Long-term impact of immediate versus deferred antiretroviral therapy on kidney health in people with HIV.

People with human immunodeficiency virus (HIV) are at risk for chronic kidney disease (CKD) due to HIV and antiretroviral therapy (ART) nephrotoxicity. Immediate ART initiation reduces mortality and is now the standard of care, but the long-term impact of prolonged ART exposure on CKD is unknown. To evaluate this, the Strategic Timing of Antiretroviral Treatment (START) trial randomized 4,684 ART-naïve adults with CD4 cell count under 500 cells/mm3 to immediate versus deferred ART. We previously reported a small but statistically significantly greater decline in estimated glomerular filtration rate (eGFR) over a median of 2.1 years in participants randomized to deferred versus immediate ART. Here, we compare the incidence of CKD events and changes in eGFR and urine albumin/creatinine ratio (UACR) in participants randomized to immediate versus deferred ART during extended follow-up. Over a median of 9.3 years, eight participants experienced kidney failure or kidney-related death, three in the immediate and five in the deferred ART arms, respectively. Over a median of five years of more comprehensive follow-up, the annual rate of eGFR decline was 1.19 mL/min/1.73m2/year, with no significant difference between treatment arms (difference deferred - immediate arm 0.055; 95% confidence interval -0.106, 0.217 mL/min/1.73m2). Results were similar in models adjusted for baseline covariates associated with CKD, including UACR and APOL1 genotype. Similarly, there was no significant difference between treatment arms in incidence of confirmed UACR 30 mg/g or more (odds ratio 1.13; 95% confidence interval 0.85, 1.51). Thus, our findings provide the most definitive evidence to date in support of the long-term safety of early ART with respect to kidney health.

Acute Hepatitis due to Primary Human Immunodeficiency Virus Infection.

The acute retroviral syndrome may present with diverse systemic manifestations and laboratory abnormalities. Here we present a rare case of primary human immunodeficiency virus (HIV) infection causing severe acute hepatitis. Liver histopathology demonstrated a pattern of lymphocytic inflammation consistent with acute hepatitis, high levels of HIV proviral DNA were detected within liver tissue, and immunofluorescence showed HIV p24 antigen within immune and parenchymal cells including hepatocytes. We review the literature pertaining to HIV infection of cell compartments within the liver and discuss the implications for HIV-associated acute liver disease.

Contrasting Cases of HIV Vasculopathy Associated Fusiform Aneurysms.

Background: Human Immunodeficiency Virus (HIV) vasculopathy encompasses the development of aneurysms, stenosis and vessel occlusions. Intracranial fusiform aneurysms in Human Immunodeficiency Virus (HIV) were originally described in children; however, HIV-associated aneurysms are increasingly recognized in adults. Purpose: We present two cases to highlight the spectrum of severity and outline instructive clinical courses. Results: Case one is a 52-year-old woman with HIV, Acquired Immunodeficiency Syndrome (AIDS)-defining progressive multifocal leukoencephalopathy (PML) and an 18 years course of cerebral aneurysms, aneurysm thrombosis and the development of right middle cerebral artery (MCA) moyamoya pattern collaterals. Case two is a 55-year-old man with AIDS-defining cerebral toxoplasmosis, complicated by IRIS and anterior and posterior circulation fusiform aneurysm formation. Conclusions: The combination of both fusiform abnormalities and Moyamoya, discussed in our first case has not been previously described. In comparison, our second case actually demonstrated improvement in vasculopathy after nine-months of antiretroviral therapy (ART) adherence.

Assessing Cardiovascular Risk in People Living with HIV: Current Tools and Limitations.

PURPOSE OF REVIEW: To provide the current state of the development and application of cardiovascular disease (CVD) prediction tools in people living with HIV (PLWH). RECENT FINDINGS: Several risk prediction models developed on the general population are available to predict CVD risk, the most notable being the US-based pooled cohort equations (PCE), the Framingham risk functions, and the Europe-based SCORE (Systematic COronary Risk Evaluation). In validation studies in cohorts of PLWH, these models generally underestimate CVD risk, especially in individuals who are younger, women, Black race, or predicted to be at low/intermediate risk. An HIV-specific CVD prediction model, the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) model, is available, but its performance is modest, especially in US-based cohorts. Enhancing CVD prediction with novel biomarkers of inflammation or coronary artery calcification is of interest but has not yet been evaluated in PLWH. Finally, studies on CVD risk prediction are lacking in diverse PLWH globally. While available risk models for CVD prediction in PLWH remain suboptimal, clinicians should remain vigilant of higher CVD risk in this population and should use any of these risk scores for risk stratification to guide preventive interventions. Focus on established traditional risk factors such as smoking remains critical in PLWH. Risk prediction functions tailored to PLWH in diverse settings will enhance clinicians' ability to deliver optimal preventive care.

Sex-based differences in antiretroviral therapy initiation, switching and treatment interruptions: global overview from the International Epidemiologic Databases to Evaluate AIDS (IeDEA).

INTRODUCTION: In 2015, the World Health Organization recommended that all HIV-infected individuals consider ART initiation as soon as possible after diagnosis. Sex differences in choice of initial ART regimen, indications for switching, time to switching and choice of second-line regimens have not been well described. The aims of this study were to describe first-line ART and CD4 count at ART initiation by sex, calendar year and region, and to analyse time to change or interruption in first-line ART, according to sex in each region. METHODS: Participating cohorts included: Southern, East and West Africa (IeDEA-Africa), North America (NA-ACCORD), Caribbean, Central/South America (CCASAnet) and Asia-Pacific including Australia (IeDEA Asia-Pacific). The primary outcomes analysed for each region and according to sex were choice of initial ART, time to switching and time to discontinuation of the first-line regimen. RESULTS AND DISCUSSION: The combined cohort data set comprised of 715,252 participants across seven regions from low- to high-income settings. The median CD4 count at treatment initiation was lower in men compared with women in nearly all regions and time periods. Women from North America and Southern Africa were more likely to switch ART compared to men (p < 0.001) with approximately 90% of women reporting a major change after 10 years in North America. Overall, after 8 years on ART, >50% of HIV- positive men and women from Southern Africa, East Africa, South and Central America remained on their original regimen. Men were more likely to have a treatment interruption compared with women in low- and middle-income countries from the Asia/Pacific region (p < 0.001) as were men from Southern Africa (p < 0.001). Greater than 75% of men and women did not report a treatment interruption after 10 years on ART from all regions except North America and Southern Africa. CONCLUSIONS: There are regional variations in the ART regimen commenced at baseline and rates of major change and treatment interruption according to sex. Some of this is likely to reflect changes in local and international antiretroviral guideline recommendations but other sex-specific factors such as pregnancy may contribute to these differences.

Body Mass Index and the Risk of Serious Non-AIDS Events and All-Cause Mortality in Treated HIV-Positive Individuals: D: A: D Cohort Analysis.

BACKGROUND: The relationship between body mass index (BMI) [weight (kg)/height (m)] and serious non-AIDS events is not well understood. METHODS: We followed D:A:D study participants on antiretroviral therapy from their first BMI measurement to the first occurrence of the endpoint or end of follow-up (N = 41,149 followed for 295,147 person-years). The endpoints were cardiovascular disease (CVD); diabetes; non-AIDS-defining cancers (NADCs) and BMI-NADCs (cancers known to be associated with BMI in general population); and all-cause mortality. Using Poisson regression models, we analyzed BMI as time-updated, lagged by 1 year, and categorized at: 18.5, 23, 25, 27.5, and 30 kg/m. RESULTS: Participants were largely male (73%) with the mean age of 40 years (SD 9.7) and baseline median BMI of 23.3 (interquartile range: 21.2-25.7). Overall, BMI showed a statistically significant J-shaped relationship with the risk of all outcomes except diabetes. The relative risk (RR) for the BMI of <18.5 and >30 (95% confidence interval) compared with 23-25, respectively, was as follows: CVD: 1.46 (1.15-1.84) and 1.31 (1.03-1.67); NADCs: 1.78 (1.39-2.28) and 1.17 (0.88-1.54); and "BMI-NADCs": 1.29 (0.66-2.55) and 1.92 (1.10-3.36). For all-cause mortality, there was an interaction by sex (P < 0.001): RR in males: 2.47 (2.12-2.89) and 1.21 (0.97-1.50); and in females: 1.60 (1.30-1.98) and 1.02 (0.74-1.42). RR remained around 1 for intermediate categories of BMI. The risk of diabetes linearly increased with increasing BMI (P < 0.001). CONCLUSIONS: Risk of CVD, a range of cancers, and all-cause mortality increased at low BMI (<18.5) and then tended to increase only at BMI > 30 with a relatively low risk at BMI of 23-25 and 25-30. High BMI was also associated with risk of diabetes.

Impact of early versus deferred antiretroviral therapy on estimated glomerular filtration rate in HIV-positive individuals in the START trial.

The impact of early ART initiation (versus deferring) on kidney function has not been studied. START was a randomised comparison of immediate versus deferred ART initiation among HIV-positive persons with CD4+ (cells/mm3) counts >500. Serum creatinine and urine dipstick protein were measured at Months 0, 1, 4, 8 and 12, and annually thereafter. The two arms were compared for changes in eGFR (mL/min/1.73 m2, calculated by CKD-EPI equation), over time using longitudinal mixed models. Of 4685 START participants, 4629 (2294 in immediate and 2335 deferred arm) were included. Median baseline CD4+ and eGFR were 651 and 111.5, respectively. ART was initiated in 2271 participants (99.0%) in the immediate and 1127 (48.3%) in the deferred arm, accounting for >94% and >19% of follow-up time, respectively. Overall, 89% started ART using a tenofovir-based regimen. Over 2.1 years median follow-up, mean eGFR was 0.56 (95% CI 0.003-1.11) higher in the immediate versus deferred arm, which was more prominent after adjustment for current tenofovir or bPI use (1.85, 95% CI 1.21-2.50) and in Black participants (30.1% overall) (3.90, 95% CI 2.84-4.97) versus non-Blacks (1.05, 95% CI 0.33-1.77) (P < 0.001 for interaction). Relative risk for proteinuria in the immediate versus deferred arm was 0.74 (95% CI 0.55-1.00) (P = 0.049). In the short-term, immediate ART initiation was associated with a modestly higher eGFR and lower proteinuria risk versus deferring ART (more pronounced in Black participants). Whether this early benefit translates into a lower risk of CKD requires further follow-up.

Changes in Cardiovascular Disease Risk Factors With Immediate Versus Deferred Antiretroviral Therapy Initiation Among HIV-Positive Participants in the START (Strategic Timing of Antiretroviral Treatment) Trial.

INTRODUCTION: HIV infection and certain antiretroviral therapy (ART) medications increase atherosclerotic cardiovascular disease risk, mediated, in part, through traditional cardiovascular disease risk factors. METHODS AND RESULTS: We studied cardiovascular disease risk factor changes in the START (Strategic Timing of Antiretroviral Treatment) trial, a randomized study of immediate versus deferred ART initiation among HIV-positive persons with CD4+ cell counts >500 cells/mm3. Mean change from baseline in risk factors and the incidence of comorbid conditions were compared between groups. The characteristics among 4685 HIV-positive START trial participants include a median age of 36 years, a CD4 cell count of 651 cells/mm3, an HIV viral load of 12 759 copies/mL, a current smoking status of 32%, a median systolic/diastolic blood pressure of 120/76 mm Hg, and median levels of total cholesterol of 168 mg/dL, low-density lipoprotein cholesterol of 102 mg/dL, and high-density lipoprotein cholesterol of 41 mg/dL. Mean follow-up was 3.0 years. The immediate and deferred ART groups spent 94% and 28% of follow-up time taking ART, respectively. Compared with patients in the deferral group, patients in the immediate ART group had increased total cholesterol and low-density lipoprotein cholesterol and higher use of lipid-lowering therapy (1.2%; 95% CI, 0.1-2.2). Concurrent increases in high-density lipoprotein cholesterol with immediate ART resulted in a 0.1 lower total cholesterol to high-density lipoprotein cholesterol ratio (95% CI, 0.1-0.2). Immediate ART resulted in 2.3% less BP-lowering therapy use (95% CI, 0.9-3.6), but there were no differences in new-onset hypertension or diabetes mellitus. CONCLUSIONS: Among HIV-positive persons with preserved immunity, immediate ART led to increases in total cholesterol and low-density lipoprotein cholesterol but also concurrent increases in high-density lipoprotein cholesterol and decreased use of blood pressure medications. These opposing effects suggest that, in the short term, the net effect of early ART on traditional cardiovascular disease risk factors may be clinically insignificant." CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00867048.

Efficacy and safety of contemporary dual-drug antiretroviral regimens as first-line treatment or as a simplification strategy: a systematic review and meta-analysis.

BACKGROUND: Some guidelines recommended two-drug antiretroviral therapies as alternative regimens to triple therapy in selected patients with the aim of reducing drug burden and toxicity and preserving future treatment options. We aimed to assess the efficacy and safety of dual-therapy versus triple therapy as first-line treatment or in treatment simplification. METHODS: For this systematic review and meta-analysis, we searched Medline, Embase (via OVID), the Cochrane Trial Registry, and major conference proceedings for randomised trials published between Jan 1, 2008, and Dec 31, 2015. We included studies comparing dual-therapy (from two independent classes) antiretroviral regimens as a first-line or a switch strategy (in virologically suppressed individuals) with standard triple-drug regimens. Our primary outcome was the risk of virological failure (non-completion=failure) at the 48 week timepoint. We did a random-effect meta-analysis to pool the relative risk (RR) or odds ratio (OR) for each of the outcomes. FINDINGS: For the primary outcome, we included 21 studies (11 first-line and ten switch studies), providing data for 4821 individuals (2478 in dual-therapy groups and 2343 in control groups). Overall, the RR of failure with dual-therapy compared with triple-therapy (control) groups was 1·14 (95% CI 0·91-1·43). In first-line studies, the RR of failure for dual-therapy versus control groups was 1·17 (0·94-1·47; I(2)=51%), which reduced to 1·05 (0·86-1·28; I(2)=26%) on exclusion of maraviroc-containing studies. In switch studies, the RR of failure for dual-therapy versus control groups was 1·21 (0·72-2·02; I(2)=67%), which reduced to 1·13 (0·64-1·99; I(2)=61%) after exclusion of maraviroc-containing studies. In patients with a baseline viral load of more than 100 000 copies per mL, RR of failure for dual-therapy versus control groups was 1·24 (1·03-1·49), which reduced to 1·18 (0·94-1·47) on excluding maraviroc-containing studies. We recorded the ORs for dual-therapy versus control groups for serious adverse events (1·16 [0·92-1·48]), adverse events (0·82 [0·52-1·28]), and mutations (2·11 [1·32-3·36]). INTERPRETATION: Dual therapy, especially with regimens excluding maraviroc, could be safe and efficacious, particularly in patients with baseline viral loads of less than 100 000 copies per mL. However, dual therapy seems to have a greater risk of selecting resistance mutations compared with standard triple therapy. FUNDING: None.

Chronic Kidney Disease and Antiretroviral Therapy in HIV-Positive Individuals: Recent Developments.

Chronic kidney disease (CKD) has emerged as an important health concern in HIV-positive individuals. Preventing long-term kidney toxicity from an antiretroviral therapy is therefore critical. Selected antiretroviral agents, especially tenofovir disoproxil fumarate (TDF) and some ritonavir-boosted protease inhibitors (PI/rs), have been associated with increased risk of CKD. However, the CKD risk attributable to these agents is overall small, especially in those with low baseline risk of CKD and normal renal function. CKD risk in HIV-positive individuals can be further minimized by timely identification of those with worsening renal function and discontinuation of potentially nephrotoxic agents. Clinicians can use several monitoring tools, including the D:A:D risk score and routine measurements of estimated glomerular filtration (eGFR) and proteinuria, to identify high-risk individuals who may require an intervention. Tenofovir alafenamide (TAF), a TDF alternative, promises to be safer in terms of TDF-associated kidney and bone toxicity. While the short-term data on TAF does indicate lower eGFR decline and lower risk of proteinuria (vs. TDF), long-term data on renal safety of TAF are still awaited. Promising results have also emerged from recent trials on alternative dual-therapy antiretroviral regimens which exclude the nucleoside(tide) reverse transcriptase class as well as possibly the PI/rs, thereby reducing the drug burden, and possibly the toxicity. However, long-term safety or benefits of these dual-therapy regimens are still unclear and will need to be studied in future prospective studies. Finally, addressing risk factors such as hypertension and diabetes will continue to be important in this population.

Plasma levels of cytokines and chemokines and the risk of mortality in HIV-infected individuals: a case-control analysis nested in a large clinical trial.

BACKGROUND: All-cause mortality and serious non-AIDS events (SNAEs) in individuals with HIV-1 infection receiving antiretroviral therapy are associated with increased production of interleukin-6 which appears to be driven by monocyte/macrophage activation. Plasma levels of other cytokines or chemokines associated with immune activation might also be biomarkers of an increased risk of mortality and/or SNAEs. METHODS: Baseline plasma samples from 142 participants enrolled into the Strategies for Management of Antiretroviral Therapy study, who subsequently died, and 284 matched controls, were assayed for levels of 15 cytokines and chemokines. Cytokine and chemokine levels were analysed individually and when grouped according to function (innate/proinflammatory response, cell trafficking and cell activation/proliferation) for their association with the risk of subsequent death. RESULTS: Higher plasma levels of proinflammatory cytokines (interleukin-6 and tumour necrosis factor-α) were associated with an increased risk of all-cause mortality but in analyses adjusted for potential confounders, only the association with interleukin-6 persisted. Increased plasma levels of the chemokine CXCL8 were also associated with all-cause mortality independently of hepatitis C virus status but not when analyses were adjusted for all confounders. In contrast, higher plasma levels of cytokines mediating cell activation/proliferation were not associated with a higher mortality risk and exhibited a weak protective effect when analysed as a group. CONCLUSION: Whereas plasma levels of interleukin-6 are the most informative biomarker of cytokine dysregulation associated with all-cause mortality in individuals with HIV-1 infection, assessment of plasma levels of CXCL8 might provide information about causes of mortality and possibly SNAEs.

Moving away from Ritonavir, Abacavir, Tenofovir, and Efavirenz (RATE)--agents that concern prescribers and patients: a feasibility study and call for a trial.

OBJECTIVES: Regimens sparing RATE (ritonavir, abacavir, tenofovir, efavirienz) agents might have better long-term safety. We conducted a feasibility exercise to assess the potential for a randomised trial evaluating RATE-sparing regimens. DESIGN: Observational. METHODS: We first calculated RATE-sparing options available to an average patient receiving RATE agents. We reviewed treatment history and all resistance assays from patients attending the St. Vincent's Hospital (Sydney) clinic and receiving ≥2 RATE agents (n = 120). A viable RATE-sparing regimen with 2 or 3 fully-active agents was constructed from the following six 'safer' agents: rilpivirine or etravirine; atazanavir; raltegravir; maraviroc; and lamivudine. Activity for each drug was predicted as 1 (full-activity), 0.5 or 0 (no activity) using the Stanford mutation database. The utility of maraviroc was calculated assuming both maraviroc activity and inactivity where unknown. The analysis was restricted to regimens for which supporting evidence was identified in the literature or conference proceedings. Finally, we calculated the proportion of patients in the nationally representative Australian HIV Observational Database (AHOD) cohort receiving ≥2 RATE agents (n = 1473) to measure the potential population-level uptake of RATE-sparing agents. RESULTS: Assuming full maraviroc activity, 117(97.5%) and 107(89.2%) individuals had at least one option with 2 or 3 active RATE-sparing agents, respectively. Assuming no maraviroc activity this decreased to 113(94.2%) and 104(86.7%), respectively. In AHOD, 837(56.8%) patients were receiving ≥2 RATE agents. CONCLUSION: Feasible treatment switch options sparing RATE agents exist for the majority of patients. Understanding the pros and cons of switching stable patients onto new RATE-sparing regimens requires evidence derived from randomised controlled trials.

Relationship between CD4 cell count and serious long-term complications among HIV-positive individuals.

PURPOSE OF REVIEW: To summarize recent findings on the relationship between CD4 cell count metrics and selected serious clinical outcomes, and to deduce implications for CD4 cell count monitoring in treated HIV infection and the timing of combination antiretroviral therapy initiation. RECENT FINDINGS: In treated HIV infection, a higher latest CD4 cell count is associated with a lower short-term risk of serious non-AIDS events (often composite endpoints) even in CD4 cell count strata more than 350/µl. Knowledge of alternate CD4 cell count metrics, such as CD4 cell count slope, nadir level and time spent under specific CD4 cell count thresholds, does not seem to confer additional prognostic information beyond that achieved by current CD4 cell count. Latest CD4 cell count is strongly associated with a short-term risk of infection-related non-AIDS malignancies, and serious hepatic events; however, the evidence is inconsistent for cardiovascular outcomes. Studies vary significantly in definitions of composite endpoints as well as the rigorousness of outcome ascertainment, which could explain the heterogeneity in results. SUMMARY: Current CD4 cell count, but not other metrics, could be an important clinical tool to predict the short-term risk of serious non-AIDS events in treated HIV-positive individuals. An earlier initiation of therapy at CD4 cell count more than 350/µl or above 500/µl is likely to improve long-term CD4 cell count metrics. Whether it provides net individual clinical benefit requires a randomized trial.

Antiretroviral regimens sparing agents from the nucleoside(tide) reverse transcriptase inhibitor class: a review of the recent literature.

The nucleoside(tide) reverse transcriptase inhibitors (NRTIs) have traditionally been an important 'back-bone' of an antiretroviral therapy (ART) regimen. However all agents have been associated with both short- and long-term toxicity. There have also been concerns regarding the efficacy and safety of a treatment sequencing strategy in which those with past exposure and/or resistance to one or more NRTIs are re-exposed to 'recycled' NRTIs in subsequent ART regimens. Newer, potent and possible safer, agents from various ART classes continue to become available. There has therefore been growing interest in evaluating NRTI-sparing regimens. In this review, we examined studies of NRTI-sparing regimens in adult HIV-positive patients with varying degrees of ART experience. We found that in treatment experienced patients currently on a failing regimen with detectable viral load, there now exists a robust evidence for the use of NRTI-sparing regimens including raltegravir with a boosted-protease inhibitor with or without a third agent. In those on a virologically suppressive regimen switching to a NRTI-sparing regimen or in those ART-naïve patients initiating an NRTI-sparing regimen, evidence is sparse and largely comes from small exploratory trials or observational studies. Overall, these studies suggest that caution needs to be exercised in carefully selecting the right candidate and agents, especially in the context of a dual-therapy regimen, to minimise the risks of virological failure. There is residual toxicity conferred by the ritonavir boost in protease-inhibitor containing NRTI-sparing regimens. Fully-powered studies are needed to explore the place of N (t)RTI-sparing regimens in the sequencing of ART. Additionally research is required to explore how to minimise the adverse effects associated with ritonavir-based pharmacoenhancement.

Changes in metabolic, inflammatory and coagulation biomarkers after HIV seroconversion--the Health in Men (HIM) Biomarker Substudy.

BACKGROUND: Biomarkers of inflammation, coagulation, lipids and vitamin D have been associated with cardiovascular and mortality risk in HIV-infected individuals. Scarce data exist on changes in these markers from pre- to post-HIV seroconversion. METHODS: The study participants were drawn from the Health in Men Study, which recruited HIV-negative homosexual men. Participants with incident HIV infection (n=26) were compared with HIV-negative controls (n=52) matched on age at enrolment, date of visit and reported intravenous drug use. Levels of metabolic (lipids and vitamin D), inflammatory (C-reactive protein and interleukin-6) and coagulation (D-dimer and fibrinogen) biomarkers were measured at pre- and post-HIV seroconversion visits and corresponding visits for controls. Random-effect models were used to compare changes in markers between cases and controls. RESULTS: The median gap between pre- and post-seroconversion or matched first and second visits in controls was 12 months. HIV seroconversion was associated with decline in high density lipoprotein (HDL-C; difference in mean change between cases and controls -0.14 mmol/l; 95% CI -0.22, -0.01; P=0.035). There were no significant differences in changes in other lipids, markers of inflammation, coagulation or vitamin D. CONCLUSIONS: Decline in HDL-C seems to be the main proatherogenic change within 1-1.5 years after HIV seroconversion. HIV seroconversion was not associated with profound changes in other lipids, or markers of inflammation, coagulation and vitamin D. Longitudinal assessment of these markers in comparable population needs further assessment.

Differences in lipid measurements by antiretroviral regimen exposure in cohorts from Asia and australia.

We explored the mean differences in routinely measured lipids (total cholesterol, triglycerides, and high-density lipoprotein cholesterol) according to exposure to different combination antiretroviral regimens in Asian (n = 2051) and Australian (predominantly Caucasian, n = 794) cohorts. The regimen was defined as at least 3 antiretroviral drugs with at least 2 nucleoside-reverse transcriptases (NRTIs) and either of at least one protease inhibitor (PI) or non-nucleoside-reverse transcriptases (NNRTIs). We categorised cART regimens as: NRTIs as tenofovir based or not; NNRTIs as nevirapine or efavirenz (but not both); and PI as atazanavir based or not. We found that the impact of various antiretroviral regimens on lipids in Asian and Australian cohorts was only different by cohort for total cholesterol (P for interaction between regimen and cohort: <0.001) but not in case of other lipids (P for interaction: >0.05). The differences in total cholesterol were however small and unlikely to be of clinical significance. Overall, tenofovir with nevirapine or atazanavir was associated with the most favorable lipids, while the PI regimens without tenofovir and atazanavir were associated with least favorable lipids. We conclude that the impact of various ART regimens on lipids is largely similar in Asian and Australian cohorts and that the newer drugs such as tenofovir and atazanavir are likely to provide similar benefit in terms of lipid profiles in both populations.

Reclassification of risk of death with the knowledge of D-dimer in a cohort of treated HIV-infected individuals.

OBJECTIVE: To evaluate the change in categories of risk of death by adding D-dimer to conventional mortality risk factors. DESIGN: Cohort study. METHODS: Data on HIV-infected participants receiving standard combination antiretroviral therapy in two clinical trials (Evaluation of Subcutaneous Proleukin in a Randomized International Trial and Strategic Management of antiretroviral therapy), who had baseline D-dimer measured, were randomly split into two equal training and a validation datasets. A multivariable survival model was built using the training dataset and included only conventional mortality risk factors measured at baseline. D-dimer was added to create the comparison model. The level of reclassification of mortality risk, for those with at least 5-years of follow-up, was then assessed by tabulating mortality risk defined as low (≤2% predicted rate), moderate (2-5%) or high (>5%). Reclassification analyses were then repeated on the validation dataset. RESULTS: The analysis population at baseline had a mean age of 43 years, median CD4(+) cell count of 535 cells/µl (IQR: 420-712), and 83% had HIV RNA of at least 500 copies/ml. In the training dataset (n=1946, 8939 person-years), there were 83 deaths at a rate of 0.93 per 100 person-years. Addition of D-dimer to the reference model resulted in 6% or fewer (P>0.05) being correctly reassigned, either up or down, to a new risk category, in both, training and validation datasets. The integrated discrimination improvement in training and validation datasets was 0.60% (P=0.084) and 0.45% (P=0.168), respectively. CONCLUSION: In this relatively well population, at the given risk cutoffs, D-dimer appeared to only modestly improve the discernment of risk. Risk reclassification provides a method for assessing the clinical utility of biomarkers in HIV cohort studies.

Long-term immunological outcomes in treated HIV-infected individuals in high-income and low-middle income countries.

PURPOSE OF REVIEW: To summarize the recent findings on long-term (at least 3-4 years) immunological responses to combination antiretroviral therapy (cART) and to compare and contrast the findings between cohorts from high-income and low-middle income countries (LMICs). RECENT FINDINGS: Cohort studies from high-income settings suggest that a majority of treated HIV-infected patients who maintain suppressed HIV viremia experience a gradual increase in CD4 cell counts for several years to normal levels. However, those who start cART at CD4 cell counts less than 200 cells/µl (as opposed to CD4 cell counts>200 cells/µl) spend several more years below the safe CD4 cell count threshold of 500 cells/µl. Cohorts from LMICs also report persistent improvements in CD4+ cell counts over first 4-5 years of follow-up. However, low-CD4 cell counts (<200 cells/µl) at the start of cART, high early mortality, and loss to follow-up in LMICs settings suggest that the observed optimistic responses may be affected by survivorship bias and should be cautiously interpreted as the optimal, rather than an average, response in LMICs populations. SUMMARY: LMICs cohorts report similar immunological responses to cART as high-income countries in first 4-5 years of follow-up. Sustaining success in these settings is dependent on timely access to first-line and future cART options, efforts to reduce loss to follow-up, and implementation of treatment guidelines. Cohorts from LMICs are encouraged to continue improving treatment programs and to continue reporting outcomes over the next decade, as surveillance for potential future blunting in responses.