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HIV-infected patients are at increased risk of nonalcoholic steatohepatitis (NASH). Vitamin E is recommended for treatment of NASH in the general population. However, its safety and efficacy among HIV-infected patients remain unknown.Single-centre, phase IV, open-label, single arm clinical trial.HIV mono-infected patients without significant alcohol intake or viral hepatitis coinfection were included. The diagnosis of NASH was based on the co-existence of fatty liver, diagnosed by controlled attenuation parameter (CAP) at least 248 dB/m and significant hepatocyte apoptosis, defined by the serum biomarker cytokeratin 18 (CK-18) greater than 130.5 U/L. Participants were treated with 800 IU daily of oral vitamin E (alpha-tocopherol) for 24 weeks, and followed for an additional 24 weeks postdiscontinuation. Generalized linear mixed effects models were used to evaluate changes in alanine aminotransferase (ALT), CAP and CK-18 at the completion of treatment and end of follow-up, controlling for pretreatment trends.A total of 27 patients were included. Four (15%) had a pretreatment liver biopsy, which confirmed the diagnosis of NASH in all cases. Compared with baseline, 24 weeks of vitamin E treatment improved ALT [-27 units/l; 95% confidence interval (CI) -37 to -17], CAP scores (-22 dB/m; 95% CI -42 to -1) and CK-18 (-123 units/l; 95% CI -201 to -46). Conversely, there was no change in BMI. No serious adverse event was reported and no patient was lost to follow-up.In this first clinical trial, we showed that vitamin E is an effective and well tolerated treatment for NASH in HIV-infected patients.

Supplemental Digital Content is available in the text, Objective: Hepatitis C virus (HCV) treatment may reduce liver-related mortality but with competing risks, other causes of mortality may undermine benefits. We examined changes in cause-specific mortality among HIV–HCV coinfected patients before and after scale-up of HCV treatment. Design: Prospective multicentre HIV–HCV cohort study in Canada. Methods: Cause-specific deaths, classified using a modified ‘Coding of Cause of Death in HIV’ protocol, were determined for two time periods, 2003–2012 and 2013–2017, stratified by age (20–49; 50–80 years). Comparison of trends between periods was performed using Poisson regression. To account for competing risks, multinomial regression was used to estimate the cause-specific hazard ratios of time and age on cause of death, from which end-stage liver disease (ESLD)-specific 5-year cumulative incidence functions were estimated. Results: Overall, 1634 participants contributed 8248 person-years of follow-up; 273 (17%) died. Drug overdose was the most common cause of death overall, followed by ESLD and smoking-related deaths. In 2013–2017, ESLD was surpassed by drug overdose and smoking-related deaths among those aged 20–49 and 50–80, respectively. After accounting for competing risks, comparing 2003–2012 to 2013–2017, ESLD deaths declined (adjusted hazards ratio: 0.18, 95% confidence interval 0.05–0.62). However, both early and late period cumulative incidence functions demonstrated increased risk of death from ESLD for patients with poor HIV control and advanced fibrosis. Conclusion: The gains made in overall mortality with HCV therapy may be thwarted if modifiable harms are not addressed. Although ESLD-related deaths have decreased over time, treatment should be further expanded, prioritizing those with advanced fibrosis.

To identify potential pathways by which a variety of factors act to lead to unsuppressed viral load.A prospective cohort of HIV-HCV co-infected adults receiving care from 18 HIV clinics across Canada was followed every 6 months between November 2012 and October 2015. Participants with at least two visits while receiving combined antiretroviral treatment (cART) were included.A path analysis was conducted on the basis of ordered sequences of multivariate logistic regressions using generalized estimating equations. The first regression model used incomplete viral suppression (viral load50 copies/ml) as the outcome of interest and all other variables (i.e. nonadherence, food insecurity, treatment attributes, and other sociodemographic, behavioural, and clinical factors) as potential predictors. Any variable determined to be a statistically significant predictor of incomplete viral suppression was then used as the next outcome of interest in the subsequent regression, until all predictors of each selected outcome were purely explanatory variables.A total of 566 participants had at least two visits. Drivers of incomplete viral suppression included injection drug use, age 45 years or less, living alone, poor health status, longer duration of HIV infection and baseline CD4 cell count less than 200 cells/μl. Nonadherence, food insecurity, and the use of multitablet regimens mediated the effects of these factors on incomplete viral suppression.Our results suggest that nonadherence, multitablet regimens, and food insecurity are key points in the pathway to incomplete HIV suppression. These are potentially amenable intervention targets that would not be revealed using traditional regression analyses.

Supplemental Digital Content is available in the text, Objective: To examine the impact of sustained virologic response (SVR) and illicit (injection and noninjection) drug use on kidney function among hepatitis C virus (HCV) and HIV co-infected individuals. Design: Longitudinal observational cohort study of HCV-HIV co-infected patients. Methods: Data from 1631 patients enrolled in the Canadian Co-Infection Cohort between 2003 and 2016 were analyzed. Patients who achieved SVR were matched 1 : 2 with chronically infected patients using time-dependent propensity scores. Linear regression with generalized estimating equations was used to model differences in estimated glomerular filtration rates (eGFR) between chronic HCV-infected patients and those achieving SVR. The relationship between illicit drug use and eGFR was explored in patients who achieved SVR. Results: We identified 384 co-infected patients who achieved SVR (53% treated with interferon-free antiviral regimens) and 768 propensity-score matched patients with chronic HCV infection. Most patients were men (78%) and white (87%), with a median age of 51 years (interquartile range: 45–56). During 1767 person-years of follow-up, 4041 eGFR measurements were available for analysis. Annual rates of decline in eGFR were similar between patients with SVR [−1.32 (ml/min per 1.73 m2)/year, 95% confidence interval (CI) −1.75 to −0.90] and chronic infection [−1.19 (ml/min per 1.73 m2) per year, 95% CI −1.55 to −0.84]. Among SVR patients, recent injection cocaine use was associated with rapid eGFR decline [−2.16 (ml/min per 1.73 m2)/year, 95% CI −4.17 to −0.16]. Conclusion: SVR did not reduce the rate of kidney function decline among HCV–HIV co-infected patients. Increased risk of chronic kidney disease in co-infection may not be related to persistent HCV replication but to ongoing injection cocaine use.

OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. HIV-infected persons without viral hepatitis are at increased risk of NAFLD. Nevertheless, data on NAFLD in HIV monoinfection are scarce. DESIGN/METHODS We prospectively investigated prevalence and predictors of NAFLD and liver fibrosis by transient elastography and associated controlled attenuation parameter (CAP) in unselected HIV-infected adults without significant alcohol intake or viral hepatitis coinfection. NAFLD was defined as CAP at least 238 dB/m. Significant liver fibrosis and cirrhosis were defined as transient elastography measurement at least 7.1 and 13 kPa, respectively. Predictors of NAFLD and significant liver fibrosis were determined using logistic regression analysis. RESULTS A total of 300 consecutive patients (mean age 50 years, 77% men; mean CD4 cell count 570 cells/μl, 90% on antiretrovirals) were included as a part of a routine screening program. Transient elastography with CAP identified NAFLD and significant liver fibrosis in 48 and 15% of cases, respectively. NAFLD was independently associated with BMI more than 25 kg/m [adjusted odds ratio (aOR) 4.86, 95% confidence interval (CI) 2.55-9.26] and elevated alanine aminotransferase (ALT) (aOR 3.17, 95% CI 1.43-7.03). Independent predictors of significant liver fibrosis were diabetes (aOR 5.84, 95% CI 1.91-17.85), elevated ALT (aOR 3.30, 95% CI 1.27-8.59) and current use of protease inhibitors (aOR 3.96, 95% CI 1.64-9.54). CONCLUSION NAFLD and significant liver fibrosis diagnosed by transient elastography with CAP are major comorbidities in unselected HIV monoinfected persons on antiretroviral therapy, particularly if metabolic conditions and elevated ALT coexist. Noninvasive screening for NAFLD should be implemented in this population to establish early interventions and prevent complications.

Objective Recent studies suggest all-cause mortality in HIV mono-infected patients approaches that of the general population. We aimed to compare participants in the Canadian Co-infection Cohort to the general population to determine if co-infected patients have had similar improvements in mortality. Design Prospective multicentre cohort study. Methods Between 2003 and 2013, deaths were captured using specific case reports and through linkage to provincial vital statistics for participants lost to follow-up. Standardized mortality ratios (SMRs) were calculated using age, sex and province-specific mortality rates from the Canadian Human Mortality Database, 2009, and compared across behavioural and clinical characteristics of participants at their most recent visit. Results Among the 1150 patients, we observed 133 deaths over 3351 person-years (4.0 per 100 person-years, 95% confidence interval 3.3, 4.6). SMRs (95% confidence interval) were: 12.1(10.1, 14.2) overall; 9.3 (7.5, 11.1) for men and 19.4 (12.7, 26.2) for women. CD4 cell counts below 200 cells/μl [25.5 (17.7, 33.3)], active injection drug use [19.9 (13.9, 25.9)] and smoking [14.9 (12.1, 17.7)] were strongly associated with excess mortality. Lowest SMRs were seen for those who had spontaneous [4.5 (-0.6, 9.5)] or treatment-induced clearance of hepatitis C virus (HCV) infection [5.1 (1.3, 8.8)]. Conversely, high SMRs were seen with advanced liver disease [17.0 (11.7, 22.3)]. In no category did SMRs approach mortality seen in the general Canadian population. Conclusions HIV-HCV co-infected persons remain at markedly increased risk for death despite antiretroviral therapy. Interventions targeting modifiable risk factors such as substance use, smoking, adherence to antiretrovirals and timely provision of HCV therapy could substantially reduce death rates.

Objective Hepatitis C virus (HCV) infection is associated with higher insulin levels and insulin resistance. We evaluated factors associated with insulin resistance in a cohort of HIV/HCV-coinfected patients and determined the effect of insulin resistance on the development of hepatic fibrosis. Methods Data were analysed from 158 nondiabetic participants in a prospective Canadian cohort of HIV/HCV-coinfected patients. Patients were defined as having insulin resistance using the homeostasis model for assessment of insulin resistance (HOMA-IR) index. Factors associated with a high index (HOMA-IR ≥ 2) were identified using multivariate logistic regression. Incidence rates of liver fibrosis [aspartate aminotransferase- to-platelet ratio index (APRI) ≥ 1.5] were calculated, and multivariate time-dependent Cox regression models used to assess the effect of baseline insulin resistance on the risk of developing an APRI score of at least 1.5 during follow-up. Results Overall, 56% had baseline HOMA-IR of at least 2. In the adjusted multivariate logistic analysis, only baseline BMI of more than 25 kg/m2 remained associated with insulin resistance [adjusted odds ratio 3.66, 95% confidence interval (CI) 1.70-7.92]. Rates of progression to significant hepatic fibrosis (APRI ≥ 1.5) were higher in those with HOMA-IR of at least 2 (16.32 per 100 person-years, 95% CI 6.68-25.97) compared with those with HOMA-IR less than 2 (7.95 per 100 person-years, 95% CI 0.16-15.75). Baseline HOMA-IR of at least 2 was associated with the development of significant fibrosis (adjusted hazard ratio 7.71, 95% CI 2.55-23.36).

Objectives: The relative success of liver transplantation in those with HIV compared to HIV-uninfected individuals remains a point of intense debate. We aimed to evaluate the effectiveness of liver transplantation in HIV-hepatitis co-infected patients using a meta-analysis and individual patient data meta-analysis as a synthetic cohort. Methods: We searched MEDLINE via PubMed, EMBASE, Cochrane CENTRAL, AIDS-LINE (inception to 2010), AMED, CINAHL, TOXNET, Development and Reproductive Toxicology, Hazardous Substances Databank, Psych-info and relevant conferences. We included cohort studies and individual case-reports evaluating survival of co-infected transplant patients. We abstracted data on cohort and case demographics and outcomes. We pooled cohorts using a random-effects analysis and created a synthetic cohort of cases using individual patient data. We confirmed this with the pooled cohort analysis. Results: We included 15 cohort studies and 49 case series with individual patient data. At 12 months, 84.4% [95% confidence interval (CI) 81.1-87.8%] of patients had survived. Within the HIV-infected population evaluated, HIV-hepatitis B virus (HBV) co-infection was associated with optimal survival. In an adjusted model, individuals positive for HBV were 8.28 (95% CI 2.26-30.33) times more likely to survive when compared to those without HBV. Further, individuals with an undetectable HIV viral load at the time of transplantation were 2.89 (95% CI 1.41-5.91) times more likely to survive when compared to those with detectable HIV viremia. Hepatitis C virus was not a predictor of patient survival when adjusted for by other key predictors [0.54 (95% CI 0.17-1.80)].

OBJECTIVE HIV is known to have a negative impact on the progression of hepatitis C virus (HCV) infection, whereas the reverse remains unclear. We examined the impact of spontaneous clearance of HCV on CD4(+) T-lymphocyte count progression before and after initiation of antiretroviral therapy (ART) in HIV-HCV coinfected adults. METHODS Data were analysed from participants in a Canadian, multisite prospective cohort of HIV-infected adults with serologic evidence of HCV infection. The rate of CD4(+) T-lymphocyte change was determined using multivariate mixed linear regression comparing chronically HCV RNA+ with spontaneous clearers (persistently HCV RNA- without HCV therapy). RESULTS Baseline characteristics of the 271 participants analysed did not differ between individuals whose HCV RNA cleared (n = 35) and those whose HCV RNA persisted (n = 236) except with respect to markers of liver disease. HCV RNA+ individuals had on average seven-times slower recovery of CD4(+) T-cells on chronic ART compared with HCV RNA-: (adjusted change in absolute CD4 cell T-lymphocyte count per year: 4 (95% confidence interval, -0.6 to 8) cells/microl vs. 26 (95% confidence interval, 12 to 41) cells/microl; P < 0.001. Analyses restricted to individuals initiating ART showed similar results. There was also a trend to greater CD4 decline prior to ART initiation among those HCV RNA+, although this did not reach statistical significance. CONCLUSION We found that CD4 cell progression is negatively affected by the presence of ongoing HCV replication in coinfected individuals initiating ART which persisted throughout stable ART suggesting active HCV infection affects immune restoration even after years of ART exposure.

BACKGROUND: The impact of antiretroviral therapy (ART) interruption in HIV-hepatitis B virus (HBV)-coinfected patients was examined in the Strategic Management of AntiRetroviral Therapy (SMART) study. METHODS: Plasma HBV DNA was measured in all hepatitis B surface antigen-positive (HBV-positive) participants at baseline, and at months 1, 2, 4, 6, 8, 10, and 12. RESULTS: Among HBV-positive participants in the ART interruption (drug conservation) (n = 72) and ART continuation (virological suppression) (n = 62) arms, HBV DNA rebound of more than 1 log from baseline at months 1-4 was seen in 31-33% (P = 0.003) and 3-4% (P = 0.017), respectively. Thirteen HBV-positive participants had HBV DNA rebound of more than 3 log, including 12 in the drug conservation arm, of which eight were on tenofovir-containing regimens. Factors independently associated with a HBV DNA rebound were drug conservation arm (P = 0.0002), nondetectable HBV DNA at baseline (P = 0.007), and black race (P = 0.03). Time to ART reinitiation was shorter (7.5, 15.6, and 17.8 months; P < 0.0001) and proportion reinitiating greater (62.5, 46.5, and 39.7%; P = 0.0002) among HBV-positive participants as compared with hepatitis C virus-positive and non-HBV/hepatitis C virus participants in the drug conservation arm. No hepatic decompensation events occurred among HBV-positive participants in either arm. CONCLUSION: HBV DNA rebound following ART interruption is common and may be associated with accelerated immune deficiency in HIV-HBV-coinfected patients

Objectives: To determine whether the initial use of non-nucleoside reverse transcriptase inhibitors (NNRTI) or protease inhibitors (PI) differentially influences subsequent HIV therapy. Design: A cohort study using a prospective clinical database in a university-based HIV clinic. Subjects: A total of 440 HIV-seropositive patients, naive or nucleoside experienced, initiating therapy with either an NNRTI or PI between January 1998 and July 2003 and followed to December 2003. Main outcome measures: Time until stopping the first regimen and until exposure to all antiretroviral classes (excluding tenofovir and enfuvirtide) according to the type of initial regimen. Results: A total of 291 subjects initiated HAART with PI and 149 with NNRTI; median follow-up 3.1 and 2.3 years, respectively. Subjects starting NNRTI remained on their initial regimens longer (median time to change 2.1 versus 1.6 years; log rank P = 0.03). Overall, subjects initiating NNRTI-based regimens were less likely to alter their therapy. Previous nucleoside exposure was an important predictor of treatment modification. Subjects initiating NNRTI-based HAART were also less likely to experience virological failure than those initiating PI-based HAART. Individuals starting with NNRTI were exposed to fewer regimens (15 versus 25% received three or fewer regimens), and showed a trend towards lower rates of three-class exposure (7 versus 12%). Conclusion: There is a high rate of treatment modification among patients initiating HAART. The initial use of NNRTI-based HAART was associated with more durable treatment and lower rates of virological failure, which may translate into a reduced need for multiple salvage therapies.

Supplemental Digital Content is available in the text, Objective: To examine the association between injection cocaine use, hepatitis C virus (HCV) infection, and chronic renal impairment (CRI). Design: Prospective observational cohort study of HIV–HCV coinfected patients. Methods: Data from 1129 participants in the Canadian Co-Infection Cohort with baseline and follow-up serum creatinine measurements between 2003 and 2014 were analyzed. Prevalent and incident cohorts were created to examine the association between self-reported past, current, and cumulative cocaine use and chronic HCV with CRI. CRI was defined as an estimated glomerular filtration rate below 70 ml/min per 1.73 m2. Multivariate logistic regression was used to calculate odds ratios, and discrete-time proportional-hazards models were used to calculate hazard ratios for cocaine use, in the two respective cohorts, adjusted for HCV RNA and important demographic, HIV disease stage, and comorbidity confounders. Results: Eighty-seven participants (8%) had prevalent CRI. Past injection cocaine use was associated with a two-fold greater risk of prevalent CRI [odds ratio 2.03, 95% confidence interval (CI) 0.96, 4.32]. During follow-up, 126 of 1061 participants (12%) developed incident CRI (31 per 1000 person-years). Compared to nonusers, heavy (≥ 3 days/week) and frequent injection cocaine users (≥75% of follow-up time) experienced more rapid progression to CRI (hazard ratio 2.65, 95% CI 1.35, 5.21; and hazard ratio 1.82, 95% CI 1.07, 3.07, respectively). There was no association between chronic HCV and CRI in either cohort. Conclusion: After accounting for HCV RNA, frequent and cumulative injection cocaine abuse was associated with CRI progression and should be taken into consideration when evaluating impaired renal function in HIV–HCV coinfection.