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[Para. 1 of Introduction]: Migration is shaping societies around the world. It has long defined settler countries, such as Canada; it is affecting communities of departure and return, ranging from the Azores to Zimbabwe; and it is increasingly impacting countries that have traditionally not considered themselves as major immigrant destinations, like many European countries. Meanwhile, individual migrants and their families experience departure, migration, and arrival differently than the communities shaped by them. From both societal and individual perspectives, we can ask whether migration accomplishes what it promises to achieve. Does migration contribute to the economic, social, and cultural well-being of societies? Do migrants and their families find a pathway to security, achieve social and economic upward mobility, and gain opportunities to participate in the political and cultural life of their arrival communities? The Promise of Migration addresses these questions through a critical lens.

Canada’s population of immigrant youth between the ages of 15 and 35 is approaching 3 million and growing rapidly. Youth are critical to Canada’s goal of recruiting immigrants to expand the economy, but there is insufficient information about their school and work experiences and inadequate support to ensure their successful integration into the workforce. This literature review investigates the connection between education and work for Canadian immigrant youth. It documents obstacles in the form of underfunded settlement services, lack of diversity in the school curriculum, inadequate English-language instruction at all levels of schooling, racially and ethnically biased streaming of students into the lowest educational track in high school, rejection of foreign school transcripts and work credentials, employers’ prejudice and discrimination, and workplace exploitation. The number and magnitude of these systemic impediments create significant obstacles for immigrant youth. A major cause of these issues is insufficient funding for immigrant services under neoliberal economic policies. The outcomes for immigrant youth include failure to finish secondary and postsecondary education, a long-term cycle of employment in low-skill, low-wage jobs, and socioeconomic hardship such as poverty and homelessness. The authors call for greater attention to this critical population and make nine recommendations that would contribute to solutions in each major issue area impacting the education of Canadian immigrant youth and their entry into the workforce.

Through six intensive and semi-structured interviews, this research paper examines the role social support networks may or may not have played in facilitating the resettlement experiences of Chinese-Vietnamese refugees living in Canada after the Vietnam War. It was observed that those who were privately-sponsored emphasized the instrumental role their benefactors played in assisting their successful resettlement, whereas those who were government-sponsored were forced to adopt a more independent mindset of forming their own social support systems. Regardless of sponsorship type, the notion of hard work was a commonality found amongst the participants. They arrived at the receiving country expecting and willing to accept conditions of underemployment and downward mobility. The effects of pre-migration enabling factors such as marital status and educational attainment are also acknowledged. Within a social support framework, theories of social capital and resiliency are used to analyze the lives of the participants after the traumatic experience of forced migration.

Background It is unknown if the greater reductions in bone mineral density (BMD) associated with initiation of tenofovir disoproxil fumarate compared with abacavir in previously untreated HIV-infected participants in the ACTG A5224s clinical trial were associated with potentially worsening tenofovir-related phosphaturia. Methods We correlated changes in BMD at the hip and spine with changes in phosphaturia [transtubular reabsorption of phosphorus (TRP) and tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR)] from entry through week 96 in those initiating tenofovir ( n = 134) versus abacavir ( n = 135) with efavirenz or atazanavir/ritonavir in A5224s. We also correlated changes in BMD with tenofovir AUC measured between weeks 4 and 24. Results Changes in TRP and TmP/GFR through week 96 between the tenofovir and abacavir arms were not significantly different (both P ≥ 0.70) and did not differ with use of efavirenz versus atazanavir/ritonavir. There were no significant correlations between changes in either TRP or TmP/GFR and with either hip or spine BMD in the tenofovir arms. Tenofovir AUC was significantly correlated with changes in hip BMD, but not spine BMD, at week 24 ( r = -0.22, P = 0.028) and week 48 ( r = -0.26, P = 0.010), but not at week 96 ( r = -0.14, P = 0.18). Conclusions Changes in phosphaturia were not different between the tenofovir and abacavir arms in A5224s. Changes in hip and spine BMD with tenofovir were not related to changes in phosphaturia. However, tenofovir exposure was weakly associated with changes in hip BMD through week 48.

Objectives Both renal disease and systemic inflammation predict non-AIDS-defining events and overall mortality in HIV-infected patients. Here, we sought to determine the relationships between renal disease and circulating inflammation markers. Methods We performed a secondary analysis of AIDS Clinical Trials Group Study A5224s to determine if markers of renal disease [urine protein:creatinine ratio (uPCR), urine albumin:creatinine ratio (uACR), and estimated glomerular filtration rate (eGFR), using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine and cystatin C-creatinine] were associated with markers of systemic inflammation [high-sensitivity C-reactive protein, interleukin-6, tumour necrosis factor (TNF)-α, soluble TNF-α receptor I (sTNFRI), sTNFRII, and soluble vascular cellular and intercellular adhesion molecules]. We correlated these renal and inflammatory markers prior to antiretroviral initiation and after 96 weeks of therapy. Results We found that eGFR (estimated using CKD-EPI cystatin C-creatinine), uPCR, and uACR were significantly correlated with most assessed markers of systemic inflammation prior to antiretroviral initiation. uPCR and eGFR (using CKD-EPI cystatin C-creatinine), but not uACR, remained significantly correlated with most of the assessed inflammatory markers after 96 weeks of antiretroviral therapy (ART). Most of these correlations, although statistically significant, were

Lower peak bone mass in early adulthood predicts subsequent fragility fractures. Antiretroviral toxicity could contribute to young HIV-infected individuals not achieving adequate peak bone mass.To determine if tenofovir disoproxil fumarate's (TDF) effect on bone mineral density (BMD) differs by age.We examined BMD data at the lumbar spine and hip from AIDS Clinical Trials Group (ACTG) A5224s and ASSERT and randomized treatment-naive studies comparing TDF/emtricitabine versus abacavir/lamivudine (with efavirenz or atazanavir/ritonavir). In this post hoc analysis, we defined the TDF effect as the difference between mean 48-week BMD per cent changes for lumbar spine and hip in individuals randomized to TDF versus abacavir. We used multivariable linear regression to compare the TDF effect in individuals younger and older than 30 years. If TDF effect by age did not differ significantly between studies, we pooled study populations. Otherwise, analyses were conducted separately within each study population.Among 652 subjects, 21% were below age 30 years. The relationship between age and TDF effect significantly differed between A5224s and ASSERT (P = 0.008 for lumbar spine; P = 0.007 for hip). In A5224s, there was more bone loss with TDF at lumbar spine and hip in subjects under 30 years old versus in older subjects ( - 4.5% vs - 1.4%; P = 0.045; - 4.3% vs - 1.6%; P = 0.026, respectively). There was no significant evidence for this age-associated TDF effect in ASSERT.There was heterogeneity in the observed effect of TDF on bone density in young adults compared to older adults, suggesting that further investigation is required to understand the impact of age on BMD decline with TDF.

Decreased bone mineral density (BMD) and osteoporotic fractures are areas of increasing concern among HIV-infected persons. Particular concern is the rapid decline in BMD after initiation of antiretroviral treatment (ART). This report describes DEXA-assessed changes in BMD and body fat in a study of fifteen antiretroviral-na?ve adults initiating abacavir/lamivudine and raltegravir for 96 weeks. Median percent changes from baseline at weeks 48 and 96 in BMD were 0.29% and -0.11% (spine); -1.25% and -1.75% (left hip). Median percent changes from baseline in fat from baseline were -0.82% and -3.04% (trunk); 2.12% and 2.01% (limb). In this pilot study, ABC/3TC + RAL treatment had limited impact on BMD and body fat.

Objective Body composition impacts physical function and mortality. We compared long-term body composition changes after antiretroviral therapy (ART) initiation in HIV-infected individuals to that in HIV-uninfected controls. Design Prospective observational study. Methods We performed dual-energy x-ray absorptiometry (DXA) approximately 7.5 years after initial DXA in available HIV-infected individuals who received DXAs during the randomized treatment trial AIDS Clinical Trials Group A5202. For controls, we used DXA results from HIV-uninfected participants in the Boston Area Community Health/Bone and Women's Interagency HIV Study cohorts. Repeated measures analyses compared adjusted body composition changes between HIV-infected and HIV-uninfected individuals. Multivariable analyses evaluated factors associated with body composition change in HIV-infected individuals. Results We obtained DXA results in 97 HIV-infected and 614 HIV-uninfected participants. Compared with controls, HIV-infected individuals had greater adjusted lean mass and total, trunk, and limb fat gain during the first 96 weeks of ART. Subsequently, HIV-infected individuals lost lean mass compared with controls. Total, trunk, and limb fat gains after 96 weeks of ART slowed in HIV-infected individuals but remained greater than in controls. Lower CD4 T-cell count was associated with lean mass and fat gain during the initial 96 weeks of ART, but subsequently no HIV-related characteristic was associated with body composition change. Conclusion Consistent with a 'return to health effect', HIV-infected individuals, especially those with lower baseline CD4 T-cell counts, gained more lean mass and fat during the first 96 weeks of ART than HIV-uninfected individuals. Continued fat gain and lean mass loss after 96 weeks may predispose HIV-infected individuals to obesity-related diseases and physical function impairment.

OBJECTIVE To compare the effect that initiating different antiretroviral therapy (ART) regimens has on weight, BMI, and lean body mass (LBM) and explore how changes in body composition are associated with bone mineral density (BMD). METHODS A5224s was a sub-study of A5202, a prospective trial of 1857 ART-naive participants randomized to blinded abacavir-lamivudine (ABC/3TC) or tenofovir DF-emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV/r). All participants underwent dual-energy absorptiometry (DXA) and abdominal computed tomography for body composition. Analyses used two-sample t-tests and linear regression. RESULTS A5224s included 269 participants: 85% men, 47% white non-Hispanic, median age 38 years, HIV-1 RNA 4.6 log10 copies/ml, and CD4 cell count 233 cells/μl. Overall, significant gains occurred in weight, BMI, and LBM at 96 weeks post-randomization (all P

We compared adjusted bone mineral density (BMD) changes between human immunodeficiency virus (HIV)-infected individuals during the first approximately 7.5 years after antiretroviral therapy (ART) initiation and HIV-uninfected controls. HIV-infected individuals (n = 97) had significantly greater adjusted BMD decline than controls (n = 614) during the first 96 weeks of ART. Subsequently, the rate of BMD decline slowed in HIV-infected individuals but remained greater than the rate of decline in HIV-uninfected individuals at the lumbar spine but not at the hip. In HIV-infected individuals after 96 weeks, no HIV- or treatment-related characteristic was associated with BMD loss, but lower lean body mass was associated with greater BMD loss at both lumbar spine and hip.

The effect of specific antiretrovirals on inflammation is unclear.A5224s was a substudy of A5202, which randomized HIV-infected treatment-naïve patients to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in a factorial design. Our analysis compared changes in inflammation markers from baseline to week 24 between ABC/3TC and TDF/FTC. Secondary analyses included changes at week 96 and comparisons of EFV vs. ATV/r.Analyses included 244 patients (85% male, 48% white non-Hispanic), median age 39 years, HIV-1 RNA 4.6 log10 copies/ml, CD4 240 cells/μl. TNF-α, soluble receptors of TNF-α (sTNFR)-I and II, soluble vascular cellular adhesion molecule (sVCAM)-1 and soluble intercellular adhesion molecule (sICAM)-1 decreased significantly at weeks 24 and 96, without significant differences between components (P ≥ 0.44). At week 24, ABC/3TC had a greater high-sensitivity C-reactive protein (hsCRP) mean fold change than TDF/FTC {1.43 vs. 0.88, estimated mean fold change percentage difference [Δ] 61.5% [95% confidence interval (CI) 13.6%, 129.5%]; P = 0.008}. Similar results were seen at week 96 (P = 0.021). At week 24 (but not 96), EFV had a greater hsCRP mean fold change than ATV/r [1.41 vs. 0.88; Δ = 60.2% (12.6%, 127.7%); P = 0.009]. IL-6 decreased significantly at week 24 with TDF/FTC but not with ABC/3TC (between-components P = 0.019). At week 96, IL-6 decreased significantly in both nucleoside reverse transcriptase inhibitor components (between-components P = 0.11). IL-6 changes were not significantly different between ATV/r and EFV at either time point (P ≥ 0.89).Soluble TNF-receptors and adhesion molecules decreased following treatment initiation and did not differ by regimens. Differences were seen on hsCRP and IL-6 changes with ABC/3TC vs. TDF/FTC and on hsCRP with EFV vs. ATV/r.

Background: Managing hypertriglyceridemia in HIV-infected patients often requires multiple pharmacologic strategies. Many protease inhibitors (PIs), one of 6 classes of drugs used to treat HIV, have been associated with hypercholesterolemia and drug interactions. For this study, we examined a dual strategy to manage hypertriglyceridemia in HIV-infected patient taking PIs: 1) switching patients to fosamprenavir (FPV), a PI with fewer drug interactions, and 2) adding prescription fish oil (LOVAZA(R)), which has been shown to reduce triglycerides. Methods: This multicenter, 24-week study enrolled 36 patients virologically suppressed (HIV-1 RNA

(See the editorial commentary by Yin and Overton, on pages 1705–7.) Background. Long-term effects of abacavir (ABC)–lamivudine (3TC), compared with tenofovir (TDF)–emtricitabine (FTC) with efavirenz (EFV) or atazanavir plus ritonavir (ATV/r), on bone mineral density (BMD) have not been analyzed. Methods. A5224s was a substudy of A5202, in which HIV-infected treatment-naive participants were randomized and blinded to receive ABC-3TC or TDF-FTC with open-label EFV or ATV/r. Primary bone end points included Dual-emission X-ray absorbtiometry (DXA)-measured percent changes in spine and hip BMD at week 96. Primary analyses were intentto-treat. Statistical tests used the factorial design and included linear regression, 2-samplet, log-rank, and Fisher’s exact tests. Results. Two hundred sixty-nine persons randomized to 4 arms of ABC-3TC or TDF-FTC with EFV or ATV/r. At baseline, 85% were male, and 47% were white non-Hispanic; the median HIV-1 RNA load was 4.6 log10 copies/ mL, the median age was 38 years, the median weight was 76 kg, and the median CD4 cell count was 233 cells/lL. At week 96, the mean percentage changes from baseline in spine and hip BMD for ABC-3TC versus TDF-FTC were -1.3% and -3.3% (P 5 .004) and -2.6% and -4.0% (P 5 .024), respectively; and for EFV versus ATV/r were -1.7% and -3.1% (P 5 .035) and -3.1% and -3.4% (P 5 .61), respectively. Bone fracture was observed in 5.6% of participants. The probability of bone fractures and time to first fracture were not different across components. Conclusions. Compared with ABC-3TC, TDF-FTC–treated participants had significantly greater decreases in spine and hip BMD, whereas ATV/r led to more significant losses in spine, but not hip, BMD than EFV. Clinical Trials Registration. NCT00118898.

In HBV/HIV-coinfected patients, the risk of end-stage liver disease and death is increased. This open-label, prospective, pilot study evaluated abacavir/lamivudine/zidovudine twice daily plus tenofovir once daily in HBV/HIV- coinfected antiretroviral-naive subjects. Nine adults (8 males) enrolled, with baseline mean HIV-1 RNA = 4.5 log10 copies/mL, HBV DNA = 9.0 log10 copies/mL, and median CD4 count =158 cells/mm 3 . No subject had baseline ALT >5x ULN. Six subjects completed the study: 1 withdrew due to non-treatment-related toxoplasmosis and 2 were lost-to-follow-up. At week 48, 100% (6/6) of remaining subjects had � 2 log10 decrease in HBV DNA, and 100% (6/6) and 83% (5/6) had HIV- 1 RNA

(2010). Simplified Maintenance Therapy With Abacavir/Lamivudine and Atazanavir After Discontinuation of Ritonavir. HIV Clinical Trials: Vol. 11, No. 3, pp. 170-173.

Background HIV clonal genotypic analysis (CG) was used to investigate whether a more sensitive analysis method would detect additional low-abundance mutations compared with population genotyping (PG) in antiretroviral-naive patients who experienced virological failure (VF) during treatment with abacavir/lamivudine/zidovudine and tenofovir. Methods HIV was analysed by PG and CG (771 baseline and 657 VF clones) from subjects with VF (confirmed HIV RNA ≥ 400 copies/mL at 24–48 weeks). Results Fourteen of 123 subjects (11%) met VF criteria; their median baseline HIV RNA was 5.4 log10 copies/mL, and 4.0 log10 copies/mL at VF. By baseline PG, 2/14 had HIV-1 with nucleoside reverse transcriptase inhibitor (NRTI) or non-NRTI mutations. By baseline CG, 9/14 had HIV-1 with NNRTI and/or NRTI mutations; 7/9 had study drug-associated mutations. By PG at VF, 10/14 had selected for resistance mutations [2, K65R; 1, M184V; and 7, thymidine analogue mutations (TAMs) ± M184V]. By CG at VF, for subjects with TAMs, T215F was more commonly detected (5/14 samples) than T215Y (2/14). For one subject who selected K65R at VF, both K65R-containing clones and TAM-containing clones (both T215A and T215F) were observed independently but not conjunctively in the same clone in a post-VF sample. Conclusions The majority of subjects with VF had major and minor mutations detected at VF; CG detected additional low-abundance variants at baseline and VF that could have influenced mutation selection pathways. Both PG and CG data suggest TAMs, not K65R selection, are the preferred resistance route, biased towards 215F selection. No HIV clone contained both K65R and T215F/Y mutations, suggesting in vivo antagonism between the two mutations. The once-daily zidovudine usage and high baseline viraemia may also have contributed to rapid selection of HIV with multiple mutations in VFs.

OBJECTIVE: Concern for potential adverse effects of antiretroviral (ARV) chemotherapy used to prevent mother-to-child HIV transmission has led the US Public Health Service to recommend long-term follow-up of ARV-exposed children. Nucleoside reverse transcriptase inhibitor ARV agents can inhibit DNA polymerase γ, impairing mitochondrial DNA (mtDNA) synthesis and resulting in depletion or dysfunction.METHODS: We measured the mtDNA content of stored peripheral blood mononuclear cells (PBMCs) of 411 healthy children who were born to HIV-uninfected women and 213 uninfected infants who were born to HIV-infected women with or without in utero and neonatal ARV exposure. Cryopreserved PBMC mtDNA was quantified by using the Primagen Retina Mitox assay.RESULTS: Geometric mean PBMC mtDNA levels were lower at birth in infants who were born to HIV-infected women. Among HIV-exposed children, mtDNA levels were lowest in those who were not exposed to ARVs, higher in those with exposure to zidovudine alone, and higher still in those with combination nucleoside reverse transcriptase inhibitor exposure. A similar pattern was observed in the corresponding women. Levels of mtDNA increased during the first 5 years of life in all HIV-exposed children but achieved normal levels only in those with ARV exposure.CONCLUSIONS: Levels of mtDNA are lower than normal in HIV-exposed children. Contrary to expectation, PBMC mtDNA levels are significantly higher in ARV-exposed, HIV-uninfected infants and their infected mothers compared with ARV-unexposed infants and women. By 5 years, levels of PBMC mtDNA rise to normal concentrations in ARV-exposed children but remain depressed in ARV-unexposed children.

BACKGROUND Antiretroviral therapy (ART) is associated with improved kidney function; however, the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) has been associated with decreased kidney function and proteinuria. METHODS We examined changes in urine protein:creatinine (UPCR) and urine albumin:creatinine (UACR) ratios in 245 ART-naive participants in A5202 randomized in a substudy to blinded NRTI (abacavir/lamivudine, ABC/3TC, n = 124 or TDF/emtricitabine, TDF/FTC, n = 121) with open-label protease inhibitor (PI) atazanavir/ritonavir or nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz. RESULTS At baseline, 18% of participants had clinically significant proteinuria (UPCR ≥200 mg/g), and 11% had clinically significant albuminuria (UACR ≥30 mg/g). The prevalence of clinically significant proteinuria and albuminuria decreased from baseline to week 96 in all treatment groups. In intention-to-treat analyses, there was a significant effect of NRTI component on fold change in UPCR (P = 0.011) and UACR (P = 0.018) from baseline to week 96, with greater improvements in participants randomized to ABC/3TC. There was no significant effect of NNRTI/PI component on fold change in UPCR (P = 0.23) or UACR (P = 0.88), and no significant interactions between NRTI and NNRTI/PI components. CONCLUSIONS In this prespecified secondary analysis, ART initiation was associated with improvements in proteinuria and albuminuria, with significantly greater improvements in participants randomized to ABC/3TC versus TDF/FTC. These are the first data from a randomized trial to suggest that initiation of TDF/FTC may not be associated with the same degree of improvement in proteinuria and albuminuria that have been reported with other regimens. Future studies should consider the long-term clinical significance of these findings.

Background The association of inflammatory biomarkers with clinical events after antiretroviral therapy initiation is unclear. Methods A5202 randomized 1857 treatment-naive subjects to abacavir/lamivudine or tenofovir-DF/emtricitabine with efavirenz or atazanavir/ritonavir. Substudy A5224s measured inflammatory biomarkers on subjects with available plasma from baseline and week 24 or 96. An exploratory analysis of the association of high-sensitivity C-reactive protein, interleukin-6 (IL-6), soluble receptors of tumor necrosis factor α (sTNF)-RI, sTNF-RII, TNF-α, soluble vascular cellular adhesion molecules (sVCAM-1), and soluble intercellular adhesion molecules (sICAM-1) with times to AIDS and to non-AIDS events used Cox proportional hazards models. Results Analysis included 244 subjects; 85% men and 48% white non-Hispanic with median age 39 years, HIV-1 RNA of 4.6 log10 copies per milliliter, and CD4 of 240 cells per microliter. Overall, 13 AIDS events (9 opportunistic infections, 3 AIDS-cancers, and 1 recurrent bacterial pneumonia) and 18 non-AIDS events (6 diabetes, 4 cancers, 3 cardiovascular, and 5 pneumonias) occurred. Higher baseline IL-6, sTNF-RI, sTNF-RII, and sICAM-1 were significantly associated with increased risk of AIDS-defining events. Adjustment for baseline HIV-1 RNA did not change results, whereas adjusting for baseline CD4 count left only sTNF-RI and sICAM-1 significantly associated with increased risk. Time-updated values of IL-6, sTNFR-I and II, and sICAM-1 were also associated with an increased risk. For non-AIDS events, only higher baseline high-sensitivity C-reactive protein was significantly associated with increased risk, whereas higher IL-6 was marginally associated with higher risk. Analyses of time-updated biomarker values showed tumor necrosis factor α to be significantly associated with increased risk, even after adjustment for antiretroviral therapy, and CD4 count or HIV-1 RNA. Conclusions Higher levels of several inflammatory biomarkers were independently associated with increased risk of AIDS and non-AIDS events.

Antiretroviral therapy (ART) may negatively affect renal function through drug toxicity mechanisms [1] or improve renal function by ameliorating the detrimental effects of untreated human immunodeficiency virus (HIV) on the kidney [2, 3]. Several studies have suggested that use of tenofovir disoproxil fumarate is associated with worse changes in estimated glomerular filtration rate (eGFR) compared with other nucleoside reverse-transcriptase inhibitors (NRTIs), and that this effect is magnified with concomitant use of protease inhibitors (PIs) [4–8]. However, not all studies have confirmed this relationship [9–11]. In the AIDS Clinical Trials Group (ACTG) 5202 trial, worse changes in eGFR (estimated as creatinine clearance using the Cockcroft-Gault equation [12]) were found with the use of tenofovir/emtricitabine compared with abacavir/lamivudine, especially when tenofovir/emtricitabine was used in combination with atazanavir/ritonavir [13]. Other observational studies have suggested that the antiretroviral PI combination atazanavir/ritonavir also negatively affects renal function [14, 15]. There is growing interest in the use of serum cystatin C as a new marker of renal function. Compared with serum creatinine, cystatin C is not affected by muscle mass and is completely eliminated by the kidney through glomerular filtration. Perhaps because of this improved ability to measure glomerular filtration, cystatin C seems to have greater utility over creatinine in predicting adverse outcomes in both the general population [16–18] and in the HIV-infected population [19, 20]. As such, newer GFR-estimating equations have been developed using cystatin C, including the 2012 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C equation, which uses cystatin C only without creatinine, and the 2012 CKD-EPI cystatin C-creatinine equation, which incorporates both markers [21]. In the general US population [18], identifying renal dysfunction with the 2012 CKD-EPI cystatin C-creatinine combined equation appears to be more predictive of cardiovascular disease, end stage renal disease, and overall mortality compared with the 2012 CKD-EPI cystatin C equation and the older 2009 CKD-EPI equation [22], the latter of which includes only serum creatinine. A recent study in women infected with HIV suggested that both of the newer 2012 cystatin C-based equations were more accurate than the 2009 CKD-EPI equation in identifying those patients with renal dysfunction with greater risk of mortality [20]. A recent American study using iohexol clearance as the reference measurement of GFR assessed the accuracy of these newer cystatin C-based equations in patients infected with HIV, most of whom were receiving antiretroviral medications, and found that that the 2012 CKD-EPI cystatin C-creatinine combined equation most accurately estimated GFR compared with the 2012 CKD-EPI cystatin C equation and the original 2009 CKD-EPI equation [23]. Another American study corroborated these findings by again finding that the 2012 CKD-EPI cystatin C-creatinine combined equation was more accurate than the other 2 CKD-EPI equations when compared with direct GFR measurement using iohexol clearance [24]. However, in a similar study conducted in Europe, no appreciable differences were found between the combined 2012 CKD-EPI equation and the 2009 CKD-EPI equation [25]. Of note, both of these HIV studies suggest that all 3 CKD-EPI equations were significantly more accurate than the Modification of Diet in Renal Disease (MDRD) equation [22], which is important given that much of our understanding of the effects of antiretrovirals on renal function from observational cohort studies used this latter equation [7, 26]. Therefore, we assessed changes in renal function using 5 different estimating equations in ACTG 5224s, a substudy of ACTG 5202, in which cystatin C was systematically measured, and assessed the nephrotoxicity profiles with commonly used once-daily regimens.

Background The association between abacavir (ABC) and cardiovascular disease (CVD) risk in HIV-infected individuals is unclear. Putative mechanisms for an effect of ABC on CVD risk including endothelial dysfunction have been proposed; however, a biological mechanism has not been established. Methods This was a cross-sectional study of HIV-infected subjects with HIV RNA levels Results There were 148 subjects (46 on ABC, 72 on TDF and 30 on AZT). Demographic characteristics were balanced across the groups except, as expected, AZT-treated participants were older, had higher CD4+ T-cell counts, and longer antiretroviral therapy duration. After adjusting for age, brachial artery diameter, and treatment duration, FMD was similar in those on ABC (3.9%) and TDF (5.4%; P=0.181). FMD was higher in those on AZT (6.1%; PConclusions Among individuals assigned to ABC or TDF in randomized clinical trials there were no significant differences in FMD or markers of inflammation and coagulation. Whether ABC contributes to risk of CVD remains unclear, but our results suggest that endothelial dysfunction, heightened inflammation, and altered coagulation are unlikely to be mechanisms by which the drug could increase CVD risk above that seen with TDF.

Background. We compare the effect of 4 different antiretroviral regimens on limb and visceral fat. Methods. A5224s was a substudy of A5202, a trial of human immunodeficiency virus type 1 (HIV-1)‐infected, treatment-naive subjects randomized to blinded abacavir-lamivudine (ABC-3TC) or tenofovir DF-emtricitabine (TDF-FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV-r). The primary endpoint was the presence of lipoatrophy (R10% loss of limb fat) at week 96 by intent-to-treat (ITT) analysis. Secondary endpoints included changes in limb and visceral fat. Statistical tests included linear regression, binomial, two-sample t test, and Fisher’s exact test. Results. A5224s enrolled 269 subjects; 85% were male, and 47% were white non-Hispanic. The subjects had a median baseline HIV-1 RNA level of 4.6 log10 copies/mL, a median age of 38 years, a median CD41 cell count of 233 cells/lL, median limb fat of 7.4 kg, median visceral adipose tissue (VAT) of 84.1 cm 2 , and VAT: total adipose tissue (TAT) ratio of 0.31. At week 96, estimated prevalence of lipoatrophy (upper 95% confidence interval [CI]) was 18% (25%) for ABC-3TC and 15% (22%) for TDF-FTC (P 5 .70); this was not significantly less than the hypothesized 15% for both (P R .55 for both). The secondary as-treated (AT) analysis showed similar results. At week 96, the estimated mean percentage change from baseline in VAT was higher for the ATV-r group than for the EFV group (26.6% vs 12.4%; P 5 .090 in ITT analysis and 30.0% vs 14.5%; P 5 .10 in AT analysis); however, the percentage change in VAT:TAT was similar by ITT and AT analysis (P R .60 for both). Results were similar for absolute changes in VAT and VAT:TAT. Conclusions. ABC-3TC‐ and TDF-FTC‐based regimens increased limb and visceral fat at week 96, with a similar prevalence of lipoatrophy. Compared to the EFV group, subjects assigned to ATV-r had a trend towards higher mean percentage increase in VAT. Clinical Trials Registration. NCT00118898.

We report the case of an integrase strand-transfer inhibitor (INI)-resistant and four-drug-class-resistant HIV-1 variant infecting an antiretroviral therapy-naive man. The virus harboured INI drug resistance substitutions (Q148H and G140S) along with multiple reverse transcriptase and protease inhibitor resistance mutations. This case illustrates an emerging need to consider the possibility of acquired INI resistance among newly diagnosed treatment-naive individuals harbouring multidrug-resistant HIV-1.

to evaluate raltegravir plus abacavir/lamivudine in antiretroviral-naïve, HIV-1-infected patients.SHIELD is an ongoing 96-week pilot study of abacavir/lamivudine 600 mg/300 mg once daily with raltegravir 400 mg twice daily among HLA-B*5701-negative adults with screening viral load (VL)1,000 copies/mL. HBsAg+ patients were excluded, as were patients with key mutation(s) to any study drug. Virologic failure (VF) was defined as either VL400 copies/mL at week 24 or confirmed virologic rebound.thirty-five patients enrolled (mean age 38.7 years). Most were white males, but 26% self-identified as Hispanic/Latino. At baseline, 34% had VL ≥ 100,000 copies/mL (median, 4.8 log10 copies/mL) and 20% had CD4 cell counts200 cells/mm3 (median, 301). One patient discontinued due to adverse events (AEs); one patient experienced VF. At week 48, 91% (32/35) had VL50 and400 copies/mL by missing/discontinuation equals failure analysis. Median CD4 cell count change from baseline was +247 cells/mm3. Five patients (14%) had treatment-related grade 2-4 AEs; no treatment-related serious AEs were reported. Over 48 weeks, median fasting lipids increased for total (+17%), LDL (+9%), and HDL (+6%) cholesterol but remained stable for triglycerides (-1%) and total:HDL cholesterol ratio (0%).in this pilot study, abacavir/lamivudine plus raltegravir was effective and generally well-tolerated over 48 weeks with modest changes in fasting lipids.

Objectives: To evaluate a potential pharmacodynamic/pharmacokinetic interaction between abacavir (ABC) and tenofovir disoproxil fumarate (TDF). Design and methods: This randomized trial compared 7 days of ABC or TDF monotherapy, separated by a 35-day washout, with 7 days of ABC + TDF dual-therapy in treatment-naive, HIV-1-infected patients. During each 7-day course, the slope of the phase I viral decay was estimated and steady-state intracellular concentrations of carbovir triphosphate (CBV-TP), deoxyguanosine triphosphate (dGTP), tenofovir diphosphate (TFV-DP) and deoxyadenosine triphosphate (dATP) were determined. Results: Twenty-one participants were randomized to initial monotherapy with ABC (n = 11) or TDF (n = 10). The addition of TDF did not increase the slope of viral decay compared to ABC alone (-0.15 log 10 per day vs. -0.16 log 10 per day, respectively). No decrease in CBV-TP or TFV-DP between monotherapy and dual-therapy was observed. However, intracellular dATP concentrations increased between monotherapy and dual-therapy [median dATP (fmol/10 6 cells) 3293 vs. 4638; P=0.08], although this difference was significant only among patients randomized to TDF [median dATP (fmol/ 10 6 cells) 3238 vs. 4534; P= 0.047]. A lower TFV-DP-to-dATP ratio was associated with reduced viral decay during dual-therapy (p=-0.5 29 ; P=0.04 5 ). Conclusion: In this study, the viral decay during ABC and TDF dual-therapy was similar to that during ABC therapy alone, suggesting a nonadditive antiviral effect. This negative pharmacodynamic interaction was not explained by changes in CBV-TP or TFV-DP concentrations. Rather, modest increases in endogenous dATP pools were associated with reduced antiviral potency of TDF during co-administration with ABC.

The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors (NRTIs) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 (HIV-1) infection, but which NRTI combination has greater efficacy and safety is not known.In a randomized, blinded equivalence study involving 1858 eligible patients, we compared four once-daily antiretroviral regimens as initial therapy for HIV-1 infection: abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine plus efavirenz or ritonavir-boosted atazanavir. The primary efficacy end point was the time from randomization to virologic failure (defined as a confirmed HIV-1 RNA levelor = 1000 copies per milliliter at or after 16 weeks and before 24 weeks, oror = 200 copies per milliliter at or after 24 weeks).A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy, according to the NRTI combination, among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more. At a median follow-up of 60 weeks, among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the time to virologic failure was significantly shorter in the abacavir-lamivudine group than in the tenofovir DF-emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P0.001), with 57 virologic failures (14%) in the abacavir-lamivudine group versus 26 (7%) in the tenofovir DF-emtricitabine group. The time to the first adverse event was also shorter in the abacavir-lamivudine group (P0.001). There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48.In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the times to virologic failure and the first adverse event were both significantly shorter in patients randomly assigned to abacavir-lamivudine than in those assigned to tenofovir DF-emtricitabine. (ClinicalTrials.gov number, NCT00118898.)

Screening for HLA-B 5701 reduces the risk of developing an abacavir hypersensitivity reaction (ABC HSR) and is recommended in all patients before initiating highly active antiretroviral therapy (HAART) with abacavir. Between September 2007 and March 2008 we conducted a study of the attitudes and practice patterns of HIV providers in the United States to identify barriers to HLA-B 5701 testing in clinical practice. Study participants who completed an educational program could receive HLA-B 5701 test kits for use in their clinical practice. Surveys were administered before and after the educational program. A total of 477 HIV providers registered to participate in the survey, and 134 providers tested a total of 874 HIV-infected subjects, of which 6% (49/874) were HLA-B 5701 positive. Of 433 providers who completed the preeducation survey, 97% indicated that the test provided clinical value and 77% anticipated barriers to testing, with cost/reimbursement the most frequently cited. Among 202 providers who completed the posteducation survey, perceptions of the test's value remained largely unchanged while the proportion of providers who anticipated or encountered barriers to testing decreased. Of providers who used HLA-B 5701 test kits, 86% (115/134) found it "very easy" or "easy" to obtain test results, 95% (127/134) found it "very easy" or "easy" to interpret results, and 89% (119/134) indicated that they planned to continue HLA-B 5701 testing after the study. The results of this study suggest that HLA-B 5701 testing is easy to use in clinical practice and is a valuable tool to help reduce the risk of developing ABC HSR.

COL40263 was a pilot 48-week, open-label, multicenter study evaluating the efficacy and safety of once-daily coformulated abacavir/lamivudine/zidovudine plus tenofovir in ART-naive, HIV-infected subjects. We examined the patterns of resistance that were selected on-therapy through 48 weeks in subjects with virologic nonresponse (VF). A total of 123 antiretroviral-naive HIV-1-infected subjects with plasma HIV-1 RNAor = 30,000copies/ml were enrolled. For subjects with confirmed VF (HIV-1 RNAor = 400 copies/ml at week 24 or later), HIV population genotypic and phenotypic analysis was performed. Of the 123 enrolled subjects, 14 (11%) had confirmed plasma HIV-1 RNAor = 400 copies/ml through week 48. Of these subjects, 3/14 had evidence of drug resistance at baseline: 2/14 had HIV with K103N, Y188F/H/L/Y, and/or T215A and 1/14 had reduced zidovudine susceptibility. At the last time point analyzed, 4/14 subjects had wild-type HIV, while 10/14 subjects had HIV with either thymidine analogue mutations (TAMS) alone (3/10), TAMS + M184V (4/10), M184V only (1/10), or K65R/K (2/10). Matched phenotype was obtained for 13/14 subjects and 8/13 (62%) subjects had reduced susceptibility to one or more study drugs: 2/13 tenofovir, 3/13 abacavir, 4/13 zidovudine, and 7/13 lamivudine. The resistance pattern in COL40263 subjects with VF differs significantly from that reported for tenofovir-containing triple-nucleoside regimens. TAMs were detected in the majority (7/10) of samples from subjects with VF who selected any resistance mutation. These data suggest that TAMs selection is a preferred resistance route of this combination, with zidovudine modulating the resistance pathway against selection for K65R.

We analyzed virologic response and safety data from six recent clinical studies conducted in antiretroviral-naïve subjects treated with ABC/3TC or its components to assess the impact of baseline viral load on efficacy and safety endpoints used in the ACTG5202 protocol.Primary endpoints were time to virologic failure (confirmed HIV-1 RNAor = 1,000 copies/mL at 16-24 weeks oror = 200 copies/mL ator = 24 weeks) and time to first grade 3 or 4 adverse event or laboratory abnormality that was at least one grade higher than at baseline. The survival distributions of both endpoints were estimated using the Kaplan-Meier method overall and by baseline viral load (100,000 vs. 100,000 copies/mL). A weighted mean of the virologic response and 95% confidence intervals (CI) were calculated by inverse-variance weighting for baseline viral load 100,000 copies/mL across studies.For subjects with baseline HIV-1 RNA 100,000 copies/mL, the rate of virologic survival ranged from 87% to 95% by 48 weeks. Few subjects treated with ABC/3TC developed grade 3 or 4 adverse events, laboratory toxicities, or changes in lipid levels. The weighted mean (CI) for the pooled virologic response was 91% (87%-96%).Based on the A5202 endpoints, ABC/3TC-containing regimens in this analysis had a high rate of virologic survival and were generally well tolerated in antiretroviral-naïve subjects regardless of baseline viral load. The pooled virologic response for ABC/3TC in our analysis is higher than the A5202 estimate.

To assess the safety and efficacy of a 4-drug, 3-tablet, once-daily (qd) regimen consisting of abacavir/lamivudine/zidovudine (ABC/3TC/ZDV; 2 tablets) and tenofovir (TDF) in antiretroviral-naïve patients with plasma HIV-1 RNA 30,000 copies/mL at 48 weeks.All participants received ABC/3TC/ZDV (300/150/300 mg) and TDF (300 mg) qd in this pilot, open-label, multicenter study. Intent-to-treat (ITT) analyses were conducted to evaluate virologic and immunologic efficacy.Of the 123 participants enrolled, 52 (42%) prematurely discontinued study for adverse events (14), were lost to follow-up (13), had virologic nonresponse (12), and withdrew for other reasons (13). At week 48, by ITT missing=failure analysis, 41% (51/123) and 51% (63/123) of participants had plasma HIV-1 RNA50 copies/mL and400 copies/mL, respectively; by ITT-observed analysis, 75% (51/68) and 93% (63/68) had plasma HIV-1 RNA50 copies/mL and400 copies/mL, respectively; 11% (14/123) met virologic nonresponse criteria. Median week 48 change in CD4+ cell count from baseline was +127 cells/mm3. Median week 48 changes from baseline for fasting lipids were as follows: cholesterol (-9 mg/dL), HDL (+1 mg/dL), LDL (-9 mg/dL), and triglycerides (-4 mg/dL).A high rate of premature discontinuations contributed to the overall suboptimal virologic response to ABC/3TC/ZDV+TDF qd; however, the regimen was not associated with high rates of virologic failure previously observed with TDF+ABC/3TC.

The objective of this study was to evaluate the efficacy, tolerability, and safety of fosamprenavir/ritonavir (FPV/r) versus efavirenz (EFV), both in combination with abacavir/lamivudine (ABC/3TC), in a population that is often underrepresented in U.S. clinical trials. Supplement: Abstracts of the Tenth International Congress on Drug Therapy in HIV Infection http://www.biomedcentral.com/content/pdf/1758-2652-13-S4-info.pdf Conference: Tenth International Congress on Drug Therapy in HIV Infection 7-11 November 2010 Glasgow, UK (Published: 8 November 2010) doi:10.1186/1758-2652-13-S4-P7 Cite this article as: Kumar et al.: SUPPORT: 48-week results of fosamprenavir/ritonavir vs efavirenz with abacavir/lamivudine in underrepresented, antiretroviral-naive patients. Journal of the International AIDS Society 2010 13(Suppl 4):P7. Full text: PubMed Central: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113075/