Zahid A Butt

Long-term effect of sustained virological response on hepatocellular carcinoma in patients with hepatitis C in Canada

BACKGROUND & AIMS Evidence is limited on hepatocellular carcinoma (HCC) risk after sustained virological response (SVR) to interferon-based treatment of hepatitis C virus (HCV) infection. We evaluated the effect of SVR on the risk of HCC and estimated its incidence in post-SVR HCV patients from a large population-based Canadian cohort. METHODS The British Columbia Hepatitis Testers Cohort includes individuals tested for HCV between 1990-2013 linked with data on their medical visits, hospitalizations, cancers, prescription drugs and mortality. Patients receiving interferon-based HCV treatments were followed from the end of treatment to HCC diagnosis, death or December 31, 2012. We examined HCC risk among those who did and did not achieve SVR using multivariable proportional hazard models with the Fine and Gray modification for competing risks. RESULTS Of 8147 individuals who received HCV treatment and were eligible for analysis, 4663 (57%) achieved SVR and 3484 (43%) did not. Each group was followed for a median of 5.6years (range: 0.5-12.9) for an HCC incidence rate of 1.1/1000 person-years (PY) among the SVR and 7.2/1000 PY among the no SVR group. The HCC incidence rate was higher among those with cirrhosis (SVR: 6.4, no SVR: 21.0/1000 PY). In the multivariable model, SVR was associated with a lower HCC risk (subdistribution hazard ratio [SHR]=0.20, 95% CI: 0.13-0.3), while cirrhosis (SHR=2.61, 95% CI: 1.68-4.04), age ⩾50years, being male and genotype 3 infection were associated with a higher HCC risk. Among those who achieved SVR, cirrhosis, age ⩾50years and being male were associated with a higher HCC risk. CONCLUSION SVR after interferon-based treatment substantially reduces but does not eliminate HCC risk, which is markedly higher among those with cirrhosis and age ⩾50years at treatment initiation. Treatment of patients at an advanced fibrosis stage with new highly effective drugs will warrant continued surveillance for HCC post-SVR. LAY SUMMARY We assessed the effect of successful hepatitis C treatment with older interferon-based treatment on the occurrence of liver cancer (hepatocellular carcinoma) and found that successful treatment prevents liver cancer. However, more people with cirrhosis and older age continued to develop liver cancer after successful treatment. Thus, treatment with new drugs among those with cirrhosis will require continued monitoring for liver cancer.

The Population Level Cascade of Care for Hepatitis C in British Columbia, Canada: The BC Hepatitis Testers Cohort (BC-HTC)

Background Population-level monitoring of hepatitis C virus (HCV) infected people across the cascade of care identifies gaps in access and engagement in care and treatment. We characterized a population-level cascade of care for HCV in British Columbia (BC), Canada and identified factors associated with leakage at each stage. Methods The BC Hepatitis Testers Cohort (BC-HTC) includes 1.5 million individuals tested for HCV, HIV, reported cases of hepatitis B, and active tuberculosis in BC from 1990 to 2013 linked to medical visits, hospitalizations, cancers, prescription drugs and mortality data. We defined six HCV cascade of care stages: 1) estimated population prevalence; 2) HCV diagnosed; 3) HCV RNA tested; 4) genotyped; 5) initiated treatment; and 6) achieved sustained virologic response (SVR). Results We estimated that 73,203 people were HCV antibody positive in BC in 2012 (undiagnosed: 18,301, 25%; diagnosed: 54,902, 75%). Of these, 56%(40,656) had HCV RNA testing; 34%(26,300) were genotyped; 12%( 8532 ) had received interferon-based therapy and 7%(5197) had SVR. Males, older birth cohorts, and HBV coinfected were less likely to undergo HCV RNA testing. Among those with chronic HCV infection, 32% had received liver-related care. Retention in liver care was more likely in those with HIV, cirrhosis, and drug/alcohol use and less likely in males and HBV coinfected. Conclusions Although there are gaps in HCV RNA testing and genotyping after HCV diagnosis, the major gap in the cascade of care was low treatment initiation. People with comorbidities progressed through the cascade of testing and care but few received treatment.

Shift in disparities in hepatitis C treatment from interferon to DAA era: A population‐based cohort study

We evaluated the shift in the characteristics of people who received interferon‐based hepatitis C virus (HCV) treatments and those who received recently introduced direct‐acting antivirals (DAAs) in British Columbia (BC), Canada. The BC Hepatitis Testers Cohort includes 1.5 million individuals tested for HCV or HIV, or reported cases of hepatitis B and active tuberculosis in BC from 1990 to 2013 linked to medical visits, hospitalization, cancer, prescription drugs and mortality data. This analysis included all patients who filled at least one prescription for HCV treatment until 31 July 2015. HCV treatments were classified as older interferon‐based treatments including pegylated interferon/ribavirin (PegIFN/RBV) with/without boceprevir or telaprevir, DAAs with RBV or PegIFN/RBV, and newer interferon‐free DAAs. Of 11 886 people treated for HCV between 2000 and 2015, 1164 (9.8%) received interferon‐free DAAs (ledipasvir/sofosbuvir: n=1075; 92.4%), while 452 (3.8%) received a combination of DAAs and RBV or PegIFN/RBV. Compared to those receiving interferon‐based treatment, people with HIV co‐infection (adjusted odds ratio [aOR]: 2.96, 95% CI: 2.31‐3.81), cirrhosis (aOR: 1.77, 95% CI: 1.45‐2.15), decompensated cirrhosis (aOR: 1.72, 95% CI: 1.31‐2.28), diabetes (aOR: 1.30, 95% CI: 1.10‐1.54), a history of injection drug use (aOR: 1.34, 95% CI: 1.09‐1.65) and opioid substitution therapy (aOR: 1.30, 95% CI: 1.01‐1.67) were more likely to receive interferon‐free DAAs. Socio‐economically marginalized individuals were significantly less likely (most deprived vs most privileged: aOR: 0.71, 95% CI: 0.58‐0.87) to receive DAAs. In conclusion, there is a shift in prescription of new HCV treatments to previously excluded groups (eg HIV‐co‐infected), although gaps remain for the socio‐economically marginalized populations.

Rapid detection of Mycobacterium tuberculosis and rifampicin resistance in extrapulmonary tuberculosis and sputum smear-negative pulmonary suspects using Xpert MTB/RIF.

Background. Tuberculosis (TB) is a serious public health problem in developing countries such as Pakistan. Rapid diagnosis of TB and detection of drug resistance are very important for timely and appropriate management of multidrug‐resistant TB (MDR‐TB). Objective. The purpose of this study was to determine the diagnostic efficacy of the Xpert MTB/RIF assay for rapid diagnosis of TB and detection of rifampicin (RIF) resistance in extrapulmonary and smear‐negative pulmonary TB suspects. Methods. A total of 98 bronchoalveolar lavage fluid (BALF) and 168 extrapulmonary specimens were processed by Xpert MTB/RIF. Culture results are considered as the gold standard for diagnosis of TB, and drug susceptibility testing for detection of RIF resistance. Diagnostic efficacy was measured in terms of sensitivity, specificity and positive and negative predictive values. Results. The Xpert MTB/RIF assay detected 40 (40.8%) of 98 BALF of presumptive pulmonary TB and 60 (35.7%) of 168 extrapulmonary specimens. Sensitivity and specificity of the Xpert MTB/RIF assay for detection of TB was 86 and 88.4%, respectively. The positive predictive value was 71.5% while negative predictive value was 95.1%. Conclusion. The Xpert MTB/RIF assay is a rapid and simple technique with high sensitivity and specificity for diagnosing TB and detecting drug resistance in extrapulmonary and smear‐negative TB cases.

Risk factors for bloodborne viral hepatitis in healthcare workers of Pakistan: a population based case–control study

Objectives A high prevalence of viral hepatitis B and C was found among healthcare workers during a province-wide screening in Sindh Province, Pakistan. A follow-up study was undertaken to identify risk factors for this high prevalence in healthcare workers. Design Population based case–control design. Setting Public sector healthcare facilities in a rural district of Pakistan. Participants Healthcare workers who were screened for hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) antibodies. 178 healthcare workers employed at the public sector clinics and hospitals of the district were approached, of which 14 refused to participate. Cases had detectable serum antibodies against HCV and the presence of HBsAg. Healthcare workers non-reactive to HCV antibodies and with no HBsAg were controls. These were matched in a ratio of 1:1. Outcome measure Detectable serum HBsAg and HCV antibody titer were taken as outcome. OR for various exposures was calculated; those with p<0.25 were entered in a multivariate logistic regression model to find out significant predictors. Results Needle stick injury (OR=6; CI95 1.4 to 23), recapping the needle (OR=5.7; CI95 1.1 to 28), wound care at accident and emergency of a hospital (OR=5.5; CI95 1 to 28), female gender (OR=3.4; CI95 1 to 12) and more than 10 years of formal education (OR=0.25; CI95 0.07 to 0.8) were associated with hepatitis C. Hepatitis B was found to be associated with trying to bend or break a needle after use (OR=4.9; CI95 1 to 24). Conclusions Healthcare workers in Pakistan are at additional risk of exposure to bloodborne pathogens. Bi-dimensional risk factors present at individual and broader health systems levels are responsible. Occupational safety, health trainings and redesigning of the curriculum for allied health professionals are required.

Identifying injection drug use and estimating population size of people who inject drugs using healthcare administrative datasets

BACKGROUND Large linked healthcare administrative datasets could be used to monitor programs providing prevention and treatment services to people who inject drugs (PWID). However, diagnostic codes in administrative datasets do not differentiate non-injection from injection drug use (IDU). We validated algorithms based on diagnostic codes and prescription records representing IDU in administrative datasets against interview-based IDU data. METHODS The British Columbia Hepatitis Testers Cohort (BC-HTC) includes ∼1.7 million individuals tested for HCV/HIV or reported HBV/HCV/HIV/tuberculosis cases in BC from 1990 to 2015, linked to administrative datasets including physician visit, hospitalization and prescription drug records. IDU, assessed through interviews as part of enhanced surveillance at the time of HIV or HCV/HBV diagnosis from a subset of cases included in the BC-HTC (n = 6559), was used as the gold standard. ICD-9/ICD-10 codes for IDU and injecting-related infections (IRI) were grouped with records of opioid substitution therapy (OST) into multiple IDU algorithms in administrative datasets. We assessed the performance of IDU algorithms through calculation of sensitivity, specificity, positive predictive, and negative predictive values. RESULTS Sensitivity was highest (90-94%), and specificity was lowest (42-73%) for algorithms based either on IDU or IRI and drug misuse codes. Algorithms requiring both drug misuse and IRI had lower sensitivity (57-60%) and higher specificity (90-92%). An optimal sensitivity and specificity combination was found with two medical visits or a single hospitalization for injectable drugs with (83%/82%) and without OST (78%/83%), respectively. Based on algorithms that included two medical visits, a single hospitalization or OST records, there were 41,358 (1.2% of 11-65 years individuals in BC) recent PWID in BC based on health encounters during 3- year period (2013-2015). CONCLUSION Algorithms for identifying PWID using diagnostic codes in linked administrative data could be used for tracking the progress of programing aimed at PWID. With population-based datasets, this tool can be used to inform much needed estimates of PWID population size.

A syndemic approach to assess the effect of substance use and social disparities on the evolution of HIV/HCV infections in British Columbia

Background Co-occurrence of social conditions and infections may affect HIV/HCV disease risk and progression. We examined the changes in relationship of these social conditions and infections on HIV and hepatitis C virus (HCV) infections over time in British Columbia during 1990–2013. Methods The BC Hepatitis Testers Cohort (BC-HTC) includes ~1.5 million individuals tested for HIV or HCV, or reported as a case of HCV, HIV, HBV, or tuberculosis linked to administrative healthcare databases. We classified HCV and HIV infection status into five combinations: HIV-/HCV-, HIV+monoinfected, HIV-/HCV+seroconverters, HIV-/HCV+prevalent, and HIV+/HCV+. Results Of 1.37 million eligible individuals, 4.1% were HIV-/HCV+prevalent, 0.5% HIV+monoinfected, 0.3% HIV+/HCV+ co-infected and 0.5% HIV-/HCV+seroconverters. Overall, HIV+monoinfected individuals lived in urban areas (92%), had low injection drug use (IDU) (4%), problematic alcohol use (4%) and were materially more privileged than other groups. HIV+/HCV+ co-infected and HIV-/HCV+seroconverters were materially most deprived (37%, 32%), had higher IDU (28%, 49%), problematic alcohol use (14%, 17%) and major mental illnesses (12%, 21%). IDU, opioid substitution therapy, and material deprivation increased in HIV-/HCV+seroconverters over time. In multivariable multinomial regression models, over time, the odds of IDU declined among HIV-/HCV+prevalent and HIV+monoinfected individuals but not in HIV-/HCV+seroconverters. Declines in odds of problematic alcohol use were observed in HIV-/HCV+seroconverters and coinfected individuals over time. Conclusions These results highlight need for designing prevention, care and support services for HIV and HCV infected populations based on the evolving syndemics of infections and social conditions which vary across groups.

Association of tobacco use and other determinants with pregnancy outcomes: a multicentre hospital-based case–control study in Karachi, Pakistan

Objectives The study aimed to identify the effects of maternal tobacco consumption during pregnancy and other factors on birth outcomes and obstetric complications in Karachi, Pakistan. Design A multicentre hospital-based case–control study. Setting Four leading maternity hospitals of Karachi. Participants A random sample of 1275 women coming to the gynaecology and obstetric department of selected hospitals for delivery was interviewed within 48 hours of delivery from wards. Cases were women with adverse birth outcomes and obstetric complications, while controls were women who had normal uncomplicated delivery. Primary and secondary outcome measures Adverse birth outcomes (preterm delivery, low birth weight, stillbirth, low Apgar score) and obstetric complications (antepartum haemorrhage, caesarean section, etc). Results Final multiple logistic regression analysis revealed that with every 1 year increase in age the odds of being a case was 1.03 times as compared with being a control. Tobacco use (adjusted OR (aOR): 2.24; 95% CI 1.56 to 3.23), having no slits in the kitchen (proxy indicator for indoor air pollution) (aOR=1.90; 95% CI 1.05 to 3.43), gravidity (aOR=0.83; 95% CI 0.73 to 0.93), non-booked hospital cases (aOR=1.87; 95% CI 1.38 to 2.74), history of stillbirth (aOR=4.06; 95% CI 2.36 to 6.97), miscarriages (aOR=1.91; 95% CI 1.27 to 2.85) and preterm delivery (aOR=6.04; 95% CI 2.52 to 14.48) were significantly associated with being a case as compared with control. Conclusions This study suggests that women who had adverse pregnancy outcomes were more likely to have exposure to tobacco, previous history of adverse birth outcomes and were non-booked cases. Engagement of stakeholders in tobacco control for providing health education, incorporating tobacco use in women in the tobacco control policy and designing interventions for tobacco use cessation is warranted. Prenatal care and health education might help in preventing such adverse events.

Differing profiles of people diagnosed with acute and chronic hepatitis B virus infection in British Columbia, Canada

AIM To describe the characteristics of people diagnosed with acute and chronic hepatitis B virus (HBV) infection in British Columbia (BC). METHODS We used data from the BC Hepatitis Testers Cohort (BC-HTC), which includes all individuals tested for hepatitis C virus (HCV) or human immunodeficiency virus (HIV) or those diagnosed with HBV or active tuberculosis in BC since 1990. These data were integrated with prescription drug, medical visit, hospitalization and mortality data. HBV cases were classified as acute or chronic according to provincial guidelines. We compared characteristics of individuals by HBV infection group (acute, chronic and negative). Factors associated with acute or chronic HBV infection were assessed with multinomial logistic regression models in comparison to the HBV negative group. RESULTS 46498 of the 1058056 eligible BC-HTC participants were diagnosed with HBV infection. 4.3% of HBV positive individuals were diagnosed with acute HBV infections while 95.7% had chronic infections. Problematic alcohol use, injection drug use, and HIV or HCV co-infection were more common among individuals diagnosed with acute HBV compared to those with chronic infections and HBV negative individuals. In multivariable multinomial logistic regression models, we observed significant associations between acute or chronic HBV diagnosis and being male, age at HBV diagnosis or birth cohort, South and East Asian ethnicity, HCV or HIV infection, and injection drug use. The odds of acute HBV decreased with increasing age among people who inject drugs, while the opposite was true for chronic HBV. Persons with acute HBV were predominantly White (78%) while those with chronic HBV were mostly East Asian (60%). Relative to Whites, East Asians had 12 times greater odds of being diagnosed with chronic HBV infection. These odds increased with increasing socioeconomic deprivation. CONCLUSION Differences in the profiles of people diagnosed with acute and chronic HBV infection necessitate differentiated screening, prevention, care and treatment programs.

Estimating the impact of early hepatitis C virus clearance on hepatocellular carcinoma risk

Although achieving sustained virological response (SVR) through antiviral therapy could reduce the risk of hepatocellular carcinoma (HCC) attributable to hepatitis C virus (HCV) infection, the impact of early viral clearance on HCC is not well defined. In this study, we compared the risk of HCC among individuals who spontaneously cleared HCV (SC), the referent population, with the risk in untreated chronic HCV (UCHC), those achieved SVR, and those who failed interferon‐based treatment (TF). The BC Hepatitis Testers Cohort (BC‐HTC) includes individuals tested for HCV between 1990‐2013, integrated with medical visits, hospitalizations, cancers, prescription drugs and mortality data. This analysis included all HCV‐positive patients with at least one valid HCV RNA by PCR on or after HCV diagnosis. Of 46 666 HCV‐infected individuals, there were 12 527 (26.8%) SC; 24 794 (53.1%) UCHC; 5355 (11.5%) SVR and 3990 (8.5%) TF. HCC incidence was lowest (0.3/1000 person‐years (PY)) in the SC group and highest in the TF group (7.7/1000 PY). In a multivariable model, compared to SC, TF had the highest HCC risk (hazard ratio (HR):14.52, 95% confidence interval (CI): 9.83‐21.47), followed by UCHC (HR: 5.85; 95% CI: 4.07‐8.41). Earlier treatment‐based viral clearance similar to SC could decrease HCC incidence by 69.4% (95% CI: 57.5‐78.0), 30% (95% CI: 10.8‐45.1) and 77.5% (95% CI: 69.4‐83.5) among UCHC, SVR and TF patients, respectively. In conclusion, using SC as a real‐world comparator group, it showed that substantial reduction in HCC risk could be achieved with earlier treatment initiation. These analyses should be replicated in patients who have been treated with direct acting antiviral therapies.