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Ninety percent of HIV‐1‐infected people worldwide harbour non‐subtype B variants of HIV‐1. Yet knowledge of resistance mutations in non‐B HIV‐1 and their clinical relevance is limited. Although a few reviews, editorials and perspectives have been published alluding to this lack of data among non‐B subtypes, no systematic review has been performed to date.With this in mind, we conducted a systematic review (1996–2008) of all published studies performed on the basis of non‐subtype B HIV‐1 infections treated with antiretroviral drugs that reported genotype resistance tests. Using an established search string, 50 studies were deemed relevant for this review.These studies reported genotyping data from non‐B HIV‐1 infections that had been treated with either reverse transcriptase inhibitors or protease inhibitors. While most major resistance mutations in subtype B were also found in non‐B subtypes, a few novel mutations in non‐B subtypes were recognized. The main differences are reflected in the discoveries that: (i) the non‐nucleoside reverse transcriptase inhibitor resistance mutation, V106M, has been seen in subtype C and CRF01_AE, but not in subtype B, (ii) the protease inhibitor mutations L89I/V have been reported in C, F and G subtypes, but not in B, (iii) a nelfinavir selected non‐D30N containing pathway predominated in CRF01_AE and CRF02_AG, while the emergence of D30N is favoured in subtypes B and D, (iv) studies on thymidine analog‐treated subtype C infections from South Africa, Botswana and Malawi have reported a higher frequency of the K65R resistance mutation than that typically seen with subtype B.Additionally, some substitutions that seem to impact non‐B viruses differentially are: reverse transcriptase mutations G196E, A98G/S, and V75M; and protease mutations M89I/V and I93L.Polymorphisms that were common in non‐B subtypes and that may contribute to resistance tended to persist or become more frequent after drug exposure. Some, but not all, are recognized as minor resistance mutations in B subtypes. These observed differences in resistance pathways may impact cross‐resistance and the selection of second‐line regimens with protease inhibitors. Attention to newer drug combinations, as well as baseline genotyping of non‐B isolates, in well‐designed longitudinal studies with long duration of follow up are needed.

AbstractIntroduction: Globally, there is a considerable burden of HCV and HIV infections among people who inject drugs (PWID) and transmission of both infections continues. Needle and syringe programme (NSP) and opioid substitution therapy (OST) coverage remains low, despite evidence demonstrating their prevention benefit. Direct‐acting antiviral therapies (DAA) with HCV cure >95% among PWID provide an opportunity to reverse rising trends in HCV‐related morbidity and mortality and reduce incidence. However, HCV testing, linkage to care, and treatment remain low due to health system, provider, societal, and patient barriers. Between 2015 and 2030, WHO targets include reducing new HCV infections by 80% and HCV deaths by 65%, and increasing HCV diagnoses from <5% to 90% and number of eligible persons receiving HCV treatment from <1% to 80%. This commentary discusses why PWID should be considered as a priority population in these efforts, reasons why this goal could be attainable among PWID, challenges that need to be overcome, and key recommendations for action.Discussion: Challenges to HCV elimination as a global health concern among PWID include poor global coverage of harm reduction services, restrictive drug policies and criminalization of drug use, poor access to health services, low HCV testing, linkage to care and treatment, restrictions for accessing DAA therapy, and the lack of national strategies and government investment to support WHO elimination goals. Key recommendations for action include reforming drug policies (decriminalization of drug use and/or possession, or providing alternatives to imprisonment for PWID; decriminalization of the use and provision of sterile needles‐syringes; and legalization of OST for people who are opioid dependent), scaling up and improving funding for harm reduction services, making health services accessible for PWID, supporting community empowerment and community‐based programmes, improving access to affordable diagnostics and medicines, and eliminating stigma, discrimination, and violence against PWID.Conclusions: The ambitious targets for HCV elimination set by WHO are achievable in many countries, but will require researchers, healthcare providers, policy makers, affected communities, advocates, the pharmaceutical and diagnostics industries, and governments around the world to work together to make this happen.

There are 31 million adults living with HIV‐1 non‐B subtypes globally, and about 10 million are on antiretroviral therapy (ART). Global evidence to guide clinical practice on ART response in HIV‐1 non‐B subtypes remains limited. We systematically searched 11 databases for the period 1996 to 2013 for evidence. Outcomes documented included time to development of AIDS and/or death, resistance mutations, opportunistic infections, and changes in CD4 cell counts and viral load. A lack of consistent reporting of all clinical end points precluded a meta‐analysis. In sum, genetic diversity that precipitated differences in disease progression in ART‐naïve populations was minimized in ART‐experienced populations, although variability in resistance mutations persisted across non‐B subtypes. To improve the quality of patient care in global settings, recording HIV genotypes at baseline and at virologic failure with targeted non‐B subtype‐based point‐of‐care resistance assays and timely phasing out of resistance‐inducing ART regimens is recommended.

AbstractIntroductionThe prevalence of hepatitis C virus (HCV) is far higher in prison settings than in the general population; thus, micro‐elimination strategies must target people in prison to eliminate HCV. We aimed to examine incarceration patterns and determine whether incarceration impacts HCV treatment uptake among Canadian HIV‐HCV co‐infected individuals in the direct‐acting antiviral (DAA) era.MethodsThe Canadian Co‐Infection Cohort prospectively follows HIV‐HCV co‐infected people from 18 centres. HCV RNA‐positive participants with available baseline information on incarceration history were included and followed from 21 November 2013 (when second‐generation DAAs were approved by Health Canada) until 30 June 2017. A Cox proportional hazards model was used to assess the effect of time‐updated incarceration status on time to treatment uptake, adjusting for patient‐level characteristics known to be associated with treatment uptake in the DAA era.ResultsOverall, 1433 participants (1032/72% men) were included; 67% had a history of incarceration and 39% were re‐incarcerated at least once. Compared to those never incarcerated, previously incarcerated participants were more likely to be Indigenous, earn <$1500 CAD/month, report current or past injection drug use and have poorly controlled HIV. There were 339 second‐generation DAA treatment initiations during follow‐up (18/100 person‐years). Overall, 48% of participants never incarcerated were treated (27/100 person‐years) compared to only 31% of previously incarcerated participants (15/100 person‐years). Sustained virologic response (SVR) rates at 12 weeks were 95% and 92% respectively. After adjusting for other factors, participants with a history of incarceration (adjusted hazard ratio (aHR): 0.7, 95% CI: 0.5 to 0.9) were less likely to initiate treatment, as were those with a monthly income <$1500 (aHR: 0.7, 95% CI: 0.5 to 0.9) or who reported current injection drug use (aHR: 0.7, 95% CI: 0.4 to 1.0). Participants with undetectable HIV RNA (aHR: 2.1, 95% CI: 1.6 to 2.9) or significant fibrosis (aHR: 1.5, 95% CI: 1.2 to 1.9) were more likely to initiate treatment.ConclusionsThe majority of HIV‐HCV co‐infected persons had a history of incarceration. Those previously incarcerated were 30% less likely to access treatment in the DAA era even after accounting for several patient‐level characteristics. With SVR rates above 90%, HCV elimination may be possible if treatment is expanded for this vulnerable and neglected group.

AbstractIntroductionThere is currently no published data on the effectiveness of DAA treatment for elimination of HCV infection in HIV‐infected populations at a population level. However, a number of relevant studies and initiatives are emerging. This research aims to report cascade of care data for emerging HCV elimination initiatives and studies that are currently being evaluated in HIV/HCV co‐infected populations in the context of implementation science theory.MethodsHCV elimination initiatives and studies in HIV co‐infected populations that are currently underway were identified. Context, intervention characteristics and cascade of care data were synthesized in the context of implementation science frameworks.ResultsSeven HCV elimination initiatives and studies were identified in HIV co‐infected populations, mainly operating in high‐income countries. Four were focused mainly on HCV elimination in HIV‐infected gay and bisexual men (GBM), and three included a combination of people who inject drugs (PWID), GBM and other HIV‐infected populations. None were evaluating treatment delivery in incarcerated populations. Overall, HCV RNA was detected in 4894 HIV‐infected participants (range within studies: 297 to 994): 48% of these initiated HCV treatment (range: 21% to 85%; within studies from a period where DAAs were broadly available the total is 57%, range: 36% to 74%). Among studies with treatment completion data, 96% of 1109 initiating treatment completed treatment (range: 94% to 99%). Among those who could be assessed for sustained virological response at 12 weeks (SVR12), 1631 of 1757 attained SVR12 (93%, range: 86% to 98%).ConclusionsEarly results from emerging research on HCV elimination in HIV‐infected populations suggest that HCV treatment uptake is higher than reported levels prior to DAA treatment availability, but approximately half of patients remain untreated. These results are among diagnosed populations and additional effort is required to increase diagnosis rates. Among those who have initiated treatment, completion and SVR rates are promising. More data are required in order to evaluate the effectiveness of these elimination programmes in the long term, assess which intervention components are effective, and whether they need to be tailored to particular population groups.

AbstractBackgroundDirect acting antivirals (DAAs) have revolutionized hepatitis C (HCV) treatment with >90% cure rates even in real‐world studies, giving hope that HCV can be eliminated. However, for DAAs to have a population‐level impact on the burden of HCV disease, treatment uptake needs to be expanded. We investigated temporal trends in HCV treatment uptake and evaluated factors associated with second‐generation DAA initiation and efficacy among key HIV‐HCV co‐infected populations in Canada.MethodsThe Canadian HIV‐HCV Co‐Infection Cohort Study prospectively follows 1699 participants from 18 centres. Among HCV RNA+ participants, we determined the incidence of HCV treatment initiation per year overall and by key populations between 2007 and 2015. Key populations were based on World Health Organization (WHO) guidelines including: people who actively inject drugs (PWID) (reporting injection drug use, last 6 months); Indigenous people; women and men who have sex with men (MSM). Multivariate Cox models were used to estimate adjusted hazard ratios (aHR) and 2‐year probability of initiating second‐generation DAAs for each of the key populations.ResultsOverall, HCV treatment initiation rates increased from 8 (95% CI, 6–11) /100 person‐years in 2013 to 28 (95% CI, 23–33) /100 person‐years in 2015. Among 911 HCV RNA + participants, there were 202 second‐generation DAA initiations (93% with interferon‐free regimens). After adjustment (aHR, 95% CI), active PWID (0.60, 0.38–0.94 compared to people not injecting drugs) and more generally, people with lower income (<$18 000 CAD/year) (0.50, 0.35, 0.71) were less likely to initiate treatment. Conversely, MSM were more likely to initiate 1.95 (1.33, 2.86) compared to heterosexual men. In our cohort, the population profile with the lowest 2‐year probability of initiating DAAs was Indigenous, women who inject drugs (5%, 95% CI 3–8%). Not having any of these risk factors resulted in a 35% (95% CI 32–38%) probability of initiating DAA treatment. Sustained virologic response (SVR) rates were >82% in all key populations.ConclusionWhile treatment uptake has increased with the availability of second‐generation DAAs, marginalized populations, already engaged in care, are still failing to access treatment. Targeted strategies to address barriers are needed to avoid further health inequities and to maximize the public health impact of DAAs.

IntroductionCombination antiretroviral therapy (ART) significantly decreases morbidity, mortality and HIV transmission. We aimed to characterize the timing of ART initiation based on CD4 cell count from 2000 to 2012 and identify factors associated with late initiation of treatment.MethodsParticipants from the Canadian Observational Cohort (CANOC), a multi‐site cohort of HIV‐positive adults initiating ART naively after 1 January 2000, in three Canadian provinces (British Columbia, Ontario and Québec) were included. Late initiation was defined as a CD4 count <200 cells/mm3 or an AIDS‐defining illness before ART initiation (baseline). Temporal trends were assessed using the Cochran–Armitage test, and independent correlates of late initiation were identified using logistic regression.ResultsIn total, 8942 participants (18% female) of median age 40 years (Q1–Q3 33–47) were included. The median baseline CD4 count increased from 190 cells/mm3 (Q1–Q3 80–320) in 2000 to 360 cells/mm3 (Q1–Q3 220–490) in 2012 (p<0.001). Overall, 4274 participants (48%) initiated ART with a CD4 count <200 cells/mm3 or AIDS‐defining illness. Late initiation was more common among women, non‐MSM, older individuals, participants from Ontario and BC (vs. Québec), persons with injection drug use (IDU) history and individuals starting ART in earlier calendar years. In sub‐analysis exploring recent (2008 to 2012) predictors using an updated CD4 criterion (<350 cells/mm3), IDU and residence in BC (vs. Québec) were no longer significant correlates of late initiation.ConclusionsThis analysis documents increasing baseline CD4 counts over time among Canadians initiating ART. However, CD4 counts at ART initiation remain below contemporary treatment guidelines, highlighting the need for strategies to improve earlier engagement in HIV care.

AbstractIntroductionRandomized trials and observational studies have consistently reported rates of sustained virological response (SVR), equivalent to hepatitis C virus (HCV) cure, as high as 95% following treatment with direct‐acting antiviral (DAA) treatment in individuals with HIV and HCV co‐infection. However, large studies assessing whether SVR rates differ according to demographic and clinical strata are lacking. Additionally, the SVR rates reported in the literature were typically computed in non‐random samples of individuals with available post‐DAA HCV‐RNA measures. Here, we aimed to estimate the probability of SVR after DAA treatment initiation in persons with HIV and HCV co‐infection overall and by demographic and clinical characteristics with and without adjustment for missing HCV‐RNA testing.MethodsWe included adults with HIV‐HCV co‐infection who received DAA treatment between 2014 and 2020 in HepCAUSAL, an international collaboration of cohorts from Europe and North America. We estimated the proportions of DAA recipients who had documented SVR (defined as an undetectable HCV‐RNA at least 12 weeks after the end of DAA treatment) overall and by strata defined by age, sex, presence of cirrhosis, calendar period, mode of HIV acquisition, CD4 cell count and HCV genotype at DAA treatment. We then compared these rates with those obtained using the parametric g‐formula to impute SVR status for individuals with no SVR assessment.Results and DiscussionA total of 4527 individuals who initiated DAA treatment (88% males, median [IQR] age 56 [50, 62] years) were included. Of the total of 642 (14%) individuals had no HCV‐RNA test on or after 12 weeks after the end of treatment. The overall observed and g‐formula imputed SVR rates were 93% (95% CI 93, 94) and 94% (95% CI 92, 95), respectively. SVR estimates were similarly high across all strata. A substantial proportion of individuals who received DAA treatment were never assessed for SVR post‐DAA and strategies for more systematic routine HCV‐RNA testing should be considered.ConclusionsOur estimates with and without adjustment for missing HCV‐RNA testing indicate SVR rates of approximately 95%, like those reported in clinical trials.