HCV-infected individuals have higher prevalence of comorbidity and multimorbidity: a retrospective cohort study.

BACKGROUND: Almost 1% of Canadians are hepatitis C (HCV)-infected. The liver-specific complications of HCV are established but the extra-hepatic comorbidity, multimorbidity, and its relationship with HCV treatment, is less well known. We describe the morbidity burden for people with HCV and the relationship between multimorbidity and HCV treatment uptake and cure in the pre- and post-direct acting antiviral (DAA) era. METHODS: We linked adults with HCV at The Ottawa Hospital Viral Hepatitis Program as of April 1, 2017 to provincial health administrative data and matched on age and sex to 5 Ottawa-area residents for comparison. We used validated algorithms to identify the prevalence of mental and physical health comorbidities, as well as multimorbidity (2+ comorbidities). We calculated direct age- and sex-standardized rates of comorbidity and comparisons were made by interferon-based and interferon-free, DAA HCV treatments. RESULTS: The mean age of the study population was 54.5 years (SD 11.4), 65% were male. Among those with HCV, 4% were HIV co-infected, 26% had liver cirrhosis, 47% received DAA treatment, and 57% were cured of HCV. After accounting for age and sex differences, the HCV group had greater multimorbidity (prevalence ratio (PR) 1.38, 95% confidence interval (CI) 1.20 to 1.58) and physical-mental health multimorbidity (PR 2.71, 95% CI 2.29-3.20) compared to the general population. Specifically, prevalence ratios for people with HCV were significantly higher for diabetes, renal failure, cancer, asthma, chronic obstructive pulmonary disease, substance use disorder, mood and anxiety disorders and liver failure. HCV treatment and cure were not associated with multimorbidity, but treatment prevalence was significantly lower among middle-aged individuals with substance use disorders despite no differences in prevalence of cure among those treated. CONCLUSION: People with HCV have a higher prevalence of comorbidity and multimorbidity compared to the general population. While HCV treatment was not associated with multimorbidity, people with substance use disorder were less likely to be treated. Our results point to the need for integrated, comprehensive models of care delivery for people with HCV.

Correction to: HCV-infected individuals have higher prevalence of comorbidity and multimorbidity: a retrospective cohort study.

After publication of the original article [1], we were notified that an author's name has been incorrectly spelled. Jeff Kwong's full name is Jeffery C. Kwong.

Removing inactive NRTIs in a salvage regimen is safe, maintains virological suppression and reduces treatment costs: results from the VERITAS study (TMC114HIV4054).

BACKGROUND: Despite the benefit of maintaining inactive Nucleotide/side reverse transcriptase inhibitors (NRTIs) in salvage regimens, they are associated with increased toxicity and treatment costs. Current evidence suggests that NRTI-sparing regimens in patients failing ART are non-inferior to NRTI-including regimens. This study aimed to evaluate the impact of removing at least one inactive NRTI on virologic, safety, and financial outcomes. METHODS: Drug-resistant, virologically suppressed patients with CD4 >250 cells/ml on a stable regimen of four or more antiretrovirals (ARVs) were enrolled in a 48-week prospective, open-label pilot trial. One inactive NRTI was removed at baseline. Patients taking over five ARVs had a second inactive NRTI removed at 24 weeks. Viral load, CD4 count, and adverse events were assessed at baseline, 24, and 48 weeks. RESULTS: Thirty-one male patients participated. Twenty-nine (94%) patients had lamivudine (3TC) or emtricitabine (FTC) removed and four patients had an additional NRTI removed. One patient was excluded at week 26 for discontinuing an active NRTI. All patients maintained undetectable viral loads at weeks 24 (100%) and 48 [PP = 100%; Intent-to-treat (ITT) = 97%]. At 48 weeks, patients had a median gain of 20 CD4 (IQR: - 50, +133; mean +39) compared to baseline. Three patients exhibited Grade III bilirubin elevation (two Grade II and one Grade III at baseline), which returned to baseline levels. No serious adverse events were observed. Removal of one or two ARVs equated to a mean annual savings of $3319 CDN (11%) and $8630 CDN (24%), respectively. CONCLUSION: Removing inactive NRTIs in patients with a controlled viral load appears to be safe, maintains virological suppression, and reduces treatment costs.

Food reservoir for Escherichia coli causing urinary tract infections.

Closely related strains of Escherichia coli have been shown to cause extraintestinal infections in unrelated persons. This study tests whether a food reservoir may exist for these E. coli. Isolates from 3 sources over the same time period (2005-2007) and geographic area were compared. The sources comprised prospectively collected E. coli isolates from women with urinary tract infection (UTI) (n = 353); retail meat (n = 417); and restaurant/ready-to-eat foods (n = 74). E. coli were evaluated for antimicrobial drug susceptibility and O:H serotype and compared by using 4 different genotyping methods. We identified 17 clonal groups that contained E. coli isolates (n = 72) from >1 source. E. coli from retail chicken (O25:H4-ST131 and O114:H4-ST117) and honeydew melon (O2:H7-ST95) were indistinguishable from or closely related to E. coli from human UTIs. This study provides strong support for the role of food reservoirs or foodborne transmission in the dissemination of E. coli causing common community-acquired UTIs.

Direct acting antiviral HCV treatment does not influence renal function.

HCV infection is associated with chronic kidney disease due to several mechanisms. Patients treated with interferon-based regimens demonstrate improved renal function and reduced incidence of chronic kidney disease. There is scarce evidence on the effect of direct acting antiviral regimens (DAAs) on renal function.We evaluated serial measures of renal function in a cohort of HCV-infected participants following completion of DAA-based treatment regimens.Measures of glomerular filtration rate (GFR) were estimated by the CKD-EPI equation. Data was recorded at end of treatment, and at 6-12 months, 12-24 months, and greater than 24 months following treatment completion. Group-based trajectory modeling was used to determine distinct GFR trajectories. Predictors of group membership were determined by multinomial regression analysis.Six trajectories were identified. One trajectory comprising 27% of the cohort demonstrated declining renal function and the others demonstrated no change in renal function over time. Baseline GFR did not predict SVR. Diabetes was associated with lower post-treatment GFR but patients with diabetes did not demonstrate a decrease in GFR over the period of evaluation. Cirrhosis and SVR were not significant predictors of GFR or GFR trajectory.There is no clinically relevant change in renal function among the majority of HCV-infected patients following completion of DAA-based treatments. Renal function does not influence the efficacy of DAA-based regimens. No consistent effect of DAA treatment and/or SVR on renal function was observed over a 2-year period following treatment completion.

Telemedicine successfully engages marginalized rural hepatitis C patients in curative care.

Background: Rurally located individuals living with hepatitis C virus (HCV) face barriers to engagement and retention in care. Telemedicine technologies coupled with highly curative direct acting antiviral (DAA) treatments may increase accessibility to HCV care while achieving high sustained virologic response (SVR) rates. We compared clinical and socio-economic characteristics, SVR, and loss to follow-up among telemedicine (TM), mixed delivery (MD), and outpatient clinic (OPC) patients receiving care through The Ottawa Hospital Viral Hepatitis Program (TOHVHP). Methods: TOHVHP clinical database was used to evaluate patients engaging HCV care between January 1, 2012, and December 31, 2016. SVR rates by HCV care delivery method (TM versus OPC versus MD) were calculated. Results: Analysis included 1,454 patients who engaged with TOHVHP at least once. Patients were aged almost 50 years on average and were predominately male and Caucasian. A greater proportion of TM patients were rurally based, were Indigenous, had a history of substance use, and had previously been incarcerated. Per-protocol DAA SVR rates for TM, OPC, and MD patients were 100% (26/26), 93% (440/472), and 94% (44/47), respectively. Loss-to-follow-up rates for HCV-treated TM and MD patients were higher (27% [10/37], 95% CI 0.58 to 0.88, and 11% [7/62], 95% CI 0.81 to 0.97, respectively) than for those followed exclusively in the OPC (5% [39/800], 95% CI 0.94 to 0.97). Conclusions: TM can successfully engage, retain, and cure rurally based HCV patients facing barriers to care. Strategies to improve TM retention of patients initiating HCV antiviral treatment are key to optimizing the impact of this model of care.

Historique: Les personnes atteintes du virus de l'hépatite C (VHC) qui habitent en milieu rural affrontent des obstacles à l'obtention et à la rétention des soins. Les technologies de télémédecine, couplées à des traitements antiviraux à action directe (AAD) hautement curatifs, peuvent accroître l'accessibilité aux soins du VHC tout en obtenant des taux élevés de réponse virologique soutenue (RVS). Les auteurs ont comparé les caractéristiques cliniques et socioéconomiques, la RVS et la perte au suivi des patients en télémédecine (TM), en prestation mixte (PM) et en clinique ambulatoire (CA) suivis par le Programme de lutte contre l'hépatite virale de l'Hôpital d'Ottawa (PLHVHO). Méthodologie: Les chercheurs ont utilisé la base de données clinique du PLHVHO pour évaluer les patients qui ont participé aux soins du VHC entre le 1er janvier 2012 et le 31 décembre 2016. Ils ont calculé le taux de RVS en fonction de la méthode de prestation des soins du VHC (TM, CA ou PM). Résultats: L'analyse incluait 1 454 patients qui ont participé au moins une fois au PLHVHO. Les patients, âgés en moyenne de près de 50 ans, étaient majoritairement blancs et de sexe masculin. Une plus forte proportion de patients en TM habitait en milieu rural, était d'origine autochtone, avait déjà consommé des substances psychoactives et avait déjà été détenue. Le taux de RVS aux AAD chez les patients en TM, en CA et en PM s'élevait à 100 % (26 sur 26), à 93 % (440 sur 472) et à 94 % (44 sur 47), respectivement. Le taux de perte au suivi des patients atteints du VHC était plus élevé en TM et en PM (27 % [dix sur 37], IC à 95 %, 0,58 à 0,88, et 11 % [sept sur 62], IC à 95 %, 0,81 à 0,97, respectivement) que chez ceux qui étaient suivis exclusivement en CA (5 % [39 sur 800], IC à 95 %, 0,94 à 0,97). Conclusions: La TM peut réussir à faire participer, retenir et guérir les patients atteints d'un VHC qui habitent en milieu rural et affrontent des obstacles à l'obtention des soins. Il est essentiel d'établir des stratégies pour améliorer la rétention des patients en TM qui entreprennent un traitement antiviral contre le VHC pour optimiser les répercussions de ce modèle de soins.

A cross-sectional study of prolonged disengagement from clinic among people with HCV receiving care in a low-threshold, multidisciplinary clinic.

Background: Disengagement from care can affect treatment outcomes of patients with hepatitis C virus (HCV). We assessed the extent and determinants of disengagement among HCV patients receiving care at the Ottawa Hospital Viral Hepatitis Program (TOHVHP). Methods: We linked clinical data of adult patients, categorized as ever or never disengaged from clinic (no TOHVHP encounters over 18 months), receiving care between April 1, 2002, and October 1, 2015, to provincial health administrative databases and calculated primary care use in the year after disengagement. We used adjusted Cox proportional hazards models to analyze variables associated with disengagement. Results: Those disengaged from care (n = 657) were younger at presentation (46.6 [SD 11.1] versus 51.9 [SD 11.0] years), p < 0.001) and had lower comorbidity. After multivariable adjustment, we observed lower hazards of disengagement among those with higher compared with lower fibrosis scores (F3, hazard ratio [HR] 0.21 [95% CI 0.08-0.57]; F4, HR 0.32 [95% CI 0.19-0.55]) and those treated compared with never treated (received direct-acting antivirals [DAAs], HR 0.71 [95% CI 0.58-0.88]; received interferon but not DAA, HR 0.66 [95% CI 0.55-0.80]). We found no association with mental health or substance use disorders. In the year after disengagement, 74.3% (n = 488), 37.1% (n = 244), and 17.7% (n = 116) had at least one family physician visit, emergency department visit, and hospitalization, respectively. Conclusions: Better integration of HCV specialty and primary care could improve disengagement rates among people with HCV.

Direct-acting antiviral hepatitis C virus treatment perturbation of the metabolic milieu.

OBJECTIVE: Hepatitis C virus (HCV), cirrhosis, and HCV medications including direct-acting antivirals (DAAs) ±ribavirin may all influence the metabolic milieu. While interferon-based regimens improve glucose tolerance, evidence is limited on DAAs. Cases of elevated lactate have recently been reported in patients treated with DAAs, and lactic acidosis is a known complication of antivirals used to treat hepatitis B virus and HIV. PATIENTS AND METHODS: Measures were evaluated at baseline, week 4, end of treatment, and 12-24 weeks after treatment. Mixed-effects modeling was used to determine factors influencing glucose and lactate over time. RESULTS: In total, 442 patients were treated (mean age 56, 65% male, 72% genotype 1, 48% cirrhotic). Glucose did not change on or after DAA treatment from baseline (P=0.51) aside from those with untreated diabetes, which declined (P=0.02). Overall, there was a decline in lactate following HCV treatment (mean 2.4-2.1 mmol/l; P<0.001). Lactate initially increased on treatment and then decreased after treatment completion in male patients treated with ribavirin. This pattern was not observed in other groups. There was no evidence of lactic acidosis with HCV nucleotide use. CONCLUSION: Distinct glucose and lactate trajectories were identified without evidence of DAA metabolic toxicity. HCV treatment does not improve random glucose levels aside from perhaps in untreated diabetic patients.

Hepatitis C Direct Acting Antivirals and Ribavirin Modify Lipid but not Glucose Parameters.

Chronic hepatitis C (HCV) infection perturbs lipid and glucose metabolism. The influenceof direct acting antiviral (DAA) treatment and ribavirin on these measures was evaluated.Furthermore, the effect of HCV cure on these parameters was assessed. Participants were allocatedto one of three 12-week treatment groups: non-cirrhotic genotype 1aparitaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) plus ribavirin; non-cirrhotic 1b-PrOD;compensated cirrhotic 1a or 1b-PrOD plus ribavirin. Fasting insulin, glucose, lipid andapolipoprotein measures were assessed at baseline, Treatment Weeks 4 and 12, and 12 and 24 weekspost-dosing. Twenty-three of 24 participants achieved SVR (PP= 23/24, 96% SVR). Overall, totalcholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels all increased intreatment and post-dosing. However, LDL-C levels decreased during treatment in ribavirinrecipients. Fasting glucose, insulin, and HOMA-IR were unchanged during treatment and 12 weekspost-treatment. By 12 weeks post-treatment, controlled attenuation parameter (CAP) scores, ameasure of steatosis, increased from baseline (mean 30.3 ± 63.5, p = 0.05). This regimen was safe andhighly effective and did not influence glucose metabolism. Ribavirin exposure may mitigate someon-treatment lipid changes. Further mechanistic studies are needed to understand how ribavirinimpacts lipid pathways, as there could be therapeutic implications. The metabolic pathophysiologyof increased CAP score with HCV treatment requires explanation.

Adherence to Post-Exposure Prophylaxis (PEP) and Incidence of HIV Seroconversion in a Major North American Cohort.

BACKGROUND: There is limited evidence on the efficacy of post-exposure prophylaxis (PEP) for sexual exposures. We sought to determine the factors associated with adherence to treatment and describe the incidence of PEP failures in a Montreal clinic. METHODS: We prospectively assessed all patients consulting for PEP following sexual exposures from October 2000 to July 2014. Patients were followed at 4 and 16 weeks after starting PEP. Treatment adherence was determined by self-report at week 4. Multivariable logistic regression was used to estimate the factors predicting adherence to treatment. RESULTS: 3547 PEP consults were included. Patients were mainly male (92%), MSM (83%) and sought PEP for anal intercourse (72%). Seventy-eight percent (n = 2772) of patients received a prescription for PEP, consisting of Tenofovir/Emtracitabine (TVD) + Lopinavir/Ritonavir (LPV) in 74% of cases, followed by Zidovudine/Lamivudine (CBV) + LPV (10%) and TVD + Raltegravir (RAL) (8%). Seventy percent of patients were adherent to treatment. Compared to TVD+LPV, patients taking CBV+LPV were less likely to adhere to treatment (OR 0.58, 95% CI 0.44-0.75), while no difference was observed for patients taking TVD+RAL (OR 1.15, 95% CI 0.83-1.59). First-time PEP consults, older and male patients were also more adherent to treatment. Ten treated patients seroconverted (0.37%) during the study period, yet only 1 case can be attributed to PEP failure (failure rate = 0.04%). CONCLUSION: PEP regimen was associated with treatment adherence. Patients were more likely to be adherent to TVD-based regimens. Ten patients seroconverted after taking PEP; however, only 1 case was a PEP failure as the remaining patients continued to engage in high-risk behavior during follow-up. One month PEP is an effective preventive measure to avoid HIV infection.

Removing inactive NRTIs in a salvage regimen is safe, maintains virological suppression and reduces treatment costs: 96 weeks post VERITAS study.

INTRODUCTION: In HIV+ patients exhibiting multidrug resistance (MDR), NRTIs often have little activity, increased toxicity, drug interactions and add unnecessary treatment costs. The 48 week VERITAS study demonstrated that these patients can have a safe and effective simplification of salvage regimen by removing inactive NRTIs as determined by genotypic data. Virological, immunological, clinical and financial outcomes were evaluated at an additional 96 weeks of follow-up. MATERIALS AND METHODS: MDR patients with an undetectable viral load (VL) on a stable regimen containing at least four ARVs (including one inactive NRTI) were enrolled in an open-label, prospective simplification trial, where one inactive NRTI was removed at baseline (BL). A second NRTI could be removed at week 24 if the regimen contained at least five ARVs at enrolment. RESULTS: 31 male patients participated. The mean length of treatment was 14 years, with a median CD4 count of 525. The BL regimen consisted of 4 ARVs in 22 patients (71%) and 5 ARVs in 9 patients (29%). 3TC or FTC was removed in 29 patients (94%), and either AZT or TDF was interrupted in 2 others. Four patients had a second NRTI stopped. One patient was removed at W26 as an active NRTI was removed for creatinine elevation. 30 well-controlled patients continued follow-up after W48. At W144, six patients had additional changes in their ARV regimen. Half were due to toxicity (jaundice, neuropathy and nephrotoxicity) while the other half were the result of treatment simplification. None of the patients exhibited virologic failure at the time of treatment change and maintained undetectable VLs throughout the entire follow-up. These six patients had a mean gain of 79 CD4 (p=0.17) compared to baseline. 22 of the 24 patients (92%) with no changes in ARV therapy after W48 had undetectable VLs. The other two had confirmed virologic failure, one with genotypic resistance. All 24 had elevated CD4 counts (mean +118 CD4, p<0.0001). No deaths or serious adverse events were observed. One or two ARV removals translated to a mean annual saving of $3319 CDN (11%) and $8630 (24%) respectively. CONCLUSIONS: Final results indicate that removing one or two inactive NRTIs from a regimen in patients taking four or more ARVs with controlled VL appears to be safe, maintains virological suppression through 144 weeks and significantly reduces treatment costs.

Assessing the role of hydration in delirium at the end of life.

PURPOSE OF REVIEW: Delirium is the most frequent neuropsychiatric disorder that affects the advanced cancer population who are receiving palliative care. There is limited evidence and much debate about the role of hydration in delirium management at the end of life. The purpose of this article is to review the literature on delirium management with regards to pharmacological management and hydration. RECENT FINDINGS: Pharmacological management is the first line of treatment for delirium, whereby antipsychotics are the medication of choice. However, they have not been approved by the United States Food and Drug Administration for delirium management as there is insufficient evidence supporting their use. Hydration is a believed to be a key component of delirium reversibility; yet there are conflicting results on its efficacy as an intervention for delirium management. As there are few studies of good methodological quality on the topic and large variations in practice, the effectiveness of hydration as an alternative management option for delirium is unclear. SUMMARY: More work is required to assess the role of hydration in delirium at the end of life. Given the lack of evidence-based research on hydration, more randomized clinical trials are needed to elucidate the effects of hydration as a delirium intervention.