Correction: Retention and viral suppression in a cohort of HIV patients on antiretroviral therapy in Zambia: Regionally representative estimates using a multistage-sampling-based approach.

[This corrects the article DOI: 10.1371/journal.pmed.1002811.].

Retention and viral suppression in a cohort of HIV patients on antiretroviral therapy in Zambia: Regionally representative estimates using a multistage-sampling-based approach.

BACKGROUND: Although the success of HIV treatment programs depends on retention and viral suppression, routine program monitoring of these outcomes may be incomplete. We used data from the national electronic medical record (EMR) system in Zambia to enumerate a large and regionally representative cohort of patients on treatment. We traced a random sample with unknown outcomes (lost to follow-up) to document true care status and HIV RNA levels. METHODS AND FINDINGS: On 31 July 2015, we selected facilities from 4 provinces in 12 joint strata defined by facility type and province with probability proportional to size. In each facility, we enumerated adults with at least 1 clinical encounter after treatment initiation in the previous 24 months. From this cohort, we identified lost-to-follow-up patients (defined as 90 or more days late for their last appointment), selected a random sample, and intensively reviewed their records and traced them via phone calls and in-person visits in the community. In 1 of 4 provinces, we also collected dried blood spots (DBSs) for plasma HIV RNA testing. We used inverse probability weights to incorporate sampling outcomes into Aalen-Johansen and Cox proportional hazards regression to estimate retention and viremia. We used a bias analysis approach to correct for the known inaccuracy of plasma HIV RNA levels obtained from DBSs. From a total of 64 facilities with 165,464 adults on ART, we selected 32 facilities with 104,966 patients, of whom 17,602 (17%) were lost to follow-up: Those lost to follow-up had median age 36 years, 60% were female (N = 11,241), they had median enrollment CD4 count of 220 cells/µl, and 38% had WHO stage 1 clinical disease (N = 10,690). We traced 2,892 (16%) and found updated outcomes for 2,163 (75%): 412 (19%) had died, 836 (39%) were alive and in care at their original clinic, 457 (21%) had transferred to a new clinic, 255 (12%) were alive and out of care, and 203 (9%) were alive but we were unable to determine care status. Estimates using data from the EMR only suggested that 42.7% (95% CI 38.0%-47.1%) of new ART starters and 72.3% (95% CI 71.8%-73.0%) of all ART users were retained at 2 years. After incorporating updated data through tracing, we found that 77.3% (95% CI 70.5%-84.0%) of new initiates and 91.2% (95% CI 90.5%-91.8%) of all ART users were retained (at original clinic or transferred), indicating that routine program data underestimated retention in care markedly. In Lusaka Province, HIV RNA levels greater than or equal to 1,000 copies/ml were present in 18.1% (95% CI 14.0%-22.3%) of patients in care, 71.3% (95% CI 58.2%-84.4%) of lost patients, and 24.7% (95% CI 21.0%-29.3%). The main study limitations were imperfect response rates and the use of self-reported care status. CONCLUSIONS: In this region of Zambia, routine program data underestimated retention, and the point prevalence of unsuppressed HIV RNA was high when lost patients were accounted for. Viremia was prevalent among patients who unofficially transferred: Sustained engagement remains a challenge among HIV patients in Zambia, and targeted sampling is an effective strategy to identify such gaps in the care cascade and monitor programmatic progress.

Reframing HIV care: putting people at the centre of antiretroviral delivery.

The delivery of HIV care in the initial rapid scale-up of HIV care and treatment was based on existing clinic-based models, which are common in highly resourced settings and largely undifferentiated for individual needs. A new framework for treatment based on variable intensities of care tailored to the specific needs of different groups of individuals across the cascade of care is proposed here. Service intensity is characterised by four delivery components: (i) types of services delivered, (ii) location of service delivery, (iii) provider of health services and (iv) frequency of health services. How these components are developed into a service delivery framework will vary across countries and populations, with the intention being to improve acceptability and care outcomes. The goal of getting more people on treatment before they become ill will necessitate innovative models of delivering both testing and care. As HIV programmes expand treatment eligibility, many people entering care will not be 'patients' but healthy, active and productive members of society. To take the framework to scale, it will be important to: (i) define which individuals can be served by an alternative delivery framework; (ii) strengthen health systems that support decentralisation, integration and task shifting; (iii) make the supply chain more robust; and (iv) invest in data systems for patient tracking and for programme monitoring and evaluation.

Integrating antiretroviral therapy into antenatal care and maternal and child health settings: a systematic review and meta-analysis.

OBJECTIVE: To determine whether integrating antiretroviral therapy (ART) into antenatal care (ANC) and maternal and child health (MCH) clinics could improve programmatic and patient outcomes. METHODS: The authors systematically searched PubMed, Embase, African Index Medicus and LiLACS for randomized controlled trials, prospective cohort studies, or retrospective cohort studies comparing outcomes in ANC or MCH clinics that had and had not integrated ART. The outcomes of interest were ART coverage, ART enrolment, ART retention, mortality and transmission of human immunodeficiency virus (HIV). FINDINGS: Four studies met the inclusion criteria. All were conducted in ANC clinics. Increased enrolment of pregnant women in ART was observed in ANC clinics that had integrated ART (relative risk, RR: 2.09; 95% confidence interval, CI; 1.78-2.46; I(2): 15%). Increased ART coverage was also noted in such clinics (RR: 1.37; 95% CI: 1.05-1.79; I(2): 83%). Sensitivity analyses revealed a trend for the national prevalence of HIV infection to explain the heterogeneity in the size of the effect of ART integration on ART coverage (P = 0.13). Retention in ART was similar in ANC clinics with and without ART integration. CONCLUSION: Although few data were available, ART integration in ANC clinics appears to lead to higher rates of ART enrolment and ART coverage. Rates of retention in ART remain similar to those observed in referral-based models.

Résumé OBJECTIF: Déterminer si l'intégration de la thérapie antirétrovirale (TAR) dans les établissements de soins prénataux (ESP) et de santé maternelle et infantile (SMI) pourrait améliorer les résultats du programme et la santé du patient. MÉTHODES: Les auteurs ont systématiquement recherché via PubMed, Embase, African Index Medicus et LILACS des essais contrôlés randomisés, des études de cohorte prospectives et des études de cohorte rétrospectives comparant les résultats des cliniques ESP ou SMI ayant ou n'ayant pas intégré la TAR. Les résultats pris en compte comprenaient la couverture, la participation et la rétention de la TAR, ainsi que la mortalité et la transmission du virus d'immunodéficience humaine (VIH). RÉSULTATS: Quatre études répondaient aux critères d'inclusion. Toutes ont été menées dans des cliniques ESP. Une participation accrue des femmes enceintes à la TAR a été observée dans les cliniques ESP qui l'avaient intégrée (risque relatif, RR: 2,09; intervalle de confiance IC à 95%: 1,78 à 2,46; I: 15%). Une couverture plus importante de la TAR a également été notée dans ces cliniques (RR: 1,37; IC à 95%: 1,05 à 1,79; I: 83%). Les analyses de sensibilité ont révélé une tendance à la prévalence nationale de l'infection par le VIH pour expliquer l'hétérogénéité de la taille de l'effet de l'intégration de la TAR sur sa couverture (P = 0,13). La rétention de la TAR était similaire dans les cliniques ESP avec ou sans intégration de la TAR. CONCLUSION: Bien que peu de données aient été disponibles, l'intégration de la TAR dans les cliniques ESP semblait entraîner une augmentation des taux de participation et de couverture de la TAR. Les taux de rétention de la TAR restent semblables à ceux qui sont observés dans les modèles de référence.

Resumen OBJETIVO: Determinar si la integración del tratamiento antirretroviral (TAR) en la atención prenatal (APN) y la salud materno-infantil (SMI) podría mejorar los resultados programáticos y del paciente. MÉTODOS: Partiendo de las bases de datos PubMed, Embase, Index Medicus de la Región de África y LiLACS, los autores realizaron búsquedas sistemáticas de ensayos controlados aleatorizados, estudios de cohortes prospectivos o estudios de cohortes retrospectivos en los que se compararon los resultados en clínicas de APN o SMI que habían y que no habían integrado el TAR. Los resultados de interés fueron la cobertura del TAR, la inclusión en el TAR, la retención en el TAR, la mortalidad y la transmisión del virus de la inmunodeficiencia humana (VIH). RESULTADOS: Cuatro estudios cumplieron los criterios de inclusión. Todos ellos se realizaron en clínicas de APN. Se observó un aumento de la inclusión de mujeres embarazadas en el TAR en aquellas clínicas de APN que se habían integrado el TAR (riesgo relativo, RR: 2,09, intervalo de confianza del 95%, IC; 1,78-2,46; I: 15%). En estas clínicas también se observó un aumento de la cobertura del TAR (RR: 1,37; IC del 95%: 1,05­1,79; I: 83%). Los análisis de sensibilidad revelaron una tendencia en la prevalencia nacional de la infección por el VIH para explicar la heterogeneidad en la magnitud del efecto de la integración del TAR sobre la cobertura del TAR (P=0,13). La retención en el TAR fue similar en las clínicas de APN con y sin integración del TAR. CONCLUSIÓN: A pesar de la escasez de los datos disponibles, la integración del TAR en las clínicas de APN parece traducirse en mayores tasas de inclusión en el TAR y de cobertura del TAR. Las tasas de retención en el TAR siguen siendo similares a las observadas en los modelos basados en derivaciones médicas.

Two patterns of cerebral metabolite abnormalities are detected on proton magnetic resonance spectroscopy in HIV-infected subjects commencing antiretroviral therapy.

INTRODUCTION: Cerebral function impairment remains problematic in subjects with chronic human immunodeficiency virus (HIV) infection despite effective combination antiretroviral therapy (cART). Using cerebral proton magnetic resonance spectroscopy ((1)H MRS), we aimed to determine if abnormalities could be detected in neurologically asymptomatic HIV-infected subjects electively commencing cART. METHODS: Therapy-naive, HIV-infected individuals and HIV-uninfected controls underwent (1)H MRS in several anatomical voxels including the mid-frontal grey matter (FGM) and right basal ganglia (RBG). Differences in cerebral metabolite ratios between groups and correlations between immune and virological status were assessed. RESULTS: Forty-six subjects were recruited (26 HIV-infected and 20 control subjects). In the HIV-infected group, mean CD4+ count (SD, cells per microlitre) and plasma HIV RNA (SD, log10 copies per millilitre) were 192 (86) and 4.71 (0.64), respectively. Choline (Cho)/Creatine (Cr) and myoinositol (MI)/Cr ratios were significantly lower in the FGM in HIV-infected subjects compared to controls (0.67 (0.14) versus 0.88 (0.49), p = 0.036, and 0.94 (0.28) and 1.17 (0.26), p = 0.008, for Cho/Cr and MI/Cr, respectively) and Cho/Cr ratio associated with CD4+ lymphocyte count (p = 0.041). N-Acetyl-aspartate (NAA)/Cho ratio was significantly lower in the RBG in HIV-infected subjects compared to controls (2.27 (0.54) versus 2.63 (0.68), p = 0.002), and this was associated with greater plasma HIV RNA load (p = 0.014). CONCLUSIONS: Two patterns of cerebral metabolite abnormalities were observed in HIV-infected subjects electively commencing cART. Greater inflammatory metabolite ratios (Cho/Cr and MI/Cr) associated with lower markers of peripheral immune markers (CD4+ lymphocyte count) in the FGM and lower neuronal metabolite ratios (NAA/Cho) associated with greater HIV viraemia in the RBG were present in HIV-infected subjects.

Efavirenz versus boosted atazanavir or zidovudine and abacavir in antiretroviral treatment-naive, HIV-infected subjects: week 48 data from the Altair study.

BACKGROUND: Antiretroviral therapy is complicated by drug interactions and contraindications. Novel regimens are needed. METHODS: This open label study randomly assigned treatment-naive, human immunodeficiency virus (HIV)-infected subjects to receive tenofovir-emtricitabine with efavirenz (Arm I), with ritonavir-boosted atazanavir (Arm II), or with zidovudine/abacavir (Arm III). Pair-wise comparisons of differences in time-weighted mean change from baseline plasma HIV-RNA to week 48 formed the primary analysis. Treatment arms were noninferior if the upper limit of the 95% confidence interval (CI) was <0.5 log(10) copies/mL. Secondary objectives included virologic, immunologic and safety end points. RESULTS: The intention-to-treat population comprised 322 patients (Arm I, n = 114; Arm II, n = 105; and Arm III, n = 103). Noninferiority for the primary end point was established. Analysis for superiority showed that Arm III was significantly less potent than Arm I (-0.20 log(10) copies/mL; 95% CI, -0.39 to -0.01 log(10) copies/mL; P = .038). The proportions of patients on each of Arm I (95%) and Arm II (96%) with <200 copies/mL were not different (P = .75), but the percentage of patients in Arm III with <200 copies/mL (82%) was significantly lower (P = .005). CD4+ cell counts did not differ. Serious adverse events were more frequent in Arm III (n = 30) than in Arm I or Arm II (n = 15 for each; P = .062). CONCLUSIONS: A novel quadruple nucleo(t)side combination demonstrated significantly less suppression of HIV replication, compared with the suppression demonstrated by standard antiretroviral therapy regimens, although it did meet the predetermined formal definition of noninferiority. Secondary analyses indicated statistically inferior virologic and safety performance. Efavirenz and ritonavir-boosted atazanavir arms were equivalent in viral suppression and safety.

Does choice of combination antiretroviral therapy (cART) alter changes in cerebral function testing after 48 weeks in treatment-naive, HIV-1-infected individuals commencing cART? A randomized, controlled study.

BACKGROUND: Neurocognitive impairment remains prevalent, despite combination antiretroviral therapy (cART). Differences between changes in cerebral function and alternative cARTs have not been prospectively assessed. METHODS: Treatment-naive, HIV-1-infected individuals randomly allocated to commence cART (tenofovir-emtricitabine plus either efavirenz [arm 1], atazanavir-ritonavir [arm 2], or zidovudine-abacavir [arm 3]) were eligible. Cerebral function tests included neurocognitive testing and assessment of cerebral metabolites using proton magnetic resonance spectroscopy in several anatomical voxels, including right frontal white matter and right basal ganglia, at baseline and after 48 weeks. N-acetylaspartate-to-creatine (NAA/Cr) ratios were calculated. Both the differences between changes in neurocognitive function and NAA/Cr ratios over 48 weeks and the study arms (arm 1 vs arm 2; arm 1 vs arm 3) were assessed. RESULTS: Thirty subjects completed study procedures (9, 9, and 12 subjects in arms 1, 2, and 3, respectively). Mean CD4+ cell counts (+/- standard deviation) were 218 +/- 87 cells/microL at baseline and 342 +/- 145 cells/microL at week 48. The mean plasma HIV-1 RNA level was <50 copies/mL for 28 of the 30 subjects at week 48. Over 48 weeks, greater improvements in identification reaction time (P = .04) and executive function (P = .02) were observed in arm 3, compared with arm 1 (0.03, -0.30, -0.50 log10 ms change in identification reaction time, in arms 1, 2, and 3, respectively). Increases in the NAA/Cr ratio were observed in all voxels (maximum 38% in right basal ganglia), with greater increases observed in arm 1 than in arm 2 (P = .03) in frontal white matter (30%, -7%, and 0% change in the NAA/Cr ratio, in arms 1, 2, and 3, respectively). CONCLUSIONS: To our knowledge, this is the first study to prospectively describe different changes in cerebral function testing parameters between different cARTs. Greater improvements in neuronal recovery (NAA/Cr ratio) were observed for recipients of tenofovir-emtricitabine plus efavirenz (arm 1), and greater improvements in neurocognitive function testing were observed for recipients of tenofovir-emtricitabine plus zidovudine-abacavir (arm 3).

Fast-Track Cities: striving to end urban HIV epidemics by 2030.

PURPOSE OF REVIEW: To provide a summary of progress achieved, lessons learned, and best practices employed in select Fast-Track Cities striving to attain and surpass the Joint United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets. RECENT FINDINGS: The 90-90-90 targets have served as a catalyst to galvanize political, programmatic, and funding support for urban HIV responses, while prompting increased community engagement. More than 300 cities and municipalities have joined the Fast-Track Cities network, pledging to attain and surpass the UNAIDS 90-90-90 targets. One city has officially surpassed the 95-95-95 targets; four cities have surpassed the 90-90-90 targets; and 34 cities have achieved one or more of the 90 targets. Across the Fast-Track Cities network, upward trends have been recorded in numerous cities and municipalities using data-driven approaches to close HIV care continuum gaps through data-driven implementation planning. SUMMARY: The Fast-Track Cities initiative has served as a catalyst for leveraging accelerated and optimized urban HIV responses to scale up HIV diagnosis, treatment, and viral suppression. Key to attaining and surpassing the 90-90-90 targets is a 'calculus for success' that includes political will, public health leadership, data-driven implementation planning, and equity-based interventions facilitated by active engagement with affected communities, notably people living with HIV.

Efficacy and Safety of Tenofovir Disoproxil Fumarate Versus Low-Dose Stavudine Over 96 Weeks: A Multicountry Randomized, Noninferiority Trial.

BACKGROUND: Reducing doses of antiretroviral drugs, including stavudine (d4T), may lower toxicity, while preserving efficacy. There are substantial concerns about renal and bone toxicities of tenofovir disoproxil fumarate (TDF). SETTING: HIV-1-infected treatment-naive adults in India, South Africa, and Uganda. METHODS: A phase-4, 96-week, randomized, double-blind, noninferiority trial compared d4T 20 mg twice daily and TDF, taken in combination with lamivudine (3TC) and efavirenz (EFV). The primary endpoint was the proportion of participants with HIV-1 RNA <50 copies per milliliter at 48 weeks. Adverse events assessments included measures of bone density and body fat. The trial is registered on Clinicaltrials.gov (NCT02670772). RESULTS: Between 2012 and 2014, 536 participants were recruited per arm. At week 96, trial completion rates were 75.7% with d4T/3TC/EFV (n = 406) and 82.1% with TDF/3TC/EFV (n = 440, P = 0.011). Noncompletion was largely due to virological failure [6.2% (33) with d4T/3TC/EFV versus 5.4% (29) with TDF/3TC/EFV; P = 0.60]. For the primary endpoint, d4T/3TC/EFV was noninferior to TDF/3TC/EFV (79.3%, 425/536 versus 80.8% 433/536; difference = -1.49%, 95% CI: -6.3 to 3.3; P < 0.001). Drug-related adverse event discontinuations were higher with d4T (6.7%, 36), than TDF (1.1%, 6; P < 0.001). Lipodystrophy was more common with d4T (5.6%, 30) than TDF (0.2%, 1; P < 0.001). Creatinine clearance increased in both arms, by 18.1 mL/min in the d4T arm and 14.2 mL/min with TDF (P = 0.03). Hip bone density measures, however, showed greater loss with TDF. CONCLUSIONS: Low-dose d4T combined with 3TC/EFV demonstrated noninferior virological efficacy compared with TDF/3TC/EFV, but mitochondrial toxicity remained high. Little renal toxicity occurred in either arm. Implications of bone mineral density changes with TDF warrant investigation.

Dyslipidemia in an Asian population after treatment for two years with protease inhibitor-containing regimens.

There are limited data about dyslipidemia in Asian patients treated with combination antiretroviral therapy. To assess the relative association of different protease-inhibitor-containing regimens with the degree of dyslipidemia, fasting lipid levels were compared during 110 weeks in 250 nucleoside-experienced but protease-inhibitor-naïve Thai patients beginning treatment with 5 protease-inhibitor-containing regimens. Regimens were (1) stavudine, didanosine, and saquinavir; (2) zidovudine, lamivudine, and saquinavir; (3) zidovudine, lamivudine, and indinavir; (4) zidovudine, lamivudine, and ritonavir-boosted indinavir; and (5) efavirenz and ritonavir-boosted indinavir. Triglyceride levels were available for all patients; total cholesterol and high-densitylipoprotein cholesterol levels were available for patients receiving indinavir. The strongest predictors of dyslipidemia after beginning protease-inhibitor-based therapy were treatment regimen and baseline dyslipidemia. Triglycerides, total cholesterol, and high-density-lipoprotein cholesterol changes from baseline to week 110 were significant in patients taking ritonavir-boosted indinavir. Efavirenz and ritonavir-boosted indinavir were associated with significant high-density-lipoprotein cholesterol increases compared with other regimens. Non-stavudine-containing non-boosted protease-inhibitor-based highly active antiretroviral treatment regimens had the least association with dyslipidemia.

High prevalence of indinavir-associated renal complications in Thai HIV-infected patients.

BACKGROUND: Indinavir (IDV) is the protease inhibitor (PI) used most often in resource-limited countries. The present study aimed to determine the prevalence of IDV-associated renal complications as well as their clinical characteristics. MATERIAL AND METHOD: The authors reviewed all patients participating in cohorts of indinavir-containing regimens at the HIV-NAT research center during the period of indinavir treatment. Patients who had pre-existing renal diseases were excluded. Renal toxicities included presence of urologic symptoms, nephrolithiasis, abnormal urine sediments, crystalluria and loss of renal function. Radiological studies of KUB system were reviewed as well. RESULTS: Two-hundred and four patients treated with IDV were included. Median (IQR) follow up period was 216 (150-312) weeks. One hundred and eighty patients were treated with ritonavir-boosted regimens at some point, and 24 patients were treated only with unboosted regimens. Leukocyturia (51.9%) was the most common finding of IDV-associated renal complications. Thirty-five percent of patients had urologic symptoms such as flank pain or dysuria. Almost half of the patients had significant loss of renal function that was associated with prolonged use of IDV The most common radiological finding was nephrolithiasis. Less common, but of greater clinical importance, are nephrocalcinosis or renal atrophy. CONCLUSION: A high prevalence of IRC was found in Thai HIV-infected patients. As long as no other cost-effective boosted PI regimens are available, strategies to prevent irreversible loss of renal function are warranted.

HIV disease progression in a patient cohort treated via a clinical research network in a resource limited setting.

OBJECTIVE: To examine HIV disease progression in a cohort of adult patients treated with antiretroviral therapy (ART) via a clinical research network in Thailand. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: A cohort of 417 patients enrolled in a series of randomized ART trials, between 1996 and December 2002. MAIN OUTCOME MEASURES: Progression to combined endpoint of AIDS defining illness or death according to baseline characteristics, ART used, immunological and virological responses to initial 6 months of ART. RESULTS: During 1677 person years of follow-up, 29 of 417 patients progressed; tuberculosis was the most common event defining progression (14 of 29 events). The rates of progression to combined endpoint or death alone were 1.7 [95% confidence interval (CI), 1.1-2.4] and 0.7 (95% CI, 0.3-1.3) per 10 person years respectively. Compared to patients with baseline CD4 cell counts > or =350 x 10/l, the adjusted hazard ratio (HR) for progression was 3.67 (95% CI, 1.31-10.27) for patients with <200 x 10 cells/l. Responses to 6 months of therapy were the strongest predictors of disease progression; compared to patients with undetectable viral load at 6 months, HR for progression was 4.95 (95% CI, 2.14-11.46) for viral load >4 log10. Compared to patients with a 6-month CD4 cell count > or =350 x 10/l, HR for progression was 5.22 (95% CI, 1.90-14.37) for patients with <200 x 10 cells/l. CONCLUSIONS: HIV-infected patients in Thailand who had access to ART, appropriate care, CD4 cell and viral load monitoring facilities via a clinical research network had progression rates comparable to those in developed countries. In this setting, ART initiation could generally be delayed until the CD4 cell count approaches 200 x 10/l.

Incidence and risk factors for rash in Thai patients randomized to regimens with nevirapine, efavirenz or both drugs.

OBJECTIVE: To determine the incidence and risk factors for rash in Thai patients taking four different non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. METHODS: HIV-positive, antiretroviral-naive patients enrolled in the 2NN study in Thailand and followed for at least 1 week were included. Patients were randomized to efavirenz (EFV) 600 mg once daily (OD) versus nevirapine (NVP) 200 mg twice daily (BD) versus NVP 400 mg OD versus NVP 400 mg OD + EFV 800 mg OD with stavudine/lamivudine. RESULTS: Of 202 patients, 95 (47%) and 69 (34.2%) developed a rash from all reasons and from NNRTI, respectively. For NNRTI-related rash the incidences were EFV (20%), NVP BD (21%), NVP OD (38%) and NVP + EFV (67%). The proportions of patients with grade I, II and III within the four treatment arms are as follows: EFV, 4.3, 13 and 2.9%; NVP BD, 2.3, 15.9 and 2.3%; NVP OD, 12.8, 19.1 and 6.4%; and NVP + EFV, 11.9, 47.6 and 7.1%. Multivariate analyses showed females with CD4 cell count > or =250 x 10 cells/l, high body mass index (>21.3 kg/m), and a rise in CD4 (> or =53 x 10 cells/l) and alanine aminotransferase (ALT) (> or =34 U/l) at week 4 to be risk factors for rash. CONCLUSIONS: Thai patients had a high incidence of NNRTI-related rash when treated with NVP + EFV or NVP OD. NVP if used BD had the same rash incidence as EFV for rash of all grades. Females, and persons with earlier HIV disease or with a large rise in CD4+ cell count after starting therapy are at greater risk for NNRTI-related rash.

Differences in the direction of change of cerebral function parameters are evident over three years in HIV-infected individuals electively commencing initial cART.

BACKGROUND: Changes in cerebral metabolite ratios (CMR) measured on 1H-MRS and changes in cognitive function (CF) are described in subjects commencing combination antiretroviral therapy (cART), although the dynamics of such changes are poorly understood. METHODS: Neuroasymptomatic, HIV-infected subjects electively commencing cART were eligible. CMR were assessed in three anatomical voxels and CF assessed at baseline, week 48 and week 144. Overall differences in absolute change in CMRs and CF parameters between 0-48 and 48-144 weeks were assessed. RESULTS: Twenty-two subjects completed study procedures. Plasma HIV-RNA was <50 copies/mL in all at week 48 and in all, but two subjects at week 144. In general, between weeks 0-48 a rise in N-acetyl-aspartate(NAA)/Creatine(Cr) ratio and a decline in myo-Inositol(mI)/Cr ratio were observed. Between weeks 48-144, small rises in NAA/Cr ratio were observed in two anatomical voxels, whereas a rise in mI/Cr ratio was observed in all anatomical locations (0.31 (0.66) and -0.27 (1.35) between weeks 0-48 and 0.13 (0.91) and 1.13 (1.71) between weeks 48-144 for absolute changes in NAA/Cr and mI/Cr (SD) in frontal-grey voxel, respectively). Global CF score improved between weeks 0-48 and then declined between weeks 48-144 (0.63 (1.16) and -0.63 (0.1.41) for mean absolute change (SD) between weeks 0-48 and weeks 48-144, respectively). CONCLUSIONS: The direction of change of cerebral function parameters differs over time in HIV-infected subjects commencing cART, highlighting the need for long-term follow-up in such studies. The changes we have observed between weeks 48-144 may represent the initial development of cerebral toxicities from cART.

Risk of severe hepatotoxicity associated with antiretroviral therapy in the HIV-NAT Cohort, Thailand, 1996-2001.

OBJECTIVE: To examine rates and predictors of severe hepatotoxicity with combination antiretroviral therapy in a developing country setting: the eight HIV-NAT randomized controlled trials in Thailand. METHODS: All patients (n = 692) received at least two nucleoside reverse transcriptase inhibitors; 215 also received a non-nucleoside reverse transcriptase inhibitor (NNRTI) and 135 also received a protease inhibitor. Severe hepatotoxicity was defined as an increase in alanine aminotransferase (ALT) level to five times the upper limit of normal and an increase of at least 100 U/l from baseline. Liver function tests were available at baseline and weeks 4, 8, 12, 24, 36 and 48. Hepatitis B virus (HBV) and hepatitis C virus (HCV) testing was performed on stored serum. RESULTS: Mean age was 32.3 years; 52% were male, 11% had Centers for Disease Control and Prevention category C HIV disease at baseline, and 22% had received prior antiretroviral therapy. Prevalence of HBV, HCV and HBV/HCV coinfection was 8.7%, 7.2%, and 0.4%, respectively. Incidence of severe hepatotoxicity was 6.1/100 person-years [95% confidence interval (CI), 4.3-8.3/100]. In multivariate analysis, predictors of severe hepatotoxicity were HBV or HCV coinfection, and NNRTI-containing therapy. Incidence of severe hepatotoxicity was particularly high among patients receiving nevaripine (18.5/100 person-years; 95% CI, 11.6-27.8) and nevirapine/efavirenz (44.4/100 person-years; 95% CI, 12.1-113.7). CONCLUSIONS: Incidence and risk factors for severe hepatotoxicity appear similar among these Thai patients to those in other racial groups. Development of standardized antiretroviral therapy regimens for developing country settings should consider potential toxicity and capabilities for monitoring of toxicity.

Impact of viral hepatitis co-infection on response to antiretroviral therapy and HIV disease progression in the HIV-NAT cohort.

OBJECTIVE: To examine the impact of viral hepatitis co-infection on HIV disease outcomes following commencement of combination antiretroviral therapy in a developing country setting. METHODS: HIV RNA suppression, CD4 cell count recovery, and HIV disease progression were examined within a cohort of Thai HIV-infected patients enrolled in eight HIV-NAT randomized controlled trials of antiretroviral therapy (n = 692). Hepatitis B virus (HBV) and hepatitis C virus (HCV) testing was performed on stored serum. RESULTS: Mean age was 32.3 years, 52% were male, 11% had CDC category C HIV disease at baseline, and 22% had received prior antiretroviral therapy. Prevalence of HBV, HCV and HBV/HCV co-infection was 8.7, 7.2 and 0.4%, respectively. Median HIV RNA reductions (log10 copies/ml) were approximately 1.5 for HIV, HIV-HBV, HIV-HCV subgroups from week 4 up to week 48. Mean increases in CD4 cell count were significantly lower among HIV-HBV and HIV-HCV subgroups at week 4 (HIV, 62 x 10(6) cells/l; HIV-HBV, 29 x 10(6) cells/l; HIV-HCV, 33 x 10(6) cells/l), however, by week 48 CD4 cell increases were similar (HIV, 115 x 10(6) cells/l; HIV-HBV, 113 x 10(6) cells/l; HIV-HCV, 97 x 10(6) cells/l). Cox regression analyses showed that HIV-HBV or HIV-HCV co-infection were not associated with a CD4 cell count increase of 100 x 10(6) cells/l over 48 weeks. Estimated progression to AIDS event or death at week 48 was 3.3% (95% confidence interval, 2.0-5.1%) for HIV, 6.7% (2.5-14.6%) for HIV-HBV, and 8.0% (2.2-20.5%) for HIV-HCV subgroups (P > 0.05). CONCLUSIONS: An early delayed CD4 count recovery among HIV/viral hepatitis co-infected patients was not sustained, and was not associated with increased HIV disease progression.

Significant differences between plasma HIV-1 RNA assays in HIV-1 subtype E infected patients treated with antiretroviral therapy.

UNLABELLED: A total of 72 HIV-1 infected Thai patients treated with didanosine (ddI) or stavudine (d4T) plus ddI at the time of interim analysis were analyzed. Sixty patients (83%) carried subtype E documented by HIV-1 V3 serotyping. HIV-1 RNA levels were measured using three commercial viral load assays. At baseline (n = 57), Quantiplex 2.0 and NucliSens 2.0 showed mean log10 HIV-1 RNA of 0.7 log10 or 5 fold lower than Amplicor 1.5 (mean 4.29 versus 5.0 log10, respectively, p < 0.001). At week 20 of treatment (n = 29), HIV-1 RNA levels were detected in 55.2%, 31%, and 33.5% of subjects tested by Amplicor 1.5, Quantiplex 2.0, and NucliSens 2.0, respectively. IN CONCLUSION: plasma HIV-1 RNA analyses showed comparable values with Quantiplex 2.0 and NucliSens 2.0 assays. In contrast, Amplicor 1.5 resulted in approximately 5 folds higher HIV-1 RNA levels and a 25% higher rate of detection of plasma HIV-1 RNA as compared to the other two assays. As the current goal of therapy is to suppress plasma viral load below the detection limit of the assays, the significant differences between the assays may influence antiretroviral efficacy evaluation and management.

Treatment 2.0: catalyzing the next phase of treatment, care and support.

PURPOSE OF REVIEW: This review provides an update on the WHO/UNAIDS Treatment 2.0 strategy by reviewing the documents and technical updates issued under the initiative. Launched in 2010, this global initiative provides a framework for the continued scale-up of access to HIV care and treatment. RECENT FINDINGS: WHO has prioritized once daily fixed-dose combination as the preferred antiretroviral (ARV) regimen to initiate HIV treatment, paving the way for programmatic simplification, with reduced toxicity and improved adherence. WHO also recommends the use of point-of-care diagnostics, with CD4 cell count technologies being implemented in the field and progress towards improving access to simplified viral load testing. The strategy also seeks mechanisms that can contribute to reducing treatment costs, such as pooled commodity procurement and public health-oriented licensing approaches. Improved service delivery, specifically through decentralization, task shifting, integration and community mobilization also has the potential to reduce costs and improve access. Support to countries has been provided through the timely release of a series of programmatic and technical updates on specific treatment-related topics. SUMMARY: The Treatment 2.0 strategy articulates how innovation and greater efficiency can make HIV care and treatment more accessible and affordable, and guide treatment and prevention scale-up.