Joseph Cox

Safety and Efficacy of Dolutegravir in Treatment-Experienced Subjects With Raltegravir-Resistant HIV Type 1 Infection: 24-Week Results of the VIKING Study

Background. Dolutegravir (DTG; S/GSK1349572), a human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, has limited cross-resistance to raltegravir (RAL) and elvitegravir in vitro. This phase IIb study assessed the activity of DTG in HIV-1–infected subjects with genotypic evidence of RAL resistance. Methods. Subjects received DTG 50 mg once daily (cohort I) or 50 mg twice daily (cohort II) while continuing a failing regimen (without RAL) through day 10, after which the background regimen was optimized, when feasible, for cohort I, and at least 1 fully active drug was mandated for cohort II. The primary efficacy end point was the proportion of subjects on day 11 in whom the plasma HIV-1 RNA load decreased by ≥0.7 log10 copies/mL from baseline or was <400 copies/mL. Results. A rapid antiviral response was observed. More subjects achieved the primary end point in cohort II (23 of 24 [96%]), compared with cohort I (21 of 27 [78%]) at day 11. At week 24, 41% and 75% of subjects had an HIV-1 RNA load of <50 copies/mL in cohorts I and II, respectively. Further integrase genotypic evolution was uncommon. Dolutegravir had a good, similar safety profile with each dosing regimen. Conclusion. Dolutegravir 50 mg twice daily with an optimized background provided greater and more durable benefit than the once-daily regimen. These data are the first clinical demonstration of the activity of any integrase inhibitor in subjects with HIV-1 resistant to RAL.

Cohort Profile: The Canadian HIV–Hepatitis C Co-infection Cohort Study

Hepatitis C virus (HCV) has emerged as one of the most vexing health problems facing HIV-infected persons. Due largely to injection drug use (IDU),430% of HIV-infected patients are co-infected with HCV in developed countries with 10 million co-infected worldwide. In 1999, 11 194 Canadians were estimated to be co-infected and this number has likely increased substantially since. HCV infection has also increasingly been reported in HIV-positive men having sex with men (MSM) who have not used injection drugs. Since the advent of highly active antiretroviral therapy (HAART) there have been dramatic reductions in morbidity and mortality from virtually all causes of illness among HIV-infected persons. One of the glaring exceptions to this trend is death from end-stage liver disease (ESLD) with rates increasing 4to 8-fold in the post-HAART era. This excess mortality may be due, in part, to improved overall survival associated with HAART, allowing competing morbidities and mortalities that were once rarely observed. In addition, HCVassociated hepatic fibrosis has been shown to progress more rapidly in the context of HIV infection, likely due to immune dysfunction. Several other factors may be at play, including chronic hepatotoxicity related to antiretrovirals, incomplete immune recovery, heavy alcohol use and problems with access and/or adherence to HAART and HCV treatment in a population with high rates of substance use. The growing burden of chronic HCV infection is expected to result in dramatic increases in the rates of cirrhosis, liver failure, hepatocellular carcinoma, transplant needs and related annual healthcare costs in Canada and worldwide. Understanding the complex interplay between sociodemographic factors, substance use, biology and treatments that may affect outcomes in co-infection is necessary to meet the challenge of providing effective

Risk of hepatitis C virus transmission through drug preparation equipment: a systematic and methodological review

Summary.  The use of blood‐contaminated drug preparation equipment is believed to be associated with the transmission of hepatitis C virus (HCV) among injection drug users (IDUs), but the extent of HCV infection risk is unclear. The objective of this review was to appraise the evidence regarding HCV incidence associated with the use of drug preparation equipment such as drug mixing containers, filters and water. In June 2007, cohort and case–control studies examining the association of HCV incidence with the sharing of drug preparation equipment were identified by searching electronic reference databases as well as the reference lists of published papers. Ten studies (seven cohort and three nested case–control) met the inclusion criteria for the review. The relative risk of HCV infection associated with drug preparation equipment were mainly between 2.0 and 5.9; however, the precision of the estimates from individual studies were marked by wide confidence intervals. Few studies exist to allow an adequate assessment of the individual contributions of containers, filters and water to HCV incidence. The major methodological limitations of reviewed studies were short follow‐up times, inadequate control of confounders and lack of exclusion of periods when IDUs were not at risk for HCV infection through drug injection. Current evidence implicating the association of drug preparation equipment with HCV incidence is limited by several methodological concerns.

How Generalizable Are the Results From Trials of Direct Antiviral Agents to People Coinfected With HIV/HCV in the Real World?

Trial results are used to support licensure, inform cost-effectiveness analyses, and guide clinical decision making. We found the majority of coinfected patients were not included in clinical trials of direct-acting antivirals, raising concerns about the generalizability of these trial results.

How generalizable are the results from trials of Direct Antiviral Agents to people coinfected with HIV/Hepatitis C virus in the real world?

Trial results are used to support licensure, inform cost-effectiveness analyses, and guide clinical decision making. We found the majority of coinfected patients were not included in clinical trials of direct-acting antivirals, raising concerns about the generalizability of these trial results.

HIV and hepatitis C virus coinfection in Canada: challenges and opportunities for reducing preventable morbidity and mortality

Hepatitis C virus (HCV) has emerged as an important health problem in the era of effective HIV treatment. However, very few data exist on the health status and disease burden of HIV/HCV‐coinfected Canadians.

Include Them and They Will Tell You: Learnings From a Participatory Process With Youth

Encouraging youth voice, visibility, and active participation in adolescent-related research is strongly advocated in the literature. In this article, we describe how participatory approaches informed by arts-based methods (e.g., reflective writing, dramatization) were used with adolescents to enhance the research process in an exploratory study designed to develop and evaluate prevention resources for sexual risk-taking behaviors.Youth aged 15 to 17 years participated in iterative focus groups conducted over a 1-year period in school settings in Prince Edward Island, Canada. Descriptions of our experiences, strategies, and insights provide evidence for guiding practice to optimize adolescent participation in research.

Early Initiation Rather Than Prolonged Duration of Antiretroviral Therapy in HIV Infection Contributes to the Normalization of CD8 T-Cell Counts

BACKGROUND CD8 T-cell counts remain elevated in human immunodeficiency virus (HIV) infection even after long-term antiretroviral therapy (ART), which is associated with an increased risk of non-AIDS-related events. We assessed the impact of ART initiation in early versus chronic HIV infection on trajectories of CD8 cell counts over time. METHODS Of 280 individuals enrolled during primary HIV infection (PHI), 251 were followed up for 24 months; 84 started ART before 6 months of infection (eART), 49 started between 6 and 24 months, and 118 remained untreated. Plasma HIV viral load (VL), CD4 and CD8 cell counts were assessed at each study visit. CD8 counts were also examined in 182 age-matched HIV-infected individuals who started ART during chronic infection and maintained undetectable plasma VL for ≥5 years. RESULTS At PHI baseline, higher CD8 cell counts were associated with more recent infection (P = .02), higher CD4 cell counts (P < .001), and higher VL (P < .001). The CD8 count in the eART group decreased from 797 to 588 cells/µL over 24 months (P < .001), to a level lower than that in untreated PHI (834 cells/µL; P = .004) or in long-term-treated patients with chronic HIV infection (743 cells/µL; P = .047). More prominent CD4 T-cell recovery was observed in the eART group than in the delayed ART group. CONCLUSIONS ART initiated in early HIV infection is associated with improved resolution of CD8 T-cell elevation compared with long-term ART initiated in chronic infection. Early ART may help reduce the risk of non-AIDS-related events by alleviating this elevation.

Rethinking approaches to risk reduction for injection drug users: differences in drug type affect risk for HIV and hepatitis C virus infection through drug-injecting networks.

Objective: To identify and compare the drug-injecting network characteristics of cocaine and heroin injectors associated with a risk of HIV and hepatitis C virus (HCV). Methods: Active injectors were recruited from syringe exchange and methadone programs. Characteristics of all participants and their social networks were elicited. Regression analysis using generalized estimating equations examined the network characteristics of injection drug users (IDUs) relative to cocaine or heroin use in the past 6 months. Results: Of 282 IDUs, 228 (81%) used cocaine and 54 (19%) used heroin as their primary injected drug. In analyses adjusted for age and gender, cocaine injectors compared with heroin injectors were more likely to live in unstable housing (odds ratio [OR] = 3.55, 95% confidence interval [CI]: 1.49 to 8.40), self-report HCV infection (OR = 4.69, 95% CI: 2.14 to 10.31), and have a greater number of IDUs in their social network (OR = 1.61, 95% CI: 1.14 to 2.28) and were less likely to be polydrug users (OR = 0.06, 95% CI: 0.02 to 0.16) and to have social support (OR = 0.97, 95% CI: 0.95 to 0.99). The injecting networks of cocaine users were more likely to have members who were older (OR = 1.08, 95% CI: 1.04 to 1.12), had a history of shooting gallery use (OR = 2.27, 95% CI: 1.08 to 4.76), and had shorter relationships with the subject (OR = 0.91, 95% CI: 0.85 to 0.97). Conclusions: Beyond personal behaviors, HIV and HCV infection risk seems to be linked to social network traits that are determined by drug type. Prevention efforts to control the spread of bloodborne viruses among IDUs could benefit from tailoring interventions according to the type of drug used.

HIV and HCV discordant injecting partners and their association to drug equipment sharing

Our objective was to examine the association between HIV and HCV discordant infection status and the sharing of drug equipment by injection drug users (IDUs). IDUs were recruited from syringe exchange and methadone treatment programmes in Montreal, Canada. Characteristics of participants and their injecting partners were elicited using a structured questionnaire. Among 159 participants and 245 injecting partners, sharing of syringes and drug preparation equipment did not differ between concordant or discordant partners, although HIV-positive subjects did not share with HIV-negative injectors. Sharing of syringes was positively associated with discordant HIV status (OR=1.85) and negatively with discordant HCV status (OR=0.65), but both results were not statistically significant. Sharing of drug preparation equipment was positively associated with both discordant HIV (OR=1.61) and HCV (OR=1.18) status, but both results were non-significant. Factors such as large injecting networks, frequent mutual injections, younger age, and male gender were stronger predictors of equipment sharing. In conclusion, IDUs do not appear to discriminate drug equipment sharing partners based at least on their HCV infection status. The results warrant greater screening to raise awareness of infection status, post-test counselling to promote status disclosure among partners, and skill-building to avoid equipment sharing between discordant partners.