Influencing HIV treatment success in India : do mobile phones really work?

Background: Sustaining treatment adherence and long-term virological suppression is a global health challenge in HIV management. Mobile phone-based interventions are increasingly harnessed to enhance medication adherence in HIV infection, although supporting evidence for implementation is limited by lack of robust efficacy trials in settings such as India. The overall aim of this thesis was to assess whether customized mobile phone reminders would improve adherence to therapy and thus decrease virological failure among HIV-infected patients initiating anti-retroviral treatment (ART) within the Indian national AIDS control program, and to investigate factors related to the success of this intervention within this population. Methods: To test the feasibility and acceptability of the mobile phone-based reminder system, we conducted a 12-month single center pilot study among 150 HIV-infected ARTexperienced patients (Study I). Subsequently we conducted a two-year randomized controlled trial at three sites in southern India (Bangalore, Mysore and Chennai), where 631 eligible ART-naïve patients were enrolled (Studies II, III, IV). The intervention consisted of weekly interactive voice reminders, along with a weekly pictorial text message for two years. Patients were monitored for pill count adherence measurements, adherence barriers, drug toxicity, CD4 counts and viral load every three months. Results: The results of the pilot study indicated good acceptability and feasibility of the intervention, however a definite beneficial effect on adherence was inconclusive. (Study I). Analysis of the randomized controlled trial revealed no observed statistically significant difference in time to virological failure or sub-optimal adherence (mean adherence <95%) between the intervention and control groups, even after adjusting for potential confounders (Study II). Virological failure was associated with lower adherence levels, non-tenofovir drug regimens and primary drug resistance. Adherence levels and barriers varied significantly over time. The commonly reported barrier, ‘forgetfulness’ was not associated with virological failure. Significant determinants of optimal adherence were older age, higher level of education, greater disclosure status, and patients’ satisfaction with health status, medications and healthcare access (Study III). ART toxicity related to zidovudine and nevirapine was associated with lower levels of adherence, particularly in the first 6 months after ART initiation (Study IV). Conclusions: The results of this thesis indicate that mobile phone-based reminders alone may not improve adherence and promote treatment success among HIV-infected patients. Adherence behavior is a complex dynamic process with a multitude of diverse influencing factors. Optimal adherence and treatment success may be better sustained by minimizing drug interruptions for medical reasons, use of safer first-line ART regimens, and strengthening both patient self-efficacy and patient-health provider relationships

High viremia and low level of transmitted drug resistance in anti-retroviral therapy-naïve perinatally-infected children and adolescents with HIV-1 subtype C infection

BACKGROUND: High plasma viremia in HIV-1 infection is associated with rapid CD4 cell decline and faster disease progression. Children with HIV infection have high viral loads, particularly in early childhood. In this study we sought to understand the relationship between duration of HIV-1 infection and viral dynamics among perinatally-infected children and adolescents in India along with transmitted drug resistance in this population. METHODS: During 2007–2011, cross-sectional samples were collected from ART-naïve children (n = 105) with perinatally-acquired HIV infection, aged 2–16 years from Bangalore, India. CD4 counts, viral load and in-house genotyping were performed and transmitted drug resistance mutations were identified using the World Health Organization recommendations for Surveillance of Drug Resistance Mutations (SDRM_2009) list. RESULTS: Among 105 children studied, 73.3% (77/105) were asymptomatic, but had a median viral load of 5.24 log copies/mL (IQR 4.62-5.66). In the adolescent age group, 54% (21/39) had high levels of viremia (median 5.14 log copies/mL) but were asymptomatic. HIV-1 subtyping identified 98% strains (103/105) as subtype C; one A1 and one unique recombinant form (URF). Transmitted NRTI resistance was 1.9% (2/105); NNRTI resistance was 4.8% (5/105) and overall prevalence of transmitted drug resistance was 5.7% (6/105). CONCLUSIONS: The high burden of plasma viremia found among untreated asymptomatic adolescents needs to be addressed both from an individual angle to halt disease progression, and from a public health perspective to arrest horizontal transmission. The low level of transmitted drug resistance among perinatally-infected children is reassuring; however with improving ART access globally, regular genotyping surveillance is indicated

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

<p>Abstract</p> <p><b>Background</b></p> <p>Understanding 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 <it>in silico </it>methods, HIV-1 tropism among a large number of Indian isolates both from primary clinical isolates as well as from database-derived sequences.</p> <p>Results</p> <p>R5-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).</p> <p>Conclusions</p> <p>High 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.</p

Emergence of new genotypes and lineages of dengue viruses during the 2012–15 epidemics in southern India

Objectives: To genotypically characterize dengue virus (DENV) isolates among dengue-infected children from 2012–13/2014–15 outbreaks in southern India. Methods: Children hospitalized with suspected dengue were tested for dengue RT-PCR targeting Capsid-preMembrane (C-prM) and Envelope (Env) regions. Following virologic confirmation (n = 612), a representative selection of DENV isolates (n = 99) were sequenced for C-prM, aligned using ClustalW and subjected to phylogenetic analysis by maximum-likelihood method in MEGA6. Results: In 2012–13 (n = 113), DENV-3 (44, 38.9%) and DENV-2 (43, 38.1%) predominated; DENV-1 (22, 19.5%) and DENV-4 (1, 0.9%) were less common. The pattern changed in 2014–15 (n = 499), when DENV-1 (329, 65.7%) predominated, followed by DENV-2 (97, 21.2%), DENV-3 (36, 6.7%) and DENV-4 (10, 2.0%). Multiple-serotype co-infections occurred in 2.7% and 5.4% in 2012–13 and 2014–15, respectively. Genotype III (GIII) of DENV-1 predominated (85.7%) in 2012–13, ceding to GI predominance (80.8%) in 2014–15. Among DENV-2, 71.9% (23/32) showed distinct clustering suggesting a new lineage, 'GIVc'. All tested DENV-4 were GIC, whose clustering pattern showed the emergence of two distinct clades. Conclusions: New genotypic/lineage variations in DENV-1 and DENV-2 may have influenced the magnitude and severity of dengue epidemics in southern India during this period. These findings emphasize the role of active surveillance of DENV serotypes/genotypes in aiding outbreak control and vaccine studies. Keywords: Dengue virus, Serotyping, Sequencing, Phylogenetics, Genotypes, Lineage

Neonatal, 1–59 month, and under-5 mortality in 597 Indian districts, 2001 to 2012: estimates from national demographic and mortality surveys

Background India has the largest number of child deaths of any country in the world, and has wide local variation in under-5 mortality. Worldwide achievement of the UN 2015 Millennium Development Goal for under-5 mortality (MDG 4) will depend on progress in the subregions of India. We aimed to estimate neonatal, 1–59 months, and overall under-5 mortality by sex for 597 Indian districts and to assess whether India is on track to achieve MDG 4. Methods We divided the 2012 UN sex-specifi c birth and mortality totals for India into state totals using relative birth rates and mortality from recent demographic surveys of 24 million people, and divided state totals into totals for the 597 districts using 3 million birth histories. We then split the results into neonatal mortality and 1–59 month mortality using data for 109 000 deaths in children younger than 5 years from six national surveys. We compared results with the 2001 census for each district. Findings Under-5 mortality fell at a mean rate of 3·7% (IQR 3·2–4·9) per year between 2001 and 2012. 222 (37%) of 597 districts are on track to achieve the MDG 4 of 38 deaths in children younger than 5 years per 1000 livebirths by 2015, but an equal number (222 [37%]) will achieve MDG 4 only after 2020. These 222 lagging districts are home to 41% of India’s livebirths and 56% of all deaths in children younger than 5 years. More districts lag behind the relevant goal for neonatal mortality (251 [42%]) than for 1–59 month mortality (197 [33%]). Just 81 (14%) districts account for 37% of deaths in children younger than 5 years nationally. Female mortality at ages 1–59 months exceeded male mortality by 25% in 303 districts in nearly all states of India, totalling about 74 000 excess deaths in girls. Interpretation At current rates of progress, MDG 4 will be met by India around 2020—by the richer states around 2015 and by the poorer states around 2023. Accelerated progress to reduce mortality during the neonatal period and at ages 1–59 months is needed in most Indian districts. Funding Disease Control Priorities 3, Canadian Institutes of Health Research, International Development Research Centre, US National Institutes of Health

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

Poor 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/Design: 600 treatment naive 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. Stepping 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.EU/HIVIN

Anemia, diet and therapeutic iron among children living with HIV: a prospective cohort study

BACKGROUND: Children living with HIV have higher-than-normal prevalence of anemia. The beneficial effect of therapeutic iron has been questioned in the setting of high prevalence of infections. This study examines anemia prevalence and effect of standard therapeutic iron on HIV disease progression among children. METHODS: Perinatally-infected children aged 2–12 years were enrolled at three sites in southern India, and were followed for 1 year with clinical assessments, dietary recall and anthropometry. Laboratory parameters included iron markers (ferritin, soluble transferrin receptor) and other micronutrient levels (vitamin A, B(12), folate). Iron was given to anemic children based on WHO guidelines. Statistical analyses including frequency distributions, chi square tests and multivariate logistic regression were performed using Stata v13.0. RESULTS: Among 240 children enrolled (mean age 7.7 years, 54.6 % males), median CD4 was 25 %, 19.2 % had advanced disease, 45.5 % had malnutrition, and 43.3 % were on antiretroviral treatment (ART) at baseline. Anemia was prevalent in 47.1 % (113/240) children. Iron deficiency was present in 65.5 %; vitamin A and vitamin B(12) deficiency in 26.6 % and 8.0 % respectively; and anemia of inflammation in 58.4 %. Independent risk factors for anemia were stunting, CD4 < 25 %, detectable viral load ≥400 copies/ml and vitamin A deficiency. Inadequate dietary iron was prominent; 77.9 % obtained less than two-thirds of recommended daily iron. Among clinically anemic children who took iron, overall adherence to iron therapy was good, and only minor self-limiting adverse events were reported. Median hemoglobin rose from 10.4 g/dl to 10.9 mg/dl among those who took iron for 3 months, and peaked at 11.3 mg/dl with iron taken for up to 6 months. Iron was also associated with a greater fall in clinical severity of HIV stage; however when adjusted for use of ART, was not associated with improvement in growth, inflammatory and CD4 parameters. CONCLUSIONS: Children living with HIV in India have a high prevalence of anemia mediated by iron deficiency, vitamin A deficiency and chronic inflammation. The use of therapeutic iron for durations up to 6 months appears to be safe in this setting, and is associated with beneficial effects on anemia, iron deficiency and HIV disease progression