaram, Chennai, took part in the study. Serial blood samples were collected predosing and at different time points after drug administration. Plasma 3TC and d4T levels were estimated by HPLC. Results: The patients’ immune status, sex or body mass index had no impact on the pharmacokinetics of 3TC. In the case of d4T, peak concentration was significantly lower in patients with CD4 cell counts < 200 cells/μl than those with ≥ 200 cells/ μl (P < 0.05), but were within the therapeutic range. The mean CD4 cell counts increased from 101 cells/μl at initiation of ART to 366 cells/μl at 12 months of treatment. Interpretation & conclusions: Blood levels of 3TC and d4T drugs that are part of generic FDCs commonly used by HIV-infected individuals in India were within the therapeutic range and not influenced by nutritional or immune status. There was a significant improvement in CD4 cell counts over 12 months of treatment. Indian generic FDCs manufactured and used widely in the developing world provide effective concentrations of antiretroviral drugs.