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1.  Improved Neuropsychological and Neurological Functioning Across Three Antiretroviral Regimens in Diverse Resource-Limited Settings: AIDS Clinical Trials Group Study A5199, the International Neurological Study 
ACTG A5199 compared the neuropsychological effects of 3 antiretroviral regimens in 860 human immunodeficiency virus–positive participants from Brazil, India, Malawi, Peru, South Africa, Thailand, and Zimbabwe. Treatment with either of the World Health Organization–recommended first-line regimens improved neurological and neuropsychological functioning.
Background. AIDS Clinical Trials Group (ACTG) A5199 compared the neurological and neuropsychological (NP) effects of 3 antiretroviral regimens in participants infected with human immunodeficiency virus type 1 (HIV-1) in resource-limited settings.
Methods. Participants from Brazil, India, Malawi, Peru, South Africa, Thailand, and Zimbabwe were randomized to 3 antiretroviral treatment arms: A (lamivudine-zidovudine plus efavirenz, n = 289), B (atazanavir, emtricitabine, and didanosine-EC, n = 293), and C (emtricitabine-tenofovir-disoproxil fumarate plus efavirenz, n = 278) as part of the ACTG PEARLS study (A5175). Standardized neurological and neuropsychological (NP) screening examinations (grooved pegboard, timed gait, semantic verbal fluency, and finger tapping) were administered every 24 weeks from February 2006 to May 2010. Associations with neurological and neuropsychological function were estimated from linear and logistic regression models using generalized estimating equations.
Results. The median weeks on study was 168 (Q1 = 96, Q3 = 192) for the 860 participants. NP test scores improved (P < .05) with the exception of semantic verbal fluency. No differences in neurological and neuropsychological functioning between treatment regimens were detected (P > .10). Significant country effects were noted on all NP tests and neurological outcomes (P < .01).
Conclusions. The study detected no significant differences in neuropsychological and neurological outcomes between randomized ART regimens. Significant improvement occurred in neurocognitive and neurological functioning over time after initiation of ARTs. The etiology of these improvements is likely multifactorial, reflecting reduced central nervous system HIV infection, better general health, and practice effects. This study suggests that treatment with either of the World Health Organization –recommended first-line antiretroviral regimens in resource-limited settings will improve neuropsychological functioning and reduce neurological dysfunction.
Clinical trials registration.  NCT00096824.
doi:10.1093/cid/cis507
PMCID: PMC3491853  PMID: 22661489
2.  Predictors of Clinical Progression in HIV-1-Infected Adults Initiating Combination Antiretroviral Therapy with Advanced Disease in the Asia-Pacific Region: Results from the TREAT Asia HIV Observational Database 
The majority of HIV-infected patients in developing countries commences combination antiretroviral therapy (cART) with advanced disease. We examined predictors of disease progression in patients initiating cART with CD4 count ≤200 cells/mm3 in the TREAT Asia HIV Observational Database. The main outcome measure was progression to either an AIDS-defining illness or death occurring 6 months after initiation of cART. We used survival analysis methods. A total of 1255 patients contributed 2696 person years of follow-up; 73 were diagnosed with AIDS and 9 died. The rate of progression to the combined end point was 3.0 per 100 person years. The factors significantly associated with a higher risk of disease progression were Indian ethnicity, infection through intravenous drug use, lower CD4 count, and hemoglobin ≤130 g/dL at 6 months. In conclusion, measurements of CD4 count and hemoglobin at month 6 may be useful for early identification of disease progression in resource-limited settings.
doi:10.1177/1545109712469684
PMCID: PMC3716846  PMID: 23422741
HIV; disease progression; antiretroviral therapy; resource-limited settings
3.  Primary prevention lessons learned from those with HIV in Chennai, India 
Sexual health  2011;8(2):199-206.
Background
As each HIV-infected individual represents a breakdown of HIV primary prevention measures, formative data from representative individuals living with HIV can help shape future primary prevention interventions. Little is known about sexual behaviours and other transmission risk factors of high-risk group members who are already HIV-infected in Chennai, India.
Methods
Semi-structured qualitative interviews were conducted with 27 HIV-infected individuals representing each high-risk group in Chennai (five men who have sex with men (MSM), five female commercial sex workers (CSW), four truckers and other men who travel for business, four injecting drug users (IDU), five married male clients of CSW, and four wives of CSW clients, MSM, truckers, and IDU).
Results
Themes relevant to HIV primary prevention included: (1) HIV diagnosis as the entry into HIV education and risk reduction, (2) reluctance to undergo voluntary counselling and testing, (3) gender and sexual roles as determinants of condom use, (4) misconceptions about HIV transmission, and (5) framing and accessibility of HIV education messages.
Conclusions
These qualitative data can be used to develop hypotheses about sexual risk taking in HIV-infected individuals in South India, inform primary prevention intervention programs, and improve primary prevention efforts overall.
doi:10.1071/SH10015
PMCID: PMC3707611  PMID: 21592434
AIDS; education; MSM; sex workers; sexual behaviour
4.  Quality of Life Among Individuals with HIV Starting Antiretroviral Therapy in Diverse Resource-Limited Areas of the World 
AIDS and Behavior  2012;16(2):266-277.
As Antiretroviral Therapy (ART) is scaled up in low- and middle-income countries, it is important to understand Quality of Life (QOL) correlates including disease severity and person characteristics and to determine the extent of between-country differences among those with HIV. QOL and medical data were collected from 1,563 of the 1,571 participants at entry into a randomized clinical trial of ART conducted in the U.S. (n = 203) and 8 resource-limited countries (n = 1,360) in the Caribbean, South America, Asia, and Africa. Participants were interviewed prior to initiation of ART using a modified version of the ACTG SF-21, a health-related QOL measure including 8 subscales: general health perception, physical functioning, role functioning, social functioning, cognitive functioning, pain, mental health, and energy/fatigue. Other measures included demographics, CD4+ lymphocyte count, plasma HIV-1 RNA viral load. Higher quality of life in each of the 8 QOL subscales was associated with higher CD4+ lymphocyte category. General health perception, physical functioning, role functioning, and energy/fatigue varied by plasma HIV-1 RNA viral load categories. Each QOL subscale included significant variation by country. Only the social functioning subscale varied by sex, with men having greater impairments than women, and only the physical functioning subscale varied by age category. This was the first large-scale international ART trial to conduct a standardized assessment of QOL in diverse international settings, thus demonstrating that implementation of the behavioral assessment was feasible. QOL indicators at study entry varied with disease severity, demographics, and country. The relationship of these measures to treatment outcomes can and should be examined in clinical trials of ART in resource-limited settings using similar methodologies.
doi:10.1007/s10461-011-9947-5
PMCID: PMC3182285  PMID: 21499794
Quality of life (QOL); Highly active antiretroviral therapy (HAART); HIV
5.  Impact of highly active antiretroviral therapy on salivary flow in patients with human-immuno deficiency virus disease in Southern India 
Aims:
To ascertain and compare between highly active antiretroviral therapy (HAART) and non-HAART patients, the stimulated salivary flow rates and unstimulated salivary flow rates (USFR and SSFR) and to correlate the salivary flow rates with immune suppression.
Materials and Methods:
One hundred human-immuno deficiency virus seropositive patients attending RAGAS-YRG CARE were examined and divided into two groups, a HAART group (patients on combination antiretroviral therapy) comprising 50 patients and a non-HAART group comprising 50 patients. The HAART group was followed every 3 months after the baseline visit (0) for a period of 9 months, during which a clinical oral examination and collection of unstimulated and stimulated saliva was done. Their salivary gland function was assessed using a xerostomia inventory during each visit. The study on non-HAART group was cross-sectional.
Statistical Analysis:
Statistical analysis were performed with the aid of the Statistical Package for the Social Sciences (SPSS version 10.05) software.
Results:
There was no significant difference in mean SSFR and USFR between the two groups at baseline. In the HAART group, the mean stimulated salivary flow rate increased from baseline to 3 months (P = 0.02), with the increase being maintained at 6 months and 9 months. When salivary flow rates were correlated with Cluster of Differentiation, CD4 counts, patients in the HAART group with a CD4 ≤ 200 at 6 months visit had a higher mean stimulated salivary flow rate when compared with patients with CD4 ≥ 200 (P = 0.02). The xerostomia inventory did not reveal any significant difference between the two groups and HAART was not significantly associated with xerostomia.
Conclusion:
In our study HAART was neither associated with xerostomia nor a reduction in salivary flow rate and immune suppression was not a significant factor for decreasing the salivary flow rate.
doi:10.4103/0973-029X.110695
PMCID: PMC3687181  PMID: 23798824
Cluster of differentiation 4 (CD4) count; highly active antiretroviral therapy; human-immuno deficiency virus; salivary flow rates
6.  A Multinational Study of Neurological Performance in Antiretroviral Therapy-Naïve HIV-1-Infected Persons in Diverse Resource-Constrained Settings 
Journal of Neurovirology  2011;17(5):438-447.
Background
Little is known about how the prevalence and incidence of neurological disease in HIV-infected patients in resource-limited settings. We present an analysis of neurological and neurocognitive function in antiretroviral naïve individuals in multinational resource-limited settings.
Methods
This prospective multinational cohort study, a substudy of a large international randomized antiretroviral treatment trial, was conducted in 7 low and middle income countries in Sub-Saharan Africa, South America, and Asia. Subjects were HIV-infected and met regional criteria to initiate antiretroviral therapy. Standardized neurological examination and a brief motor-based neuropsychological examination were administered.
Results
860 subjects were studied. Overall 249 (29%) had one or more abnormalities on neurological examinations, but there was a low prevalence of HIV-associated dementia (HAD) and minor neurocognitive disorder (MND). Twenty percent of subjects had evidence of peripheral neuropathy. There were significant differences across countries (p<.001) in neuropsychological test performance.
Conclusions
In this first multinational study of neurological function in antiretroviral naïve individuals in resource-limited settings, there was a substantial prevalence of peripheral neuropathy and low prevalence of dementia and other CNS diseases. There was significant variation in neurocognitive test performance and neurological examination findings across countries. These may reflect cultural differences, differences in HIV-related and unrelated diseases, and variations in test administration across sites. Longitudinal follow-up after antiretroviral treatment initiation may help to define more broadly the role of HIV in these differences as well as the impact of treatment on performance.
doi:10.1007/s13365-011-0044-3
PMCID: PMC3362044  PMID: 21786076
HIV; resource-limited; cognitive impairment; CNS; neuropsychological examination
7.  Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings 
PLoS Medicine  2012;9(8):e1001290.
Thomas Campbell and colleagues report findings of a randomized trial conducted in multiple countries regarding the efficacy of antiretroviral regimens with simplified dosing.
Background
Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.
Methods and Findings
1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure.
An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72–1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39–0.64 for women; HR 0.79, CI 0.62–1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12–2.04; p = 0.007).
Conclusion
EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.
Trial Registration
www.ClinicalTrials.gov NCT00084136
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Despite the enormous gains in reducing HIV-related illness and death over the past decade, there are still considerable challenges to meeting the global goal of universal access to highly active antiretroviral treatment—a combination of effective drugs that attack the HIV virus in various ways—to everyone living with HIV/AIDS who could benefit from treatment. In recognition of the related financial, technical, and system obstacles to providing universal access to HIV treatment, in 2010 the UN agency responsible for HIV/AIDS—UNAIDS—launched an ambitious plan called Treatment 2.0, which aims to simplify the way HIV treatment is currently provided. One of the main focuses of Treatment 2.0 is to simplify drug regimes for the treatment of HIV and to make treatment regimes less toxic. In line with Treatment 2.0, the World Health Organization currently recommends that antiretroviral regimens for the initial treatment of HIV should include two nucleoside reverse transcriptase inhibitors (zidovudine or tenofovir disoproxil fumarate [DF] with lamivudine or emtricitabine) and a non-nucleoside reverse transcriptase inhibitor (efavirenz or nevirapine.)
Why Was This Study Done?
Most of the evidence about the safety and effectiveness of clinical trials come from clinical trials in high-income countries and thus is not generally representative of the majority of people with HIV. So in this study, the researchers conducted a randomized controlled trial in diverse populations in many different settings to investigate whether antiretroviral regimens administered once daily were as effective as twice-daily regimens and also whether a regimen containing the drug atazanavir administered once daily was as safe and effective as a regimen containing efavirenz—data from previous studies have suggested that atazanavir has characteristics, such as its side effect profile, which may make it more suitable for low income settings.
What Did the Researchers Do and Find?
The researchers recruited eligible patients from centers in Brazil, Haiti, India, Malawi, Peru, South Africa, Thailand, the United States, and Zimbabwe—almost half (47%) were women. Then the researchers randomly assigned participants to one of three regimens: efavirenz 600 mg daily plus co-formulated lamivudine-zidovudine 150 mg/300 mg twice daily (EFV+3TC-ZDV); or atazanavir 400 mg once daily, plus didanosine-EC 400 mg once daily, plus emtricitabine 200 mg once daily (ATV+DDI+FTC); or efavirenz 600 mg once daily plus coformulated emtricitabine-tenofovir-DF 200 mg/300 mg once daily (EFV+FTC-TDF). During the study period ATV+DDI+FTC was found to be inferior to EFV+3TC-ZDV, so the Multinational Data Safety Monitoring Board ordered this arm of the trial to stop. Then a year later, due to the low number of treatment failures (deaths, severe HIV disease, or serious opportunistic infections) in the remaining two arms, the board advised the trial to stop early. So the researchers analyzed the data obtained up to this point and pooled the results from all of the centers.
The researchers found that during an average of 184 weeks of follow-up, there were 95 treatment failures (18%) among 526 participants taking EFV+FTC-TDF compared to 98 failures among 519 participants taking EFV+3TC-ZDV. During an average 81 weeks follow-up, there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV. As for safety, 243 (46%) participants assigned to EFV+FTC-TDF reached a safety endpoint (grade 3 disease, abnormal lab measurement, or the need to change drug) compared to 313 (60%) in the EFV+3TC-ZDV group. Importantly, the researchers found that there was greater risk of safety events for women assigned to EFV+3TC-ZDV and also that the atazanavir-based regimen had a higher relative efficacy in women compared to men.
What Do These Findings Mean?
These findings suggest that in diverse populations, EFV+FTC-TDF is as effective as EFV+3TC-ZDV but importantly, the once-daily dosing of EFV+FTC-TDF makes this regimen useful for the initial treatment of HIV, especially in low-income countries. Therefore, as per the guidance in Treatment 2.0, EFV+FTC-TDF in a single combination tablet that can be taken once a day is an attractive option. These findings also indicate that as ATV+DDI+FTC was found to be inferior to the other regimens, this combination should not be used in the initial treatment of HIV. These findings also add to the evidence that antiretroviral efficacy and safety can differ between women and men and support further development of sex-specific recommendations for antiretroviral regimen options.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001290.
The UNAIDS website has more information about Treatment 2.0; and the WHO website provides technical information
For an introduction to the treatment of HIV/AIDS see http://www.avert.org/treatment.htm; the AVERT site also has personal stories from women living with HIV/AIDS
AIDSmap provides information for individuals and communities affected by HIV/AIDS
The ACTG website provides information about research to improve treatment of HIV and related complications
doi:10.1371/journal.pmed.1001290
PMCID: PMC3419182  PMID: 22936892
8.  Mean CD4 cell count changes in patients failing a first-line antiretroviral therapy in resource-limited settings 
BMC Infectious Diseases  2012;12:147.
Background
Changes in CD4 cell counts are poorly documented in individuals with low or moderate-level viremia while on antiretroviral treatment (ART) in resource-limited settings. We assessed the impact of on-going HIV-RNA replication on CD4 cell count slopes in patients treated with a first-line combination ART.
Method
Naïve patients on a first-line ART regimen with at least two measures of HIV-RNA available after ART initiation were included in the study. The relationships between mean CD4 cell count change and HIV-RNA at 6 and 12 months after ART initiation (M6 and M12) were assessed by linear mixed models adjusted for gender, age, clinical stage and year of starting ART.
Results
3,338 patients were included (14 cohorts, 64% female) and the group had the following characteristics: a median follow-up time of 1.6 years, a median age of 34 years, and a median CD4 cell count at ART initiation of 107 cells/μL. All patients with suppressed HIV-RNA at M12 had a continuous increase in CD4 cell count up to 18 months after treatment initiation. By contrast, any degree of HIV-RNA replication both at M6 and M12 was associated with a flat or a decreasing CD4 cell count slope. Multivariable analysis using HIV-RNA thresholds of 10,000 and 5,000 copies confirmed the significant effect of HIV-RNA on CD4 cell counts both at M6 and M12.
Conclusion
In routinely monitored patients on an NNRTI-based first-line ART, on-going low-level HIV-RNA replication was associated with a poor immune outcome in patients who had detectable levels of the virus after one year of ART.
doi:10.1186/1471-2334-12-147
PMCID: PMC3573925  PMID: 22742573
HIV-1; CD4 count; CD4 slope; HIV-RNA threshold; Resource limited settings
9.  Sexual risk behaviors among HIV-infected South Indian couples in the HAART era: implications for reproductive health and HIV care delivery 
AIDS care  2011;23(6):722-733.
The current study examines sexual behaviors among HIV-infected Indians in primary care, where access to highly active antiretroviral therapy (HAART) has recently increased. Between January to April 2008, we assessed the sexual behaviors of 247 HIV-infected South Indians in care. Multivariable logistic regression models were used to determine predictors of being in a HIV-seroconcordant primary relationship, being sexually active, and reporting unprotected sex. Over three-fourths (80%) of participants were HAART-experienced. Among the 58% of participants who were currently in a seroconcordant relationship, one-third were serodiscordant when first tested for HIV. Approximately two-thirds (63.2%) of participants were sexually active; 9.0% reported unprotected sex. In the multivariable analyses, participants who were in a seroconcordant primary relationship were more likely to have children, use alcohol, report unprotected sex, and have been enrolled in care for >12 months. Sexually active participants were more likely to be on HAART, have a prior tuberculosis diagnosis, test Herpes simplex type 2 antibody seropositive, and have low general health perceptions. Participants who reported unprotected sex were more likely to be in a seroconcordant relationship, be childless, want to have a child, and use alcohol. We did not document an association between HAART and unprotected sex. Among HIV-infected Indians in primary care, predictors of unprotected sex included alcohol use and desire for children. Prevention interventions for Indian couples should integrate reproductive health and alcohol use counseling at entry into care.
doi:10.1080/09540121.2010.525616
PMCID: PMC3095699  PMID: 21293990
HIV; AIDS; sexual behavior; HAART; India
10.  Tuberculosis in HIV Programmes in Lower-Income Countries: Practices and Risk Factors 
SUMMARY
Background
Tuberculosis (TB) is a common diagnosis in HIV-infected patients on antiretroviral therapy (ART).
Objective
To describe TB-related practices in ART programmes in lower-income countries and identify risk factors for TB in the first year of ART.
Methods
Programme characteristics were assessed by standardized electronic questionnaire. Patient data from 2003-2008 were analyzed and incidence rate ratios (IRRs) calculated using Poisson regression models.
Results
Fifteen ART programmes in 12 countries in Africa, South America and Asia were included. Chest X-ray, sputum microscopy and culture were available free of charge in 13 (86.7%), 14 (93.3%) and eight (53.3%) programmes, respectively. Eight sites (53.3%) used directly observed therapy and five (33.3%) routinely administered isoniazid preventive therapy (IPT). A total of 19,413 patients aged ≥16 years contributed 13,227 person-years of follow-up; 1,081 new TB events were diagnosed. Risk factors included CD4 cell count (adjusted IRR comparing >350 cells/μL with <25 cells/μL 0.46, 95% CI 0.33-0.64, P<0.0001), gender (adjusted IRR comparing women with men 0.77, 0.68-0.88, P=0.0001) and use of IPT (IRR 0.24, 95% CI 0.19-0.31, p<0.0001).
Conclusions
Diagnostic capacity and practices vary widely across ART programmes. IPT prevented TB but was used in few programmes. More efforts are needed to reduce the burden of TB in HIV co-infected patients in lower income countries.
doi:10.5588/ijtld.10.0249
PMCID: PMC3140103  PMID: 21756512
tuberculosis; HIV; prevention; access; diagnostics; treatment practices; antiretroviral therapy; lower income countries; immunodeficiency; risk factor
11.  Timing of Antiretroviral Therapy for HIV-1 Infection and Tuberculosis 
The New England Journal of Medicine  2011;365(16):1482-1491.
Background
Antiretroviral therapy (ART) is indicated during tuberculosis (TB) treatment of patients infected with HIV-1, but the urgency to start ART at TB diagnosis for patients of varying levels of immune compromise is not known.
Methods
We conducted an open label, randomized study comparing immediate (within 2 weeks of TB treatment initiation) to early (8–12 weeks) ART among HIV-1 infected patients with CD4+ lymphocytes < 250/mm3 and suspected TB. The primary study endpoint was proportion of patients who survived without an AIDS-defining illness at 48 weeks.
Results
809 patients with median baseline CD4+ lymphocytes of 77 cells/mm3 and HIV-1 RNA of 5.43 log10 copies/mL were enrolled. In the immediate arm, 12.9% of patients experienced an AIDS-defining illness or death by 48 weeks compared to 16.1% in the early arm (p=0.45; 95% confidence interval (CI) for difference: −1.8%, 8.1%). In patients with screening CD4+ lymphocytes <50 cells/mm3, 15.5% of patients on the immediate arm vs. 26.6% on early ART experienced an AIDS defining illness or death (p=0.02; difference CI: 1.5%, 20.5%). TB immune reconstitution inflammatory syndrome (IRIS) was more common with immediate ART (11% vs. 5%: p=0.002). Viral suppression at 48 weeks was 74% and did not differ between arms (p=0.38).
Conclusion
Overall, immediate ART did not reduce AIDS-defining illnesses and death compared to early ART. For persons with CD4+ lymphocytes < 50 cells/mm3, immediate ART had 42% less AIDS defining illnesses and death compared to early ART. (ClinicalTrial.gov number NCT00108862.)
doi:10.1056/NEJMoa1013607
PMCID: PMC3327101  PMID: 22010914
12.  Safety, Tolerability, and efficacy of second-line generic protease inhibitor containing HAART after first-line failure among South Indian HIV-infected patients 
Introduction
We describe the safety, tolerability, and efficacy of protease inhibitor (PI) containing HAART among patients switching from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based highly active antiretroviral therapy (HAART) from a clinical setting in South India.
Methods
We assessed a prospective cohort of 91 HIV-infected patients with at least 12 months of clinical follow-up on second line ritonvair boosted PI-based therapy between August 2003 and December 2008.
Results
Over three-fourths of patients met the WHO criteria for immunological failure at the time of switch. The median time to switch was 758 days. Patients demonstrated consistent increases in their CD4 cell counts during the first 12 months, by which time the median CD4 cell count was 322 cells/ul. The most common adverse events within the first year after switch were nausea (14.8%), lipodystrophy (10.4%), and peripheral neuropathy (7.0%). Patients switching to ATV-based regimens compared to those switching to IDV-based regimens had similar immunological and clinical outcomes.
Conclusions
Given the therapeutic success of utilizing second-line PI-containing HAART after experiencing treatment failure, further efforts must be taken to expand access to second-line HAART so that more patients can benefit from these drugs.
doi:10.1177/1545109710382780
PMCID: PMC3128549  PMID: 21266320
HIV; AIDS; India; HAART; second-line therapy; protease inhibitors
13.  Predictors of Nonadherence to Highly Active Antiretroviral Therapy Among HIV-Infected South Indians in Clinical Care: Implications for Developing Adherence Interventions in Resource-Limited Settings 
AIDS Patient Care and STDs  2010;24(12):795-803.
Abstract
In light of the increasing availability of generic highly active antiretroviral therapy (HAART) in India, further data are needed to examine variables associated with HAART nonadherence among HIV-infected Indians in clinical care. We conducted a cross-sectional analysis of 198 HIV-infected South Indian men and women between January and April 2008 receiving first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART. Nonadherence was defined as taking less than 95% of HAART doses in the last 1 month, and was examined using multivariable logistic regression models. Half of the participants reported less than 95% adherence to HAART, and 50% had been on HAART for more than 24 months. The median CD4 cell count was 435 cells per microliter. An increased odds of nonadherence was found for participants with current CD4 cell counts greater than 500 cells per microliter (adjusted odds ratio [AOR]: 2.22 [95% confidence interval {CI}: 1.04–4.75]; p = 0.038), who were on HAART for more than 24 months (AOR: 3.07 [95% CI: 1.35–7.01]; p = 0.007), who reported alcohol use (AOR: 5.68 [95%CI: 2.10-15.32]; p = 0.001), who had low general health perceptions (AOR: 3.58 [95%CI: 1.20-10.66]; p = 0.021), and who had high distress (AOR: 3.32 [95%CI: 1.19-9.26]; p = 0.022). This study documents several modifiable risk factors for nonadherence in a clinic population of HIV-infected Indians with substantial HAART experience. Further targeted culturally specific interventions are needed that address barriers to optimal adherence.
doi:10.1089/apc.2010.0153
PMCID: PMC3011993  PMID: 21091232
14.  Antiretroviral therapy in Indian setting: When & what to start with, when & what to switch to? 
With the rapid scale up of antiretroviral therapy, there is a dramatic decline in HIV related morbidity and mortality in both developed and developing countries. Several new safe antiretroviral, and newer class of drugs and monitoring assays are developed recently. As a result the treatment guideline for the management of HIV disease continue to change. This review focuses on evolving science on Indian policy - antiretroviral therapy initiation, which drugs to start with, when to change the initial regimen and what to change.
doi:10.4103/0971-5916.92626
PMCID: PMC3284090  PMID: 22310814
Antiretroviral drugs; antiretroviral therapy; ART; CD4; HIV; IRIS; viral load
15.  Sex-associated Differences in Pre-Antiretroviral Therapy Plasma HIV-1 RNA in Diverse Areas of the World Vary by CD4 Cell Count 
Antiviral therapy  2011;16(7):1057-1062.
Background
Sex differences in the natural history of HIV infection may vary between resource-rich and resource-limited settings.
Objective
Baseline characteristics from a randomized clinical trial of treatment naïve subjects conducted at sites in Africa, Asia, the Caribbean, and North and South America were analyzed to determine if there were significant differences by sex.
Results
Of the 1571 participants, 740 (47.1%) were women. Women had higher mean screening CD4 cell counts (average 15 cells higher, (p<0.001), lower mean hemoglobin and creatinine clearance, a lower mean baseline HIV-1 viral load (4.85 log10 vs. 5.05 log10 copies/mL (P<0.001)) and were less likely to have a prior AIDS diagnosis than men. The sex difference in viral load difference was related to CD4 cell count, however it was independent of country and persisted within the strata with CD4 < 200 cells/mm3.
Conclusion
Women in resource limited settings have lower levels of plasma HIV-1 RNA and appear to present for enrollment into a clinical trials at an earlier stage of disease than men. The biologic basis for lower viral in women compared to men remains unexplained. It will be important to determine if the sex differences observed at baseline impact clinical outcomes once the PEARLS clinical trial is completed.
doi:10.3851/IMP1872
PMCID: PMC3205462  PMID: 22024521
viral load; sex; international; clinical trial; CD4 cell count
16.  Prioritising prevention strategies for patients in Antiretroviral Treatment Programmes in Resource-Limited Settings 
AIDS care  2010;22(6):775-783.
Expanded access to antiretroviral therapy (ART) offers opportunities to strengthen HIV prevention in resource-limited settings. We invited 27 ART programmes from urban settings in Africa, Asia and South America to participate in a survey, with the aim to examine what preventive services had been integrated in ART programmes. Twenty-two programmes participated; 8 (36%) from South Africa, 2 from Brazil, 2 from Zambia and 1 each from Argentina, India, Thailand, Botswana, Ivory Coast, Malawi, Morocco, Uganda and Zimbabwe. Twenty-one sites (96%) provided health education and social support, and 18 (82%) provided HIV testing and counselling. All sites encouraged disclosure of HIV infection to spouses and partners, but only 11 (50%) had a protocol for partner notification. Twenty-one sites (96%) supplied male condoms, 7 (32%) female condoms and 20 (91%) provided prophylactic ART for the prevention of mother-to-child transmission. Seven sites (33%) regularly screened for sexually transmitted infections (STI). Twelve sites (55%) were involved in activities aimed at women or adolescents, and 10 sites (46%) in activities aimed at serodiscordant couples. Stigma and discrimination, gender roles and funding constraints were perceived as the main obstacles to effective prevention in ART programmes. We conclude that preventive services in ART programmes in lower income countries focus on health education and the provision of social support and male condoms. Strategies that might be equally or more important in this setting, including partner notification, prompt diagnosis and treatment of STI, and reduction of stigma in the community, have not been implemented widely.
doi:10.1080/09540120903349102
PMCID: PMC2888993  PMID: 20473792
17.  The TREAT Asia HIV Observational Database 
Background
Relatively little is known regarding HIV disease natural history and response to antiretroviral treatments among Asian people infected with HIV. The Therapeutics Research, Education, and AIDS Training in Asia (TREAT Asia) HIV Observational Database (TAHOD) is a recently established collaborative observational cohort study that aims to assess HIV disease natural history in treated and untreated patients in the Asia-Pacific region.
Methods
Observational data are collected on HIV-infected patients from 11 sites in the Asia-Pacific region. Data are centrally aggregated for analyses, with the first baseline and retrospective data transferred in September 2003. Retrospective data were analyzed to assess the response to highly active antiretroviral treatment (HAART) over a 6-month period in terms of changes in CD4 count and proportions of patients achieving an undetectable HIV viral load (<400 copies/mL).
Results
By the end of May 2004, 1887 patients had been recruited to the TAHOD. Seventy-two percent of patients were male, with median age 36 years. Seventy-eight percent of patients reported HIV infection through heterosexual contact. Forty-three percent of patients had a previous AIDS diagnosis, of whom 55% had tuberculosis. The mean 6-month CD4 count increase was 115 cells/μL (SD = 127) after starting triple-combination therapy. Smaller CD4 count increases were associated with a higher CD4 count before starting treatment, prior treatment with monotherapy or double therapy, and treatment with a HAART regimen containing a nucleoside reverse transcriptase inhibitor (NRTI) and/or protease inhibitor (PI) but without a non-nucleoside reverse transcriptase inhibitor (NNRTI). Five hundred and ninety-eight patients started HAART and had a viral load assessment at 6 months, with 69% attaining an undetectable viral load. Older patients, patients not exposed to HIV through heterosexual contact, and patients treated with HAART containing NRTIs and NNRTIs but without PIs were found to be more likely to achieve an undetectable level.
Conclusion
Analyses of retrospective data in the TAHOD suggest that the overall response to HAART in Asian populations is similar to that seen in Western countries.
doi:10.1097/01.qai.0000145351.96815.d5
PMCID: PMC3070962  PMID: 15671802
HIV; antiretroviral treatment; observational database; Asia and the Pacific
18.  Genital lesions: An indication for changing ART regimen 
Genital lesions are common in HIV positive patients and aetiology for these are mainly due to HSV, HPV or bacterial. They usually respond to HAART, antiviral or antimicrobials. We are presenting a young patient on HAART with non-healing genital ulcer lesions for sixteen months. He responded well to a change in ART regimen within a period of 15 days. This happened after a change to a more potent ART regimen.
doi:10.4103/0253-7184.81253
PMCID: PMC3139287  PMID: 21799575
ART Change; chronic genital ulcer; HIV; AIDS
20.  Measures of site resourcing predict virologic suppression, immunologic response and HIV disease progression following highly active antiretroviral therapy (HAART) in the TREAT Asia HIV Observational Database (TAHOD) 
HIV medicine  2010;11(8):519-529.
Objectives
Surrogate markers of HIV disease progression are HIV RNA in plasma viral load (VL) and CD4 cell count (immune function). Despite improved international access to antiretrovirals, surrogate marker diagnostics are not routinely available in resource-limited settings. Therefore, the objective was to assess effects of economic and diagnostic resourcing on patient treatment outcomes.
Methods
Analyses were based on 2333 patients initiating highly active antiretroviral therapy (HAART) from 2000 onwards. Sites were categorized by World Bank country income criteria (high/low) and annual frequency of VL (≥ 3, 1–2 or <1) or CD4 (≥ 3 or <3) testing. Endpoints were time to AIDS/death and change in CD4 cell count and VL suppression (<400 HIV-1 RNA copies/mL) at 12 months. Demographics, Centers for Disease Control and Prevention (CDC) classification, baseline VL/CD4 cell counts, hepatitis B/C coinfections and HAART regimen were covariates. Time to AIDS/death was analysed by proportional hazards models. CD4 and VL endpoints were analysed using linear and logistic regression, respectively.
Results
Increased disease progression was associated with site-reported VL testing less than once per year [hazard ratio (HR)=1.4; P=0.032], severely symptomatic HIV infection (HR=1.4; P=0.003) and hepatitis C virus coinfection (HR=1.8; P=0.011). A total of 1120 patients (48.2%) had change in CD4 cell count data. Smaller increases were associated with older age (P<0.001) and `Other' HIV source exposures, including injecting drug use and blood products (P=0.043). A total of 785 patients (33.7%) contributed to the VL suppression analyses. Patients from sites with VL testing less than once per year [odds ratio (OR)=0.30; P<0.001] and reporting `Other' HIV exposures experienced reduced suppression (OR=0.28; P<0.001).
Conclusion
Low measures of site resourcing were associated with less favourable patient outcomes, including a 35% increase in disease progression in patients from sites with VL testing less than once per year.
doi:10.1111/j.1468-1293.2010.00822.x
PMCID: PMC2914850  PMID: 20345881
antiretroviral therapy; Asia; CD4 counts; diagnostic monitoring; viral load
21.  Evaluation of two human immunodeficiency virus-1 genotyping systems: ViroSeq™ 2.0 and an in-house method 
Journal of virological methods  2009;159(2):211-216.
Commercial HIV-1 genotypic resistance assays are very expensive, particularly for use in resource-constrained settings like India. Hence a cost effective in-house assay for drug resistance was validated against the standard ViroSeq™ HIV-1 Genotyping System 2.0 (Celera Diagnostics, CA, USA). A total of 50 samples were used for this evaluation (21 proficiency panels and 29 clinical isolates). Known resistance positions within HIV-1 protease (PR) region (1–99 codons) and HIV-1 reverse-transcriptase (RT) region (1–240 codons) were included. The results were analysed for each codon as follows: (i) concordant; (ii) partially concordant; (iii) indeterminate and (iv) discordant. A total of 2750 codons (55 codons per patient sample × 50 samples) associated with drug resistance (1050 PR and 1700 RT) were analysed. For PR, 99% of the codon results were concordant and 1% were partially concordant. For RT, 99% of the codon results were concordant, 0.9% were partially concordant and 0.1% were discordant. No indeterminate results were observed and the results were reproducible. Overall, the in-house assay provided comparable results to those of US FDA approved ViroSeq™, which costs about a half of the commercial assay ($ 100 vs. $ 230), making it suitable for resource-limited settings.
doi:10.1016/j.jviromet.2009.03.021
PMCID: PMC2923210  PMID: 19490976
ViroSeq™ HIV-1 genotyping; In-house HIV-1 drug resistance assay; Concordance; Mixtures; Indeterminate rate; HIV-1 genotyping evaluation
22.  Two Sides of the Same Story: Alcohol Use and HIV Risk Taking in South India 
AIDS and behavior  2010;14(Suppl 1):S136-S146.
This qualitative study examines the role of alcohol in sexual risk among male migrant workers and female sex workers in two South Indian states. Most men reported using alcohol for increased energy and courage prior to their sexual experiences and to reduce feelings of loneliness and isolation. Sex workers, on the other hand, often stated that they avoided alcohol prior to sex in order to stay alert and reduce the risk of violence. Both groups reported that drinking often increased male aggression and reduced condom use. Research is needed to examine the prevalence of these patterns as well as factors associated with sexual risk and violence, in order to develop targeted interventions for these groups. Future risk reduction programs may benefit from addressing safer ways of meeting the needs expressed by the participants. This may include strategies to defuse volatile situations, safe ways of improving the sexual experience, and interventions aimed at alleviating loneliness and isolation for migrants.
doi:10.1007/s10461-010-9722-z
PMCID: PMC2900584  PMID: 20544382
Male migrant workers; Female sex workers; Alcohol; HIV risk-taking; India
23.  Two Sides of the Same Story: Alcohol Use and HIV Risk Taking in South India 
AIDS and Behavior  2010;14(Suppl 1):136-146.
This qualitative study examines the role of alcohol in sexual risk among male migrant workers and female sex workers in two South Indian states. Most men reported using alcohol for increased energy and courage prior to their sexual experiences and to reduce feelings of loneliness and isolation. Sex workers, on the other hand, often stated that they avoided alcohol prior to sex in order to stay alert and reduce the risk of violence. Both groups reported that drinking often increased male aggression and reduced condom use. Research is needed to examine the prevalence of these patterns as well as factors associated with sexual risk and violence, in order to develop targeted interventions for these groups. Future risk reduction programs may benefit from addressing safer ways of meeting the needs expressed by the participants. This may include strategies to defuse volatile situations, safe ways of improving the sexual experience, and interventions aimed at alleviating loneliness and isolation for migrants.
doi:10.1007/s10461-010-9722-z
PMCID: PMC2900584  PMID: 20544382
Male migrant workers; Female sex workers; Alcohol; HIV risk-taking; India
24.  Deferred modification of antiretroviral regimen following documented treatment failure in Asia: results from the TREAT Asia HIV Observational Database (TAHOD) 
HIV medicine  2009;11(1):31-39.
Objective
The aim of the study was to examine the rates and predictors of treatment modification following combination antiretroviral therapy (cART) failure in Asian patients with HIV enrolled in the TREAT Asia HIV Observational Database (TAHOD).
Methods
Treatment failure (immunological, virological and clinical) was defined by World Health Organization criteria. Countries were categorized as high or low income by World Bank criteria.
Results
Among 2446 patients who initiated cART, 447 were documented to have developed treatment failure over 5697 person-years (7.8 per 100 person-years). A total of 253 patients changed at least one drug after failure (51.6 per 100 person-years). There was no difference between patients from high- and low-income countries [adjusted hazard ratio (HR) 1.02; P = 0.891]. Advanced disease stage [Centers for Disease Control and Prevention (CDC) category C vs. A; adjusted HR 1.38, P = 0.040], a lower CD4 count (≥ 51 cells/μL vs. ≤ 50 cells/μL; adjusted HR 0.61, P = 0.022) and a higher HIV viral load (≥ 400 HIV-1 RNA copies/mL vs. < 400 copies/mL; adjusted HR 2.69, P < 0.001) were associated with a higher rate of treatment modification after failure. Compared with patients from low-income countries, patients from high-income countries were more likely to change two or more drugs (67% vs. 49%; P = 0.009) and to change to a protease-inhibitor-containing regimen (48% vs. 16%; P< 0.001).
Conclusions
In a cohort of Asian patients with HIV infection, nearly half remained on the failing regimen in the first year following documented treatment failure. This deferred modification is likely to have negative implications for accumulation of drug resistance and response to second-line treatment. There is a need to scale up the availability of second-line regimens and virological monitoring in this region.
doi:10.1111/j.1468-1293.2009.00738.x
PMCID: PMC2863153  PMID: 19601993
antiretroviral treatment; Asia Pacific region; observational cohort; treatment failure
25.  Gender-Based Differences in Treatment and Outcome among HIV Patients in South India 
Journal of Women's Health  2008;17(9):1471-1475.
Abstract
Objective
To describe gender-based differences in disease progression, treatment, and outcome among patients receiving highly active antiretroviral therapy (HAART) in South India.
Methods
Therapy-naïve patients initiating HAART between February 1996 and June 2006 at a tertiary HIV referral center in Chennai, South India, were analyzed using the YRG CARE HIV Observational Database. Patients with 1 year of follow-up after initiating HAART were examined to investigate immunological and clinical outcomes, including the development of adverse events to therapy and opportunistic infections.
Results
All previously therapy-naïve patients who initiated HAART with at least 1 year of follow-up (n = 1972) were analyzed. At enrollment into care, women had higher CD4 counts, lower hemoglobin, and higher body mass index (BMI) than their male counterparts (p < 0.05). At the time of initiating therapy, women had higher CD4 counts and lower hemoglobin (p < 0.05); women continued to have higher CD4 counts at 12 months (p < 0.05). After 1 year following HAART initiation, significantly more men developed tuberculosis and Pneumocystis jiroveci pneumonia (p < 0.05), more women experienced lactic acidosis and nausea, and more men developed immune reconstitution syndrome (p < 0.05).
Conclusions
Significant physiological, immunological, and clinical differences exist between men and women initiating HAART in a resource-limited setting in South India. Future studies should examine whether clinical management strategies should be different for men and women in resource-limited settings.
doi:10.1089/jwh.2007.0670
PMCID: PMC2945934  PMID: 18954236

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