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1.  Profile and Response to Anti-Tuberculosis Treatment among Elderly Tuberculosis Patients Treated under the TB Control Programme in South India 
PLoS ONE  2014;9(3):e88045.
Introduction
The demographic transition in India has resulted in an increase in the elderly population. There is limited data on the profile of elderly tuberculosis (TB) patients and their treatment outcomes in India.
Objective
To compare the clinical profile, presentation and response to anti-TB treatment among elderly (≥60 yrs) and younger (15–59 yrs) TB patients treated under the Revised National TB Control programme.
Methodology
Retrospective cohort analysis of TB patients treated from May 1999 to December 2004 in one Tuberculosis Unit of Tiruvallur district, South India.
Results
Records of 865 elderly and 4343 younger TB patients were examined: elderly were more likely to be male (84% vs. 71%), smokers (46% vs.37%), illiterate (63% vs. 45%), identified by active case finding through survey (19% vs. 11%), have pulmonary TB (96% vs. 91%) and initial smear negative disease (46% vs. 36%) compared to younger (for all p<0.001). Among a total of 352 elderly and 1933 younger new smear positive pulmonary TB, the elderly had higher loss to follow-up (15% vs. 11%; p = 0.03) and death rates (9% vs. 4%; p<0.001). Mycobacterium tuberculosis susceptibility to first line anti-TB drugs did not differ (elderly 87% vs. younger 84%) (p = 0.20). Side effects related to anti-TB drugs were reported by a higher proportion of elderly patients (63% vs. 54%) (p = 0.005). Previously treated patients had similar treatment outcomes in both the groups.
Conclusion
Elderly TB patients are less likely to have smear positive disease. Newly diagnosed elderly TB patients are more likely to be lost to follow-up or die and report drug side effects. Suitable interventions need to be developed for effective management and better treatment outcomes of TB in the elderly.
doi:10.1371/journal.pone.0088045
PMCID: PMC3949670  PMID: 24618888
2.  Prevalence of Tobacco Use in Urban, Semi Urban and Rural Areas in and around Chennai City, India 
PLoS ONE  2013;8(10):e76005.
Background
Tobacco use leads to many health complications and is a risk factor for the occurrence of cardio vascular diseases, lung and oral cancers, chronic bronchitis etc. Almost 6 million people die from tobacco-related causes every year. This study was conducted to measure the prevalence of tobacco use in three different areas around Chennai city, south India.
Methods
A survey of 7510 individuals aged > = 15 years was undertaken covering Chennai city (urban), Ambattur (semi-urban) and Sriperumbudur (rural) taluk. Details on tobacco use were collected using a questionnaire adapted from both Global Youth Tobacco Survey and Global Adults Tobacco Survey.
Results
The overall prevalence of tobacco use was significantly higher in the rural (23.7%) compared to semi-urban (20.9%) and urban (19.4%) areas (P value <0.001) Tobacco smoking prevalence was 14.3%, 13.9% and 12.4% in rural, semi-urban and urban areas respectively. The corresponding values for smokeless tobacco use were 9.5%, 7.0% and 7.0% respectively. Logistic regression analysis showed that the odds of using tobacco (with smoke or smokeless forms) was significantly higher among males, older individuals, alcoholics, in rural areas and slum localities. Behavioural pattern analysis of current tobacco users led to three groups (1) those who were not reached by family or friends to advice on harmful effects (2) those who were well aware of harmful effects of tobacco and even want to quit and (3) those are exposed to second hand/passive smoking at home and outside.
Conclusions
Tobacco use prevalence was significantly higher in rural areas, slum dwellers, males and older age groups in this region of south India. Women used mainly smokeless tobacco. Tobacco control programmes need to develop strategies to address the different subgroups among tobacco users. Public health facilities need to expand smoking cessation counseling services as well as provide pharmacotherapy where necessary.
doi:10.1371/journal.pone.0076005
PMCID: PMC3788037  PMID: 24098418
3.  Clinical Impact and Cost-Effectiveness of Expanded Voluntary HIV Testing in India 
PLoS ONE  2013;8(5):e64604.
Background
Despite expanding access to antiretroviral therapy (ART), most of the estimated 2.3 to 2.5 million HIV-infected individuals in India remain undiagnosed. The questions of whom to test for HIV and at what frequency remain unclear.
Methods
We used a simulation model of HIV testing and treatment to examine alternative HIV screening strategies: 1) current practice, 2) one-time, 3) every five years, and 4) annually; and we applied these strategies to three population scenarios: 1) the general Indian population (“national population”), i.e. base case (HIV prevalence 0.29%; incidence 0.032/100 person-years [PY]); 2) high-prevalence districts (HIV prevalence 0.8%; incidence 0.088/100 PY), and 3) high-risk groups (HIV prevalence 5.0%; incidence 0.552/100 PY). Cohort characteristics reflected Indians reporting for HIV testing, with a median age of 35 years, 66% men, and a mean CD4 count of 305 cells/µl. The cost of a rapid HIV test was $3.33. Outcomes included life expectancy, HIV-related direct medical costs, incremental cost-effectiveness ratios (ICERs), and secondary transmission benefits. The threshold for “cost-effective” was defined as 3x the annual per capita GDP of India ($3,900/year of life saved [YLS]), or for “very cost-effective” was <1x the annual per capita GDP ($1,300/YLS).
Results
Compared to current practice, one-time screening was very cost-effective in the national population (ICER: $1,100/YLS), high-prevalence districts (ICER: $800/YLS), and high-risk groups (ICER: $800/YLS). Screening every five years in the national population (ICER: $1,900/YLS) and annual screening in high-prevalence districts (ICER: $1,900/YLS) and high-risk groups (ICER: $1,800/YLS) were also cost-effective. Results were most sensitive to costs of care and linkage-to-care.
Conclusions
In India, voluntary HIV screening of the national population every five years offers substantial clinical benefit and is cost-effective. Annual screening is cost-effective among high-risk groups and in high-prevalence districts nationally. Routine HIV screening in India should be implemented.
doi:10.1371/journal.pone.0064604
PMCID: PMC3669338  PMID: 23741348
4.  Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome (TB-IRIS) in HIV Patients with Culture Confirmed Pulmonary Tuberculosis in India and the Potential Role of IL-6 in Prediction 
PLoS ONE  2013;8(5):e63541.
Background
The incidence, manifestations, outcome and clinical predictors of paradoxical TB-IRIS in patients with HIV and culture confirmed pulmonary tuberculosis (PTB) in India have not been studied prospectively.
Methods
HIV+ patients with culture confirmed PTB started on anti-tuberculosis therapy (ATT) were followed prospectively after anti-retroviral therapy (ART) initiation. Established criteria for IRIS diagnosis were used including decline in plasma HIV RNA at IRIS event. Pre-ART plasma levels of interleukin (IL)-6 and C-reactive protein (CRP) were measured. Univariate and multivariate logistic regression models were used to evaluate associations between baseline variables and IRIS.
Results
Of 57 patients enrolled, 48 had complete follow up data. Median ATT-ART interval was 28 days (interquartile range, IQR 14–47). IRIS events occurred in 26 patients (54.2%) at a median of 11 days (IQR: 7–16) after ART initiation. Corticosteroids were required for treatment of most IRIS events that resolved within a median of 13 days (IQR: 9–23). Two patients died due to CNS TB-IRIS. Lower CD4+ T-cell counts, higher plasma HIV RNA levels, lower CD4/CD8 ratio, lower hemoglobin, shorter ATT to ART interval, extra-pulmonary or miliary TB and higher plasma IL-6 and CRP levels at baseline were associated with paradoxical TB-IRIS in the univariate analysis. Shorter ATT to ART interval, lower hemoglobin and higher IL-6 and CRP levels remained significant in the multivariate analysis.
Conclusion
Paradoxical TB–IRIS frequently complicates HIV-TB therapy in India. IL-6 and CRP may assist in predicting IRIS events and serve as potential targets for immune interventions.
doi:10.1371/journal.pone.0063541
PMCID: PMC3656926  PMID: 23691062
5.  Evaluation of Tuberculosis Diagnostics in Children: 2. Methodological Issues for Conducting and Reporting Research Evaluations of Tuberculosis Diagnostics for Intrathoracic Tuberculosis in Children. Consensus From an Expert Panela 
The Journal of Infectious Diseases  2012;205(Suppl 2):S209-S215.
Confirming the diagnosis of childhood tuberculosis is a major challenge. However, research on childhood tuberculosis as it relates to better diagnostics is often neglected because of technical difficulties, such as the slow growth in culture, the difficulty of obtaining specimens, and the diverse and relatively nonspecific clinical presentation of tuberculosis in this age group. Researchers often use individually designed criteria for enrollment, diagnostic classifications, and reference standards, thereby hindering the interpretation and comparability of their findings. The development of standardized research approaches and definitions is therefore needed to strengthen the evaluation of new diagnostics for detection and confirmation of tuberculosis in children.
In this article we present consensus statements on methodological issues for conducting research of Tuberculosis diagnostics among children, with a focus on intrathoracic tuberculosis. The statements are complementary to a clinical research case definition presented in an accompanying publication and suggest a phased approach to diagnostics evaluation; entry criteria for enrollment; methods for classification of disease certainty, including the rational use of culture within the case definition; age categories and comorbidities for reporting results; and the need to use standard operating procedures. Special consideration is given to the performance of microbiological culture in children and we also recommend for alternative methodological approaches to report findings in a standardized manner to overcome these limitations are made. This consensus statement is an important step toward ensuring greater rigor and comparability of pediatric tuberculosis diagnostic research, with the aim of realizing the full potential of better tests for children.
doi:10.1093/infdis/jir879
PMCID: PMC3334504  PMID: 22476719
6.  Evaluation of Tuberculosis Diagnostics in Children: 1. Proposed Clinical Case Definitions for Classification of Intrathoracic Tuberculosis Disease. Consensus From an Expert Panel 
The Journal of Infectious Diseases  2012;205(Suppl 2):S199-S208.
There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.
doi:10.1093/infdis/jis008
PMCID: PMC3334506  PMID: 22448023
7.  The influence of stigma on HIV risk behavior among men who have sex with men in Chennai, India 
AIDS care  2012;24(11):1401-1406.
Stigma has been shown to increase vulnerability to HIV acquisition in many settings around the world. However, limited research has been conducted examining its role among men who have sex with men (MSM) in India, whose HIV prevalence is far greater than the general population. In 2009, 210 MSM in Chennai completed an interviewer-administered assessment, including questions about stigma, sexual-risk, demographics, and psychosocial variables. More than one fifth of the MSM reported unprotected anal sex (UAS) in the past three months. Logistic regression procedures were used to examine correlates of having experienced stigma. The 11-item stigma scale had high internal consistency reliability (Cronbach's alpha=0.99). Almost 2/5ths (39%) reported a high-level of experienced stigma (≥12 mean scale-score) in their lifetime, and the mean stigma scale score was 12 (SD=2.0). Significant correlates of having experienced prior stigma, after adjusting for age and educational attainment, included: identifying as a kothi (feminine acting/appearing and predominantly receptive in anal sex) compared to a panthi (masculine appearing, predominantly insertive) (AOR= 63.23; 95% CI: 15.92, 251.14; p<0.0001); being “out” about one's MSM behavior (AOR=5.63; 95% CI: 1.46, 21.73; p=0.01); having clinically significant depressive symptoms (AOR=2.68; 95% CI: 1.40, 5.12; p=0.003); and engaging in sex work in the prior 3 months (AOR=4.89; 95% CI: 2.51, 9.51; p<0.0001). These findings underscore the need to address psychosocial issues of Indian MSM. Unless issues such as stigma are addressed, effective HIV prevention interventions for this hidden population remain a challenge.
doi:10.1080/09540121.2012.672717
PMCID: PMC3634562  PMID: 22519945
men who have sex with men; MSM; depression; India; HIV; stigma
8.  UNSEEN AND UNHEARD: PREDICTORS OF SEXUAL RISK BEHAVIOR AND HIV INFECTION AMONG MEN WHO HAVE SEX WITH MEN IN CHENNAI, INDIA 
In India men who have sex with men (MSM) are stigmatized, understudied, and at high risk for HIV. Understanding the impact of psychosocial issues on HIV risk behavior and HIV infection can help shape culturally relevant HIV prevention interventions. Peer outreach workers recruited 210 MSM in Chennai who completed an interviewer-administered psychosocial assessment battery and underwent HIV testing and counseling. More than one fifth (46/210) reported unprotected anal intercourse in the past 3 months, 8% tested positive for HIV, and 26% had previously participated in an HIV prevention intervention. In a multivariable logistic-regression model controlling for age, MSM subpopulation (kothi, panthi, or double-decker), marital status, and religion, significant predictors of any unprotected anal intercourse were being less educated (adjusted odds ratio [AOR] = .54; p = .009), not having previously participated in an HIV prevention program (AOR = 3.75; p = .05), having clinically significant depression symptoms (AOR = 2.8; p = .02), and lower self-efficacy (AOR = .40; p < .0001). Significant predictors of testing positive for HIV infection were: being less educated (AOR = .53; .05) and not currently living with parent(s) (AOR = 3.71; p = .05). Given the prevalence of HIV among MSM, efforts to reach hidden subpopulations of MSM in India are still needed. Such programs for MSM in India may need to address culturally-relevant commonly co-occurring psychosocial problems to maximize chances of reducing risk for infection.
doi:10.1521/aeap.2009.21.4.372
PMCID: PMC3623672  PMID: 19670971
9.  Efficacy of a Six-Month versus a 36-Month Regimen for Prevention of Tuberculosis in HIV-Infected Persons in India: A Randomized Clinical Trial 
PLoS ONE  2012;7(12):e47400.
Background
The optimal duration of preventive therapy for tuberculosis (TB) among HIV-infected persons in TB-endemic countries is unknown.
Methods
An open-label randomized clinical trial was performed and analyzed for equivalence. Seven hundred and twelve HIV-infected, ART-naïve patients without active TB were randomized to receive either ethambutol 800 mg and isoniazid 300 mg daily for six-months (6EH) or isoniazid 300 mg daily for 36-months (36H). Drugs were dispensed fortnightly and adherence checked by home visits. Patients had chest radiograph, sputum smear and culture performed every six months, in addition to investigations if they developed symptoms. The primary endpoint was incident TB while secondary endpoints were all-cause mortality and adverse events. Survival analysis was performed on the modified intent to treat population (m-ITT) and rates compared.
Findings
Tuberculosis developed in 22 (6.4%) of 344 subjects in the 6EH arm and 13 (3.8%) of 339 subjects in the 36H arm with incidence rates of 2.4/100py (95%CI- 1.4–3.5) and 1.6/100py (95% CI-0.8–3.0) with an adjusted rate ratio (aIRR) of 1.6 (0.8–3.2). Among TST-positive subjects, the aIRR of 6EH was 1.7 (0.6–4.3) compared to 36H, p = 0.8. All-cause mortality and toxicity were similar in the two arms. Among 15 patients with confirmed TB, 4 isolates were resistant to isoniazid and 2 were multidrug-resistant.
Interpretation
Both regimens were similarly effective in preventing TB, when compared to historical incidence rates. However, there was a trend to lower TB incidence with 36H. There was no increase in isoniazid resistance compared to the expected rate in HIV-infected patients.
The trial is registered at ClinicalTrials.gov, NCT00351702.
doi:10.1371/journal.pone.0047400
PMCID: PMC3522661  PMID: 23251327
10.  Role of pharmacogenomics in the treatment of tuberculosis: a review 
Background:
Tuberculosis is one of the major public health problems worldwide. Modern antituberculous treatment can cure most patients; cure rates > 95% are achieved with standard short-course chemotherapy regimens containing isoniazid, rifampicin, pyrazinamide, and ethambutol among patients with drug-susceptible strains of tuberculosis; however, a small proportion do not respond to treatment or develop serious adverse events. Pharmacogenomic studies of drugs used in the treatment of tuberculosis could help us understand intersubject variations in treatment response. In this review, we compiled pharmacogenomic data on antituberculous drugs that were available from different settings that would give a better insight into the role of pharmacogenomics in the treatment of tuberculosis, thereby enhancing the efficacy and limiting the toxicity of existing antituberculosis medications.
Methods:
The PubMed database was searched from 1960 to the present using the keywords “tuberculosis”, “antituberculosis treatment”, “isoniazid”, “rifampicin”, “pyrazinamide”, “ethambutol”, “pharmacogenomics”, and “polymorphism”. Abstracts from meetings and review articles were included.
Conclusion:
Studies conducted in different settings suggest that pharmacogenomics plays a significant role in isoniazid metabolism, and impacts both treatment efficacy and frequency of adverse reactions. Single nucleotide polymorphisms influencing plasma rifampicin concentrations are also reported. No data are available regarding other first-line drugs, ie, ethambutol and pyrazinamide. There is a need to incorporate pharmacogenomics into clinical trials of tuberculosis in order to understand the factors impacting therapeutic success and occurrence of adverse drug effects.
doi:10.2147/PGPM.S15454
PMCID: PMC3513231  PMID: 23226065
tuberculosis; antituberculous treatment; pharmacogenomics; polymorphism; drug metabolism
11.  Factors influencing plasma nevirapine levels: a study in HIV-infected children on generic antiretroviral treatment in India 
Background
Nevirapine is an important component of paediatric combination HIV therapy. Adequate drug exposure is necessary in order to achieve long-lasting viral suppression.
Objectives
To study the influence of age, drug dose and formulation type, nutritional status and CYP2B6 516G>T polymorphism on blood concentrations of nevirapine in children treated with generic antiretroviral drugs.
Methods
A multicentre study was conducted at four sites in India. HIV-infected children receiving generic nevirapine-based fixed-dose combinations were recruited. Trough and 2 h nevirapine plasma concentrations were determined by HPLC. Characterization of the CYP2B6 gene polymorphism was performed using direct sequencing. Clinical and nutritional status was recorded. Groups were compared using the Mann–Whitney U-test and multivariable logistic regression analysis was performed to identify factors contributing to low drug levels.
Results
Ninety-four children of median age 78 months were studied; 60% were undernourished or stunted. Stunted children had a significantly lower 2 h nevirapine concentration compared with non-stunted children (P < 0.05); there were no significant differences in trough concentrations between different nutritional groups. Nevirapine levels were significantly higher in children with TT compared with GG and GT CYP2B6 genotypes (P < 0.01). Children ≤3 years had a 3.2 (95% confidence interval 1.07–9.45) times higher risk of having sub-therapeutic nevirapine concentrations.
Conclusions
Nevirapine blood concentrations are affected by many factors, most notably age ≤3 years; a combination of young age, stunting and CYP2B6 GG or GT genotype could potentially result in sub-therapeutic nevirapine concentrations. Dosing recommendations for children should be reviewed in the light of these findings.
doi:10.1093/jac/dkr075
PMCID: PMC3143437  PMID: 21393201
nutritional status; CYP2B6 516G > T polymorphism; pharmacokinetics
12.  The Cost-Effectiveness of Tuberculosis Preventive Therapy for HIV-Infected Individuals in Southern India: A Trial-Based Analysis 
PLoS ONE  2012;7(4):e36001.
Background
Regimens for isoniazid-based preventive therapy (IPT) for tuberculosis (TB) in HIV-infected individuals have not been widely adopted given concerns regarding efficacy, adherence and drug resistance. Further, the cost-effectiveness of IPT has not been studied in India.
Methods
We used an HIV/TB model to project TB incidence, life expectancy, cost and incremental cost-effectiveness of six months of isoniazid plus ethambutol (6EH), thirty-six months of isoniazid (36H) and no IPT for HIV-infected patients in India. Model input parameters included a median CD4 count of 324 cells/mm3, and a rate ratio of developing TB of 0.35 for 6EH and 0.22 for 36H at three years as compared to no IPT. Results of 6EH and 36H were also compared to six months of isoniazid (6H), three months of isoniazid plus rifampin (3RH) and three months of isoniazid plus rifapentine (3RPTH).
Results
Projected TB incidence decreased in the 6EH and 36H regimens by 51% and 62% respectively at three-year follow-up compared to no IPT. Without IPT, projected life expectancy was 136.1 months at a lifetime per person cost of $5,630. 6EH increased life expectancy by 0.8 months at an additional per person cost of $100 (incremental cost-effectiveness ratio (ICER) of $1,490/year of life saved (YLS)). 36H further increased life expectancy by 0.2 months with an additional per person cost of $55 (ICER of $3,120/YLS). The projected clinical impact of 6EH was comparable to 6H and 3RH; however when compared to these other options, 6EH was no longer cost-effective given the high cost of ethambutol. Results were sensitive to baseline CD4 count and adherence.
Conclusions
Three, six and thirty-six-month regimens of isoniazid-based therapy are effective in preventing TB. Three months of isoniazid plus rifampin and six-months of isoniazid are similarly cost-effective in India, and should be considered part of HIV care.
doi:10.1371/journal.pone.0036001
PMCID: PMC3340407  PMID: 22558301
13.  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 vice-versa 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.
doi:10.4103/0971-5916.92630
PMCID: PMC3284094  PMID: 22310818
Co-infection; diagnosis; drug resistance; IRIS; treatment; tuberculosis
14.  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 non-governmental organizations that work with the community to play in providing culturally relevant HIV prevention programmes for MSM.
doi:10.4103/0971-5916.92637
PMCID: PMC3284100  PMID: 22310824
HIV; India; men who have sex with men; MSM; mental health; stigma
15.  Dyslipidemia among HIV-infected Patients with Tuberculosis Taking Once-daily Nonnucleoside Reverse-Transcriptase Inhibitor–Based Antiretroviral Therapy in India 
HIV-infected patients with tuberculosis who initiate nonnucleoside reverse-transcriptase-based anti-retroviral treatment in combination with rifampicin-based antituberculosis treatment demonstrate increases in total cholesterol, low-density cholesterol, and high-density cholesterol levels but no change in blood glucose level after 1 year. Cholesterol increases were more frequent among patients receiving efavirenz.
Background. Our aim was to study the incidence and pattern of dyslipidemia among human immunodeficiency virus (HIV)–infected patients with tuberculosis (TB) who received once-daily antiretroviral therapy (ART).
Methods. Antiretroviral-naive HIV-infected patients with TB were recruited to a trial of once-daily nonnucleoside reverse-transcriptase inhibitor (NNRTI)–based ART and treated with rifampicin-based thrice-weekly antituberculosis treatment (ATT); participants were randomized to receive didanosine (250/400 mg) and lamivudine (300 mg) with either efavirenz (600 mg) or nevirapine (400 mg) once-daily after an intensive phase of ATT. Fasting triglyceride (TG) level, total cholesterol (TC) level, low-density cholesterol (LDL-c) level and high-density cholesterol (HDL-c) level were measured at baseline and at 6 and 12 months. Lipid levels at 6 and 12 months were compared with baseline values with use of repeated measures analyses. McNemar test was used to compare the proportion of patients with lipid abnormality at baseline versus at 12 months, and χ2 test was used to compare between the 2 groups.
Results. Of 168 patients (79% men; mean age, 36 years; mean weight, 42 kg; median CD4+ cell count, 93 cells/mm3), 104 received efavirenz-based ART, and 64 received nevirapine-based ART. After 6 months, TC levels increased by 49 mg/dL, LDL-c levels by 30 mg/dL, and HDL-c levels increased by 18 mg/dL (P < .001 for all). At baseline and at 12 months, TC was >200 mg/dL for 1% and 26% of patients, respectively; LDL-c level was >130 mg/dL for 3% and 23%, respectively; HDL-c level was <40 mg/dL for 91% and 23%, respectively; and blood glucose level was >110 mg/dL for 14% and 13%, respectively. TC level >200 mg/dL was more common among patients who received efavirenz than among those who received nevirapine (32% vs 16%; P = .04).
Conclusions. HIV-infected patients with TB who initiate NNRTI-based ART undergo complex changes in lipid profile, highlighting the importance of screening and treating other cardiovascular disease risk factors in this population.
doi:10.1093/cid/ciq195
PMCID: PMC3060904  PMID: 21252141
16.  Dose Adjustment of the Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) during Concurrent Rifampicin-Containing Tuberculosis Therapy: One Size does not Fit All 
Importance of the field
HIV/TB coinfection is common and associated with high mortality. Simultaneous highly active antiretroviral therapy (HAART) during TB treatment is associated with substantial survival benefit but drug-drug interactions complicate NNRTI dosing.
Areas covered in this review
We reviewed the impact of rifampicin-containing TB therapy on the NNRTIs pharmacokinetics and clinical outcome. Pub Med database was searched from 1966 to July 2009, using the terms efavirenz, rifampicin, nevirapine, pharmacokinetics, pharmacogenetics, HIV, TB, CYP2B6, CYP3A4 and metabolism. References from identified articles and abstracts from meetings were also reviewed.
What the reader will gain
A comprehensive review of the literature on this subject including pharmacokinetic and clinical studies. Most studies were small, observational or underpowered to detect the true effect of rifampicin on NNRTI-based therapy. None of the studies controlled for genetic factors and there was limited data on children.
Take home message
There was insufficient data to make definitive recommendations about dose adjustment of the NNRTIs during rifampin-containing therapy. Current data suggest that standard dose of efavirenz or nevirapine is adequate in most HIV/TB co-infected adults. However, more research is needed in pediatric populations as well as to define role of drug-gene interactions.
doi:10.1517/17425250903393752
PMCID: PMC2939445  PMID: 19968575
Drug interactions; Efavirenz; HIV; Nevirapine; Rifampicin; Tuberculosis
17.  HIV Prevention Interventions in Chennai, India: Are Men Who Have Sex with Men Being Reached? 
AIDS Patient Care and STDs  2009;23(11):981-986.
Abstract
India has the greatest number of HIV infections in Asia and the third highest total number of infected persons globally. Men who have sex with men (MSM) are considered by the Government of India's National AIDS Control Organization (NACO) a “core risk group” for HIV in need of HIV prevention efforts. However there is a dearth of information on the frequency of participation in HIV prevention interventions and subsequent HIV risk and other correlates among MSM in India. Recruited through peer outreach workers, word of mouth and snowball sampling techniques, 210 MSM in Chennai completed an interviewer-administered assessment, including questions about participating in any HIV prevention interventions in the past year, sexual risk taking, demographics, MSM identities, and other psychosocial variables. Bivariate and multivariable logistic regression procedures were used to examine behavioral and demographic correlates with HIV prevention intervention participation. More than a quarter (26%) of the sample reported participating in an HIV prevention intervention in the year prior to study participation. Participants who reported engaging in unprotected anal sex (UAS; odds ratio [OR] = 0.28; p = 0.01) in the 3 months prior to study enrollment were less likely to have participated in an HIV prevention program in the past year. MSM who were older (OR = 1.04; p = 0.05), kothis (feminine acting/appearing and predominantly receptive partners in anal sex) compared to panthis (masculine appearing, predominantly insertive partners; OR = 5.52, p = 0.0004), those with higher educational attainment (OR = 1.48, p = 0.01), being “out” about having sex with other men (OR = 4.03, p = 0.0001), and MSM who reported ever having been paid in exchange for sex (OR = 2.92, p = 0.001) were more likely to have reported participation in an HIV prevention intervention in the preceding year. In a multivariable model, MSM reporting UAS in the prior 3 months were less likely to have participated in an HIV prevention intervention (AOR = 0.34, p = 0.04). MSM who were older (AOR = 1.05, p = 0.05), those with higher educational attainment (AOR = 1.92, p = 0.0009), and MSM who were “out” about having sex with other men (AOR = 2.71, p = 0.04) were more likely to have reported participating in an HIV prevention program. Findings suggest that exposure to HIV prevention interventions may be protective against engaging in UAS for some MSM in India. Understanding predictors of participation in an HIV prevention intervention is helpful for identifying Indian MSM who might have had no exposure to HIV prevention information and skills building, hence allowing researchers and prevention workers to focus efforts on individuals at greatest need.
doi:10.1089/apc.2009.0092
PMCID: PMC2859779  PMID: 19821722
18.  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.
PMCID: PMC3028950  PMID: 21149999
Drug resistance; HIV; nevirapine; pregnancy
19.  Impact of HIV/AIDS on Mothers in Southern India: A Qualitative Study 
AIDS and behavior  2008;13(5):989-996.
The purpose of this study is to explore the perceptions and needs of mothers living with HIV to gain greater insights into the challenges they face in relation to their health seeking behavior, fears around disclosure, and issues related to stigma and discrimination. This qualitative study utilized focus groups consisting of a sample of 60 HIV-infected mothers recruited from a large maternity hospital and STD clinic in Chennai, India. Discrimination by physicians and other health care workers has been a major impediment expressed by mothers living with HIV in accessing quality health care. Mothers living with HIV are increasingly concerned about how and when to disclose their HIV status to their children and the repercussions which could result from disclosure. The findings of this study call for urgent intervention strategies taking into consideration these various concerns and needs of mothers living with HIV and their children.
doi:10.1007/s10461-008-9478-x
PMCID: PMC2949417  PMID: 18941883
HIV; Mothers; India; Qualitative research
20.  Cost-Effectiveness of HIV Testing Referral Strategies among Tuberculosis Patients in India 
PLoS ONE  2010;5(9):e12747.
Background
Indian guidelines recommend routine referral for HIV testing of all tuberculosis (TB) patients in the nine states with the highest HIV prevalence, and selective referral for testing elsewhere. We assessed the clinical impact and cost-effectiveness of alternative HIV testing referral strategies among TB patients in India.
Methods and Findings
We utilized a computer model of HIV and TB disease to project outcomes for patients with active TB in India. We compared life expectancy, cost, and cost-effectiveness for three HIV testing referral strategies: 1) selective referral for HIV testing of those with increased HIV risk, 2) routine referral of patients in the nine highest HIV prevalence states with selective referral elsewhere (current standard), and 3) routine referral of all patients for HIV testing. TB-related data were from the World Health Organization. HIV prevalence among TB patients was 9.0% in the highest prevalence states, 2.9% in the other states, and 4.9% overall. The selective referral strategy, beginning from age 33.50 years, had a projected discounted life expectancy of 16.88 years and a mean lifetime HIV/TB treatment cost of US$100. The current standard increased mean life expectancy to 16.90 years with additional per-person cost of US$10; the incremental cost-effectiveness ratio was US$650/year of life saved (YLS) compared to selective referral. Routine referral of all patients for HIV testing increased life expectancy to 16.91 years, with an incremental cost-effectiveness ratio of US$730/YLS compared to the current standard. For HIV-infected patients cured of TB, receiving antiretroviral therapy increased survival from 4.71 to 13.87 years. Results were most sensitive to the HIV prevalence and the cost of second-line antiretroviral therapy.
Conclusions
Referral of all patients with active TB in India for HIV testing will be both effective and cost-effective. While effective implementation of this strategy would require investment, routine, voluntary HIV testing of TB patients in India should be recommended.
doi:10.1371/journal.pone.0012747
PMCID: PMC2940842  PMID: 20862279
21.  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.
PMCID: PMC2853745  PMID: 19942751
Generic FDCs; India; lamivudine; pharmacokinetics; stavudine
22.  Perceptions of Tuberculosis Patients on Provider-Initiated HIV Testing and Counseling - A Study from South India 
PLoS ONE  2009;4(12):e8389.
Background
The acceptability and feasibility of provider-initiated HIV testing and counseling (PITC) in many settings across Asia with concentrated HIV epidemics is not known. A pilot study of the PITC policy undertaken within the public health care systems in two districts in India offered the opportunity to understand patient's perspectives on the process of referral for HIV testing and linking to HIV treatment and care.
Methods
We conducted a cross-sectional study of randomly selected TB patients registered by the TB control program between July and November 2007 in two districts in south India. Trained interviewers met patients shortly after TB diagnosis and administered a structured questionnaire. Patients were assessed regarding their experience with HIV status assessment, referral for counseling and testing, and for HIV-infected patients the counseling itself and subsequent referral for HIV treatment and care.
Results
Of the 568 interviewed TB patients, 455 (80%) reported being referred for HIV testing after they presented to the health facility for investigations or treatment for TB. Over half the respondents reported having to travel long distances and incurred financial difficulties in reaching the Integrated Counselling and Testing Centre (ICTC) and two-thirds had to make more than two visits. Only 48% reported having been counseled before the test. Of the 110 HIV-infected patients interviewed, (including 43 with previously-known positive HIV status and 67 detected by PITC), 89 (81%) reported being referred for anti-retroviral treatment (ART); 82 patients reached the ART centre but only 44 had been initiated on ART.
Conclusions
This study provides the first evidence from India that routine, provider-initiated voluntary HIV testing of TB patients is acceptable, feasible and can be achieved with very high efficiency under programmatic conditions. While PITC is useful in identifying new HIV-infected patients so that they can be successfully linked to ART, the convenience and proximity of testing centres, quality of HIV counseling, and efficiency of ART services need attention.
doi:10.1371/journal.pone.0008389
PMCID: PMC2791227  PMID: 20041167
23.  Feasibility of Provider-Initiated HIV Testing and Counselling of Tuberculosis Patients Under the TB Control Programme in Two Districts of South India 
PLoS ONE  2009;4(11):e7899.
Background
Provider-initiated HIV testing and counselling (PITC) is internationally recommended for tuberculosis (TB) patients, but the feasibility, effectiveness, and impact of this policy on the TB programme in India are unknown. We evaluated PITC of TB patients across two districts in India considered to have generalized HIV epidemics, Tiruchirappalli (population 2.5 million) and Mysore (population 2.8 million).
Methodology/Principal Findings
Starting June 2007, healthcare providers in both districts were instructed to ascertain HIV status for all TB patients, and refer those with unknown HIV status to the nearest Integrated Counselling and Testing Centre (ICTC)—often in the same facility—for counselling and voluntary HIV testing. All TB patients registered from June 2007 to March 2008 were followed prospectively. Field investigators assessed PITC practices and abstracted data from routine TB programme records and HIV counselling registers to determine the proportion of TB patients appropriately evaluated for HIV infection. Patient records were traced to determine the efficiency of referral links to HIV care and antiretroviral treatment (ART). Between July 2007 and March 2008, 5299 TB patients were registered in both study districts. Of the 4701 with unknown HIV status at the time of TB treatment initiation, 3368 (72%) were referred to an ICTC, and 3111 (66%) were newly tested for HIV. PITC implementation resulted in the ascertainment of HIV status for 3709/5299 (70%) of TB patients, and detected 200 cases with previously undiagnosed HIV infection. Overall, 468 (8.8%) of all registered TB patients were HIV-infected; 177 (37%) were documented to have also received any ART.
Conclusions
With implementation of PITC in India, HIV status was successfully ascertained for 70% of TB patients. Previously undiagnosed HIV-infection was detected in 6.4% of those TB patients newly tested, enabling referral for life-saving anti-retroviral treatment. ART uptake, however, was poor, suggesting that PITC implementation should include measures to strengthen and support ART referral, evaluation, and initiation.
doi:10.1371/journal.pone.0007899
PMCID: PMC2774514  PMID: 19936067
24.  Filarial/Human Immunodeficiency Virus Coinfection in Urban Southern India 
The disease course of human immunodeficiency virus (HIV) is often altered by existing or newly acquired coinfections. Treatment or prevention of these concomitant infections often improves the quality and duration of life of HIV-infected persons. The impact of helminth infections on infections with HIV is less clear. However, HIV is frequently most problematic in areas where helminth infections are common. In advance of the widespread distribution of drugs for elimination of lymphatic filariasis, we assessed the prevalence of active Wuchereria bancrofti infection among HIV-positive patients in Chennai, India at two time points separated by four years. We found that the overall prevalence of W. bancrofti infections among HIV-positive persons was 5–9.5%, and there were no quantitative differences in circulating filarial antigen levels between HIV-positive and HIV-negative filarial-infected patients.
PMCID: PMC2596056  PMID: 18840744
25.  CYP2B6 G516T Polymorphism but Not Rifampin Coadministration Influences Steady-State Pharmacokinetics of Efavirenz in Human Immunodeficiency Virus-Infected Patients in South India▿  
The dose of efavirenz during concomitant rifampin (RMP) administration is a matter of debate. We studied the influence of RMP coadministration on the steady-state pharmacokinetics of efavirenz in human immunodeficiency virus type 1 (HIV-1)-infected patients in South India. Fifty-seven HIV-tuberculosis (TB)-coinfected and 15 HIV-1-infected patients receiving combination antiretroviral therapy (CART) with an efavirenz (600 mg once daily)-containing regimen were recruited. HIV-TB-coinfected patients were receiving treatment with RMP-containing regimens. A complete pharmacokinetic study was conducted with 19 HIV-TB patients on two occasions (with and without RMP). Trough concentrations of efavirenz were measured in the remaining 38 patients during RMP coadministration. The 15 HIV-infected patients underwent complete pharmacokinetic sampling on one occasion. Plasma efavirenz was estimated by high-performance liquid chromatography, and genotyping of CYP2B6 G516T polymorphism was performed by sequencing. Peak and trough concentrations and exposure to efavirenz were significantly higher in TT than in GT and GG genotype patients (P < 0.001). Although RMP coadministration decreased the peak and trough concentrations and exposure to efavirenz by 17.8, 20.4, and 18.6%, respectively, the differences were not statistically significant. The trough concentration of efavirenz was subtherapeutic (less than 1.0 μg/ml) in 6 (8%) of 72 patients. In this South Indian population of HIV-infected patients, CYP2B6 G516T polymorphism but not RMP coadministration significantly influenced the pharmacokinetics of efavirenz; patients with the TT genotype had very high blood levels of efavirenz. While a small proportion of patients had subtherapeutic efavirenz levels, the clinical implications are uncertain, as all had good immunological responses to CART.
doi:10.1128/AAC.00899-08
PMCID: PMC2650539  PMID: 19124658

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