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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.

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

Supplemental Digital Content is Available in the Text., 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

Background: One of the many challenges which come together with the implementation of antiretroviral therapy (ART) in settings with limited resources is the monitoring of toxicity. This monitoring increases costs of ART and strains resources. We therefore investigated the necessity for laboratory toxicity monitoring of ART in Thailand. Design, methods and participants: A prospective Thai cohort of 417 HIV-infected patients were enrolled in randomized clinical trials investigating ART. Time-dependent occurrence of grade III/IV abnormal laboratory values as defined by the AIDS Clinical Trial Group was analysed. Results: During a median observation period of 3.7 years (2.4-4.3) 142 grade III/IV toxicities occurred in 101 (24.2%) patients. Hepatic toxicity (n = 33, 7.9%), hypercholesterolaemia (n = 57, 13.7%), hypertriglyceridaemia (n = 26, 6.2%), anaemia (n = 16, 3.8%) and low platelet counts (n = 8, 1.9%) were frequently observed. Anaemia and low platelets occurred early and during the first 2 years of ART. Hepatic toxicity was seen early and throughout the observation period. Hypertriglyceridaemia and hypercholesterolaemia occurred throughout the observation period, and increased over time. Hypercreatininaemia and hyperglycaemia occurred once after 120 and 132 weeks. ART was changed or interrupted for grade III/IV hepatic toxicity, anaemia and hyperglycaemia only. The incidence rate for grade III/IV toxicity was between 5.56 (95% CI, 6.76-18.02) for low platelet counts and 41.18 (31.77-53.39) per 1000 patient years for hypercholesterolaemia. Antiretrovirals used were zidovudine, stavudine, lamivudine, zalcitabine, didanosine, efavirenz, saquinavir, ritonavir and indinavir. Conclusions: Grade III/IV toxicity is frequently observed in Thai patients treated with ART. The simple and inexpensive monitoring of ALT and haemoglobin could prevent most serious short-term toxicity. Long-term toxicity can be addressed with a yearly monitoring of triglycerides, cholesterol, glucose and creatinine if nephrotoxic drugs are used

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., Izukanji Sikazwe and co-workers report on the use of routine program data to estimate retention of patients in HIV care in Zambia., Author summary Why was this study done? Retention and HIV RNA suppression in HIV treatment programs represent critical metrics of success, but regionally representative estimates in longitudinal cohorts remain uncommon. Most treatment programs, whether at the national or sub-national level, lack data systems able to capture patient movement across facilities, which may lead to underestimates of retention. HIV RNA suppression levels from routine program monitoring or large-scale cross-sectional studies may miss patients who are lost to follow-up, and therefore those who had been on treatment, thus underestimating the prevalence of viremia. Intensive ascertainment of care status and HIV RNA levels in a numerically small but randomly selected sample of patients with unknown outcomes can improve our understanding of treatment success in real-world program settings. What did the researchers do and find? We used a multistage sampling approach, in which we first selected facilities and then, within each facility, selected a random sample of patients who were lost to follow-up—defined as no contact with a health facility for 90 or more days after last their missed appointment—for intensive tracing. We also collected dried blood spots in Lusaka Province to determine viral load levels in both a sample of lost patients and in-care patients to estimate the prevalence of viremia in both populations. We found that among 165,464 patients on treatment in 64 facilities, 28,111 (17%) were lost to follow-up. We traced 2,892 of the lost (16%): and found 412 (14%) had died and 1,751 (61%) remained alive. Of those alive, 1,293 (74%) continued to receive treatment, 255 (15%) had stopped, and care status could not be determined in 12%. Among all ART patients, using data known to the program before tracing, retention was 67.7% at 2 years; after incorporating findings among the lost patients, retention was 91.2%. Among 1,044 participants with a viral load determination (901 in care and 143 who were lost), viremia was present in 18.1% of those in care, 71.3% of those lost to follow-up (49.8% of those lost and in care elsewhere and 83.9% of those lost and not in care), and 24.8% overall. What do these findings mean? We found that patient retention in public ART facilities in Zambia was higher than apparent in data collected during routine care and monitoring. Estimates of viremia that do not account for elevated levels in patients who stop treatment (and are lost to follow-up from cohort studies) or are missing from cross-sectional studies may overestimate treatment success. Viremia among patients lost from one facility who reported engagement in a new facility was markedly higher than among patients who remained engaged in their original facility: Even though durable discontinuation from care was relatively infrequent, strategies to consistently engage patients to enhance retention and viral suppression are urgently needed.

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.

To determine whether integrating antiretroviral therapy (ART) into antenatal care (ANC) and maternal and child health (MCH) clinics could improve programmatic and patient outcomes.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).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.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%: 1,05–1,79; 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.ملخص الغرض : تحديد ما إذا كان دمج العلاج بمضادات الفيروسات القهقرية في عيادات الرعاية السابقة للولادة وصحة الأم والطفل سيؤدي إلى تحسين الحصائل البرمجية وحصائل المرضى. الطريقة : قام المؤلفون بإجراء بحث منهجي في قواعد بيانات PubMed وEmbase وAfrican Index Medicus وLiLACS بخصوص التجارب العشوائية التي أُجريت في بيئة مراقبة أو الدراسات الأترابية الاستطلاعية أو الدراسات الأترابية الاستعادية لمقارنة الحصائل في عيادات الرعاية السابقة للولادة أو صحة الأم والطفل التي دمجت ولم تدمج العلاج بمضادات الفيروسات القهقرية. وكانت الحصائل المهمة هي تغطية العلاج بمضادات الفيروسات القهقرية والتسجيل في العلاج بمضادات الفيروسات القهقرية وإبقاء العلاج بمضادات الفيروسات القهقرية ومعدل الوفيات وانتقال فيروس العوز المناعي البشري (HIV). النتائج حققت أربع دراسات معايير الإدراج. وقد أجريت جميعها في عيادات الرعاية السابقة للولادة. ولوحظت زيادة في تسجيل السيدات الحوامل في العلاج بمضادات الفيروسات القهقرية في عيادات الرعاية السابقة للولادة التي دمجت العلاج بمضادات الفيروسات القهقرية (الاختطار النسبي: 2.09؛ فاصل الثقة 95 %: من 1.78 إلى 2.46؛ إحصاء I : 15 %). ولوحظت أيضاً زيادة في تغطية العلاج بمضادات الفيروسات القهقرية في هذه العيادات (الاختطار النسبي: 1.37؛ فاصل الثقة 95 %: من 1.05 إلى 1.79؛ إحصاء I : 83 %). وأظهرت تحليلات الحساسية اتجاهاً لانتشار عدوى فيروس العوز المناعي البشري على الصعيد الوطني بُغية توضيح التغايرية في حجم تأثير دمج العلاج بمضادات الفيروسات القهقرية على تغطية العلاج بمضادات الفيروسات القهقرية ( الاحتمال =0.13). وتشابه الإبقاء في العلاج بمضادات الفيروسات القهقرية في عيادات الرعاية السابقة للولادة التي دمجت أو لم تدمج العلاج بمضادات الفيروسات القهقرية. الاستنتاج : على الرغم من قلة البيانات المتاحة، يبدو أن دمج العلاج بمضادات الفيروسات القهقرية في عيادات الرعاية السابقة للولادة سيؤدي إلى ارتفاع معدلات التسجيل في العلاج بمضادات الفيروسات القهقرية وتغطيته. وتظل معدلات الإبقاء في العلاج بمضادات الفيروسات القهقرية مشابهة لتلك التي لوحظت في النماذج المستندة على الإحالة.摘要 目的: 确定将抗逆转录病毒疗法（ART）纳入产前护理（ANC）和母婴保健（MCH）诊所是否可以改善规范化患者治疗效果。 方法: 作者系统检索PubMed、Embase、非洲医学引文索引和LiLACS进行随机对照试验、前瞻性队列研究或者回顾性队列研究，比较纳入ART和没有纳入ART的ANC或MCH诊所的效果。关注的效果是ART覆盖范围、ART招募、ART保持、艾滋病毒（HIV）的死亡率和传播。 结果: 有四项研究符合纳入标准。所有研究都在ANC诊所执行。在纳入ART的ANC诊所内观察到孕妇ART入组增加（相对风险，RR：2.09；95% 置信区间，CI；1.78-2.46；I：15%）。这些诊所中还注意到ART覆盖范围的增加（RR：1.37；95% CI：1.05-1.79；I：83%）。敏感性分析显示出艾滋病毒感染患病率的全国趋势，解释了在ART覆盖范围方面ART整合效果的大小的异质性（P = 0.13）。纳入和不纳入ART的ANC诊所在ART保持方面相似。 结论: 虽然可用的数据很少，在ANC诊所中纳入ART仍显示出会产生更高的ART入组和ART覆盖率。在基于转介的模型中观察到的ART保持相似。Резюме Цель: Определить, может ли интеграция антиретровирусной терапии (АРТ) в клиниках дородовой помощи (ДРП) и клиниках охраны здоровья матери и ребенка (ОЗМиР) содействовать достижению программных целей и улучшить результаты лечения пациентов. Методы: Авторы выполняли систематический поиск в базах данных PubMed, Embase, African Index Medicus и LiLACS результатов рандомизированных контролируемых испытаний, проспективных и ретроспективных когортных исследований, сравнивая результаты в клиниках ДРП или ОЗМиР, в которых проводилась и не проводилась интеграция АРТ. К числу результатов, представляющих интерес, относился охват АРТ, прием на АРТ, ретенция АРТ, смертность и передача вируса иммунодефицита человека (ВИЧ). Результаты: Четыре исследования соответствовали критериям включения. Все они были проведены в клиниках ДРП. Увеличение числа беременных женщин, вовлеченных в АРТ, наблюдается в клиниках ДРП, которые осуществили интеграцию АРТ (относительный риск, ОР: 2,09; 95% доверительный интервал (ДИ) – 1,78-2,46; I: 15%). Увеличение охвата АРТ было также отмечено в данных клиниках (ОР: 1,37; 95% ДИ: 1,05–1,79; I: 83%). Анализы чувствительности показали, что тенденцию к распространению на национальном уровне ВИЧ-инфекции объясняет неоднородность влияния эффекта интеграции АРТ на охват АРТ (P = 0,13). Ретенция АРТ была одинаковой в клиниках ДРП как с интегрированной АРТ, так и без нее. Вывод: Хотя количество имеющихся данных было невелико, интеграция АРТ в клиниках ДРП, похоже, ведет к росту числа приемов на АРТ и охвата АРТ. Темпы ретенции АРТ остаются аналогичными тем, которые наблюдаются в моделях, в которых используется направление к врачу-специалисту.

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 HIVinfected subjects electively commencing cART. Methods Therapy-naive, HIV-infected individuals and HIVuninfected 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), p00.036, and 0.94 (0.28) and 1.17 (0.26), p00.008, for Cho/Cr and MI/Cr, respectively) and Cho/Cr ratio associated with CD4+ lymphocyte count (p00.041). NAcetyl-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), p00.002), and this was associated with greater plasma HIV RNA load (p00.014). 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.

It could be postulated that due to lifestyle factors, patients with poor antiretroviral therapy (ART) adherence may also have risky sexual behaviour potentially leading to HIV transmission. There are limited data regarding unprotected sex risk and ART adherence in resource limited settings and our study set out to investigate these in an HIV clinic in Bangkok. Patients completed an anonymous questionnaire regarding their relationship details, ART adherence, sexual behaviour, alcohol and drug use and HIV transmission beliefs. Laboratory findings and medical history were also collected. Unprotected sex risk (USR) was defined as inconsistent condom use with a partner of negative or unknown HIV status. Five hundred and twelve patients completed the questionnaire. Fifty seven per cent of patients reported having taken ARV >95% of the time in the last month and 58% had been sexually active in the previous 30 days. Only 27 patients (5%) were classified as having USR in our cohort. Multivariate analysis showed USR was associated with female gender (OR 2.9, 95% CI 1.2-7.0, p0.02) but not with adherence, age, type or number of partners, recreational drug or alcohol use nor beliefs about HIV transmission whilst taking ART. Levels of USR in this resource limited setting were reassuringly low and not associated with poor ART adherence; as all USR patients had undetectable viral loads onward HIV transmission risk is likely to be low but not negligible. Nonetheless condom negotiation techniques, particularly in women, may be useful in this group.

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 1. 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. La delivrance des soins du VIH dans le deploiement initial rapide des soins et du traitement du VIH a ete basee sur des modeles existants dans les cliniques, qui sont courants dans les regions beneficiant d’importantes ressources et largement indifferenciees pour les besoins individuels. Un nouveau cadre est propose ici pour le traitement base selon les intensites variables de soins, adaptes aux besoins specifiques des differents groupes de personnes a travers la cascade de soins. L’intensite des services est caracterisee par quatre elements de delivrance: (1) les types de services delivres, (2) l’emplacement de la delivrance des services, (3) Les prestataires des services de sante et (4) la frequence des services de sante. La facon dont ces elements sont developpes dans un cadre de prestation de services peut varier selon les pays et les populations, l’intention etant d’ameliorer les resultats d’acceptabilite et des soins. Le but d’obtenir plus de personnes sous traitement avant qu’ils ne tombent malades necessitera des modeles innovateurs de prestation a la fois pour depistage et pour les soins. Comme les programmes VIH etendent l’eligibilite au traitement, beaucoup de gens qui entrent dans les soins ne seront pas des “malades- mais des elements sains de la societe, actifs et productifs. Afin de tenir le cadre a l’echelle, il sera important de: (1) definir les individus qui peuvent etre traites par un cadre alternatif de prestation, (2) renforcer les systemes de sante qui soutiennent la decentralisation, l’integration et le transfert des tâches; (3) rendre la chaine d’approvisionnement plus robuste et (4) investir dans des systemes de donnees pour le suivi des patients et pour le suivi et l’evaluation du programme. Los servicios de atencion del VIH durante el inicio de la primera etapa de rapida expansion del tratamiento y cuidados del VIH estaban basados en modelos clinicos existentes, comunes en lugares con abundancia de recursos y poco diferenciados en cuanto a necesidades individuales. Aqui se propone un nuevo marco para el tratamiento basado en intensidades variables de cuidados, hecho a medida segun las necesidades especificas de los diferentes grupos de individuos a lo largo del tratamiento. La intensidad del servicio se caracteriza por cuatro componentes de entrega: (1) tipologia de los servicios ofrecidos, (2) lugar de entrega de los servicios, (3) proveedor de los servicios sanitarios, y (4) frecuencia de los servicios sanitarios. El como estos componentes conforman un marco de entrega de servicios variara segun el pais y la poblacion, con la intencion de mejorar la aceptabilidad y los resultados de los cuidados. El objetivo de conseguir que mas personas reciban tratamiento antes de que enfermen requerira de modelos innovadores en la oferta tanto de pruebas para deteccion como de los cuidados. A medida que los programas para el VIH expandan los criterios de elegibilidad para el tratamiento, muchas de las personas que comiencen a recibir cuidados no seran “pacientes- sino miembros sanos, activos y productivos de la sociedad. Con el fin de expandir la escala de esta estructura, seria importante: (1) definir cuales individuos pueden ser atendidos dentro de un marco de entrega de servicios alternativo; (2) fortalecer los sistemas sanitarios que apoyan la descentralizacion, integracion y delegacion de funciones; (3) robustecer la cadena de proveedores; e (4) invertir en sistemas de datos para el seguimiento de pacientes y para la monitorizacion y evaluacion de programas.

Objective Nucleoside reverse transcriptase (NRTI) sparing is a favourable option for patients with NRTI failure or toxicity. Methods Patients judged to be failing NRTI therapy were enrolled in a single-arm, open-label study of indinavir/ritonavir (IDV/r) 800/100 mg twice a day (bid)+efavirenz (EFV) 600 mg once a day (qd). The primary endpoint was the change in time-weighted average HIV RNA from baseline. The initial 48-week protocol was extended to 96 weeks by a single amendment. Analysis was by intention to treat. Results Sixty-one patients (23 female) were enrolled in the study. Baseline median inter-quartile range (IQR) NRTI exposure was 4.4 (3.9–4.7) years; baseline median viral load was 4.09 log10 HIV-1 RNA copies/mL (range 3.75–4.61 log10 copies/mL); baseline median CD4 count was 169 cells/μL (range 60–277 cells/μL). The mean (SD) change in time-weighted average HIV RNA from baseline at 48 and 96 weeks was −2.1 (0.7) and −2.1 (0.8) log10 copies/mL respectively, resulting in 87% and 69% of patients with HIV RNA

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 (Cl), 1.1-2.4] and 0.7 (95% Cl, 0.3-1.3) per 10 person years respectively. Compared to patients with baseline CD4 cell counts >= 350 x 10(6)/l, the adjusted hazard ratio (HR) for progression was 3.67 (95% Cl, 1.31-10.27) for patients with 4 log(10). Compared to patients with a 6-month CD4 cell count >= 350 x 10(6)/l, HR for progression was 5.22 (95% Cl, 1.90-14.37) for patients with

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 incidence were EFV (20%) NVP BD (21%) NVPOD (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 5.9 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 =250 x 10(6) cells/l high body mass index (>21.3 kg/m(2) and a rise in CD4 (=53 x 10(6) cells/l) and alanine aminotransferase (ALT) (=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. (authors)

The purpose of this article is to discuss ways in which HIV-NAT’s experience might be instructive for the international research community. Certain principles have guided the development of HIV-NAT; these are: 1. Draw on the resources of pre-existing organizations. 2. Begin with modest goals in order to maximize the likelihood of good initial outcomes. 3. Do not expect questions about sustainability to be fully resolved before the launch. 4. Promote clinical and laboratory practices that meet international research standards. 5. Work closely with government health officials. 6. Expand slowly and carefully. 7. Use accomplishments to leverage greater support from fund providers. 8. Perform studies that are of interest to both local and international constituencies. 9. Be willing to take on a regional leadership role. The first section below describes some of the organization’s achievements. The second and third sections discuss how the nine principles listed above are believed to account for the achievements of HIVNAT. It is hoped that by sharing information about HIV-NAT’s experience we can help to expand the scope and the impact of HIV clinical research that simultaneously promotes the interests of both developed and developing countries. (excerpt)

In a prospective open-label study, 41 male subjects received nelfinavir, zidovudine, and lamivudine stratified as either: early stage (ES; negative/indeterminate Western blot; n = 19) or late stage (LS; positive Western blot; n = 22) primary HIV-1 infection. Despite higher median baseline HIV-1 RNA levels and lower CD4(+) cell numbers in the ES subjects, a significantly greater decline in viral load (-3.46 vs. -2.83 log(10) copies/ml; p = 0.023) and increase in CD4(+) cell number (+85 vs. +41 cells/month increase, p = 0.01) were observed over the first 3 months of therapy such that both groups had comparable results at 1 year. The proportion with HIV-1 RNA50 copies/mL at 1 year was similar (9 of 19 ES subjects and 11 of 22 LS subjects by intention-to-treat analysis). Memory CD4(+) cell numbers, and activated CD4(+) percentages, were also significantly improved in ES subjects. Despite poorer prognostic markers at baseline ES subjects achieved responses similar to those of LS subjects after 1 year of treatment.

Epidemic modeling suggests that a major scale-up in HIV treatment could have a dramatic impact on HIV incidence. This has led both researchers and policymakers to set a goal of an “AIDS-Free Generation.” One of the greatest obstacles to achieving this objective is the number of people with undiagnosed HIV infection. Despite recent innovations, new research strategies are needed to identify, engage, and successfully treat people who are unaware of their infection.

Each January, the HIV Netherlands-Australia-Thailand Research Collaboration (HIV–NAT) organizes this symposium on HIV medicine. The symposium aims to present a comprehensive review of the management of HIV infection to physicians from Thailand and the Asia-Pacific region. This review includes updates on antiretroviral therapy, new research and efforts to improve access to care. The major sponsors were the Foundations for AIDS Research through its TREAT Asia Initiative, Australia’s National Centre in HIV Epidemiology and Clinical Research and Thailand’s National Health Security Office, IDS Marketing, Bristol Myersquibb and Merck & Co, Inc. The Symposium attracts more than 500 participants from Thailand, Laos, Myanmar, Vietnam, Cambodia, Indonesia, India, Singapore, Hong Kong, Taiwan, China, Bangladesh, Papua New Guinea, Australia, The Netherlands and South Korea.

The symposium is organized each January by the HIV Netherlands, Australia, Thailand Research Collaboration. The objectives of the Symposium are to provide physicians from Thailand and the Asia–Pacific region with a comprehensive review of the management of HIV infection, including updates on antiretroviral therapies and strategies, new research and efforts to improve access to care. The major sponsors were the Foundation for AIDS Research through its TREAT Asia Initiative, Australia’s National Centre in HIV Epidemiology and Clinical Research and Thailand’s National Health Security Office. Over the years, the Symposium has regularly attracted more than 500 participants from Thailand, Laos, Myanmar, Vietnam, Cambodia, Indonesia, India, Singapore, Hong Kong, Taiwan, China, Bangladesh, Papua New Guinea, Australia and Korea.

In the past few years, major advances have been made in the field of primary HIV-1 infection. Several studies have reevaluated the clinical syndrome. The emergence of new molecular laboratory techniques has permitted a detailed analysis of viral dynamics and subsequent immunologic changes. Measurements of subsets of T-lymphocytes have allowed greater insight into the early pathogenesis of HIV-1 disease. There is now evidence that HIV-1-specific cytotoxic T-lymphocytes occur early during primary HIV-1 infection and are probably the most important immune defense against HIV-1. However, HIV-1 immune escape mutants have been identified during primary infection, which may be one reason for the failure of the immune system to completely eradicate the virus. Cytokines have been shown to play a role in primary HIV-1 infection, and the therapy of primary infection has gained more interest due to the introduction of potent triple combinations, including protease inhibitors.

In the context of emerging evidence related to preexposure prophylaxis and HIV treatment as prevention, an evidence summit was held in mid-2012 to discuss the current state of the science and to provide a platform for consensus building around whether and how these prevention strategies might be implemented globally. Health care providers, researchers, policy makers, people living with HIV/AIDS, and representatives of government authorities, donor agencies, pharmaceutical companies, advocacy organizations, and professional associations attended from 52 countries. An international advisory committee was convened to identify key messages and recommendations based upon the data presented and discussed at the summit. The advisory committee further worked to develop this consensus statement meant to assist relevant stakeholders in taking stock and mapping out a route forward to enhance the HIV prevention armamentarium.

Human immunodeficiency virus type 1 (HIV-1) variants with reduced in vitro sensitivity to zidovudine, conferred by specific mutations in the viral reverse transcriptase, emerge during prolonged therapy. Late-stage disease and declining CD4 cell count are associated with more rapid emergence of these resistant variants. Isolates of HIV-1 from seroconverters were screened for the zidovudine-resistance marker mutation at codon 215. HIV-1 with the altered genotype was detected in 5 (8.2%) of 61 patients soon after onset of symptomatic primary illness and from the sex partner of 1 patient. These transmitted resistant viruses were either replaced by strains susceptible to zidovudine within a few months of infection or persisted for up to 1 year in the absence of prolonged zidovudine therapy. The resistant genotype persisted in 3 of 5 seroconverters but in 2 patients had reverted to wild type at 48 and 52 weeks. Primary infection with zidovudine-resistant variants of HIV-1 was not associated with a more severe symptomatic primary illness or more rapid CD4 cell decline at 1 year after infection.

In settings where medications and viral load (VL) monitoring are limited by cost, clinicians need reliable ways to assess patient adherence to therapy. We assessed sensitivity and specificity of two self-reported adherence tools (a visual analogue scale [VAS] and the CASE [Center for Adherence Support Evaluation] adherence index), against a standard of detectable VL, with 288 patients from three sites in Thailand. We also assessed predictors of non-adherence. The sensitivity and specificity of the VAS 50 copies/mL were 26% and 90%, 19% and 95%, respectively. Against a VL ≥1000 copies/mL sensitivities increased to 55% and 36%, respectively, and specificities were unchanged. Attending a clinic not staffed by HIV specialists (odds ratio [OR] 3.14; 95% confidence interval [CI] 1.19–8.34) and being educated to primary school level or less (OR 2.24; 95% CI 1.01–4.94) were associated with self-reported adherence

Global scale-up of antiretroviral therapy (ART) in low- and middle-income countries (LMICs) is an unprecedented public health achievement. With planned efforts of expanded ART access including earlier treatment initiation and the use of antiretroviral (ARV) drugs for prophylaxis, increasing levels of HIV drug resistance (HIVDR) are expected. Several factors may lead to selection and transmission of significant HIVDR in LMICs, which will lead to decreased population-level efficacy of standard first- and second-line ART regimens. These factors include low genetic barrier of some ARVs to resistance development, drug–drug interactions, inappropriate prescribing practices, interruption of drug supply, poor retention in care and lack of routine viral load monitoring. To maximize long-term effectiveness of available ARVs, policy makers and programme managers in LMICs should routinely monitor programme factors associated with emergence and transmission of HIVDR and implement routine HIVDR surveillance following standardized methods. When surveillance results suggest the need for action, specific public health interventions must be taken to adjust ART programme functioning to minimize further emergence and transmission of HIVDR. In this paper, we review ARV drug, HIV, patient and programme-related determinants of HIVDR. Additionally, we summarize the World Health Orgnization's global HIVDR surveillance and prevention strategy and describe resulting public health and policy implications.

Background Improvements in neurocognitive (NC) function have been associated with commencing antiretroviral therapy in HIV-infected subjects. However, the dynamics of such improvements are poorly understood. Methods We assessed changes in NC function via a validated computerized battery (CogState™, Melbourne, Victoria, Australia) at baseline and after 24 and 48 weeks in a subset of therapy-naive neuro-asymptomatic HIV-infected subjects, randomized to commence three different antiretroviral regimens. Results Of 28 subjects enrolled in the study, nine, eight and 11 were randomly allocated to commence tenofovir/emtricitabine with efavirenz (arm 1), atazanavir/ritonavir (arm 2) and zidovudine/abacavir (arm 3), respectively. Overall improvements in NC function were observed at week 24 and function continued to improve at week 48 (changes in z-score for overall cognitive global score of 0.16 and 0.18 at weeks 24 and 48, respectively). Within the NC speed domains, generally greater improvements were observed in arms 2 and 3, compared with arm 1 (changes in z-score for composite speed scores at weeks 24/48 of 0.16/0.16, –0.29/–0.24 and –0.15/–0.31 in arms 1, 2 and 3, respectively; P = 0.04 for change at week 48 in arm 3 versus arm 1). Finally, improvements in executive function occurred later (only observed at week 48) and were driven by improvements in arm 3 (z-score changes of 0.23, 0.06 and –0.78 in arms 1, 2 and 3, respectively; P = 0.02 for change in arm 3 versus arm 1). Conclusion Improvements in NC function continue over the first year after initiating antiretroviral therapy in neuro-asymptomatic HIV-infected subjects.

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

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

Objective: Although studies have shown reductions in mortality from AIDS after the introduction of combination antiretroviral treatment (cART), little is known about cause-specific mortality in low-income settings in the cART era. We explored predictors of AIDS and non-AIDS mortality and compared cause-specific mortality across high-income and low-income settings in the Asia-Pacific region. Methods: We followed patients in the Asia Pacific HIV Observational Database from the date they started cART (or cohort enrolment if cART initiation was identified retrospectively), until the date of death or last follow-up visit. Competing risks methods were used to estimate the cumulative incidence, and to investigate predictors, of AIDS and non-AIDS mortality. Results: Of 4252 patients, 215 died; 89 from AIDS, 97 from non-AIDS causes and 29 from unknown causes. Age more than 50 years [hazard ratio 4.29; 95% confidence interval (CI) 2.10-8.79] and CD4 cell counts less than or equal to 100 cells/μl (hazard ratio 8.59; 95% CI 5.66-13.03) were associated with an increased risk of non-AIDS mortality. Risk factors for AIDS mortality included CD4 cell counts less than or equal to 100 cells/μl (hazard ratio 34.97; 95% CI 18.01-67.90) and HIV RNA 10 001 or more (hazard ratio 4.21; 95% CI 2.07-8.55). There was some indication of a lower risk of non-AIDS mortality in Asian high-income, and possibly low-income, countries compared to Australia. Conclusion: Immune deficiency is associated with an increased risk of AIDS and non-AIDS mortality. Older age predicts non-AIDS mortality in the cART era. Less conclusive was the association between country-income level and cause-specific mortality because of the relatively high proportion of unknown causes of death in low-income settings.

In HIV patients who discontinue highly active antiretroviral therapy (HAART), the degree of HIV RNA suppression at the time of treatment interruption may predict success of re-treatment after the interruption (STI). A case-control substudy of the Staccato trial in Thailand included CD4-guided STI subjects with HIV RNA > 50 copies /ml (virological failure cases, n=11) and HIV RNA < 50 copies/ml (controls, n=22) after 12-24 weeks of HAART re-treatment following a median of 2 STI cycles. Controls were matched for age, gender and pre-ART CD4 count. HIV RNA with 5 copies/ml detection limit was determined on pre-virological failure samples. HIV RNA increased in cases compared to controls with each successive STI cycle (p-trend across time-points 0.004). The last HIV RNA below 50 copies/ml was significantly higher among cases compared to controls (p=.004). Measuring HIV RNA below 50 copies/ml may be useful in predicting virological failure to STI.

Objective The aim of the study was to investigate the influence of highly active antiretroviral therapy (HAART) on iron status and, conversely, the influence of iron status on the response to HAART. Methods Ferritin levels were retrospectively determined in stored plasma from 138 HAART-naive, moderately immunosuppressed HIV-infected Thai patients participating in a structured treatment interruption trial. Ferritin levels were determined at three predefined time-points: (1) HAART initiation; (2) HAART discontinuation; and (3) HAART resumption. Results At baseline, 31% and 16% of the HIV-infected patients included in the study had high (>200 ng/mL) and low (

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.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.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.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.

Introduction The use of HIV protease inhibitors (PIs) in a ritonavir (RTV)-boosted form is now common. However, randomized data comparing boosted with unboosted PI strategies are scarce. Methods This randomized, open-label trial compared indinavir (IDV) 800 mg three times daily with IDV/RTV 800/100 mg twice daily, both given with zidovudine (AZT)/lamivudine (3TC) twice daily in individuals with at least 3 months previous AZT experience. The primary endpoint was the time-weighted average change in HIV RNA from baseline. Designed as a 48-week study, follow-up continued until week 112. Primary analysis is by intention to treat. Results One hundred and three patients commenced therapy and are included in the analysis. Patients had a median of 29 months past nucleoside reverse transcriptase inhibitor (NRTI) exposure. Baseline median (interquartile range) log10 HIV RNA was 4.0 (3.3–4.5) and CD4+T-cell count 166 (40–323) cells/μl. After 112-weeks of study there was no significant difference observed between arms in the mean (sd) change in time-weighted average HIV RNA from baseline (-1.6 [1.1] HIV RNA copies/week/ml three times daily arm; -1.4 [1.1] HIV RNA copies/week/ml twice daily arm; P=0.3). Both arms were associated with substantial toxicity expressed as serious adverse events and study drug interruptions. The twice daily arm experienced greater dyslipidaemia. Mean (sd) changes in time-weighted CD4+ T-cell count from baseline were similar [88 (84) cells/week/μl three times daily arm; 70 [109] cells/week/μl twice daily arm; P=0.3). Conclusions RTV-boosted IDV 800/100 mg twice daily demonstrated comparable efficacy to unboosted IDV 800mg three times daily dosing. Both regimens were associated with substantial toxicity. Use of lower doses of RTV-boosted IDV may result in better tolerability without loss of efficacy and warrant further research.

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

Item does not contain fulltext OBJECTIVES: To describe the pharmacokinetics and pharmacodynamics of indinavir with or without low-dose ritonavir in human immunodeficiency virus (HIV)-infected Thai patients. PATIENTS AND METHODS: Thirty-six HIV-1-infected patients who participated in HIV-NAT 005 study gave informed consent to record a pharmacokinetic curve 4 weeks after starting a regimen containing either indinavir 800 mg every 8 h (n = 19) or indinavir 800 mg + ritonavir 100 mg every 12 h (n = 17). Indinavir plasma concentrations were measured by HPLC. Pharmacokinetic parameters were calculated by non-compartmental methods. RESULTS: The median (interquartile range; IQR) body weight of the 36 patients (11 females and 25 males) was 60 (54-72) kg. Median and IQR values for indinavir AUC, Cmax and Cmin were 20.9 (13.1-27.0) mg x h/L, 8.1 (6.6-9.4) mg/L and 0.13 (0.09-0.27) mg/L, respectively, for indinavir 800 mg every 8 h, and 49.2 (42.5-60.4) mg x h/L, 10.6 (8.5-13.2) mg/L and 0.68 (0.43-0.77) mg/L, respectively, for indinavir 800 mg + ritonavir 100 mg every 12 h. These values are not largely different from values found in Caucasian patients, with the exception of relatively high peak levels of indinavir in Thai subjects. Cut-off values for optimal virological efficacy were an indinavir Cmin of 0.10 and 0.25 mg/L for the every 8 h and the every 12 h regimen, respectively; patients with an indinavir AUC greater than 30 (every 8 h regimen) or 60 (every 12 h regimen) mg x h/L were at increased risk of developing nephrotoxicity. CONCLUSIONS: Indinavir pharmacokinetics and pharmacodynamics in Thai HIV-1-infected patients are similar to those described in Caucasian patients, despite an overall lower body weight in this population

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, p0.001). 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.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.

To evaluate treatment response, durability and tolerance of a four-drug regimen including saquinavir and ritonavir in combination with either zidovudine/lamivudine or stavudine/lamivudine.Observational cohort of HIV-positive individuals.Viral load, CD4+ and CD8+ T lymphocyte counts were assessed at intervals of 1-3 months in subjects commencing therapy between July 1996 and November 1996. Adverse events were evaluated as well as risk factors for therapeutic failures.A group of 56 male patients were included and followed for 48 weeks. Of these, 66% had already taken a protease inhibitor. Viral load dropped by a median 1.98 log10 HIV RNA copies/ml from baseline (interquartile range: 1.49-2.46) and became undetectable (400 copies/ml) in 68% of patients. Response varied: 9% were non-responders (HIV RNA reduction0.5 log10 copies/ml) and 23% were incomplete responders (nadir of HIV RNA400 copies/ml). After 48 weeks, viral load remained undetectable in 49%. Median CD4+ T lymphocyte count increased from 191 x 10(6) to 418 x 10(6) cells/l (range, 241-537 x 10(6) cells/l). Although protease inhibitor and nucleoside pretreatment selected for drug-resistant viral mutants, only the protease inhibitor experience was identified as a risk factor for therapeutic failure. Adverse events occurred in 73% of patients and led to a change of therapy in 9%.Despite advanced HIV disease and pretreatment with multiple antiretroviral drugs, a strong initial treatment response to this drug regimen was observed. However, virological failure occurred in 51% of patients after 48 weeks and frequent adverse events complicated therapy.

Globally, national pharmacovigilance systems rely on spontaneous reporting in which suspected adverse drug reactions (ADRs) are reported to a national coordinating centre by health professionals, manufacturers or patients. Spontaneous reporting systems are the easiest to establish and the cheapest to run but suffer from poor-quality reports and underreporting. It is difficult to estimate rates and frequencies of ADRs through spontaneous reporting. Public health programmes need to quantify and characterize risks to individuals and communities from their medicines, to minimize harm and improve use, to sustain public confidence in the programmes, and to track problems due to medication errors and poor quality medicines. Additional methods are therefore needed to monitor the quantitative aspects of medicine safety, to better identify specific risk factors and high-risk groups, and to characterize ADRs associated with specific medicines and in specific populations. The present paper introduces two methods, cohort event monitoring and targeted spontaneous reporting, that are being implemented by the WHO, in its public health programmes, to complement spontaneous reporting. The advantages and disadvantages of these methods and how each can be applied in clinical practice are discussed.