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Introduction: We explored associations of inflammatory and immune activation biomarkers at baseline and percentage gain in peripheral and trunk fat and lean mass over 96 weeks in patients with confirmed virological failure initiating lopinavir-anchored second-line antiretroviral therapy (ART) regimens., Method: We measured baseline plasma concentration of interleukin (IL)-6, tumour necrosis factor (TNF), neopterin, IL-6, high-sensitivity C-reactive protein (hs-CRP), D-dimer, soluble cluster of differentiation 14 (sCD14), and soluble CD163 in 123 participants of the SECOND-LINE body composition substudy. Linear regression assessed the association between biomarkers and percentage gain in limb/trunk fat and lean mass, adjusting for age, nucleoside or nucleotide reverse transcriptase inhibitor (N(t)RTI) use, body mass index, ethnicity, smoking, viral load, CD4+ T-cell counts, smoking, duration of ART use, and cholesterol., Results: Mean (standard deviation) age was 38 (7.3) years, CD4+ T-cell count was 252 (185.9) cells/μl, human immunodeficiency virus viral load was 4.2 (0.9) log10 copies/ml, 47% (58/123) were in the N(t)RTI arm (vs. raltegravir [RAL] arm in 53%); 56.1% (69/123) were females. In adjusted analyses, for every log10 increase in baseline levels of IL-6, neopterin, and D-dimer, the percentage gain in peripheral fat over 96 weeks was 11.8% (95% confidence interval [CI]: 0.9-22.6, P = 0.033); neopterin, 11.2% (95% CI: 3.2-19.2, P = 0.007); D-dimer 9.6% (95% CI: 3.1-15.9, P = 0.004), respectively. The associations remained significant when analysis was stratified by N(t)RTI vs. RAL and included only patients with viral suppression at week 48. A significant gradient in lean mass gain was seen across quartiles of IL-6, TNF, neopterin, hsCRP, D-dimer, and sCD14., Conclusion: Inflammatory biomarkers provide important mechanistic insights into the pathogenesis of limb fat and lean mass changes independently of ART., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Despite successful ART in people living with HIV infection (PLHIV) they experience increased morbidity and mortality compared with HIV-negative controls. A dominant paradigm is that gut-associated lymphatic tissue (GALT) destruction at the time of primary HIV infection leads to loss of gut integrity, pathological microbial translocation across the compromised gastrointestinal barrier and, consequently, systemic inflammation. We aimed to identify and measure specific changes in the gastrointestinal barrier that might allow bacterial translocation, and their persistence despite initiation of antiretroviral therapy (ART)., Method: We conducted a cross-sectional study of the gastrointestinal (GIT) barrier in PLHIV and HIV-uninfected controls (HUC). The GIT barrier was assessed as follows: in vivo mucosal imaging using confocal endomicroscopy (CEM); the immunophenotype of GIT and circulating lymphocytes; the gut microbiome; and plasma inflammation markers Tumour Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6); and the microbial translocation marker sCD14., Results: A cohort of PLHIV who initiated ART early, during primary HIV infection (PHI), n=5), and late (chronic HIV infection (CHI), n=7) infection were evaluated for the differential effects of the stage of ART initiation on the GIT barrier compared with HUC (n=6). We observed a significant decrease in the CD4 T-cell count of CHI patients in the left colon (p=0.03) and a trend to a decrease in the terminal ileum (p=0.13). We did not find evidence of increased epithelial permeability by CEM. No significant differences were found in microbial translocation or inflammatory markers in plasma. In gut biopsies, CD8 T-cells, including resident intraepithelial CD103+ cells, did not show any significant elevation of activation in PLHIV, compared to HUC. The majority of residual circulating activated CD38+HLA-DR+ CD8 T-cells did not exhibit gut-homing integrins α4ß7, suggesting that they did not originate in GALT. A significant reduction in the evenness of species distribution in the microbiome of CHI subjects (p=0.016) was observed, with significantly higher relative abundance of the genus Spirochaeta in PHI subjects (p=0.042)., Conclusion: These data suggest that substantial, non-specific increases in epithelial permeability may not be the most important mechanism of HIV-associated immune activation in well-controlled HIV-positive patients on antiretroviral therapy. Changes in gut microbiota warrant further study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor has declared a shared affiliation, though no other collaboration with one of the authors NS at the time of review., (Copyright © 2021 Mak, Zaunders, Bailey, Seddiki, Rogers, Leong, Phan, Kelleher, Koelsch, Boyd and Danta.)

Background: To investigate metabolic changes associated with second-line antiretroviral therapy (ART) following virological failure of first-line ART., Methods: SECOND-LINE was an open-label randomized controlled trial. Participants were randomized 1:1 to receive ritonavir-boosted lopinavir (LPV/r) with 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTI group) or raltegravir (RAL group). 210 participants had a dual energy X-ray absorptiometry (DXA)-scan at baseline, week 48 and 96. We categorized participants according to second-line ART backbone: thymidine analogue (ta-NRTI) + lamivudine/emtricitabine (3[F]TC; ta-NRTI group); tenofovir (TDF)+3(F)TC (TDF group); TDF+ta-NRTI ±3(F)TC (TDF+ta-NRTI group); RAL. Changes in fasted total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, TC/HDL-cholesterol ratio, triglycerides and glucose from baseline to week 96 were examined. We explored the association between metabolic and DXA-assessed soft-tissue changes. Linear regression methods were used., Results: We analysed 454 participants. Participants in RAL group had greater TC increases, TC (adjusted mean difference [aMD]=0.65, 95% CI 0.33, 0.96), LDL-c (aMD=0.38, 95% CI 0.15, 0.61) and glucose (aMD=0.47, 95% CI -0.01, 0.92) compared to TDF group, and had greater increases in TC (aMD=0.65, 95% CI 0.28, 1.03), HDL-c (aMD=0.12, 95% CI 0.02, 0.23) and LDL-c (aMD=0.41, 95% CI 0.13, 0.69) compared to TDF+ta-NRTI group. TC/HDL ratio and triglycerides increased in all groups without significant differences between groups. A 1 kg increase in trunk fat mass was associated with an increase in TC., Conclusions: We observed metabolic changes of limited clinical significance in the relatively young population enrolled in this study. However, the metabolic changes observed may have greater clinical significance in older people living with HIV or those with other concomitant cardiovascular risks.

Background: Lipoatrophy is one of the most feared complications associated with the use of nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). We aimed to assess soft-tissue changes in participants with HIV who had virological failure of a first-line antiretroviral (ART) regimen containing a non-nucleoside reverse transcriptase inhibitor plus two N(t)RTIs and were randomly assigned to receive a second-line regimen containing a boosted protease inhibitor given with either N(t)RTIs or raltegravir., Methods: Of the 37 sites that participated in the randomised, open-label, non-inferiority SECOND-LINE study, eight sites from five countries (Argentina, India, Malaysia, South Africa, and Thailand) participated in the body composition substudy. All sites had a dual energy x-ray absorptiometry (DXA) scanner and all participants enrolled in SECOND-LINE were eligible for inclusion in the substudy. Participants were randomly assigned (1:1), via a computer-generated allocation schedule, to receive either ritonavir-boosted lopinavir plus raltegravir (raltegravir group) or ritonavir-boosted lopinavir plus two or three N(t)RTIs (N[t]RTI group). Randomisation was stratified by site and screening HIV-1 RNA. Participants and investigators were not masked to group assignment, but allocation was concealed until after interventions were assigned. DXA scans were done at weeks 0, 48, and 96. The primary endpoint was mean percentage and absolute change in peripheral limb fat from baseline to week 96. We did intention-to-treat analyses of available data. This substudy is registered with ClinicalTrials.gov, number NCT01513122., Findings: Between Aug 1, 2010, and July 10, 2011, we recruited 211 participants into the substudy. The intention-to-treat population comprised 102 participants in the N(t)RTI group and 108 participants in the raltegravir group, of whom 91 and 105 participants, respectively, reached 96 weeks. Mean percentage change in limb fat from baseline to week 96 was 16·8% (SD 32·6) in the N(t)RTI group and 28·0% (37·6) in the raltegravir group (mean difference 10·2%, 95% CI 0·1-20·4; p=0·048). Mean absolute change was 1·04 kg (SD 2·29) in the N(t)RTI group and 1·81 kg (2·50) in the raltegravir group (mean difference 0·6, 95% CI -0·1 to 1·3; p=0·10)., Interpretation: Our findings suggest that for people with virological failure of a first-line regimen containing efavirenz plus tenofovir and lamivudine or emtricitabine, the WHO-recommended switch to a ritonavir-boosted protease inhibitor plus zidovudine (a thymidine analogue nucleoside reverse transcriptase inhibitor) and lamivudine might come at the cost of peripheral lipoatrophy. Further study could help to define specific groups of people who might benefit from a switch to an N(t)RTI-sparing second-line ART regimen., Funding: The Kirby Institute and the Australian National Health and Medical Research Council., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: WHO-recommended second-line antiretroviral therapy (ART) of a pharmacologically enhanced (boosted) protease inhibitor plus nucleoside or nucleotide reverse transcriptase inhibitors (NtRTIs) might be compromised by resistance. Results of the 96 week SECOND-LINE randomised trial showed that NtRTI-sparing ART with ritonavir-boosted lopinavir and raltegravir (raltegravir-group) provided non-inferior efficacy to ritonavir-boosted lopinavir and two or three NtRTIs (NtRTI-group) in participants with virological failure composed of a first-line regimen of a non-nucleoside reverse transcriptase inhibitor plus two NtRTIs. We report the relation of baseline virological resistance with virological failure and emergent resistance on study., Methods: As part of the randomised open-label SECOND-LINE trial, second-line ART NtRTI selection was made by either genotype (local laboratory) or algorithm. Genotypic resistance for the entire cohort at baseline was assessed on stored samples at a central laboratory. Virological failure was defined as plasma viral load greater than 200 copies per mL. Baseline viral isolates were assigned genotypic sensitivity scores (GSSs) by use of the Stanford HIV Database version 6.3.1: a global GSS (gGSS), defined as the combined GSS for lamivudine or emtricitabine, abacavir, zidovudine, stavudine, didanosine, and tenofovir and a specific GSS (sGSS) defined as the GSS for the ART regimen initiated by a specific participant. Emergent resistance was reported on samples with a viral load greater than 500 copies per mL. We used multivariate logistic regression with backward elimination to assess predictors of virological failure and emergent resistance., Findings: From April 19, 2010, to July 22, 2013, 271 patients were included in the NtRTI group and and 270 in the raltegravir group. In the NtRTI group 215 had available baseline sequence data, and 240 had viral load measurements at 96 weeks; in the raltegravir group 236 had baseline sequence data and 255 had viral load measurements at 96 weeks. Median (IQR) gGSS was 3.0 (1.3-4.3) in the NtRTI group and 3.0 (1.0-4.3) in the raltegravir group. The median sGSS in the NtRTI group was 1.0 (0.5-1.8). Multivariate analysis showed significant associations between virological failure and less than complete adherence at week 4 (odds ratio [OR] 2.18, 95%CI 1.07-4.47; p=0·03) and week 48 (2.49, 1.09-5.69; p=0.03), baseline plasma viral load greater than 100,000 copies per mL (3.43, 1.70-6.94; p=0.0006), baseline gGSS >4.25 (4.73, 1.94-11.6; p=0.0007), and being Hispanic (3.13, 1.21-8.13; p=0.02) or African (3.49, 1.68-7.28; p=0.0008) rather than Asian. We observed emergent major mutations in one (1%) of 129 participants for protease (both groups), eight (13%) of 64 for reverse transcriptase (NtRTI group) and 16 (20%) of 79 for integrase. Emergent resistance was associated with the raltegravir group (OR 2.47, 95% CI 1.02-5.99; p=0.05), baseline log10 viral load (1.83, 1.12-2.97; p=0.02), and absence of the Lys65Arg (K65R) or Lys70Glu (K70E) mutation at baseline (3.18, 1.12-9.02; p=0.03)., Interpretation: Poor adherence was a major determinant of virological failure in people on second-line ART. In settings with limited resources, investment in optimisation of adherence rather than implementation of drug resistance testing might be advisable., Funding: University of New South Wales Australia, Merck, AbbVie, and the Foundation for AIDS Research., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: There have been improvements in combination antiretroviral therapy (cART) over the past 15 years. The aim of this analysis was to assess whether improvements in ART have resulted in improvements in surrogates of HIV outcome., Methods: Patients in the Australian HIV Observational Database who initiated treatment using mono/duo therapy prior to 1996, or using cART from 1996 onwards, were included in the analysis. Patients were stratified by era of ART initiation. Median changes in CD4(+) T-cell count and the proportion of patients with detectable HIV viral load (>400 copies/ml) were calculated over the first 4 years of treatment. Probabilities of treatment switch were estimated using the Kaplan-Meier method., Results: A total of 2,753 patients were included in the analysis: 28% initiated treatment <1996 using mono/duo therapy and 72% initiated treatment ≥1996 using cART (30% 1996-1999, 12% 2000-2003, 11% 2004-2007 and 19% ≥2008). Overall CD4(+) T-cell count response improved by later era of initiation (P<0.001), although 2000-2003 CD4(+) T-cell count response was less than that for 1996-1999 (P=0.007). The average proportion with detectable viral load from 2 to 4 years post-treatment commencement by era was: <1996 mono/duo 0.69 (0.67-0.71), 1996-1999 cART 0.29 (0.28-0.30), 2000-2003 cART 0.22 (0.20-0.24), 2004-2007 cART 0.09 (0.07-0.10) and ≥2008 cART 0.04 (0.03-0.05). Probability of treatment switch at 4 years after initiation decreased from 53% in 1996-1999 to 29% after 2008 (P<0.001)., Conclusions: Across the five time-periods examined, there have been incremental improvements for patients initiated on cART, as measured by overall response (viral load and CD4(+) T-cell count) and also increased durability of first-line ART regimens.

Objective: To compare bone mineral density (BMD) changes over 96 weeks in adults virologically failing standard first-line therapy, randomized to raltegravir plus lopinavir/ritonavir (RAL + LPV/r) or conventional 2-3 nucleoside/nucleotide reverse transcriptase inhibitors [N(t)RTIs] + LPV/r second-line therapy., Methods: Participants underwent dual-energy x-ray absorptiometry at baseline and weeks 48 and 96 to measure total hip and lumbar spine BMD. Analyses were adjusted for gender, body mass index, and smoking. Linear regression was used to compare between-group differences, logistic regression for low BMD (hip or spine Z-score ≤ -2) incidence, and multivariate linear regression to determine predictors of BMD change. This work represents the extension and final results of the previously published initial 48 weeks of the study., Results: The population included 210 adults from 5 middle-income countries: 52% females, 52% Asians, 43% Africans, mean age, 39 years (SD, 8 years). In the 2-3 N(t)RTI group (vs. RAL), BMD reduction was greater at the spine (mean change, -4.9% vs. -3.5%; adjusted difference, -1.9%; 95% confidence interval: -3.3 to -0.5%, P = 0.009) and hip (-4.1% vs. -2.2%; -1.9%; -3.4 to -0.4; P = 0.012). BMD decrease was greatest at 48 weeks with stabilization to week 96. Overall, low BMD occurred in 15 participants (7.9%), with no between-group differences. Independent predictors for bone loss included lower body mass index (regression coefficient: hip, -0.18% and spine, -0.26% per 1 kg/m), longer tenofovir exposure (hip, -0.74% and spine, -1.0% per year), greater change in CD4 to week 12 (hip, -5.11% per 10-fold higher), and higher baseline HIV-RNA (spine, -0.7% per 10-fold higher)., Conclusions: Over 96 weeks, there was greater BMD decrease with 2-3 N(t)RTI + LPV/r compared with RAL + LPV/r; the relative decrease at the spine was greater than the hip. BMD decreases with second-line antiretroviral therapy largely occurred in the first 48 weeks with stabilization, but no recovery thereafter.

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.

Objective: To compare changes over 48 weeks in body fat, lipids, Metabolic Syndrome and cardiovascular disease risk between patients randomised 1:1 to lopinavir/ritonavir (r/LPV) plus raltegravir (RAL) compared to r/LPV plus 2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) as second-line therapy., Methods: Participants were HIV-1 positive (>16 years) failing first-line treatment (2 consecutive HIV RNA >500 copies/mL) of NNRTI +2N(t)RTI. Whole body dual energy x-ray absorptiometry was performed at baseline and week 48. Data were obtained to calculate the Metabolic Syndrome and Framingham cardiovascular disease (CVD) risk score. Linear regression was used to compare mean differences between arms. Logistic regression compared incidence of metabolic syndrome. Associations between percent limb fat changes at 48 weeks with baseline variables were assessed by backward stepwise multivariate linear regression. Analyses were adjusted for gender, body mass index and smoking status., Results: 210 participants were randomised. The mean (95% CI) increase in limb fat over 48 weeks was 15.7% (5.3, 25.9) or 0.9 kg (0.2, 1.5) in the r/LPV+N(t)RTI arm and 21.1% (11.1, 31,1) or 1.3 kg (0.7, 1.9) in the r/LPV+RAL arm, with no significant difference between treatment arms (-5.4% [-0.4 kg], p>0.1). Increases in total body fat mass (kg) and trunk fat mass (kg) were also similar between groups. Total:HDL cholesterol ratio was significantly higher in the RAL arm (mean difference -0.4 (1.4); p = 0.03), there were no other differences in lipid parameters between treatment arms. There were no statistically significant differences in CVD risk or incidence of Metabolic Syndrome between the two treatment arms. The baseline predictors of increased limb fat were high viral load, high insulin and participant's not taking lipid lowering treatment., Conclusion: In patients switching to second line therapy, r/LPV combined with RAL demonstrated similar improvements in limb fat as an N(t)RTI + r/LPV regimen, but a worse total:HDL cholesterol ratio over 48 weeks., Trial Registration: This clinical trial is registered on Clinicaltrials.gov, registry number NCT00931463 http://clinicaltrials.gov/ ct2/show/NCT00931463?term = NCT00931463&rank = 1.

Background: In the Asia-Pacific region many countries have adopted the WHO's public health approach to HIV care and treatment. We performed exploratory analyses of the factors associated with first major modification to first-line combination antiretroviral therapy (ART) in resource-rich and resource-limited countries in the region., Methods: We selected treatment naive HIV-positive adults from the Australian HIV Observational Database (AHOD) and the TREAT Asia HIV Observational Database (TAHOD). We dichotomised each country's per capita income into high/upper-middle (T-H) and lower-middle/low (T-L). Survival methods stratified by income were used to explore time to first major modification of first-line ART and associated factors. We defined a treatment modification as either initiation of a new class of antiretroviral (ARV) or a substitution of two or more ARV agents from within the same ARV class., Results: A total of 4250 patients had 961 major modifications to first-line ART in the first five years of therapy. The cumulative incidence (95% CI) of treatment modification was 0.48 (0.44-0.52), 0.33 (0.30-0.36) and 0.21 (0.18-0.23) for AHOD, T-H and T-L respectively. We found no strong associations between typical patient characteristic factors and rates of treatment modification. In AHOD, relative to sites that monitor twice-yearly (both CD4 and HIV RNA-VL), quarterly monitoring corresponded with a doubling of the rate of treatment modifications. In T-H, relative to sites that monitor once-yearly (both CD4 and HIV RNA-VL), monitoring twice-yearly corresponded to a 1.8 factor increase in treatment modifications. In T-L, no sites on average monitored both CD4 & HIV RNA-VL concurrently once-yearly. We found no differences in rates of modifications for once- or twice-yearly CD4 count monitoring., Conclusions: Low-income countries tended to have lower rates of major modifications made to first-line ART compared to higher-income countries. In higher-income countries, an increased rate of RNA-VL monitoring was associated with increased modifications to first-line ART.

Objective: Combination antiretroviral therapy (cART) has greatly improved the life expectancy of people living with HIV (PLHIV). Our study aims to project the life expectancy of PLHIV in a resource-rich setting in the context of the currently available antiretroviral treatments., Methods: Patient antiretroviral treatment data were sourced from an observational cohort of 3434 predominantly male (94.2%) PLHIV in Australia over the period 1997-2010. These data were analyzed in a computer simulation model to calculate the distribution of time until exhaustion of all treatment options and expected effect on mortality. Standardized mortality ratios were used to simulate expected survival before and after treatment exhaustion., Results: We estimated that the median time until exhaustion of currently available treatment options is 45.5 years [interquartile range (IQR) 34.0-61.0 years]. However, 10% of PLHIV are expected to exhaust all currently available cART options after just 25.6 years. PLHIV who start currently available cART regimens at age 20 years are expected to live to a median age of 67.4 (IQR 53.2-77.7) years. This is a substantial improvement on no cART [27.7 (IQR 23.8-32.0) years] but is still substantially less than the median general population mortality age [82.2 (IQR 74.0-87.8) years]. The life expectancy gap between PLHIV and the general population is greatest for those infected at younger ages., Conclusion: As treatment options are exhausted, a substantial difference in life expectancy between PLHIV and the general population could be expected even in resource-rich settings, particularly for people who acquire HIV at a younger age or who are currently highly treatment experienced.

The unprecedented, successful collaborative international effort to provide universal access to HIV care, including effective antiretroviral therapy, has reached a crucial point. Global economic downturn, changing donor priorities, and competing priorities in the health sector threaten the target of provision of 15 million people with HIV/AIDS with treatment by 2015, as agreed by the UN General Assembly. This aspiration has received added impetus from the finding that treatment prevents transmission by reduction of infectiousness of patients. In this report we critically review success thus far and examine efforts to optimise delivery of HIV care including antiretroviral therapy in low-income and middle-income countries for four main domains: treatment strategy, drug dosing, monitoring, and service delivery., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: New antiretroviral drug classes provide opportunities to explore novel regimens., Methods: HIV+ adults (<50 copies/mL) receiving atazanavir (ATV) were randomized to raltegravir (RAL) 400 mg + ATV 300 mg twice daily (q12h) for 4 weeks followed by RAL 800 mg + ATV/ritonavir 300/100 mg once daily (q24h) for 4 weeks or vice versa. Validated assays quantitated RAL and ATV plasma concentrations. Primary endpoint was geometric mean ratio (GMR) of ATV minimum concentration (Cmin) for q24h/q12h. Equivalence was 90% confidence interval (CI) of GMR lying between 0.80 and 1.25. Participants could consent to a total 48-week follow-up., Results: Twenty-five men, mean age 45 (range, 35-57) years, were evaluated. ATV and RAL demonstrated considerable pharmacokinetic variability. There was no period or sequence effect for pharmacokinetic parameters (P > 0.1 all measures). Ninety percent CIs of ATV GMR C(min) [1.30 (90% CI: 1.08 to 1.58)] and RAL GMR C(min) [0.48 (90% CI: 0.31 to 0.75)] demonstrated nonequivalence. Seventy-six percent consented to follow-up. There were no serious adverse events and no discontinuations due to adverse events over 48 weeks; HIV RNA remained undetectable., Conclusions: In virologically suppressed adults, regimens comprising ATV plus RAL were efficacious and safe. ATV q12h troughs were lower than ritonavir-boosted atazanavir q24h; RAL q24h troughs were lower than q12h.

Objective: The optimum selection and sequencing of combination antiretroviral therapy to maintain viral suppression can be challenging. The HIV Resistance Response Database Initiative has pioneered the development of computational models that predict the virological response to drug combinations. Here we describe the development and testing of random forest models to power an online treatment selection tool., Methods: Five thousand, seven hundred and fifty-two treatment change episodes were selected to train a committee of 10 models to predict the probability of virological response to a new regimen. The input variables were antiretroviral treatment history, baseline CD4 cell count, viral load and genotype, drugs in the new regimen, time from treatment change to follow-up and follow-up viral load values. The models were assessed during cross-validation and with an independent set of 50 treatment change episodes by plotting receiver-operator characteristic curves and their performance compared with genotypic sensitivity scores from rules-based genotype interpretation systems., Results: The models achieved an area under the curve during cross-validation of 0.77-0.87 (mean = 0.82), accuracy of 72-81% (mean = 77%), sensitivity of 62-80% (mean = 67%) and specificity of 75-89% (mean = 81%). When tested with the 50 test cases, the area under the curve was 0.70-0.88, accuracy 64-82%, sensitivity 62-80% and specificity 68-95%. The genotypic sensitivity scores achieved an area under the curve of 0.51-0.52, overall accuracy of 54-56%, sensitivity of 43-64% and specificity of 41-73%., Conclusion: The models achieved a consistent, high level of accuracy in predicting treatment responses, which was markedly superior to that of genotypic sensitivity scores. The models are being used to power an experimental system now available via the Internet.

Purpose of Review: Access to second-line therapy in low- and middle-income countries has been limited to date. The WHO predicts that between 500 000 and 800 000 HIV-infected people on first-line combination antiretroviral therapy will require switch to second-line therapy by 2010. This paper aims to describe and review access to second-line therapy in low- and middle-income countries at present and examine future possibilities., Recent Findings: The majority of HIV-infected patients failing first-line combination antiretroviral therapy is identified by way of routine monitoring of clinical and immunological status as a surrogate for virological monitoring. Evidence suggests that immunological and clinical monitoring lack both sensitivity and specificity for virological failure. Consequently, at treatment failure, patients have often selected a degree of resistance within the nucleoside/nucleotide reverse transcriptase inhibitor class that questions the efficacy of using nucleoside/nucleotide reverse transcriptase inhibitors in a second-line regimen. There is a paucity of good-quality evidence on which to base guidelines and policy. Optimally, a second-line regimen would be simple, potent, tolerable and lend itself to provision according to the successful 'public health' approach., Summary: Provision of second-line therapy to HIV-infected individuals failing first-line therapy is a major challenge to the ongoing success of access to HIV care programmes in low- and middle-income countries. The optimal second-line combination antiretroviral therapies are unknown. Research trials to help define best practice are in advanced stages of development and implementation.

Despite the success of combination antiretroviral therapy (ART) in improving clinical outcomes, treatment failure remains a significant challenge, particularly for highly treatment-experienced patients. This review evaluates current issues in the management of HIV-infected, treatment-experienced patients. It may provide guidance in selecting active, tolerable drug combinations that promote a reasonable quality of life, full adherence and a durable treatment response. Current treatment guidelines and clinical trial data were reviewed to identify reasons for treatment failure and to summarize therapy options for treatment-experienced and highly treatment-experienced patients. Current treatment options include nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and inhibitors of viral fusion, entry and integration. The use of NRTIs may be limited by resistance and short- and long-term toxicities. Resistance has restricted the NNRTI class with cross-resistance preventing their sequential use. Etravirine, a next-generation NNRTI, however, demonstrates effective virological suppression in patients with baseline NNRTI resistance. Boosted PIs are key components of ART for treatment-experienced patients. The newer boosted PIs tipranavir and darunavir have demonstrated impressive activity in patients with resistance to NRTIs, NNRTIs and PIs, as well as in less treatment-experienced patients for darunavir. The fusion inhibitor enfuvirtide has demonstrated efficacy in heavily treatment-experienced patients, although injection-site reactions can be problematical. The recently approved integrase inhibitor raltegravir has also shown impressive potency and tolerability in highly treatment-experienced patients. Finally, the entry inhibitor maraviroc has also been approved recently, although its use is somewhat limited by the need for HIV tropism testing. The availability of potent next-generation PIs, NNRTIs, integrase and entry-inhibitors may offer improved therapy for treatment-experienced patients, including those with multiresistant virus. These new drugs may reduce HIV immunological and clinical progression and in doing so may also reduce treatment costs.

It is not fully elucidated whether patients who receive antiretroviral therapy (ART) can maintain continued CD4 count increases. Previous studies suggested a plateau 2-4 years after treatment initiation. We aimed to characterize the evolution of CD4 counts in HIV-infected individuals receiving long-term suppressive ART, by performing a retrospective study of patients who maintained viral suppression (HIV RNA <400 copies/ml) for > or =5 years. We used linear regression models to determine for each individual whether the CD4 count continued to increase or plateau. Furthermore, we estimated whether the slope of the CD4 count for each individual became zero, which we defined as the CD4 set-point. We assessed factors associated with continued CD4 count rise, reaching a CD4 set-point and time to the CD4 set-point. Fifty-nine patients were included. The median baseline CD4 count was 238 (IQR, 120-360) cells/microl and the median duration on ART was 7.6 (IQR, 5.9-9.3) years. On ART, CD4 count continued to increase in 37 subjects (63%). Significant predictors of continued CD4 count increase included a lower baseline log10 HIV RNA (OR, 0.35; 95% CI, 0.14-0.89; p=0.026) and a shorter duration on ART (OR, 0.65; 95% CI, 0.47-0.91; p=0.021). Twenty-four (41%) subjects reached a set-point after a median 4.3 (IQR 1.8-6.4) years on ART. A lower baseline CD4 percentage was associated with both a longer time to reach the CD4 set-point and a lower CD4 count at the CD4 set-point. These findings suggest that CD4 count may continue to increase in some patients after several years of ART. Our results point to an advantage to commencing ART at higher CD4+ T cell strata. These data should be considered when estimating the optimal time to initiate ART.

Purpose of Review: The introduction of combination antiretroviral therapy (cART) led to substantial reductions in HIV-associated morbidity and mortality. However, the regimens in the early cART era were cumbersome and toxic. The introduction of new ART agents, fixed-dose combinations and novel strategies for cART delivery such as ritonavir 'boosting' of HIV-protease inhibitors have led to a perception of improvements in the tolerability and durability of contemporary cART regimens. It is in turn assumed that these developments have led to improved outcomes in the latter era of cART., Recent Findings: Both cohort studies and randomized clinical trials suggest improvements in cART outcomes over calendar time. Key associated factors include reduced pill burden and dosing interval and improved tolerability and reduced toxicity of newer ART. A critical appreciation of the association between ART adherence and regimen durability has been important. Cohorts in recent times have included more patients who are completely ART-naïve at therapy initiation., Summary: The prognosis of HIV infection in developed countries is in the order of 40 years after cART initiation. An appreciation of the factors associated with long-term control of HIV viraemia is essential for the optimal management of the HIV-infected individual in contemporary practice.

Combination antiretroviral therapy (ART) has dramatically altered the prognosis of individuals infected with HIV. In the past 5 years there has been a concerted effort to increase access to ART in the developing world. The evidence to date suggests that adherence to therapy and clinical outcomes in developing world programmes are at least the equal of those observed in developed countries. Although access to first-line therapy is reasonably well established, there is a substantial and unacceptable mortality rate in the first 6 months after initiation of ART, particularly in those with low CD4 cell counts and late-stage disease. Failure of first-line ART is inevitable in a proportion of patients. Access to second-line ART regimens in developing countries is problematic, mainly because of the expense of HIV protease inhibitors (PIs). Access to second-line ART may be facilitated by novel strategies using the existing recommended agents or by the use of new agents or classes. Refinement of programmes in the developing world must be underpinned by the same rigorous scientific research effort that has characterized the success of the effort in the developed world. Therefore, the funding bodies responsible for the roll-out of antiretroviral access across the globe must mandate, incorporate and fund clinical research as an intrinsic aspect of combination ART roll-out programmes.

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

Background: Addition of efavirenz (600 mg) to indinavir/ritonavir (800/100 mg) results in significant decreases in indinavir levels in healthy volunteers. This study evaluated the steady-state pharmacokinetics of indinavir/ritonavir at 800/100 mg twice daily (bid) in combination with efavirenz at 600 mg once daily (qd) in HIV-infected Thai subjects who used this nucleoside-sparing combination in The HIV Netherlands Australia Thailand Research Collaboration 009 study., Methods: At week 4 of the study, 12-hour pharmacokinetic profiles for indinavir/ritonavir were obtained for 20 HIV-infected subjects. For efavirenz, the concentrations at 12 hours and 24 hours (Cmin) after dosing were assessed., Results: All subjects (10 males and 10 females) completed the study. The geometric mean area under the concentration versus time curve, Cmin, and maximum plasma concentration of indinavir were 45.7 mg/(L. h) (95% confidence interval [CI], 39.8-52.5), 0.32 mg/L (95% CI, 0.24-0.44), and 11.1 mg/L (95% CI, 9.4-13.0), respectively. A >10-fold variation in indinavir Cmin was observed. All subjects had an indinavir Cmin that was at least comparable with the reported mean population Cmin of indinavir at 800 mg thrice daily without ritonavir (0.15 mg/L). The geometric mean concentration at 12 hours and Cmin of efavirenz were 3.1 mg/L (95% CI, 2.5-3.7) and 2.1 mg/L (95% CI, 1.6-2.6), respectively., Conclusions: Despite the known pharmacokinetic interaction between efavirenz and indinavir/ritonavir, the combination of indinavir/ritonavir at 800/100 mg bid and efavirenz at 600 mg qd results in adequate minimum concentrations of both indinavir and efavirenz for treatment-naive patients.

Background: The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study has developed predictive risk scores for cardiovascular disease (CVD) and chronic kidney disease (CKD, defined as confirmed estimated glomerular filtration rate [eGFR] ≤ 60 ml/min/1.73 m2) events in HIV-positive people. We hypothesized that participants in D:A:D at high (>5%) predicted risk for both CVD and CKD would be at even greater risk for CVD and CKD events.Methods and Findings: We included all participants with complete risk factor (covariate) data, baseline eGFR > 60 ml/min/1.73 m2, and a confirmed (>3 months apart) eGFR < 60 ml/min/1.73 m2 thereafter to calculate CVD and CKD risk scores. We calculated CVD and CKD event rates by predicted 5-year CVD and CKD risk groups (≤1%, >1%-5%, >5%) and fitted Poisson models to assess whether CVD and CKD risk group effects were multiplicative. A total of 27,215 participants contributed 202,034 person-years of follow-up: 74% male, median (IQR) age 42 (36, 49) years, median (IQR) baseline year of follow-up 2005 (2004, 2008). D:A:D risk equations predicted 3,560 (13.1%) participants at high CVD risk, 4,996 (18.4%) participants at high CKD risk, and 1,585 (5.8%) participants at both high CKD and high CVD risk. CVD and CKD event rates by predicted risk group were multiplicative. Participants at high CVD risk had a 5.63-fold (95% CI 4.47, 7.09, p < 0.001) increase in CKD events compared to those at low risk; participants at high CKD risk had a 1.31-fold (95% CI 1.09, 1.56, p = 0.005) increase in CVD events compared to those at low risk. Participants' CVD and CKD risk groups had multiplicative predictive effects, with no evidence of an interaction (p = 0.329 and p = 0.291 for CKD and CVD, respectively). The main study limitation is the difference in the ascertainment of the clinically defined CVD endpoints and the laboratory-defined CKD endpoints.Conclusions: We found that people at high predicted risk for both CVD and CKD have substantially greater risks for both CVD and CKD events compared with those at low predicted risk for both outcomes, and compared to those at high predicted risk for only CVD or CKD events. This suggests that CVD and CKD risk in HIV-positive persons should be assessed together. The results further encourage clinicians to prioritise addressing modifiable risks for CVD and CKD in HIV-positive people. [ABSTRACT FROM AUTHOR]

A number of antiviral agents used against Human Immunodeficiency Virus (HIV) infection and hepatitis B virus (HBV) mono or co-infection have been associated with real nephrotoxicity (including tenofovir disoproxil fumarate (TDF), atazanavir, indinavir and lopinavir) or apparent changes in renal function (e.g. cobicistat, ritonavir, rilpivirine and dolutegravir). Patients with HIV are at higher risk of acute and chronic renal dysfunction, so baseline assessment and ongoing monitoring of renal function is an important part of routine management of patients with HIV. Given the paucity of evidence in this area, we sought to establish a consensus view on how routine monitoring could be performed in Australian patients on ART regimens, especially those involving TDF. A group of nephrologists and prescribers (an HIV physician and a hepatologist) were assembled by Gilead to discuss practical and reasonable renal management strategies for patients particularly those on TDF-based combination regimens (in the case of those with HIV-infection) or on TDF-monotherapy (in the case of HBV-mono infection). The group considered which investigations should be performed as part of routine practice, their frequency, and when specialist renal referral is warranted. The algorithm presented suggests testing for serum creatinine along with plasma phosphate and an assessment of urinary protein (rather than albumin) and glucose. Here we advocate baseline tests of renal function at initiation of therapy. If creatinine excretion inhibitors (e.g. cobicistat or rilpivirine) are used as part of the ART regimen, we suggest creatinine is rechecked at 4 weeks and this value used as the new baseline. Repeat testing is suggested at 3-monthly intervals for a year and then at least yearly thereafter if no abnormalities are detected. In patients with abnormal baseline results, renal function assessment should be performed at least 6 monthly. In HBV mono-infected patients advocate that a similar testing protocol may be logical. [ABSTRACT FROM AUTHOR]