Anita Shet

Causes of neonatal and child mortality in India: a nationally representative mortality survey.

BACKGROUNDnMore than 2·3 million children died in India in 2005; however, the major causes of death have not been measured in the country. We investigated the causes of neonatal and child mortality in India and their differences by sex and region.nnnMETHODSnThe Registrar General of India surveyed all deaths occurring in 2001-03 in 1·1 million nationally representative homes. Field staff interviewed household members and completed standard questions about events that preceded the death. Two of 130 physicians then independently assigned a cause to each death. Cause-specific mortality rates for 2005 were calculated nationally and for the six regions by combining the recorded proportions for each cause in the neonatal deaths and deaths at ages 1-59 months in the study with population and death totals from the United Nations.nnnFINDINGSnThere were 10,892 deaths in neonates and 12,260 in children aged 1-59 months in the study. When these details were projected nationally, three causes accounted for 78% (0·79 million of 1·01 million) of all neonatal deaths: prematurity and low birthweight (0·33 million, 99% CI 0·31 million to 0·35 million), neonatal infections (0·27 million, 0·25 million to 0·29 million), and birth asphyxia and birth trauma (0·19 million, 0·18 million to 0·21 million). Two causes accounted for 50% (0·67 million of 1·34 million) of all deaths at 1-59 months: pneumonia (0·37 million, 0·35 million to 0·39 million) and diarrhoeal diseases (0·30 million, 0·28 million to 0·32 million). In children aged 1-59 months, girls in central India had a five-times higher mortality rate (per 1000 livebirths) from pneumonia (20·9, 19·4-22·6) than did boys in south India (4·1, 3·0-5·6) and four-times higher mortality rate from diarrhoeal disease (17·7, 16·2-19·3) than did boys in west India (4·1, 3·0-5·5).nnnINTERPRETATIONnFive avoidable causes accounted for nearly 1·5 million child deaths in India in 2005, with substantial differences between regions and sexes. Expanded neonatal and intrapartum care, case management of diarrhoea and pneumonia, and addition of new vaccines to immunisation programmes could substantially reduce child deaths in India.nnnFUNDINGnUS National Institutes of Health, International Development Research Centre, Canadian Institutes of Health Research, Li Ka Shing Knowledge Institute, and US Fund for UNICEF.

Design of a randomized trial to evaluate the influence of mobile phone reminders on adherence to first line antiretroviral treatment in South India - the HIVIND study protocol

BackgroundPoor adherence to antiretroviral treatment has been a public health challenge associated with the treatment of HIV. Although different adherence-supporting interventions have been reported, their long term feasibility in low income settings remains uncertain. Thus, there is a need to explore sustainable contextual adherence aids in such settings, and to test these using rigorous scientific designs. The current ubiquity of mobile phones in many resource-constrained settings, make it a contextually appropriate and relatively low cost means of supporting adherence. In India, mobile phones have wide usage and acceptability and are potentially feasible tools for enhancing adherence to medications. This paper presents the study protocol for a trial, to evaluate the influence of mobile phone reminders on adherence to first-line antiretroviral treatment in South India.Methods/Design600 treatment naïve patients eligible for first-line treatment as per the national antiretroviral treatment guidelines will be recruited into the trial at two clinics in South India. Patients will be randomized into control and intervention arms. The control arm will receive the standard of care; the intervention arm will receive the standard of care plus mobile phone reminders. Each reminder will take the form of an automated call and a picture message. Reminders will be delivered once a week, at a time chosen by the patient. Patients will be followed up for 24 months or till the primary outcome i.e. virological failure, is reached, whichever is earlier. Self-reported adherence is a secondary outcome. Analysis is by intention-to-treat. A cost-effectiveness study of the intervention will also be carried out.DiscussionStepping up telecommunications technology in resource-limited healthcare settings is a priority of the World Health Organization. The trial will evaluate if the use of mobile phone reminders can influence adherence to first-line antiretrovirals in an Indian context.Trial RegistrationTrial registration: ISRCTN79261738.

Effect of mobile telephone reminders on treatment outcome in HIV: evidence from a randomised controlled trial in India

Objective To assess whether customised mobile phone reminders would improve adherence to therapy and thus decrease virological failure among HIV infected patients starting antiretroviral treatment (ART). Design Randomised controlled trial among HIV infected patients initiating antiretroviral treatment. Setting Three diverse healthcare delivery settings in south India: two ambulatory clinics within the Indian national programme and one private HIV healthcare clinic. Participants 631 HIV infected, ART naïve, adult patients eligible to initiate first line ART were randomly assigned to mobile phone intervention (n=315) or standard care (n=316) and followed for 96 weeks.. Intervention The intervention consisted of customised, interactive, automated voice reminders, and a pictorial message that were sent weekly to the patients’ mobile phones for the duration of the study. Main outcome measures The primary outcome was time to virological failure (viral load >400 copies/mL on two consecutive measurements). Secondary outcomes included ART adherence measured by pill count, death rate, and attrition rate. Suboptimal adherence was defined as mean adherence <95%. Results Using an intention-to-treat approach we found no observed difference in time to virological failure between the allocation groups: failures in the intervention and standard care arms were 49/315 (15.6%) and 49/316 (15.5%) respectively (unadjusted hazard ratio 0.98, 95% confidence interval 0.67 to 1.47, P=0.95). The rate of virological failure in the intervention and standard care groups were 10.52 and 10.73 per 100 person years respectively. Comparison of suboptimal adherence was similar between both groups (unadjusted incidence rate ratio 1.24, 95% CI 0.93 to 1.65, P=0.14). Incidence proportion of patients with suboptimal adherence was 81/300 (27.0%) in the intervention arm and 65/299 (21.7%) in the standard care arm. The results of analyses adjusted for potential confounders were similar, indicating no significant difference between the allocation groups. Other secondary outcomes such as death and attrition rates, and subgroup analysis also showed comparable results across allocation groups. Conclusions In this multicentre randomised controlled trial among ART naïve patients initiating first line ART within the Indian national programme, we found no significant effect of the mobile phone intervention on either time to virological failure or ART adherence at the end of two years of therapy. Trial registration Current Controlled Trials ISRCTN79261738.

Molecular Epidemiology of HIV-1 Subtypes in India: Origin and Evolutionary History of the Predominant Subtype C

Background India has the third largest HIV-1 epidemic with 2.4 million infected individuals. Molecular epidemiological analysis has identified the predominance of HIV-1 subtype C (HIV-1C). However, the previous reports have been limited by sample size, and uneven geographical distribution. The introduction of HIV-1C in India remains uncertain due to this lack of structured studies. To fill the gap, we characterised the distribution pattern of HIV-1 subtypes in India based on data collection from nationwide clinical cohorts between 2007 and 2011. We also reconstructed the time to the most recent common ancestor (tMRCA) of the predominant HIV-1C strains. Methodology/Principal Findings Blood samples were collected from 168 HIV-1 seropositive subjects from 7 different states. HIV-1 subtypes were determined using two or three genes, gag, pol, and env using several methods. Bayesian coalescent-based approach was used to reconstruct the time of introduction and population growth patterns of the Indian HIV-1C. For the first time, a high prevalence (10%) of unique recombinant forms (BC and A1C) was observed when two or three genes were used instead of one gene (p<0.01; pu200a=u200a0.02, respectively). The tMRCA of Indian HIV-1C was estimated using the three viral genes, ranged from 1967 (gag) to 1974 (env). Pol-gene analysis was considered to provide the most reliable estimate [1971, (95% CI: 1965–1976)]. The population growth pattern revealed an initial slow growth phase in the mid-1970s, an exponential phase through the 1980s, and a stationary phase since the early 1990s. Conclusions/Significance The Indian HIV-1C epidemic originated around 40 years ago from a single or few genetically related African lineages, and since then largely evolved independently. The effective population size in the country has been broadly stable since the 1990s. The evolving viral epidemic, as indicated by the increase of recombinant strains, warrants a need for continued molecular surveillance to guide efficient disease intervention strategies.

Naturally Occurring Polymorphisms and Primary Drug Resistance Profile Among Antiretroviral-Naive Individuals in Bangalore, India

Although India has a large burden of HIV infection, good access to first-line antiretroviral therapy is widely available. However, understanding HIV resistance-associated mutations and polymorphisms is critical for continued success. The RT region of the HIV-1 pol gene was studied among 21 ART-naive HIV-1-infected individuals from South India. In addition, 421 published Indian HIV-1 subtype C sequences were analyzed for time trends in polymorphism frequency. Among primary isolates, all HIV-1 isolates were subtype C, and drug-resistant mutations were identified among two (9.56%) subjects. Mutations included E138A (etravirine resistance associated) and L210LS (thymidine analog mutation). The overall frequency of specific polymorphisms was similar to frequencies reported from different regions of India. Novel mutations were observed at positions Q23P/H and A129AG among isolates from our clinical cohort. Over a span of 10 years, the median polymorphism frequency among ART-naive subjects has remained unchanged, suggesting the slow evolution of HIV-1 subtype C in India.

TB treatment outcomes among TB-HIV co-infections in Karnataka, India: how do these compare with non-HIV tuberculosis outcomes in the province?

BackgroundIndia accounts for 23% of the global incidence of TB cases; it also has an estimated 2.3 million HIV infections. Of the 2 million TB incident cases, 5% occurred in HIV infected persons. The country has large national TB and HIV control programs. This paper describes characteristics of TB-HIV co-infection cases registered under the program in Karnataka province, India. Treatment outcomes for coinfected patients are compared with those for TB patients in the province.MethodsProgram reports from the National AIDS Control program and the National TB control program for Karnataka province (a high HIV prevalence state, population 61 million) were analysed. Data from patients registered in each program in 2010–2011 was studied.ResultsOf the 6,480 adult co-infections, a third occurred in women; 78% of patients were initiated on ART. Among the cohort 73% had pulmonary TB, and 46% reported sputum positivity for acid fast bacilli. Treatment success among co-infected patients not on ART (54%) were significantly lower compared to those already on ART (80%); death and default rates were higher in the non-ART group. Treatment success proportions (75%) for the co-infected patients were similar to those for the 51,966 patients registered under the TB program. Death rates among co-infected patients (15%) were twice as high as for TB patients under the program, though default and failure rates were lower.ConclusionCo-infected patients already on ART demonstrated better TB outcomes in than those not on ART. Compared to those with TB only, co-infected patients had similar TB treatment success rates and lower rates of treatment default and failure. Integration of TB-HIV collaborative activities will strengthen our battle to control TB and HIV globally.

Influence of Adverse Drug Reactions on Treatment Success: Prospective Cohort Analysis of HIV-Infected Individuals Initiating First-Line Antiretroviral Therapy in India

Introduction Adverse drug reactions related to antiretroviral therapy (ART) remain a challenge in resource-limited settings, often causing significant morbidity and impaired adherence leading to treatment failure. This 2-year prospective study aimed to describe patterns and predictors of adverse reactions to first-line ART and assess the impact of these events on treatment success. Methods Between 2010–2013, 321 ART-naïve eligible adults were enrolled at two clinics in southern India. ART regimens included zidovudine or stavudine plus lamivudine, plus nevirapine or efavirenz. Pill count adherence, immunological and virological monitoring, and laboratory-based adverse drug reactions were measured prospectively and analyzed. Results Among 321 patients in the study, 289 (90.0%) patients experienced at least 1 adverse reaction, and 85 (26.5%) experienced at least 1 severe reaction. The incidence rate was 52 and 15 per 100 person-years for all reactions and severe reactions respectively. The cumulative incidence of zidovudine-induced anemia was 37.1% over 2 years. At 12 and 24 months, the proportion of patients with optimal adherence, undetectable viral load and CD4 counts >350 cells/mm3 were similar between patients who experienced or did not experience severe adverse drug reactions. Conclusions Our results highlight the high frequency of ART-related adverse drug reactions among individuals initiating first-line ART in India, underscoring the importance of detailed counseling and monitoring for maintaining ART durability. Severe drug-induced anemia needs to be addressed urgently with alternative first-line agents, and close laboratory surveillance. High treatment efficacy despite decreased drug safety seen here may be because patients have limited treatment options. Our results support the use of currently recommended safer first-line ART regimens that minimize the risk of severe life-threatening toxicities and provide for a better quality of life. Trial registration ISRTCN Registry: ISRCTN79261738.

Co-receptor tropism prediction among 1045 Indian HIV-1 subtype C sequences: Therapeutic implications for India

BackgroundUnderstanding co-receptor tropism of HIV-1 strains circulating in India will provide key analytical leverage for assessing the potential usefulness of newer antiretroviral drugs such as chemokine co-receptor antagonists among Indian HIV-infected populations. The objective of this study was to determine using in silico methods, HIV-1 tropism among a large number of Indian isolates both from primary clinical isolates as well as from database-derived sequences.ResultsR5-tropism was seen in 96.8% of a total of 1045 HIV-1 subtype C Indian sequences. Co-receptor prediction of 15 primary clinical isolates detected two X4-tropic strains using the C-PSSM matrix. R5-tropic HIV-1 subtype C V3 sequences were conserved to a greater extent than X4-tropic strains. X4-tropic strains were obtained from subjects who had a significantly longer time since HIV diagnosis (96.5 months) compared to R5-tropic strains (20.5 months).ConclusionsHigh prevalence of R5 tropism and greater homogeneity of the V3 sequence among HIV-1 subtype C strains in India suggests the potential benefit of CCR5 antagonists as a therapeutic option in India.

Mobile phones to support adherence to antiretroviral therapy: what would it cost the Indian National AIDS Control Programme?

Adherence to antiretroviral treatment (ART) is critical to maintaining health and good clinical outcomes in people living with HIV/AIDS. To address poor treatment adherence, low‐cost interventions using mobile communication technology are being studied. While there are some studies that show an effect of mobile phone reminders on adherence to ART, none has reported on the costs of such reminders for national AIDS programmes. This paper aims to study the costs of mobile phone reminder strategies (mHealth interventions) to support adherence in the context of Indias National AIDS Control Program (NACP).

High concordance of genotypic coreceptor prediction in plasma-viral RNA and proviral DNA of HIV-1 subtype C: implications for use of whole blood DNA in resource-limited settings

OBJECTIVESnGenotypic tropism testing (GTT) of HIV is increasingly used prior to the initiation of CCR5 antagonist therapy in HIV-infected individuals. Normally performed on plasma-derived virus, the test is challenging when performed in patients with suppressed viraemia. We aimed to evaluate the performance of cell-associated proviral DNA against plasma-derived viral RNA as the genetic material for GTT in an Indian clinical setting.nnnMETHODSnFrom 52 HIV-1-infected individuals, the env V3 region was successfully amplified and sequenced from both proviral DNA and plasma RNA paired samples having a viral load >2500 copies/mL (nu200a=u200a42) and from proviral DNA only in 10 antiretroviral therapy (ART)-experienced patients with a viral load <500 copies/mL. GTT was performed using the Geno2Pheno algorithm with the interpretative false positive rate (FPR) cut-off of 10%.nnnRESULTSnAmong paired samples, 40 of 42 patients harboured subtype C strains. Plasma RNA tropism prediction revealed X4 tropism in 4 of 42 (9.5%). A high concordance of 97.6% in tropism prediction was noted in simultaneous RNA/DNA samples (38 R5 and 3 X4). Discordance was observed in one sample showing R5 tropism in proviral DNA and X4 tropism in plasma RNA. Comparison of Geno2Pheno FPRs in both the plasma and proviral compartments showed good correlation (overall, ru200a=u200a0.87; ART-naive patients, ru200a=u200a0.79; ART-failing patients, ru200a=u200a0.97). GTT was successfully performed in all 10 whole blood DNA samples having a viral load <500 copies/mL, all showing R5 tropism.nnnCONCLUSIONSnHigh concordance in tropism prediction from proviral DNA and plasma-viral RNA suggests that prediction of viral tropism using proviral DNA is accurate and feasible in resource-limited clinical settings, particularly in patients with low or suppressed viraemia.