Srikanth Tripathy

Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials.

BACKGROUND UNICEF/WHO recommends that infants born to HIV-infected mothers who do not have access to acceptable, feasible, affordable, sustainable, and safe replacement feeding should be exclusively breastfed for at least 6 months. The aim of three trials in Ethiopia, India, and Uganda was to assess whether daily nevirapine given to breastfed infants through 6 weeks of age can decrease HIV transmission via breastfeeding. METHODS HIV-infected women breastfeeding their infants were eligible for participation. Participants were randomly assigned to receive either single-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborns after birth) or 6 week extended-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborn babies after birth plus nevirapine 5 mg daily from days 8-42 for the infant). The randomisation sequences were generated by computer at a central data coordinating centre. The primary endpoint was HIV infection at 6 months of age in infants who were HIV PCR negative at birth. Analyses were by modified intention to treat, excluding infants with missing specimens and those with indeterminate or confirmed HIV infection at birth. These studies are registered with ClinicalTrials.gov, numbers NCT00074399, NCT00061321, and NCT00639938. FINDINGS 2024 liveborn infants randomised in the study had at least one specimen tested before 6 months of age (1047 infants in the single-dose group and 977 infants in the extended-dose group). The modified intention-to-treat population included 986 infants in the single-dose group and 901 in the extended-dose group. At 6 months, 87 children in the single-dose group and 62 in the extended-dose group were infected with HIV (relative risk 0.80, 95% CI 0.58-1.10; p=0.16). At 6 weeks of age, 54 children in the single-dose group and 25 in the extended-dose group were HIV positive (0.54, 0.34-0.85; p=0.009). 393 infants in the single-dose group and 346 in the extended-dose group experienced grade 3 or 4 serious adverse events during the study (p=0.54). INTERPRETATION Although a 6-week regimen of daily nevirapine might be associated with a reduction in the risk of HIV transmission at 6 weeks of age, the lack of a significant reduction in the primary endpoint-risk of HIV transmission at 6 months-suggests that a longer course of daily infant nevirapine to prevent HIV transmission via breast milk might be more effective where access to affordable and safe replacement feeding is not yet available and where the risks of replacement feeding are high. FUNDING US National Institutes of Health; US National Institute of Allergy and Infectious Diseases; Fogarty International Center.

Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide

Results are presented of the incidence of hepatitis, nearly always with jaundice, among 1686 patients in clinical trials of the treatment of spinal tuberculosis, of tuberculosis meningitis and of pulmonary tuberculosis with short-course regimens containing rifampicin, isoniazid, streptomycin and pyrazinamide. The incidence was high in patients treated with daily regimens of isoniazid and rifampicin: 16-39% in children with tuberculous meningitis, 10% in patients with spinal tuberculosis (non-surgical cases), and 2-8% in those with pulmonary tuberculosis. Hepatitis, in those receiving rifampicin occurred more often in slow than in rapid acetylators of isoniazid, the proportions amongst those whose acetylator phenotype had been determined being 11% of 317 slow acetylators and 1% of 244 rapid acetylators. In children with tuberculous meningitis, the risk of hepatitis with isoniazid 20 mg/kg (39%) was higher than that with 12 mg/kg (16%), and appreciably lower in patients given rifampicin twice-weekly (5%) rather than daily (21%). There was no indication that pyrazinamide contributed to the hepatic toxicity.

Nevirapine Resistance and Breast-Milk HIV Transmission: Effects of Single and Extended-Dose Nevirapine Prophylaxis in Subtype C HIV-Infected Infants

Background Daily nevirapine (NVP) prophylaxis to HIV-exposed infants significantly reduces breast-milk HIV transmission. We assessed NVP-resistance in Indian infants enrolled in the “six-week extended-dose nevirapine” (SWEN) trial who received single-dose NVP (SD-NVP) or SWEN for prevention of breast-milk HIV transmission but who also acquired subtype C HIV infection during the first year of life. Methods/Findings Standard population sequencing and cloning for viral subpopulations present at ≥5% frequency were used to determine HIV genotypes from 94% of the 79 infected Indian infants studied. Timing of infection was defined based on when an infants blood sample first tested positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six weeks of age had a significantly higher prevalence of NVP-resistance than those who received SD-NVP, by both standard population sequencing (92% of 12 vs. 38% of 29; p = 0.002) and low frequency clonal analysis (92% of 12 vs. 59% of 29; p = 0.06). Likelihood of infection with NVP-resistant HIV through breast-milk among infants infected after age six weeks was substantial, but prevalence of NVP-resistance did not differ among SWEN or SD-NVP exposed infants by standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00) and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72). Types of NVP-resistance mutations and patterns of persistence at one year of age were similar between the two groups. NVP-resistance mutations did differ by timing of HIV infection; the Y181C variant was predominant among infants diagnosed in the first six weeks of life, compared to Y188C/H during late breast-milk transmission. Conclusions/Significance Use of SWEN to prevent breast-milk HIV transmission carries a high likelihood of resistance if infection occurs in the first six weeks of life. Moreover, there was a continued risk of transmission of NVP-resistant HIV through breastfeeding during the first year of life, but did not differ between SD-NVP and SWEN groups. As with SD-NVP, the value of preventing HIV infection in a large number of infants should be considered alongside the high risk of resistance associated with extended NVP prophylaxis. Trial Registration ClinicalTrials.gov NCT00061321

Short course chemotherapy for tuberculous lymphadenitis in children.

OBJECTIVE--To assess the efficacy of a short course chemotherapy regimen for treating tuberculosis of the lymph nodes in children. DESIGN--Open, collaborative, outpatient clinical trial. SETTING--Outpatient department of the Tuberculosis Research Centre, paediatric surgery departments of the Institute of Child Health and Hospital for Children and the Government Stanley Hospital, Madras, South India. PATIENTS--Children aged 1-12 years with extensive, multiple site, superficial tuberculous lymphadenitis confirmed by biopsy (histopathology or culture). INTERVENTIONS--Patients were treated with a fully supervised intermittent chemotherapy regimen consisting of streptomycin, rifampicin, isoniazid, and pyrazinamide three times a week for two months followed by streptomycin and isoniazid twice a week for four months on an outpatient basis. Surgery was limited to biopsy of nodes for diagnosis and assessment. MAIN OUTCOME MEASURES--Response to chemotherapy was assessed by regression of lymph nodes and healing of sinuses and abscesses during treatment and follow up. Compliance with treatment and frequency of adverse reactions were also estimated. RESULTS--197 Patients were admitted to the study and 168 into the analysis. The regimen was well tolerated and compliance was good with 101 (60%) patients receiving the prescribed chemotherapy within 15 days of the stipulated period of six months. Those whose chemotherapy extended beyond that period received the same total number of doses. Clinical response was favourable in most patients at the end of treatment. Sinuses and abscesses healed rapidly. Residual lymphadenopathy (exceeding 10 mm diameter) was present in 50 (30%) patients at the end of treatment; these nodes were biopsied. Fresh nodes, increase in size of nodes, and sinuses and abscesses occurred both during treatment and follow up. After 36 months of follow up after treatment only 5 (3%) patients required retreatment for tuberculosis. CONCLUSION--Tuberculous lymphadenitis in children can be successfully treated with a short course chemotherapy regimen of six months.

Sensitivity and specificity of rapid HIV testing of pregnant women in India

OBJECTIVE Efforts to prevent HIV transmission from mother to infants in settings like India may benefit from the availability of reliable methods for rapid and simple HIV screening. Data from India on the reliability of rapid HIV test kits are limited and there are no data on the use of rapid HIV tests for screening of pregnant women. METHODS Pregnant women attending an antenatal clinic and delivery room in Pune agreed to participate in an evaluation of five rapid HIV tests, including (a) a saliva brush test (Oraquick HIV-1/2, Orasure Technologies Inc.), (b) a rapid plasma test (Oraquick HIV-1/2) and (c) three rapid finger prick tests (Oraquick HIV-1/2; HIV-1/2 Determine, Abbott; NEVA HIV-1/2 Cadila). Results of the rapid tests were compared with three commercial plasma enzyme immunoassay (EIA) tests (Innotest HIV AB EIA, Lab systems/ELISCAN HIV AB EIA, UBI HIV Ab EIA). RESULTS Between September 2000 and October 1, 2001, 1258 pregnant women were screened for HIV using these rapid tests. Forty-four (3.49%) of the specimens were HIV-antibody-positive by at least two plasma EIA tests. All of the rapid HIV tests demonstrated excellent specificity (96-100%). The sensitivity of the rapid tests ranged from 75-94%. The combined sensitivity and specificity of a two-step algorithm for rapid HIV testing was excellent for a number of combinations of the five rapid finger stick tests. CONCLUSION In this relatively low HIV prevalence population of pregnant women in India, the sensitivity of the rapid HIV tests varied, when compared to a dual EIA algorithm. In general, the specificity of all the rapid tests was excellent, with very few false positive HIV tests. Based upon these data, two different rapid HIV tests for screening pregnant women in India would be highly sensitive, with excellent specificity to reliably prevent inappropriate use of antiretroviral therapy for prevention of vertical HIV transmission.

Incidence of common opportunistic infections in HIV-infected individuals in Pune, India: analysis by stages of immunosuppression represented by CD4 counts

BACKGROUND Opportunistic infections (OIs) influence the morbidity and mortality due to HIV infections. Data from India on the incidence of OIs among HIV-infected individuals by stages of immunodeficiency are scarce. METHODS Between September 2002 and November 2004, HIV-infected individuals were enrolled in a prospective study in Pune. They were clinically and immunologically evaluated quarterly. Incidence rates of specific OIs were calculated. RESULTS Median CD4 counts in HIV-infected male and female patients at baseline were 197/mm(3) and 413/mm(3), respectively. Tuberculosis was the most common OI with an incidence of 15.4 (95% CI 12.2-19.2) per 100 person-years, followed by oral candidiasis 11.3 (95% CI 8.6-14.5), herpes zoster 10.1 (95% CI 7.6-13.1), and cryptococcal meningitis 1.7 (95% CI 0.8-3.1) per 100 person-years. Patients with baseline CD4 counts of <200/mm(3) were six times more likely to develop OIs compared to those with CD4 counts of >350/mm(3) (p<0.001). CONCLUSIONS The high incidence of commonly reported OIs in Indian HIV-infected individuals highlights the need for early screening and also the need to increase awareness in healthcare providers, in order to improve decisions regarding prophylaxis for prevention and appropriate therapeutic intervention. Emphasis needs to be given to the early diagnosis and management of tuberculosis in HIV-infected individuals.

Effect of storage of sputum specimens at room temperature on smear and culture results

A study of 41 specimens of sputum stored for up to 28 days at room temperature in a tropical country showed that smear results were not affected by storage, the positivity being 83% before storage and 80-83% after. The culture positivity was 88% before storage, and 83%, 68%, 22%, 13% and 0% after 3, 7, 14, 21 and 28 days of storage respectively. The reduction in positivity on storage attains significance at 7 days (P = 0.05). Another study involved 163 specimens of sputum and storage for 3, 5 or 7 days. Each specimen was examined before storage and after 2 periods of storage, at random. The smear results were again not affected. There was, however, significant loss of viability, the proportion culture positive being reduced from 92% before storage to 83% at 3 days (P = 0.05), 71% at 5 days (P less than 0.01) and 63% at 7 days (P less than 0.001). The contamination rate was 5%, 7%, 12% and 18% respectively. It is concluded that sputum should not be stored at room temperature for longer than 3 days for culture but it can be stored for 4 weeks without any loss of smear-positivity.

Species level identification of non-tuberculous mycobacteria from South Indian BCG trial area during 1981

In 1981, non-tuberculous mycobacteria (NTM) were obtained from 8.6% of 16 907 sputum specimens in a trial in the Chingleput district of Madras state to test the efficacy of BCG vaccination in the prevention of tuberculosis, but from only 0.6% of 672 autoclaved specimens cultured as part of a quality control procedure. This finding suggested that the NTM were truly derived from the sputum of the BCG trial subjects. The mycobacterial species could be identified in 966 (96.6%) of the first 1000 isolates of NTM: 54.6% were potential pathogens and 73.0% were slow growing. The species isolated most frequently were M. avium/intracellulare (22.6% of all NTM), M. terrae (12.5%) and M. scrofulaceum (10.5%). Those species accounting for 8-5% of all NTM were M. fortuitum, M. chelonei, M. flavescens, M. gordonae and M. vaccae.

Profile of Primary Resistance in HIV-1-Infected Treatment-Naive Individuals from Western India

The majority of the HIV drug resistance (HIVDR) testing studies have focused on subtype B virus. The predominance of subtype C in the Indian subcontinent along with greater access to antiretroviral therapy (ART) necessitates studies on HIVDR genotyping. We determined the prevalence of mutations associated with protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), and nonnucleoside reverse transcriptase inhibitors (NNRTI) from plasma of 40 antiretroviral drug-naive study participants in Indian HIV-1 pol gene sequences. Of these, 36 sequences belonged to subtype C, two to subtype A1, and two were subtype A1C recombinants. The heterosexual route was the most common route of transmission. Drug resistance-associated mutations were observed in 10% (4/40) of the study participants. The resistance mutation observed in the protease gene was V82A, whereas in the RT gene, M41L, D67N, M184V, and A98G were documented. This is the first study reporting major protease mutations by genotyping in ART-naive individuals from western India.

Pretreatment HIV Drug Resistance and HIV-1 Subtype C Are Independently Associated With Virologic Failure: Results From the Multinational PEARLS (ACTG A5175) Clinical Trial

BACKGROUND Evaluation of pretreatment HIV genotyping is needed globally to guide treatment programs. We examined the association of pretreatment (baseline) drug resistance and subtype with virologic failure in a multinational, randomized clinical trial that evaluated 3 antiretroviral treatment (ART) regimens and included resource-limited setting sites. METHODS Pol genotyping was performed in a nested case-cohort study including 270 randomly sampled participants (subcohort), and 218 additional participants failing ART (case group). Failure was defined as confirmed viral load (VL) >1000 copies/mL. Cox proportional hazards models estimated resistance-failure association. RESULTS In the representative subcohort (261/270 participants with genotypes; 44% women; median age, 35 years; median CD4 cell count, 151 cells/µL; median VL, 5.0 log10 copies/mL; 58% non-B subtypes), baseline resistance occurred in 4.2%, evenly distributed among treatment arms and subtypes. In the subcohort and case groups combined (466/488 participants with genotypes), used to examine the association between resistance and treatment failure, baseline resistance occurred in 7.1% (9.4% with failure, 4.3% without). Baseline resistance was significantly associated with shorter time to virologic failure (hazard ratio [HR], 2.03; P = .035), and after adjusting for sex, treatment arm, sex-treatment arm interaction, pretreatment CD4 cell count, baseline VL, and subtype, was still independently associated (HR, 2.1; P = .05). Compared with subtype B, subtype C infection was associated with higher failure risk (HR, 1.57; 95% confidence interval [CI], 1.04-2.35), whereas non-B/C subtype infection was associated with longer time to failure (HR, 0.47; 95% CI, .22-.98). CONCLUSIONS In this global clinical trial, pretreatment resistance and HIV-1 subtype were independently associated with virologic failure. Pretreatment genotyping should be considered whenever feasible. CLINICAL TRIALS REGISTRATION NCT00084136.