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In countries that have not implemented universal antiretroviral treatment (ART), loss to follow-up (LTFU) during pre-ART care remains a problem. We conducted semi-structured interviews with 41 HIV-infected persons who were LTFU during pre-ART care from a prospective cohort of persons newly diagnosed with HIV infection in Freetown, Sierra Leone, in 2012-2013. Interviews determined whether the participant disengaged or transferred care and explored the reasons for being LTFU. Of the 41 participants, 34 (83%) disengaged from care. For persons who disengaged from care, socioeconomic barriers emerged as a dominant theme in both ART-eligible and -ineligible groups while psychosocial barriers emerged as a dominant theme in the ART-ineligible group. Structural barriers emerged as a dominant theme for participants who transferred care. Interventions designed to address socioeconomic and psychosocial barriers may help reduce disengagement from pre-ART care.

Background: Dolutegravir (DTG) is a once-daily unboosted second-generation integrase-inhibitor that along with two nucleoside reverse transcriptase inhibitors is one of several regimens recommended by the United States, United Kingdom and European Union for first-line antiretroviral treatment of people with HIV infection. Our objective was to review the evidence for the efficacy and safety of DTG-based first-line regimens compared to efavirenz (EFV)-based regimens., Methods: We conducted a systematic review. We comprehensively searched a range of databases as well as conference abstracts and a trials registry. We used Cochrane methods in screening and data collection and assessed each study's risk of bias with the Cochrane tool. We meta-analyzed data using a fixed-effects model. We used GRADE to assess evidence quality., Results: From 492 search results, we identified two randomized controlled trials, reported in five peer-reviewed articles and one conference abstract. One trial tested two DTG-based regimens (DTG + abacavir (ABC) + lamivudine (3TC) or DTG + tenofovir + emtricitabine) against an EFV-based regimen (EFV+ ABC+3TC). The other trial tested DTG+ABC+3TC against EFV+ABC+3TC. In meta-analysis, DTG-containing regimens were superior to EFV-containing regimens at 48 weeks and at 96 weeks (RR = 1.10, 95% CI 1.04-1.16; and RR = 1.12, 95% CI 1.04-1.21, respectively). In one trial, the DTG-containing regimen was superior at 144 weeks (RR = 1.13, 95% CI 1.02-1.24). DTG-containing regimens were superior in reducing treatment discontinuation compared to those containing EFV at 96 weeks and at 144 weeks (RR = 0.27, 95% CI 0.15-0.50; and RR = 0.28, 95% CI 0.16-0.48, respectively). Risk of serious adverse events was similar in each regimen at 96 weeks (RR = 1.15, 95% CI 0.80-1.63) and 144 weeks (RR = 0.93, 95% CI 0.68-1.29). Risk of bias was moderate overall, as was GRADE evidence quality., Conclusions: DTG-based regimens should be considered in future World Health Organization guidelines for initial HIV treatment., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Antiretroviral therapy and prophylaxis during the antepartum, intrapartum and postpartum periods, cesarean delivery and avoidance of breast milk significantly reduce vertical transmission of HIV., Objective: To evaluate the effectiveness prevention of mother-to-child transmission of HIV and determine the rate of vertical transmission in a public sexually transmitted infection and HIV referral center in Salvador, Bahia, in the period immediately prior to the initiation of universal antiretroviral therapy in pregnant women., Methods: Cross-sectional study using data collected from medical records of children born to HIV infected mothers in Bahia from 2005 to 2008 who were referred to the Reference Center for Diagnosis and Research of Sexually Transmitted Diseases and HIV/AIDS for care., Results: Of 232 HIV-exposed infants, 19 (8.2%) had confirmed HIV infection. One hundred eighty-eight (81%) mothers received antenatal care, 120 (52%) antepartum antiretroviral therapy or prophylaxis, and 168 (72%) intrapartum zidovudine. Two hundred twenty-three (96%) infants received zidovudine. In multivariable models, the combination of intrapartum and postpartum antiretroviral prophylaxis was associated with decreased adjusted odds of mother-to-child transmission., Conclusions: Low levels of antenatal screening and access to prevention of mother-to-child transmission were significant limitations in the cascade of prevention of mother-to-child transmission at our center in this period., (Copyright © 2015 Elsevier Editora Ltda. All rights reserved.)

Background: Kaposi sarcoma (KS) remains the second most frequently diagnosed HIV-related malignancy (HRM) worldwide and most common HRM in sub-Saharan Africa where HIV is most prevalent and human herpesvirus 8 (HHV-8), the precipitating agent for the development of KS, is endemic. The majority of KS patients would likely benefit from systemic chemotherapy in addition to the initiation of antiretroviral therapy (ART). However, as paediatric staging and treatment criteria are not readily available, there are no uniform treatment criteria., Objectives: To describe the efficacy and effectiveness of current treatment options for HIV-associated KS in ART-treated paediatric populations., Search Methods: We used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language., Selection Criteria: Randomised controlled trials, cohort studies, and case-control studies of HIV-infected infants and children <18 years old treated with ART and diagnosed with KS., Data Collection and Analysis: Abstracts of all studies identified by electronic or bibliographic scanning were examined independently by two authors. We initially identified 920 references and examined 15 in detail for study eligibility. Data were abstracted independently using a standardised abstraction form., Main Results: After initially screening 920 titles, 15 full-text articles were closely examined by two authors. We identified four cohort studies that met our inclusion criteria for data extraction, coding, and potential meta-analysis.Using the Newcastle-Ottawa Scale and Cochrane risk of bias assessments, all observational studies had cohorts that were representative of average (treated and untreated) HIV-infected children with Kaposi sarcoma. For all outcomes of interest, no study adjusted for any other potential confounders. Two of four observational studies either explicitly described complete follow up of the study participants and/or described the characteristics of the participants lost to follow up.The use of ART together with a chemotherapeutic regimen versus ART alone appears to increase the likelihood of KS remission in HIV-infected children diagnosed with KS, although data are sparse and not adequately adjusted for staging of disease and comorbidities. Additionally, though data are sparse, the use of ART together with a chemotherapeutic regimen versus chemotherapy alone in some analyses appears to increase the likelihood of KS remission and reduce the risk of death in HIV-infected children diagnosed with KS.In this analysis, we found that the quality of evidence was very low due to small sample sizes and a paucity of paediatric literature., Authors' Conclusions: Data describing the efficacy of different treatment options for pediatric KS, to include chemotherapy and ART, are sparse. However, the use of ART together with a chemotherapy regimen may be superior to the use of ART alone or of chemotherapy alone.

Introduction: While the rate of vertically transmitted HIV infection has fallen in most regions of Brazil, there have been no similar decreases in northern and northeastern Brazil., Objective: The objective of this study was to evaluate the risk factors associated with vertical transmission in the state of Sergipe in northeastern Brazil., Methods: This was a retrospective cohort study. We recorded clinic and registry data for all HIV-infected pregnant women and exposed children diagnosed in Sergipe from 1990 to 2011., Results: We identified 538 deliveries and 561 HIV-exposed infants (23 sets of twins). One hundred one (18.9%) infants were HIV-infected. In the multivariate analysis, infant antiretroviral prophylaxis was a significant protective factor (adjusted odds ratio (aOR) 0.07, 95% confidence interval (CI) 0.01-0.41, p=0.003). Breastfeeding was marginally associated with an increased odds of perinatal transmission (aOR 4.52, 95% CI 0.78-26.17, p = 0.092). The attributable risk percentage for breastfeeding over the study period was 91.0%. Transmission decreased from 91 per 100 live births before 1997 to 2 per 100 in 2011 following the adoption of the prevention protocol., Conclusion: Transmission declined over the study period. The screening of pregnant women and timely initiation of prophylaxis and therapy are issues that require further attention., (Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Modifications to combination antiretroviral drug therapy (CART) regimens can occur for a number of reasons, including adverse drug effects. We investigated the frequency of and reasons for antiretroviral drug modifications (ADM) during the first 3 years after initiation of CART, in a closed cohort of CART-naïve adult patients who started treatment in the period 1998-2007 in Croatia., Material and Methods: We calculated differential toxicity rates by the Poisson method. In multivariable analysis, we used a discrete-time regression model for repeated events for the outcome of modification due to drug toxicity., Results: Of 321 patients who started CART, median age was 40 years, 19% were women, baseline CD4 was <200 cells/mm3 in 71%, and viral load was ≥100 000 copies/mL in 69%. Overall, 220 (68.5%) patients had an ADM; 124 (56%) of these had ≥1 ADM for toxicity reasons. Only 12.7% of individuals starting CART in the period 1998-2002 and 39.4% in the period 2003-2007 remained on the same regimen after 3 years. The following toxicities caused ADM most often: lipoatrophy (22%), gastrointestinal symptoms (20%), and neuropathy (18%). Only 5% of drug changes were due to virologic failure. Female sex (hazard ratio [HR], 2.42 95%; confidence intervals, 1.39-4.24) and older age (HR, 1.42 per every 10 years) were associated with toxicity-related ADM in the first 3 months of a particular CART regimen, but after 3 months of CART they were not., Conclusions: Less toxic and better-tolerated HIV treatment options should be available and used more frequently in Croatia.

Background: Antiretroviral drugs have been shown to reduce risk of mother-to-child transmission of human immunodeficiency virus (HIV) and are also widely used for post-exposure prophylaxis for parenteral and sexual exposures. Sexual transmission may be lower in couples in which one partner is infected with HIV and the other is not and the infected partner is on antiretroviral therapy (ART)., Objectives: To determine if ART use in an HIV-infected member of an HIV-discordant couple is associated with lower risk of HIV transmission to the uninfected partner compared to untreated discordant couples., Search Methods: We used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language., Selection Criteria: Randomised controlled trials (RCT), cohort studies and case-control studies of HIV-discordant couples in which the HIV-infected member of the couple was being treated or not treated with ART DATA COLLECTION AND ANALYSIS: Abstracts of all trials identified by electronic or bibliographic scanning were examined independently by two authors. We initially identified 3,833 references and examined 87 in detail for study eligibility. Data were abstracted independently using a standardised abstraction form., Main Results: One RCT and nine observational studies were included in the review. These ten studies identified 2,112 episodes of HIV transmission, 1,016 among treated couples and 1,096 among untreated couples. The rate ratio for the single randomised controlled trial was 0.04 [95% CI 0.00, 0.27]. All index partners in this study had CD4 cell counts at baseline of 350-550 cells/µL. Similarly, the summary rate ratio for the nine observational studies was 0.58 [95% CI 0.35, 0.96], with substantial heterogeneity (I(2)=64%). After excluding two studies with inadequate person-time data, we estimated a summary rate ratio of 0.36 [95% CI 0.17, 0.75] with substantial heterogeneity (I(2)=62%). We also performed subgroup analyses among the observational studies to see if the effect of ART on prevention of HIV differed by the index partner's CD4 cell count. Among couples in which the infected partner had ≥350 CD4 cells/µL, we estimated a rate ratio of 0.12 [95% CI 0.01, 1.99]. In this subgroup, there were 247 transmissions in untreated couples and 30 in treated couples., Authors' Conclusions: ART is a potent intervention for prevention of HIV in discordant couples in which the index partner has ≤550 CD4 cells/µL. A recent multicentre RCT confirms the suspected benefit seen in earlier observational studies and reported in more recent ones. Questions remain about durability of protection, the balance of benefits and adverse events associated with earlier therapy, long-term adherence and transmission of ART-resistant strains to partners. Resource limitations and implementation challenges must also be addressed.Counselling, support, and follow up, as well as mutual disclosure, may have a role in supporting adherence, so programmes should be designed with these components. In addition to ART provision, the operational aspects of delivering such programmes must be considered.

Background: More than 34 million people are presently living with HIV infection. Antiretroviral therapy (ART) can help these people to live longer, healthier lives, but adherence to ART can be difficult. Mobile phone text-messaging has the potential to help promote adherence in these patients., Objectives: To determine whether mobile phone text-messaging is efficacious in enhancing adherence to ART in patients with HIV infection., Search Methods: Using the Cochrane Collaboration's validated search strategies for identifying randomised controlled trials and reports of HIV interventions, along with appropriate keywords and MeSH terms, we searched a range of electronic databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), MEDLINE (via PubMed), PsycINFO, Web of Science, and the World Health Organization (WHO) Global Index Medicus. The date range was from  01 January 1980 to 01 November 2011. There were no limits to language or publication status., Selection Criteria: Randomised controlled trials (RCTs) in which patients or their caregivers (in the case of infants and children) of any age, in any setting, and receiving ART were provided with mobile phone text messages as a means of promoting adherence to ART., Data Collection and Analysis: Two authors independently examined the abstracts of all identified trials. We initially identified 243 references. Seventeen full-text articles were closely reviewed. Both authors abstracted data independently, using a pre-designed, standardised data collection form. When appropriate, data were combined in meta-analysis., Main Results: Two RCTs from Kenya were included in the review. One trial compared short weekly text messages against standard care. The other trial compared short daily, long daily, short weekly and long weekly messages against standard care. Both trials were with adult patients.In the trial comparing only short weekly messages to standard care, text messaging was associated with a lower risk of non-adherence at 12 months (RR 0.77, 95% CI 0.63 to 0.93) and with the non-occurrence of virologic failure at 12 months (RR 0.83, 95% CI 0.69 to 0.99).In the trial that compared different intervals and lengths for text-messaging to standard care, long weekly text-messaging was not significantly associated with a lower risk of non-adherence compared to standard care (RR 0.79, 95% CI 0.60 to 1.04). Patients receiving weekly text-messages of any length were at lower risk of non-adherence at 48 weeks than were patients receiving daily messages of any length (RR 0.79, 95% CI 0.64 to 0.99). There were no significant differences between weekly text-messaging of any length (RR 1.01, 95% CI 0.75 to 1.37) and between short or long messaging at either interval (RR 0.99, 95% CI 0.78 to 1.27). Compared to standard care, any daily text-messaging, whether short or long, did not reduce the risk for non-adherence (RR 0.99, 95% CI 0.82 to 1.20).In meta-analysis of both trials, any weekly text-messaging (i.e. whether short or long messages) was associated with a lower risk of non-adherence at 48-52 weeks (RR 0.78, 95% CI 0.68 to 0.89). The effect of short weekly text-messaging was also significant (RR 0.77, 95% CI 0.67 to 0.89)., Authors' Conclusions: There is high-quality evidence from the two RCTs that mobile phone text-messaging at weekly intervals is efficacious in enhancing adherence to ART, compared to standard care. There is high quality evidence from one trial that weekly mobile phone text-messaging is efficacious in improving HIV viral load suppression. Policy-makers should consider funding programs proposing to provide weekly mobile phone text-messaging as a means for promoting adherence to antiretroviral therapy. Clinics and hospitals should consider implementing such programs. There is a need for large RCTs of this intervention in adolescent populations, as well as in high-income countries.

Background: Achieving and maintaining high levels of medication adherence are required to achieve the full benefits of antiretroviral therapy (ART), yet suboptimal adherence among children is common in both developed and developing countries., Objectives: To conduct a systematic review of the literature of evaluations of interventions for improving paediatric ART adherence., Search Methods: We created a comprehensive search strategy in order to identify all studies relevant to this topic. In July 2010, we searched the following electronic databases: EMBASE, MEDLINE, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, LILACS, Web of Science, Web of Social Science, NLM Gateway (supplemented by a manual search of the most recent abstracts not included in the Gateway database). We searched abstracts from the International AIDS Conference from 2002 to 2010, the International AIDS Society Conference on Pathogenesis, Treatment and Prevention from 2003 to 2009, and from the Conference on Retroviruses and Opportunistic Infections from 1997 to 2010. We used search strategies determined by the Cochrane Review Group on HIV/AIDS. We also contacted researchers who work in this field and checked reference lists of related systematic reviews and of all included studies., Selection Criteria: Randomised and non-randomised controlled trials of interventions to improve adherence to ART among children and adolescents (age ≤18 years) were included. Studies had to report adherence to ART as an outcome., Data Collection and Analysis: After one author performed an initial screening to exclude citations that did not meet the inclusion criteria, two authors did a second screening of those citations that likely met the criteria. For all articles that passed the second screening, full articles were pulled in order to make a final determination. Two authors then extracted data and graded methodological quality independently. Differences were resolved through discussion., Main Results: Four studies met the inclusion criteria. No single intervention was evaluated by more than one trial. Two studies were conducted in low-income countries. Two studies were randomised controlled trials (RCT), and two were non-randomised trials. An RCT of a home-based nursing programme showed a positive effect of the intervention on knowledge and medication refills (p=.002), but no effect on CD4 count and viral load. A second RCT of caregiver medication diaries showed that the intervention group had fewer participants reporting no missed doses compared to the control group (85% vs. 92%, respectively), although this difference was not statistically significant (p=.08). The intervention had no effect on CD4 percentage or viral load. A non-randomised trial of peer support group therapy for adolescents demonstrated no change in self-reported adherence, yet the percentage of participants with suppressed viral load increased from 30% to 80% (p=.06). The second non-randomised trial found that the percentage of children achieving >80% adherence was no different between children on a lopinavir-ritonavir (LPV/r) regimen compared to children on a non-nucleoside reverse transcriptase regimen (p=.781). However, the proportion of children achieving virological suppression was significantly greater for children on the LPV/r regimen than for children on the NNRTI-containing regimen (p=.002)., Authors' Conclusions: A home-based nursing intervention has the potential to improve ART adherence, but more evidence is needed. Medication diaries do not appear to have an effect on adherence or disease outcomes. Two interventions, an LPV/r-containing regimen and peer support therapy for adolescents, did not demonstrate improvements in adherence, yet demonstrated greater viral load suppression compared to control groups, suggesting a different mechanism for improved health outcomes. Well-designed evaluations of interventions to improve paediatric adherence to ART are needed.

Background: Antiretroviral drugs have been shown to reduce risk of mother-to-child transmission of human immunodeficiency virus (HIV) and are also widely used for post-exposure prophylaxis for parenteral and sexual exposures. Observational data, ecological studies and models suggest that sexual transmission may be lower in couples in which one partner is infected with HIV and the other is not and the infected partner is on antiretroviral therapy (ART)., Objectives: To determine if ART use in an HIV-infected member of an HIV-discordant couple is associated with lower risk of HIV transmission to the uninfected partner compared to untreated discordant couples., Search Strategy: We used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language., Selection Criteria: Randomised controlled trials, cohort studies and case-control studies of HIV-discordant couples in which the HIV-infected member of the couple was being treated or not treated with ART DATA COLLECTION AND ANALYSIS: Abstracts of all trials identified by electronic or bibliographic scanning were examined independently by two authors. We initially identified 1814 references and examined 24 in detail for study eligibility. Data were abstracted independently using a standardised abstraction form., Main Results: One randomised controlled trial and seven observational studies were included in the review. These eight studies identified 464 episodes of HIV transmission, 72 among treated couples and 392 among untreated couples. The rate ratio for the single randomised controlled trial was 0.04 [95% CI 0.00, 0.27]. All index partners in this study had CD4 cell counts at baseline of 350-550 cells/µL. Similarly, the summary rate ratio for the seven observational studies was 0.34 [95% CI 0.13, 0.92], with substantial heterogeneity (I(2)=73%). After excluding two studies with inadequate person-time data, we estimated a summary rate ratio of 0.16 [95% CI 0.07, 0.35] with no noted heterogeneity (I(2)=0%). We also performed subgroup analyses among the observational studies to see if the effect of ART on prevention of HIV differed by the index partner's CD4 cell count. Among couples in which the infected partner had ≥350 CD4 cells/µL, we estimated a rate ratio of 0.02 [95% CI 0.00, 2.87]. In this subgroup, there were 61 transmissions in untreated couples and none in treated couples., Authors' Conclusions: ART is a potent intervention for prevention of HIV in discordant couples in which the index partner has ≤550 CD4 cells/µL. A new multicentre randomised controlled trial confirms the suspected benefit seen in earlier observational studies. Questions remain about durability of protection, the balance of benefits and adverse events associated with earlier therapy, long-term adherence and transmission of ART-resistant strains to partners. Resource limitations and implementation challenges must also be addressed.Counselling, support, and follow up, as well as mutual disclosure, may have a role in supporting adherence, so programmes should be designed with these components. In addition to ART provision, the operational aspects of delivering such programmes must be considered.

Background: Antiretroviral drugs have been shown to reduce risk of mother-to-child transmission of human immunodeficiency virus (HIV) and are also widely used for post-exposure prophylaxis for parenteral and sexual exposures. Observational data, ecological studies and models suggest that sexual transmission may be lower in couples in which one partner is infected with HIV and the other is not and the infected partner is on antiretroviral therapy (ART)., Objectives: To determine if ART use in an HIV-infected member of an HIV-discordant couple is associated with lower risk of HIV transmission to the uninfected partner compared to untreated discordant couples., Search Strategy: We used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language., Selection Criteria: Randomised controlled trials, cohort studies and case-control studies of HIV-discordant couples in which the HIV-infected member of the couple was being treated or not treated with ART DATA COLLECTION AND ANALYSIS: Abstracts of all trials identified by electronic or bibliographic scanning were examined independently by two authors. We initially identified 1814 references and examined 23 in detail for study eligibility. Data were abstracted independently using a standardised abstraction form., Main Results: Seven observational studies and no randomised controlled trials were included in the review. These seven studies identified 436 episodes of HIV transmisison, 71 among treated couples and 365 among untreated couples. The summary rate ratio for all seven studies was 0.34 [95% CI 0.13, 0.92], with substantial heterogeneity (I(2)=73%). After excluding two studies with inadequate person-time data, we found a summary rate ratio of 0.16 [95% CI 0.07, 0.35] with no noted heterogeneity (I(2)=0%). We also performed subgroup analyses to see if the effect of ART on prevention of HIV differed by the index partner's CD4 cell count. Among couples in which the infected partner had >350 CD4 cells/µL, we estimated a rate ratio of 0.02 [95% CI 0.00, 2.87]. In this subgroup, there were 61 transmissions in untreated couples and none in treated couples., Authors' Conclusions: ART appears to be a potent intervention for prevention of HIV in discordant couples. However, the most important question from a clinical standpoint is whether being in a serodiscordant sexual relationship and having >350 CD4 cells/µL should be an indication for ART. In our analysis, there were broad confidence intervals in this subgroup, overlapping the null hypothesis of no effect. There is currently one large randomised controlled trial in the field, whose results are scheduled to be ready in 2015. Significant questions remain about durability of protection, when to start treating an infected partner (for instance, at diagnosis or at a specific CD4 level) and transmission of ART-resistant strains to partners.

Background: The introduction of highly active antiretroviral therapy (ART) as treatment for HIV infection has greatly improved mortality and morbidity for adults and children living with HIV around the world. Two of the most common medications given in first-line ART are the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine (AZT) and the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir (TDF)., Objectives: To assess the efficacy, safety, and tolerability of TDF compared with AZT in combination with one NRTI and one non-nucleoside reverse transcriptase inhibitor (NNRTI) as part of first-line ART for HIV-infected people in resource-limited settings, Search Strategy: Standard Cochrane methods were used to search electronic databases and conference proceedings with relevant search terms without limits to language., Selection Criteria: Randomised controlled trials of HIV-infected patients aged 5 years and older were included. Primary outcomes of interest included mortality, serious adverse events, virologic response to ART, and adherence/tolerance/retention. Secondary outcomes included immunologic response to ART, development of ART drug resistance, and prevention of sexual transmission of HIV., Data Collection and Analysis: Two authors assessed each reference for inclusion and exclusion criteria established a priori. Data were abstracted independently using a standardised abstraction form., Main Results: Two randomised controlled trials contributed to this literature, enrolling 586 participants, and found no critical difference between TDF and AZT in regards to serious adverse events or virologic response. The trials did find higher rates of adherence and immunologic response in TDF-containing regimens compared with those containing AZT. The quality of the literature to support this conclusion is moderate to high. Drug resistance was more common for TDF than AZT, but the quality of this literature is low, with only one study reporting this outcome. It should be noted that the two studies compared two different drugs in addition to TDF and AZT; one had lamivudine (3TC) and nevirapine (NVP) and the other had emtricitabine (FTC) and efavirenz (EFV)., Authors' Conclusions: We conclude that for the critical outcomes of virologic response and serious adverse events, initial ART regimens containing TDF are equivalent to those containing AZT. However, TDF is superior to AZT in terms of immunologic response and adherence and less frequent emergence of resistance. How much the other drugs in the regimens contributed to these findings is unclear, and true head-to-head trials are still warranted. The role of each drug in initial ART likely will be driven by their specific toxicities.

Background: The introduction of highly active antiretroviral therapy (ART) as treatment for HIV infection has greatly improved mortality and morbidity for adults and children living with HIV around the world. Two common medications given in first-line antiretroviral therapy are the nucleoside reverse transcriptase inhibitors (NRTI) stavudine (d4T) or zidovudine (AZT)., Objectives: To assess the efficacy of d4T compared to AZT in combination with one NRTI and one non-nucleoside reverse transcriptase inhibitor (NNRTI), two additional NNRTIs, or one NRTI and one protease inhibitor (PI), as part of first-line ART for HIV-infected people in low-resource settings., Search Strategy: Standard Cochrane methods were used to search electronic databases and conference proceedings with relevant search terms without limits to language., Selection Criteria: Randomised controlled trials of HIV-infected patients 5 years of age and older were included. Primary outcomes of interest included mortality, severe adverse events, virologic response to ART, and adherence/tolerance/retention. Secondary outcomes included immunologic response to ART, development of ART drug resistance, and prevention of sexual transmission of HIV., Data Collection and Analysis: Two authors assessed each reference for inclusion and exclusion criteria established a priori. Data were abstracted independently using a standardised abstraction form., Main Results: Nine randomised controlled trials were identified as meeting the inclusion criteria. The nine trials enrolled 2,159 participants but looked at a multiplicity of drug combinations. Despite this, a reasonably robust literature suggests no statistically significant difference between the two drug combinations, including severe adverse events and adherence/tolerance/retention. The quality of the literature was found overall to be low to very low for all key outcomes. Only one study reported on drug resistance, and no studies reported on sexual transmission of HIV. The length of follow-up time and study settings varied greatly., Authors' Conclusions: While ideally future research would focus on direct comparison of standard therapeutic combinations of d4T+3TC+an NNRTI and AZT+3TC+an NNRTI to compare these regimens more directly, it is unlikely that additional trials will be mounted. Observational studies should focus on understanding outcomes, including toxicity and tolerability, in low- and middle-income countries.

Background: According to consensus, initiation of therapy is best based on CD4 cell count, a marker of immune status, rather than on viral load, a marker of virologic replication. For patients with advanced symptoms, treatment should be started regardless of CD4 count. However, the point during the course of HIV infection at which antiretroviral therapy (ART) is best initiated in asymptomatic patients remains unclear. Guidelines issued by various agencies provide different initiation recommendations according to resource availability. This can be confusing for clinicians and policy-makers when determining the best time to initiate therapy. Optimizing the initiation of ART is clearly complex and must, therefore, be balanced between individual and broader public health needs., Objectives: To assess the evidence for the optimal time to initiate ART in treatment-naive, asymptomatic, HIV-infected adults, Search Strategy: We formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress). In August 2009, we searched the following electronic journal and trial databases: MEDLINE, EMBASE, and CENTRAL. We also searched the electronic conference database of NLM Gateway, individual conference proceedings and prospective trials registers. We contacted researchers and relevant organizations and checked reference lists of all included studies., Selection Criteria: Randomized controlled trials that compared the effect of ART consisting of three drugs initiated early in the disease at high CD4 counts as defined by the trial. Early initiation could be at levels of 201-350, 351-500, or >500 cells/microL, with the comparison group initiating ART at CD4 counts below 200 x 10(6) cells/microL or as defined by the trial., Data Collection and Analysis: Two review authors independently assessed study eligibility, extracted data, and graded methodological quality. Data extraction and methodological quality were checked by a third author who resolved differences when these arose. Where clinically meaningful to do so, we meta-analysed dichotomous outcomes using the relative risk (RR) and report the 95% confidence intervals (95% CIs)., Main Results: One completed trial (N = 816) and one sub-group (N = 249) of a larger trial met inclusion criteria. We combined the mortality data for both trials comparing initiating ART at CD4 levels at 350 cells/microL or between 200 and 350 cells/microL with deferring initiation of ART to CD4 levels of 250 cells/microL or 200 cells/microL. There was a statistically significant reduction in death when starting ART at higher CD4 counts. Risk of death was reduced by 74% (RR = 0.26; 95% CI: 0.11, 0.62; P = 0.002). Risk of tuberculosis was reduced by 50% in the groups starting ART early; this was not statistically significant, with the reduction as much as 74% or an increased risk of up to 12% (RR = 0.54; 95% CI: 0.26, 1.12; P = 0.01). Starting ART at enrollment (when participants had CD4 counts of 350 cells/microL) rather than deferring to starting at a CD4 count of 250 cells/microL reduced the risk of disease progression by 70%; this was not statistically significant, with the reduction in risk as much as 97% or an increased risk of up to 185% (RR = 0.30; 95% CI: 0.03, 2.85; P = 0.29).One RCT found no statistically significant difference in the number of independent Grade 3 or 4 adverse events occurring in the early and standard ART groups when we conducted an intention-to-treat analysis (RR = 1.72; 95% CI: 0.98, 3.03; P = 0.06). However, when analyzing only participants who actually commenced ART in the deferred group (n = 160), the trial authors report a statistically significant increase in the incidence of zidovudine-related anaemia (8.1%) compared with those in the early initiation group (3.4%) (RR = 0.42; 95% CI: 0.20, 0.88; P = 0.02)., Authors' Conclusions: There is evidence of moderate quality that initiating ART at CD4 levels higher than 200 or 250 cells/microL reduces mortality rates in asymptomatic, ART-naive, HIV-infected people. Practitioners and policy-makers may consider initiating ART at levels

The aim of this study was evaluation of ultrasound (US) as a tool for the assessment of lipoatrophy in a population of HIV-infected patients. We enrolled a convenience sample of 151 HIV-infected Caucasian participants (males, 79%) who were treated for at least 1 year with combination antiretroviral therapy (CART) in Zagreb, Croatia. US measurements of subcutaneous fat thickness were done over the malar, brachial, and crural region. We determined sensitivity and specificity of US as a diagnostic tool for lipoatrophy using receiver-operating curves and concordant patient and clinician assessment as our reference for the presence of lipoatrophy. HIV was acquired through heterosexual contact in 50% of participants and by sex between men in 42%. The mean current CD4 cell count was 503.1 cells=mm3 (standard deviation [SD] = 250.8). Seventy-seven (51%) participants were treated with stavudine and 91 (64%) with a protease inhibitor for at least 6 months. Nineteen (13%)participants had lipoatrophy in at least one anatomic site. Sensitivity of US ranged from 67%-71%, specificity from 65%-71%, positive and negative predictive values ranged from 11%-20% and 96-97%, respectively. US diagnosed lipoatrophy was more frequently found in patients with a history of stavudine treatment and in females. Patients with lipoatrophy had a longer duration of CART than those without lipoatrophy. US is a useful tool in ruling out the presence of clinical lipoatrophy in patients on CART. Using this objective measure of subcutaneous fat may be useful in helping clinicians make decisions about changing therapy.

Lipoatrophy and lipohypertrophy have been observed during long-term combination antiretroviral therapy (CART). We investigated whether consumption of a Mediterranean diet is associated with lower risk of body-shape changes in Croatian patients treated with CART. Between May 2004 and June 2005, we conducted a cross-sectional study of 136 adults with HIV-1 infection who were treated with CART for at least 1 year. Lipoatrophy and lipohypertrophy were assessed by self-report and physical examination. Adherence to a Mediterranean diet was determined by a 150-item questionnaire; a 0-9 point diet scale was created that stratified respondents as having low adherence (<4 points) and moderate to high adherence (> or =4 points). Lipoatrophy was present in 41% and lipohypertrophy in 32% of participants. Non-smokers with a dietary score > or =4 had the lowest risk for lipoatrophy. Stavudine use, female gender, and duration of CART were also independently associated with a higher risk of lipoatrophy. A dietary score of > or =4 was associated with lower risk of lipohypertrophy (adjusted OR 0.3, 95% CI 0.1-0.7; P = 0.012). Female gender, longer duration of CART, and longer known duration of HIV infection prior to CART were also independently associated with higher risk of lipohypertrophy. In conclusion, Croatians who did not smoke and moderately or highly adhered to the Mediterranean diet were least likely to have the clinical syndrome of lipoatrophy. Moderate to high adherence to a Mediterranean diet was associated with a lower risk of lipohypertrophy.

Background: Highly active antiretroviral therapy has reduced the morbidity and mortality of patients with HIV/AIDS. A common first-line ART regimen includes a non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTIs). If treatment failure occurs, a change to second-line therapy is necessary., Objectives: This meta-analysis aimed to assess the optimum antiretroviral regimen for patients with HIV who fail first-line therapy (ART-naive) with d4T+3TC+NVP; d4T+3TC+EFV; ZDV+3TC+NVP; and ZDV+3TC+EFV., Search Strategy: Electronic databases and conference proceedings were searched with relevant search terms without limits to language., Selection Criteria: Randomised controlled trials of HIV-infected adult patients administered second-line ART after virologic failure of a first-line regimen were included. The primary outcome measure included the proportion of patients achieving undetectable plasma HIV RNA concentration (viral load). Secondary outcome measures included change in mean CD4 cell count, clinical resolution of symptoms, rate of adverse events, rate of change in therapy for failure, rate of change in therapy for toxicity, and mortality., Data Collection and Analysis: Two authors assessed each reference for inclusion and exclusion criteria established a priori. Data were abstracted independently using a standardised abstraction form., Main Results: Twenty-one records were identified in total, 6 of which were duplicates. None of the records met inclusion criteria., Authors' Conclusions: There is insufficient evidence to evaluate second-line therapies in patients with HIV who fail first-line treatment with d4T+3TC+NVP; d4T+3TC+EFV; ZDV+3TC+NVP; and ZDV+3TC+EFV. Current recommendations are based on available resources and results from individualised treatment decisions based on resistance testing and clinician choice.

Background: A favourable regimen for people infected with HIV/AIDS is one that provides optimal efficacy, durability of antiretroviral activity, tolerability, and has low adverse effects and drug-drug interactions. The combination of the non-nucleoside reverse transcriptase inhibitor nevirapine (NVP), and two nucleoside reverse transcriptase inhibitors, stavudine (d4T) and lamivudine (3TC), is widely used as first-line therapy, especially in low-resource countries. Analysis of the efficacy, durability and tolerability of the regimen is thus important to clinicians, consumers and policy-makers living in both rich and poor countries., Objectives: To examine the efficacy of the stavudine, lamivudine and nevirapine regimen for the treatment of HIV infection and AIDS in adults., Search Strategy: We used the comprehensive search strategy developed specifically by the Cochrane HIV/AIDS Review Group to identify HIV/AIDS randomised controlled trials, and searched the following electronic databases: MEDLINE (searched July 2004); Embase (searched October 2004); and CENTRAL (July 2004). This search was supplemented with a search of AIDSearch (April 2005) to identify relevant conference abstracts, as well as searching reference lists of all eligible articles. The search was not limited by language or publication status., Selection Criteria: Randomised controlled trials of the stavudine, lamivudine and nevirapine regimen, compared with any other regimens for treating HIV/AIDS, in antiretroviral treatment-naive or antiretroviral treatment-experienced adults., Data Collection and Analysis: Two reviewers independently assessed the methodological quality of the trials and extracted data., Main Results: Our search resulted in 1,148 records, of which two studies described trials that met our inclusion criteria. One trial was a small single-centre Australian trial of 70 antiretroviral-naive participants, while the other trial was a large, multicentre trial, conducted in 14 countries, of 1,216 antiretroviral-naive participants. In both trials over 60% of participants were male. As the therapeutic combinations compared in both trials were not identical, it was not possible to conduct a meta-analysis to increase the power of the results. The main findings, therefore, are from the much larger trial, which was of a high quality. This trial found that there was no statistically significant difference in the efficacy (measured by treatment failure) between nevirapine and efavirenz (EFZ), when used in combination with 3TC and d4T (RR = 1.16; 95%CI: 0.95, 1.41). There was no statistically significant difference between once daily or twice-daily dosing of NVP, when used in combination with 3TC and d4T (RR = 1.00; 95%CI: 0.83; 1.21). It also showed that, compared with NVP plus EFZ, 3TC and d4T, a once-daily dosing of NVP, in combination with 3TC and d4T, performs better in averting treatment failure (RR = 0.82; 95%CI: 0.67, 1.00) than does twice-daily dosing of NVP with 3TC and d4T (RR = 0.82; 95%CI: 0.69; 0.97). Frequency of toxicity was higher in participants receiving NVP, compared with EFZ., Authors' Conclusions: The combination of nevirapine, 3TC and d4T is as efficacious as a combination of efavirenz, 3TC and d4T. Once-daily NVP with twice-daily 3TC and d4T is as efficacious as twice-daily NVP, 3TC and d4T. However, toxicity may be increased in the once-daily NVP regime. Additional trials of sufficient duration are required to provide better evidence for the use of this combination as a first line therapy. Ideally, trials should use standardised assessment measures especially with respect to measuring viral load, so that results can be compared and combined in meta-analyses.

Background: Combination antiretroviral therapy administered to HIV-infected individuals has been shown to decrease viral replication, improve immunologic function and delay the progression of HIV infection. However, because patient adherence to complicated combination-therapy antiretroviral regimens is difficult and because of concerns regarding the cumulative toxicity of antiretroviral drugs, regimens that utilize fewer antiretroviral agents are desirable., Objectives: To compare the use three- or four- versus two-drug antiretroviral maintenance regimens following successful initial therapy for HIV infection., Search Strategy: The following electronic databases were searched for relevant randomized trials or reviews: 1. MEDLINE for the years 1982-May 2003 using the search terms human immunodeficiency virus, antiretroviral therapy, maintenance therapy, zidovudine, lamivudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, AIDS, anti-HIV agents, HIV infection and HIV seropositivity. 2. AIDSLINE for the years 1982- May 2003 using the search terms antiretroviral therapy, maintenance therapy, zidovudine, lamivudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, anti-HIV agents. 3. The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Clinical Trials Register in the Cochrane Library, through May 2003. 4. AIDSTRIALS, a specialist registry of current and completed trials maintained by the U.S. National Library of Medicine through May 2003. The abstracts of relevant conferences, including the International Conferences on AIDS, the Conference on Retroviruses and Opportunistic Infections, the Infectious Disease Society of America annual meeting and the Interscience Conference on Antimicrobial Agents and Chemotherapy, as indexed by AIDSLINE, were also reviewed. Reference lists of all review articles and primary articles identified were also searched., Selection Criteria: Randomized controlled trials in which HIV-infected adults who had successfully completed initial three- or four-drug antiretroviral therapy were randomized to maintenance therapy with three or four drugs or maintenance therapy with two drugs. Successful initial therapy was defined by a plasma viral load of less than 500 copies/ml., Data Collection and Analysis: Two reviewers assessed eligibility and trial quality. Attempts were made to contact the authors of the included abstract. Data on the number of patients experiencing loss of viral suppression were abstracted by two reviewers. The data were pooled, where appropriate, to yield odds ratios, using random effects models., Main Results: Four trials were identified including three published studies and one abstract. Compared to three- or four-drug maintenance therapy, maintenance therapies including fewer drugs were associated with a higher risk of virologic failure (loss of HIV suppression to non-detectable levels). Combining the results of all four studies yielded an odds ratio of 5.55 (95% confidence interval, 3.14 - 9.80). Similar results were obtained when the one abstract was excluded (odds ratio, 5.48; 95% confidence interval, 2.82 - 10.65). Performing subgroup analyses of studies using similar induction and maintenance regimens gave similar results. Maintenance regimens of zidovudine and lamivudine compared to maintenance regimens with zidovudine, lamivudine and indinavir, were associated with significantly higher rates of virologic failure (odds ratio, 4.57; 95% confidence interval, 1.80 - 11.58). Similarly, maintenance regimens that discontinued one or more protease inhibitor after including them in induction therapy were also associated with a significantly higher risk of virologic failure (odds ratio, 6.15; 95% confidence interval, 3.40 -11.10)., Reviewer's Conclusions: Although it is desirable to reduce the number of antiretroviral drugs given in combination therapy for reasons of compliance and toxicity, maintenance regimens with fewer drugs are associated with significantly increased resistance and risk of loss of viral suppression. Successful initial therapy, as evidenced by suppression of viral load, should not be modified in the maintenance phase unless clinically necessary.

Background: Combination antiretroviral therapy administered to HIV-infected individuals has been shown to improve immunologic function and delay the progression of HIV infection. However, because patient adherence to complicated combination-therapy antiretroviral regimens is difficult and because of concerns regarding cumulative toxicity of antiretroviral drugs, regimens that utilize fewer antiretroviral agents are desirable., Objectives: To compare the use three- or four- versus two-drug antiretroviral maintenance regimens following successful induction therapy for HIV infection., Search Strategy: The following electronic databases were searched for relevant randomized trials or reviews: 1. MEDLINE for the years 1982-1999 using the search terms human immunodeficiency virus, antiretroviral therapy, maintenance therapy, zidovudine, lamivudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, AIDS, anti-HIV agents, HIV infection and HIV seropositivity 2. AIDSLINE for the years 1982-1999 using the search terms antiretroviral therapy, maintenance therapy, zidovudine, lamidvudine, indinavir, stavudine, saquinivir, nelfinavir, didanosine, zalcitabine, ritonovir, anti-HIV agents 3. The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Clinical Trials Register in the Cochrane Library, Issue 2, 1999. 4. The specialist register of trials maintained by the Cochrane Collaborative Review Group on HIV Infection and AIDS 5. AIDSTRIALS, a specialist registry of current and completed trials maintained by the U.S. National Library of Medicine The abstracts of relevant conferences, including the International Conferences on AIDS, the Conference on Retroviruses and Opportunistic Infections, the Infectious Disease Society of America annual meeting and the Interscience Conference on Antimicrobial Agents and Chemotherapy, as indexed by AIDSLINE, were also reviewed. All reference lists of all review articles and primary articles identified were searched., Selection Criteria: Randomized controlled trials in which HIV-infected adults who had successfully completed three- or four-drug antiretroviral induction therapy were randomized to maintenance therapy with three or four drugs or maintenance therapy with two drugs. Successful induction therapy was defined by a plasma viral load of less than 500 copies/ml., Data Collection and Analysis: Two reviewers assessed eligibility and trial quality. Attempts were made to contact the authors of the included abstract. Data on the number of patients experiencing loss of viral suppression were abstracted by two reviewers. The data were pooled, where appropriate, to yield odds ratios, using random effects models., Main Results: Four trials were identified including three published studies and one abstract. Compared to three- or four-drug maintenance therapy, maintenance therapies including fewer drugs were associated with a higher risk of virologic failure (loss of HIV suppression to non-detectable levels). Combining the results of all four studies yielded an odds ratio of 5.55 (95% confidence interval, 3.14 - 9.80). Similar results were obtained when the one abstract was excluded (odds ratio, 5.48; 95% confidence interval, 2.82 - 10.65). Performing subgroup analyses of studies using the same induction and maintenance regimens gave similar results. Maintenance regimens of zidovudine and lamivudine compared to maintenance regimens with zidovuine, lamivudine and indinavir, were associated with significantly higher rates of virologic failure (odds ratio, 4.57; 95% confidence interval, 1.80 - 11.58). Similarly, maintenance regimens that discontinued one or more protease inhibitor after including them in induction therapy were also associated with a significantly higher risk of virologic failure (odds ratio, 6.15; 95% confidence interval, 3.40 -11.10). (ABSTRACT TRUNCATED)