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Introduction: HIV infection causes pathological changes in the natural killer (NK) cell compartment that can be only partially restored by antiretroviral therapy (ART). We investigated NK cells phenotype and function in children with perinatally acquired HIV (PHIV) and long-term viral control (five years) due to effective ART in a multicentre cross-sectional European study (CARMA, EPIICAL consortium). The impact of age at ART start and viral reservoir was also evaluated. Methods: Peripheral blood mononuclear cells (PBMCs) from 40 PHIV who started ART within two years of life (early treated patients (ET), 6 months), with at least five years of HIV-1 suppression ( Results: A significantly higher frequency of [CD56.sup.neg] NK cells was found in LT compared with ET. We further found in LT a positive correlation of [CD56.sup.neg] NK cells with HIV-1 DNA. LT also displayed increased expression of the NKG2D and NKp46 activating receptors and perforin compared with ET. Moreover, [CD107a.sup.+] and [IFN-[gamma].sup.+] frequencies in non-stimulated NK were associated with HIV-1 DNA in LT patients. Finally RNA-Seq analysis showed in LT an up-regulation of genes related to NKactivating pathways and susceptibility to apoptosis compared with ET. Conclusions: We show that early initiation of ART during infancy preserves the NK compartment and is associated with lower HIV-1 reservoir. Such condition persists over adolescence due to long-term viral control achieved through effective ART. Keywords: cohort studies; HIV care continuum; immunology; paediatrics; ARV; viral suppression Additional information may be found under the Supporting Information tab for this article., 1 | INTRODUCTION HIV-1-induced immunological impairment begins during acute infection and is only partially restored in children with perinatally acquired HIV (PHIV) if antiretroviral therapy (ART) is introduced during the [...]

Introduction: Achieving optimaladherence to antiretroviraltherapy (ART) among adolescents living with HIV (ALWHIV) is challenging, especially in low-resource settings. To help accurately determine who is at risk of poor adherence, we developed and internally validated models comprising multi-levelfactors that can help to predict the individualized risk of poor adherence among ALWHIV in a resource-limited setting such as Uganda. Methods: We used data from a sample of 637 ALWHIV in Uganda who participated in a longitudinalstudy, 'Suubi+Adherence' (2012 to 2018). The modelwas developed using the Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression to select the best subset of multi-levelpredictors (individual, household, community or economic-related factors) of poor adherence in one year's time using 10-fold cross-validation. Seventeen potentialpredictors included in the modelwere assessed at 36 months of follow-up, whereas adherence was assessed at 48 months of follow-up. Model performance was evaluated using discrimination and calibration measures. Results: For the model predicting poor adherence, five of the 17 predictors (adherence history, adherence self-efficacy, family cohesion, child poverty and group assignment) were retained. Its ability to discriminate between individuals with and without poor adherence was acceptable; area under the curve (AUC) = 69.9; 95% CI: 62.7, 72.8. There was no evidence of possible areas of miscalibration (test statistic = 1.20; p = 0.273). The overallperformance of the modelwas good. Conclusions: Our findings support prediction modelling as a useful tool that can be leveraged to improve outcomes across the HIV care continuum. Utilizing information from multiple sources, the risk prediction score tool applied here can be refined further with the ultimate goalof being used in a screening toolby practitioners working with ALWHIV. Specifically, the tool could help identify and provide early interventions to adolescents at the highest risk of poor adherence and/or viral non-suppression. However, further fine-tuning and external validation may be required before wide-scale implementation. Keywords: HIV/AIDS; ART adherence; adolescents; viral load; prediction modelling, 1 INTRODUCTION Persons living with HIV must initiate and consistently adhere to antiretroviral therapy (ART) to ensure HIV viral suppression [1], avoid drug resistance [2,3], and maintain adequate immune functioning [...]

Introduction: Kaposi's sarcoma (KS) remains the most frequent malignancy in persons living with HIV (PWH) in Latin America. We examined KS trends and outcomes from Latin American clinical sites in the era of increased access to antiretroviral therapy (ART). Methods: Cohorts in Brazil, Peru, Mexico, Honduras, Argentina and Chile contributed clinical data of PWH [greater than or equal to]16 years old from 2000 to 2017, excluding patients with KS diagnosed before clinic enrolment. We compared KS incidence over time using multivariable incidence rate ratios. Predictors of KS before/at or after ART initiation and of mortality after KS were examined using Cox regression. Results: Of 25 981 PWH, 481 had incident KS, including 200 ART-naive and 281 ART-treated patients. From 2000 to 2017, the incidence of KS decreased from 55.1 to 3.0 per 1000 person-years. In models adjusting for CD4 and other factors, the relative risk for KS decreased from 2000 to 2008. Since 2010, the adjusted risk of KS increased in the periods before and 90 days after ART. In addition to low CD4 and male-to-male sex, KS risk after ART was associated with age and history of other AIDS-defining illnesses. Mortality after KS (approximately 25% after five years) was not associated with either year of KS diagnosis nor timing of diagnosis relative to ART initiation. Conclusions: KS incidence in Latin America has remained stable in recent years and risk is highest before and shortly after ART initiation. Early diagnosis of HIV and ART initiation remain critical priorities in the region. Keywords: Kaposi's sarcoma; HIV; antiretroviral therapy; incidence; mortality; Latin America, 1 | INTRODUCTION Kaposi's sarcoma (KS) is a frequent type of cancer among persons living with HIV (PWH) in Latin America [1]. In the United States, KS incidence dramatically fell [...]

Introduction: Evaluating outcomes of paediatric patients with HIV provides crucial data for clinicians and policymakers. We analysed mortality and clinical events rates among children, adolescents, and youth with perinatally acquired HIV (PHIV) aged 0 to 24 years stratified by time-varying age and CD4, before and after antiretroviral therapy (ART), in the paediatric IeDEA multiregional collaboration (East, West, Central and Southern Africa, Asia-Pacific, and Central/South America and the Caribbean). Methods: ART-naive children with HIV enrolled before age 10 (proxy for perinatal infection) at IeDEA sites between 2004 and 2016, with [greater than or equal to]1 CD4 measurement during follow-up were included. We estimated incidence rates (IR) and 95% confidence intervals (95% CI) of mortality and first occurrence of WHO-4 and WHO-3 events, excluding tuberculosis, during person-years (PY) spent within different age ( Results: In the pre-ART period, 49 137 participants contributed 51 966 PY of follow-up (median enrolment age: 3.9 years). The overall pre-ART IRs were 2.8/100 PY (95% CI: 2.7 to 2.9) for mortality, 3.3/100 PY (95% CI: 3.0 to 3.5) for first occurrence of a WHO-4 event, and 7.0/100 PY (95% CI: 6.7 to 7.4) for first occurrence of a WHO-3 event. Lower CD4 and younger age strata were associated with increased rates of both mortality and first occurrence of a clinical event. In the post-ART period, 52 147 PHIVY contributed 207 945 PY (ART initiation median age: 4.5 years). Overall mortality IR was 1.4/100 PY (95% CI: 1.4 to 1.5) and higher in low CD4 strata; patients at each end of the age spectrum (19) had increased mortality post-ART. IRs for first occurrence of WHO-4 and WHO-3 events were 1.3/100 PY (95% CI: 1.2 to 1.4) and 2.1/100 PY (95% CI: 2.0 to 2.2) respectively. These were also associated with lower CD4 and younger age strata. Conclusions: Mortality and incidence of clinical events were highest in both younger (19 years) youth with PHIV. Scaling-up services for 19 years (adolescent- and youth-focused health services) is critical to improve outcomes among PHIVY. Keywords: HIV; paediatrics; adolescents; mortality; severe morbidity, 1 | INTRODUCTION With the rollout of antiretroviral therapy (ART), children living with perinatally acquired HIV (PHIV) are now surviving into adolescence and young adulthood [1-3]. In 2016, of the [...]

Byline: Ravinder. Singh, Shesh. Maurya, Namrata. Das, Sushil. Kabra, Rakesh. Lodha, Bimal. Das OBJECTIVES: Evaluation of immunological factors responsible for discordant virological responses postcombination antiretroviral therapy (cART) in human immunodeficiency [...]

Introduction: The South East Asia Research Collaboration in HIV (SEARCH) RV411 clinical trial in Thailand was a systematic investigation of analytic treatment interruption (ATI) in individuals diagnosed and treated since Fiebig stage I acute HIV infection. Here, we explore decision-making processes and perceptions of trial participation in a phase I trial that raised important ethical considerations, to identify potential areas of improvement in this relatively new field of HIV research. Similar considerations apply to other HIV phase I trials, especially those involving ATI, making this trial a model to identify challenges and opportunities in promoting informed choice. Methods: Using longitudinal semi-structured interviews and a validated questionnaire, we examined how decisions to join or decline the trial were made, whether there was evidence of decisional conflict, and reactions to the trial outcomes. We also explored contrasting views and experiences in this small trial cohort. We report analyses of data from these questionnaires and interviews, conducted from February through December of 2016 with the 14 SEARCH cohort participants who either joined (n = 8) or declined (n = 6) participation in RV411. Results: The eight participants and six decliners had low overall decisional conflict, which remained low over time. Decision making was more difficult for decliners than participants, at least initially. While all interviewees described being satisfied with their decisions, our study identified important negative consequences for a few individuals, including seroconversion, negative experiences with optional procedures and disappointment due to rapid viral rebound. Conclusions: Although our results reflect the experiences of a small group invited to join this trial, our overall finding of low decisional conflict even while some individuals reported negative experiences provides lessons for clinical trial investigators. We developed points-to-consider in helping participants make informed choices, to support participants during the trial and to support decliners in their decisions. Keywords: phase I clinical trials; HIV clinical trials; analytic treatment interruption; research ethics; informed consent; qualitative research, 1 | INTRODUCTION In 2009, the South East Asia Research Collaboration in HIV (SEARCH) at the Thai Red Cross AIDS Research Centre began diagnosing and treating individuals with acute HIV [...]

Background Global HIV treatment programs have sought to lengthen the interval between clinical encounters for people living with HIV (PLWH) who are established on antiretroviral treatment (ART) to reduce the burden of seeking care and to decongest health facilities. The overall effect of reduced visit frequency on HIV treatment outcomes is however unknown. We conducted a systematic review and meta-analysis to evaluate the effect of implementation strategies that reduce the frequency of clinical appointments and ART refills for PLWH established on ART. Methods and findings We searched databases between 1 January 2010 and 9 November 2021 to identify randomized controlled trials (RCTs) and observational studies that compared reduced (6- to 12-monthly) clinical consultation or ART refill appointment frequency to 3- to 6-monthly appointments for patients established on ART. We assessed methodological quality and real-world relevance, and used Mantel-Haenszel methods to generate pooled risk ratios (RRs) with 95% confidence intervals for retention, viral suppression, and mortality. We evaluated heterogeneity quantitatively and qualitatively, and overall evidence certainty using GRADE. Searches yielded 3,955 records, resulting in 10 studies (6 RCTs, 3 observational studies, and 1 study contributing observational and RCT data) representing 15 intervention arms with 33,599 adults ([greater than or equal to]16 years) in 8 sub-Saharan African countries. Reduced frequency clinical consultations occurred at health facilities, while reduced frequency ART refills were delivered through facility or community pharmacies and adherence groups. Studies were highly pragmatic, except for some study settings and resources used in RCTs. Among studies comparing reduced clinical consultation frequency (6- or 12-monthly) to 3-monthly consultations, there appeared to be no difference in retention (RR 1.01, 95% CI 0.97-1.04, p = 0.682, 8 studies, low certainty), and this finding was consistent across 6- and 12-monthly consultation intervals and delivery strategies. Viral suppression effect estimates were markedly influenced by under-ascertainment of viral load outcomes in intervention arms, resulting in inconclusive evidence. There was similarly insufficient evidence to draw conclusions on mortality (RR 1.12, 95% CI 0.75-1.66, p = 0.592, 6 studies, very low certainty). For ART refill frequency, there appeared to be little to no difference in retention (RR 1.01, 95% CI 0.98-1.06, p = 0.473, 4 RCTs, moderate certainty) or mortality (RR 1.45, 95% CI 0.63-3.35, p = 0.382, 4 RCTs, low certainty) between 6-monthly and 3-monthly visits. Similar to the analysis for clinical consultations, although viral suppression appeared to be better in 3-monthly arms, effect estimates were markedly influence by under-ascertainment of viral load outcomes in intervention arms, resulting in overall inclusive evidence. This systematic review was limited by the small number of studies available to compare 12- versus 6-monthly clinical consultations, insufficient data to compare implementation strategies, and lack of evidence for children, key populations, and low- and middle-income countries outside of sub-Saharan Africa. Conclusions Based on this synthesis, extending clinical consultation intervals to 6 or 12 months and ART dispensing intervals to 6 months appears to result in similar retention to 3-month intervals, with less robust conclusions for viral suppression and mortality. Future research should ensure complete viral load outcome ascertainment, as well as explore mechanisms of effect, outcomes in other populations, and optimum delivery and monitoring strategies to ensure widespread applicability of reduced frequency visits across settings., Author(s): Noelle Le Tourneau 1,*, Ashley Germann 2, Ryan R. Thompson 2, Nathan Ford 3,4, Sheree Schwartz 2, Laura Beres 2, Aaloke Mody 1, Stefan Baral 2, Elvin H. Geng [...]

Introduction: South Africa is moving into a new era of HIV treatment with 'treat all' policies where people may be on treatment for most of their lives. We need to understand treatment outcomes and facilitators of long-term antiretroviral treatment (ART) adherence and retention-in-care in the South African context. In one of the first studies to investigate long-term treatment outcomes in South Africa, we aimed to describe ten-year patient outcomes at a large public-sector HIV clinic in Johannesburg and explore patient experiences of the treatment programme over this time in order to ascertain factors that may aid or hinder long-term adherence and retention. Methods: We conducted a cohort analysis (n = 6644) and in-depth interviews (n = 24) among HIV-positive adults initiating first-line ART between April 2004 and March 2007. Using clinical records, we ascertained twelve-month and ten-year all-cause mortality and loss to follow-up (LTF). Cox proportional hazards regression was used to identify baseline predictors of attrition (mortality and LTF (>3 months late for the last scheduled visit)) at twelve months and ten years. Twenty-four patients were purposively selected and interviewed to explore treatment programme experiences over ten years on ART. Results: Excluding transfers, 79.5% (95% confidence intervals (CI): 78.5 to 80.5) of the cohort were alive, in care at twelve months dropping to 35.1% (95% CI: 33.7 to 36.4) at ten years. Over 44% of deaths occurred within 12 months. Tenyear all-cause mortality increased, while LTF decreased slightly, with age. Year and age at ART initiation, sex, nationality, baseline CD4 count, anaemia, body mass index and initiating regimen were predictors of ten-year attrition. Among patients interviewed, the pretreatment clinic environment, feelings of gratitude and good fortune, support networks, and self-efficacy were facilitators of care; side effects, travel and worsening clinical conditions were barriers. Participants were generally optimistic about their futures and were committed to continued care. Conclusions: This study demonstrates the complexities of long-term chronic HIV treatment with declining all-cause mortality and increasing LTF over ten years. Barriers to long-term retention still present a significant challenge. As more people become eligible for ART in South Africa under 'treatment for all,' new healthcare delivery challenges will arise; interventions are needed to ensure long-term programme successes continue. Keywords: South Africa; HIV/AIDS; long-term ART treatment outcomes; loss to follow-up; attrition; adherence, 1 | INTRODUCTION The 2015 World Health Organization (WHO) recommendation to offer treatment to all HIV-positive persons regardless of CD4 count [1] has compressed the HIV care cascade, removing several [...]

Author(s): Daniel I. S. Rosenbloom [1]; Alison L. Hill [2]; Sarah B. Laskey [3]; Robert F. Siliciano (corresponding author) [3, 4] ARISING FROM R. Lorenzo-Redondo et al . Nature 530, [...]

: Introduction: The World Health Organisation recommends to Treat All people with HIV, irrespective of CD4 count. However, people with CD4 counts >500 cells/µL may be asymptomatic and therefore less motivated to adhere to antiretroviral therapy (ART). We aimed to assess whether people initiated with CD4 counts >500 cells/µL had worse treatment outcomes compared to those initiated at lower CD4 counts. Methods: We performed a retrospective cohort study among non‐pregnant adults initiating ART at eight public clinics in South Africa between September 2016, when Treat All was implemented, and August 2017. We assessed whether initiation CD4 count >500 cells/µL was associated with the outcomes of attrition (death, lost to follow‐up or treatment interruption >180 days), and viraemia >1000 copies/mL, by twelve months using Cox proportional hazards and Poisson regression models. Results and discussion: Among 4952 patients initiating ART, the median age was 32.4 years (interquartile range (IQR) 27.2 to 39.7), 58.9% were women and 30.3% had an initiation CD4 count >500 cells/µL. After twelve months, 3382 (68.3%) were retained in care, 303 (6.1%) had transferred to another clinic, 1010 (20.4%) were lost to follow‐up, 232 (4.7%) had a treatment interruption >180 days and 25 (0.5%) were known to have died. Overall, 1267 experienced attrition at a median time of 91 days (IQR 23 to 213), with 302 of these (23.8%) experiencing attrition immediately after their ART initiation visit. Among those in care at twelve months with viral load results, 4.6% had viraemia. In multivariable analysis, the hazard of attrition was similar between patients newly eligible for ART with CD4 counts >500 cells/µL compared to those with CD4 ≤500 cells/µL (adjusted hazard ratio 1.03, 95% confidence interval (CI) 0.90 to 1.17). The risk of viraemia was lower among patients with CD4 counts >500 cells/µL compared to those with CD4 ≤500 cells/µL (adjusted risk ratio 0.58, 95% CI 0.37 to 0.92). Conclusions: After implementation of Treat All in South African public clinics, we found that patients newly eligible for ART with initiation CD4 counts >500 cells/µL had comparable or better outcomes compared to those with lower CD4 counts. These finding support ongoing implementation of Treat All in our setting., Introduction In 2015 the World Health Organization (WHO) introduced its Treat All guidelines, which recommend antiretroviral therapy (ART) for all people living with HIV (PLHIV), including those with CD4 counts [...]

Author(s): Katherine M Bruner [1]; Alexandra J Murray [1]; Ross A Pollack [1]; Mary G Soliman [1]; Sarah B Laskey [1]; Adam A Capoferri [1, 2]; Jun Lai [1]; Matthew [...]

Current antiretroviral therapy (ART) is not sufficient to completely suppress disease progression in the CNS, as indicated by the rising incidence of HIV-1-associated neurocognitive disorders (HAND) among infected individuals on ART. It is not clear why some HIV-1-infected patients develop HAND, despite effective repression of viral replication in the circulation. SIV-infected nonhuman primate models are widely used to dissect the mechanisms of viral pathogenesis in the CNS. Here, we identified 4 amino acid substitutions in the cytoplasmic tail of viral envelope glycoprotein gp41 of the neurovirulent virus SIVsm804E that enhance replication in macrophages and associate with enhanced antagonism of the host restriction factor BM stromal cell antigen 2 (BST-2). Rhesus macaques were inoculated with a variant of the parental virus SIVsmE543-3 that had been engineered to contain the 4 amino acid substitutions present in gp41 of SIVsm804E. Compared with WT virus-infected controls, animals infected with mutant virus exhibited higher viral load in cerebrospinal fluid. Together, these results are consistent with a potential role for BST-2 in the CNS microenvironment and suggest that BST-2 antagonists may serve as a possible target for countermeasures against HAND., Introduction Prior to development of antiretroviral drugs, infection by HIV-1 frequently led to development of HIV-associated dementia (HAD) in infected individuals (1). HAD can be accompanied by neuropathological abnormalities referred [...]

The recently completed HIV prevention trials network study 052 is a landmark collaboration demonstrating that HIV transmission in discordant couples can be dramatically reduced by treating the infected individual with antiretroviral therapy (ART). However, the cellular and virological events that occur in the female reproductive tract (FRT) during ART that result in such a drastic decrease in transmission were not studied and remain unknown. Here, we implemented an in vivo model of ART in BM/liver/thymus (BLT) humanized mice in order to better understand the ability of ART to prevent secondary HIV transmission. We demonstrated that the entire FRT of BLT mice is reconstituted with human [CD4.sup.+] cells that are shed into cervicovaginal secretions (CVS). A high percentage of the [CD4.sup.+] T cells in the FRT and CVS expressed CCR5 and therefore are potential HIV target cells. Infection with HIV increased the numbers of [CD4.sup.+] and [CD8.sup.+] T cells in CVS of BLT mice. Furthermore, HIV was present in CVS during infection. Finally, we evaluated the effect of ART on HIV levels in the FRT and CVS and demonstrated that ART can efficiently suppress cell-free HIV-RNA in CVS, despite residual levels of HIV-RNA* cells in both the FRT and CVS., Introduction Most clinical trials of HIV prevention have aimed at preventing HIV acquisition by topical or systemic administration of preventative antiretroviral drugs to uninfected individuals (1-10). Results from these clinical [...]

: Introduction: Multiple comorbidities among HIV‐positive individuals may increase the potential for polypharmacy causing drug‐to‐drug interactions and older individuals with comorbidities, particularly those with cognitive impairment, may have difficulty in adhering to complex medications. However, the effects of age‐associated comorbidities on the treatment outcomes of combination antiretroviral therapy (cART) are not well known. In this study, we investigated the effects of age‐associated comorbidities on therapeutic outcomes of cART in HIV‐positive adults in Asian countries. Methods: Patients enrolled in the TREAT Asia HIV Observational Database cohort and on cART for more than six months were analysed. Comorbidities included hypertension, diabetes, dyslipidaemia and impaired renal function. Treatment outcomes of patients ≥50 years of age with comorbidities were compared with those Results: The incidence of virologic failure was 7.72/100 person‐years. Virological failure was less likely in patients with better adherence and higher CD4 count at cART initiation. Those acquiring HIV through intravenous drug use were more likely to have virological failure compared to those infected through heterosexual contact. On univariate analysis, patients aged Conclusions: In our Asia regional cohort, age‐associated comorbidities did not affect virologic outcomes of cART. Among those with comorbidities, patients, Introduction Combination antiretroviral therapy (cART) has dramatically improved the survival and quality of life for people living with HIV. A growing proportion of patients are over the age of 50 [...]

: Introduction: Retention on antiretroviral therapy (ART) is critical for the successful adoption of the test and treat policy by sub‐Saharan African countries, and for realizing the United Nations programme on HIV and AIDS target of 90‐90‐90. This qualitative study explores HIV positive clients’ reasons for discontinuing ART under the MaxART test and treat implementation study in Swaziland. Methods: Clients identified as lost to follow‐up (LTFU) in the programme database, who had initiated ART under the intervention arm of the MaxART study, were purposively selected from two facilities. LTFU was defined as stopping ART refill for three months or longer from the date of last appointment, and not being classified as transferred out or deceased. Semi‐structured face‐to‐face interviews were conducted with nine clients and one treatment supporter between July and August 2017. All interviews were conducted in the local language, audio‐recorded, summarized or transcribed and translated to English for thematic analysis. Results: Respondents described mobility as the first step in a chain of events that affected retention in care. It was entwined with precarious employment, care delivery, interactions with health workers, lack of social support, anticipated stigma and ART‐related side‐effects, including the exacerbation of hunger. The chains of events involved several intersecting reasons that occurred one after the other as a series of contiguous and linked events that led to clients’ eventual discontinuation of ART. The individual accounts of step‐by‐step decision‐making revealed the influence of multi‐layered contexts and the importance of critical life‐events. Conclusions: Clients’ reasons for abandoning ART are a complex, inextricably interwoven chain of events rather than a single occurrence. Mobility is often the first step in the process and commonly results from precarious economic and social circumstances. Currently the health system poorly caters to the reality of people's mobile lives. Interventions should seek to increase healthcare workers’ understanding of the chain of events leading up to discontinuation on ART and the social dilemmas that clients face., Introduction Between 2000 and 2015, the number of people living with HIV (PLHIV) who access antiretroviral therapy (ART) saw a thirty‐fold global increase: from 250,000 to more than 17 million. [...]

Background: The rapid increase in the use of mobile phones across sub-Saharan Africa over the past years have opened the door to the use of Digital adherence tools (DATs) to [...]

Background: As stavudine remains an important and widely prescribed drug in resource‐limited settings, the effect of a reduced dose of stavudine (from 40 mg to 30 mg) on outcomes of highly active antiretroviral therapy (HAART) remains an important public health question. Methods: We analyzed prospectively collected data from the Themba Lethu Clinic in Johannesburg, South Africa. We assessed the relationship between stavudine dose and six‐ and/or 12‐month outcomes of stavudine substitution, failure to suppress viral load to below 400 copies/ml, development of peripheral neuropathy, lipoatrophy and hyperlactatemia/lactic acidosis. Since individuals with a baseline weight of less than 60 kg were expected to have received the same dose of stavudine throughout the study period, analysis was restricted to individuals who weighed 60 kg or more at baseline. Data were analyzed using logistic regression. Results: Between 1 April 2004 and 30 September 2009, 3910 patients were initiated on antiretroviral therapy (ART) with a recorded stavudine dose and were included in the analysis. Of these, 2445 (62.5%) received a 40 mg stavudine dose while 1565 (37.5%) received 30 mg. In multivariate analysis, patients receiving a 40 mg dose were more likely to discontinue stavudine use (adjusted odds ratio, OR 1.71; 95% confidence limits, CI 1.13‐2.57) than those receiving 30 mg by 12 months on ART. Additionally, patients receiving 40 mg doses of stavudine were more likely to report peripheral neuropathy (OR 3.12; 95% CI 1.86‐5.25), lipoatrophy (OR 11.8; 95% CI 3.2‐43.8) and hyperlactatemia/lactic acidosis (OR 8.37; 95% CI 3.83‐18.29) in the same time period. Failure to suppress HIV viral load within 12 months of HAART initiation was somewhat more common among those given 40 mg doses (OR 1.62; 95% CI 0.88, 2.97) although this result lacked precision. Sensitivity analyses accounting for death and loss to follow up generally supported these estimates. Conclusions: Lower stavudine dosage is associated with fewer reports of several stavudine‐associated adverse events and also a lower risk of stavudine discontinuation within the first year on ART., Background Stavudine (d4T) is a nucleoside analogue that has been widely used as part of highly active antiretroviral therapy (HAART). Despite being highly effective [1,2], use of stavudine‐based regimens has [...]

“No virus, no transmission.” Studies have repeatedly shown that viral load (the quantity of virus present in blood and sexual secretions) is the strongest predictor of HIV transmission during unprotected sex or transmission from infected mother to child. Effective treatment lowers viral load to undetectable levels. If one could identify and treat all HIV‐infected people immediately after infection, the HIV/AIDS epidemic would eventually disappear. Such a radical solution is currently unrealistic. In reality, not all people get tested, especially when they fear stigma and discrimination. Thus, not all HIV‐infected individuals are known. Of those HIV‐positive individuals for whom the diagnosis is known, not all of them have access to therapy, agree to be treated, or are taking therapy effectively. Some on effective treatment will stop, and in others, the development of resistance will lead to treatment failure. Furthermore, resources are limited: should we provide drugs to asymptomatic HIV‐infected individuals without indication for treatment according to guidelines in order to prevent HIV transmission at the risk of diverting funding from sick patients in urgent need? In fact, the preventive potential of anti‐HIV drugs is unknown. Modellers have tried to fill the gap, but models differ depending on assumptions that are strongly debated. Further, indications for antiretroviral treatments expand; in places like Vancouver and San Francisco, the majority of HIV‐positive individuals are now under treatment, and the incidence of new HIV infections has recently fallen. However, correlation does not necessarily imply causation. Finally, studies in couples where one partner is HIV‐infected also appear to show that treatment reduces the risk of transmission. More definite studies, where a number of communities are randomized to either receive the “test‐and‐treat” approach or continue as before, are now in evaluation by funding agencies. Repeated waves of testing would precisely measure the incidence of HIV infection. Such trials face formidable logistical, practical and ethical obstacles. However, without definitive data, the intuitive appeal of “test‐and‐treat” is unlikely to translate into action on a global scale. In the meantime, based on the available evidence, we must strive to provide treatment to all those in medical need under the current medical guidelines. This will lead to a decrease in HIV transmission while “test‐and‐treat” is fully explored in prospective clinical trials., Review Approximately 2.7 million new HIV infections were diagnosed in 2009, mostly in resource‐poor countries. In 2009, the estimated number of new HIV infections was approximately 21% lower than at [...]

Background: Non‐AIDS‐defining malignancies (NADM) are becoming a major cause of mortality in the era of highly active antiretroviral therapy. We wished to investigate the incidence, risks factors and outcome of NADM in an urban cohort. Methods: We carried out an observational cohort of HIV patients with 12,746 patient‐years of follow up between January 2002 and March 2009. Socio‐demographics and clinical characteristics of patients diagnosed with NADM were retrospectively compared with the rest of the cohort. Causes of death and risk factors associated with NADM were assessed using logistic regression. Survival analyses were performed with Kaplan‐Meier estimates. Cancer incidences were compared with those of the general population of the Brussels‐Capital Region using the standardized incidence ratio (SIR). Results: Forty‐five NADM were diagnosed. At inclusion in the study, patients with NADM were older than patients without NADM (47 years vs. 38 years, p < 0.001), had a longer history of HIV infection (59 months vs. 39 months, p = 0.0174), a lower nadir CD4 count (110 cells/mm[sup.3] vs. 224 cells/mm[sup.3], p < 0.0001) and a higher rate of previous AIDS events (33% vs. 20%, p = 0.0455) and of hepatitis C virus co‐infection (22.2% vs. 10%, p = 0.0149). In multivariate analysis, age over 45 at baseline (OR 3.25; 95% CI 1.70‐6.22) and a nadir CD4 count of less than 200 cells/mm[sup.3] (OR 3.10; 95% CI 1.40‐6.87) were associated with NADM. NADM were independently associated with higher mortality in the cohort (OR 14.79; 95% CI 6.95‐31.49). Women with cancer, the majority of whom were of sub‐Saharan African origin, had poorer survival compared with men. The SIR for both sexes were higher than expected for Hodgkin's lymphoma (17.78; 95% CI 6.49‐38.71), liver cancers (8.73; 95% CI 2.35‐22.34), anal cancers (22.67; 95% CI 8.28‐49.34) and bladder cancers (3.79; 95% CI 1.02‐9.70). The SIR for breast cancer was lower in women (SIR 0.29; 95% CI 0.06‐0.85). Conclusions: Age over 45 and a nadir CD4 count of less than 200 cells/mm[sup.3] were predictive of NADM in our cohort. Mortality was high, especially in sub‐Saharan African women. Cancers with increased incidences were Hodgkin's lymphoma and anal, bladder and liver cancers in both sexes; women had a lower incidence of breast cancer., Background HIV infection is associated with an increased incidence of certain types of cancer, i.e., Kaposi sarcoma, non‐Hodgkin's lymphoma and cervical cancer, all linked with profound immunosuppression [1]. These cancers [...]

In preparation for a proposed intervention at an antiretroviral therapy (ART) clinic in Durban, South Africa, we explored the dynamics and patterns of cellular phone use among this population, in order to ascertain whether clinic contact via patients' cellular phones was a feasible and acceptable modality for appointment reminders and adherence messages. Adults, who were more than 18 years old, ambulatory, and who presented for treatment at the clinic between October-December 2007, were consecutively recruited until the sample size was reached (n = 300). A structured questionnaire was administered, including questions surrounding socio-demographics, cellular phone availability, patterns of use, and acceptability of clinic contact for the purpose of clinic appointment reminders and adherence support. Most respondents (n = 242; 81%) reported current ownership of a cellular phone with 95% utilizing a prepaid airtime service. Those participants who currently owned a cellular phone reported high cellular phone turnover due to theft or loss (n = 94, 39%) and/or damage (n = 68, 28%). More females than men switched their cell phones off during the day (p = 0.002) and were more likely to not take calls in certain social milieus (p [less than or equal to] 0.0001). Females were more likely to share their cell phone with others (p = 0.002) or leave it in a place where someone could access it (p = 0.005). Most respondents were willing to have clinic contact via their cellular phones, either verbally (99%) or via text messages (96%). The use of cellular phones for intervention purposes is feasible and should be further investigated. The findings highlight the value of gender-based analyses in informing interventions. DOI: 10.1089/apc.2010.0146

Global scale-up of antiretroviral therapy (ART) has focused on clinical outcomes with little attention on its impact on existing health systems. In June-August 2008, we conducted a formative evaluation on ART scale-up and clinic operations at three clinics in Uganda to generate lessons for informing policy and larger public health care systems. Site visits and semistructured interviews with 10 ART clients and 6 providers at each clinic were used to examine efficiency of clinic operations (patient flow, staff allocation to appropriate duties, scheduling of clinic visits, record management) and quality of care (attending to both client and provider needs, and providing support for treatment adherence and retention). Clients reported long waiting times but otherwise general satisfaction with the quality of care. Providers reported good patient adherence and retention, and support mechanisms for clients. Like clients, providers mentioned long waiting times and high workload as major challenges to clinic expansion. Providers called for more human resources and stress-release mechanisms to prevent staff burnout. Both providers and clients perceive these clinics to be delivering good quality care, despite the recognition of congested clinics and long waiting times. These findings highlight the need to address clinic efficiency as well as support for providers in the context of rapid scale-up. DOI: 10.1089/apc.2010.0108

In resource-limited settings, beliefs about disclosing a child's HIV status and the subsequent impacts of disclosure have not been well studied. We sought to describe how parents and guardians of HIV-infected children view the impact of disclosing a child's HIV status, particularly for children's antiretroviral therapy (ART) adherence. A qualitative study was conducted using involving focus groups and interviews with parents and guardians of HIV-infected children receiving ART in western Kenya. Interviews covered multiple aspects of the experience of having children take medicines. Transcribed interview dialogues were coded for analysis. Data were collected from 120 parents and guardians caring for children 0-14 years (mean 6.8 years, standard deviation [SD] 6.4); 118 of 120 had not told the children they had HIV. Children's caregivers (parents and guardians) described their views on disclosure to children and to others, including how this information-sharing impacted pediatric ART adherence, children's well-being, and their social relationships. Caregivers believed that disclosure might have benefits such as improved ART adherence, especially for older children, and better engagement of a helping social network. They also feared, however, that disclosure might have both negative psychological effects for children and negative social effects for their families, including discrimination. In western Kenya, caregivers' views on the risks and benefits to disclosing children's HIV status emerged a key theme related to a family's experience with HIV medications, even for families who had not disclosed the child's status. Assessing caregivers' views of disclosure is important to understanding and monitoring pediatric ART. DOI: 10.1089/apc.2010.0079

Objectives. We examined changes in socioeconomic status (SES) and Black to White inequalities in HIV/AIDS mortality in the United States before and after the introduction of highly active antiretroviral therapy (HAART). Methods. Taking a fundamental cause perspective, we used negative binomial regression to analyze trends in county-level gender-, race-, and age-specific HIV/ AIDS mortality rates among those aged 15 to 64 years during the period 1987-2005. Results. Although HIV/AIDS mortality rates decreased once HAART became available, the declines were not uniformly distributed among population groups. The associations between SES and HIV/AIDS mortality and between race and HIV/AIDS mortality, although present in the pre-HAART period, were significantly greater in the peri- and post-HAART periods, with higher SES and White race associated with the greatest declines in mortality during the post-HAART period. Conclusions. Our findings support the fundamental cause hypothesis, as the introduction of a life-extending treatment exacerbated inequalities in HIV/AIDS mortality by SES and by race. In addition to a strong focus on factors that improve overall population health, more effective public health interventions and policies would facilitate an equitable distribution of health-enhancing innovations. (Am J Public Health. 2010;100:1053-1059. doi: 10.2105/AJPH.2009.170241)

We examined the relationships between survival after AIDS diagnosis and outpatient mental health service use among men with history of highly active antiretroviral therapy (HAART). Analysis involved 1913 black and 1684 white men with AIDS who received HIV care in 2003 in the Veterans Affairs health care system. Negative binomial regression was used to assess the association between service use and length of AIDS diagnosis. Patients with longer survival after AIDS had higher rates of outpatient visits for stress and adjustment disorders as well as for mood, anxiety, and sexual disorders. Blacks had more visits for stress and adjustment disorders (7.4 versus 5.1; p < 0.05). Multiple regression analysis showed that prolonged survival after AIDS (incident rate ratios [IRR] = 1.87; 95% confidence interval [CI] = 1.25-2.77), having CD4 cell count less than 200 cells/[mm.sup.3] (IRR = 1.91; 95% CI = 1.19-3.04), and mortality (IRR = 3.84; 95% CI = 1.29-11.43) were associated with greater number of visits for mood, anxiety, and sexual disorders. Injection drug users (IRR = 3.52; 95% CI = 1.94-6.38), men who have sex with men (IRR = 2.87; 95% CI = 1.62-5.06), and patients with AIDS-defining illness (IRR = 2.48; 95% CI = 1.474.17) had greater rates of visits for stress and adjustment disorders. Survival after AIDS is associated with mental health service use. As more HIV-infected persons survive longer, adequate risk assessment of mental health concerns that considers race and HIV risk factors should be undertaken to effectively address the impact of mental health on treatment outcomes and mortality. DOI: 10.1089/apc.2009.0177

Patients infected with HIV treated with highly active antiretroviral therapy (HAART) frequently develop body physical changes (BPC) that have an important psychosocial burden. The purpose of this study was to determine the prevalence of BPC observed by HIV-infected patients and their attending physicians and to assess the impact BPC had on daily life. In this epidemiologic multicenter study, patients with HIV infection and their treating physicians filled out parallel questionnaires about their perceptions of specific BPC and their impact on daily activities. A total of 965 patient-physician questionnaires were collected across 98 health centers. Patient's mean age was 43.7 [+ or -] 8.5 years and 72.6% were men. Adjusted prevalence of perceived BPC by patients and physicians was 55.1% (95% confidence interval [CI]: 52.0-58.1) and 55.2% (95% CI: 52.1-58.2), respectively (p = 1.000). Overall patient-physician agreement concerning perception of BPC was 83% (p < 0.0005). The most common BPC was lipoatrophy, described by 46.8% (95% CI: 43.7-49.8) of patients and 49.4% (95% CI: 46.3-52.5) of physicians (p = 0.033) followed by lipohypertrophy. No gender differences were observed in the global prevalence of BPC (p = 0.649). However, significantly more women reported lipoatrophy of the lower limbs (p = 0.009) and buttocks (p = 0.007), as well as lipohypertrophy (p = 0.007), than men; 58.2% (95% CI: 54.0-62.4) patients noted that BPC negatively affected their daily activities. This study reflects the high prevalence of patient and physician-perceived BPC in the HIV population, and the adverse impact on daily life. Physicians should be aware of the psychosocial consequences of BPC in HIV patients in order to improve patient well-being. DOI: 10.1089/apc.2009.0191

Background: Information is currently limited on the long‐term follow up of HIV‐1 infected women who are on highly active antiretroviral therapy (HAART) that contains nevirapine and lamivudine and who were previously exposed to antiretroviral drugs for the prevention of mother to child transmission (PMTCT) of HIV. Methods: We studied the 36‐month immunological response to HAART in HIV‐1 infected women in Côte d'Ivoire. The women were previously exposed to antiretroviral drug regimens for PMTCT, including single‐dose nevirapine and/or short‐course zidovudine with or without lamivudine. All HAART regimens included a non‐nucleoside reverse transcriptase inhibitor. Results: At 36 months: the median absolute increase in CD4+ T cell count was +359 cells/mm[sup.3] (IQR: 210‐466) in 200 women who had undergone 36‐month follow‐up visits; +359 cells/mm[sup.3] (IQR: 222‐491) in 88 women not exposed to PMTCT antiretrovirals; and +363 cells/mm[sup.3] (IQR: 200‐464) in 112 women exposed to at least one antiretroviral PMTCT regimen. Overall, 49 (19.8%) of the 247 women who initiated HAART met the immunological failure criteria at least once during follow up. The overall probability of immunological failure was 0.08 (95% CI: 0.12‐0.15) at 12 months, and 0.21 (95% CI: 0.16‐0.27) at 36 months. No difference was observed according to the presence or absence of resistance mutations to nevirapine or lamivudine in women tested at four weeks postpartum. In addition, at 36 months, 23% of women were lost to follow up, dead or had stopped their treatment. Conclusions: A non‐nucleoside reverse transcriptase inhibitor‐based antiretroviral regimen, initiated a year or more after PMTCT exposure and that includes nevirapine, remains a good option for at least the first 36 months of treatment., Background Information is currently limited on the long‐term follow‐up of HIV‐1 infected women who are on highly active antiretroviral therapy (HAART) containing nevirapine (NVP) and lamivudine (3TC) and who were [...]

Background: In vitro studies suggest that reducing cholesterol inhibits HIV replication. However, this effect may not hold in vivo, where other factors, such as cholesterol's immunomodulatory properties, may interact. Methods: Fasting blood samples were obtained on 165 people living with HIV at baseline and after 24 weeks on highly active antiretroviral therapy (HAART). Participants were classified as hypocholesterolemic (HypoCHL; 150 mg/dl) and were compared on viro‐immune outcomes. Results: At baseline, participants with HypoCHL (40%) exhibited lower CD4 (197 ± 181 vs. 295 ± 191 cells/mm3, p = 0.02) and CD8 (823 ± 448 vs. 1194 ± 598 cells/mm[sup.3], p = 0.001) counts and were more likely to have detectable viral loads (OR = 3.5, p = 0.01) than non‐HypoCHL controls. After HAART, participants with HypoCHL were twice as likely to experience a virological failure >400 copies (95% CI 1‐2.6, p = 0.05) and to exhibit Conclusions: The study implicates, for the first time, HypoCHL with impaired HAART effectiveness, including limited CD4 repletion by the thymus and suboptimal viral clearance., Background During the course of HIV disease, disturbances of lipid metabolism have been observed long before the introduction of highly active antiretroviral therapy (HAART) and included hypocholesterolemia (HypoCHL; Conversely, the [...]

Background: Our intention was to compare the rate of immunological progression prior to antiretroviral therapy (ART) and the virological response to ART in patients infected with subtype B and four non‐B HIV‐1 subtypes (A, C, D and the circulating recombinant form, CRF02‐AG) in an ethnically diverse population of HIV‐1‐infected patients in south London. Methods: A random sample of 861 HIV‐1‐infected patients attending HIV clinics at King's and St Thomas' hospitals' were subtyped using an in‐house enzyme‐linked immunoassay and env sequencing. Subtypes were compared on the rate of CD4 cell decline using a multi‐level random effects model. Virological response to ART was compared using the time to virological suppression (< 400 copies/ml) and rate of virological rebound (> 400 copies/ml) following initial suppression. Results: Complete subtype and epidemiological data were available for 679 patients, of whom 357 (52.6%) were white and 230 (33.9%) were black African. Subtype B (n = 394) accounted for the majority of infections, followed by subtypes C (n = 125), A (n = 84), D (n = 51) and CRF02‐AG (n = 25). There were no significant differences in rate of CD4 cell decline, initial response to highly active antiretroviral therapy and subsequent rate of virological rebound for subtypes B, A, C and CRF02‐AG. However, a statistically significant four‐fold faster rate of CD4 decline (after adjustment for gender, ethnicity and baseline CD4 count) was observed for subtype D. In addition, subtype D infections showed a higher rate of virological rebound at six months (70%) compared with subtypes B (45%, p = 0.02), A (35%, p = 0.004) and C (34%, p = 0.01) Conclusions: This is the first study from an industrialized country to show a faster CD4 cell decline and higher rate of subsequent virological failure with subtype D infection. Further studies are needed to identify the molecular mechanisms responsible for the greater virulence of subtype D., Introduction The world‐wide HIV epidemic has been characterized by increasing genetic diversity, with multiple distinct viral subtypes, as well as sub‐subtypes, and circulating recombinant forms (CRFs) [1‐3]. At present, specific [...]

In 2007 an estimated 33 million people were living with HIV; 67% resided in sub‐Saharan Africa, with 35% in eight countries alone. In 2007, there were about 1.4 million HIV‐positive tuberculosis cases. Globally, approximately 4 million people had been given highly active antiretroviral therapy (HAART) by the end of 2008, but in 2007, an estimated 6.7 million were still in need of HAART and 2.7 million more became infected with HIV. Although there has been unprecedented investment in confronting HIV/AIDS ‐ the Joint United Nations Programme on HIV/AIDS estimates $13.8 billion was spent in 2008 ‐ a key challenge is how to address the HIV/AIDS epidemic given limited and potentially shrinking resources. Economic disparities may further exacerbate human rights issues and widen the increasingly divergent approaches to HIV prevention, care and treatment. HIV transmission only occurs from people with HIV, and viral load is the single greatest risk factor for all modes of transmission. HAART can lower viral load to nearly undetectable levels. Prevention of mother to child transmission offers proof of the concept of HAART interrupting transmission, and observational studies and previous modelling work support using HAART for prevention. Although knowing one's HIV status is key for prevention efforts, it is not known with certainty when to start HAART. Building on previous modelling work, we used an HIV/AIDS epidemic of South African intensity to explore the impact of testing all adults annually and starting persons on HAART immediately after they are diagnosed as HIV positive. This theoretical strategy would reduce annual HIV incidence and mortality to less than one case per 1000 people within 10 years and it would reduce the prevalence of HIV to less than 1% within 50 years. To explore HAART as a prevention strategy, we recommend further discussions to explore human rights and ethical considerations, clarify research priorities and review feasibility and acceptability issues., Introduction The trajectory of the beginning of the modern era of public health can be traced from Jenner's inoculation of James Phipps in England in 1796 to the last case [...]