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We determined the optimal HCV treatment prioritization strategy for interferon-free (IFN-free) HCV direct-acting antivirals (DAAs) by disease stage and risk status incorporating ...treatment of people who inject drugs (PWID).
A dynamic HCV transmission and progression model compared the cost-effectiveness of treating patients early vs. delaying until cirrhosis for patients with mild or moderate fibrosis, where PWID chronic HCV prevalence was 20, 40 or 60%. Treatment duration was 12weeks at £3300/wk, to achieve a 95% sustained viral response and was varied by genotype/stage in alternative scenarios. We estimated long-term health costs (in £UK=€1.3=$1.5) and outcomes as quality adjusted life-years (QALYs) gained using a £20,000 willingness to pay per QALY threshold. We ranked strategies with net monetary benefit (NMB); negative NMB implies delay treatment.
The most cost-effective group to treat were PWID with moderate fibrosis (mean NMB per early treatment £60,640/£23,968 at 20/40% chronic prevalence, respectively), followed by PWID with mild fibrosis (NMB £59,258 and £19,421, respectively) then ex-PWID/non-PWID with moderate fibrosis (NMB £9,404). Treatment of ex-PWID/non-PWID with mild fibrosis could be delayed (NMB -£3,650). In populations with 60% chronic HCV among PWID it was only cost-effective to prioritize DAAs to ex-PWID/non-PWID with moderate fibrosis. For every one PWID in the 20% chronic HCV setting, 2 new HCV infections were averted. One extra HCV-related death was averted per 13 people with moderate disease treated. Rankings were unchanged with reduced drug costs or varied sustained virological response/duration by genotype/fibrosis stage.
Treating PWID with moderate or mild HCV with IFN-free DAAs is cost-effective compared to delay until cirrhosis, except when chronic HCV prevalence and reinfection risk is very high.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background. Interventions such as opiate substitution therapy (OST) and high-coverage needle and syringe programs (HCNSP) cannot substantially reduce hepatitis C virus (HCV) prevalence among people ...who inject drugs (PWID). HCV antiviral treatment may prevent onward transmission. We project the impact of combining OST, HCNSP, and antiviral treatment on HCV prevalence/incidence among PWID. Methods. An HCV transmission model among PWID was used to project the combinations of OST, HCNSP, and antiviral treatment required to achieve different prevalence and incidence reductions within 10 years for 3 chronic prevalence scenarios and the impact of HCV treatment if only delivered through OST programs. Multivariate and univariate sensitivity analyses were performed. Results. Large reductions (>45%) in HCV chronic prevalence over 10 years require HCV antiviral treatment. Scaling up OST and HCNSP substantially reduces the treatment rate required to achieve specific HCV prevalence reductions. If OST and HCNSP coverage were increased to 40% each (no coverage at baseline), then annually treating 10, 23, or 42 per 1000 PWID over 10 years would halve prevalence for 20%, 40%, or 60% baseline chronic HCV prevalences, respectively. Approximately 30% fewer treatments are necessary with new direct-acting antivirals. If coverage of OST and HCNSP is 50% at baseline, similar prevalence reductions require higher treatment rates for the same OST and HCNSP coverage. Conclusions. Combining antiviral treatment with OST with HCNSP is critical for achieving substantial reductions (>50%) in HCV chronic prevalence over 10 years. Empirical studies are required on how best to scale up antiviral treatment and combine treatment with other interventions.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Background. Although guidelines recommend that people who inject drugs (PWID) should not be excluded from hepatitis C (HCV) treatment, some services remain reluctant to treat PWID. The aim of this ...review was to investigate sustained virologic response (SVR), adherence, discontinuation, and HCV reinfection among PWID. Methods. A search of Medline, Embase, and Cochrane databases (between 2002 and January 2012) was conducted for primary articles/conference abstracts examining HCV treatment outcomes in PWID. Meta-analysis was used to obtain pooled estimates of SVR, adherence, discontinuation, and HCV reinfection. Results. Ten primary articles and 1 conference abstract met the inclusion criteria. Across 6 studies (comprising 314 drug users, of whom 141 45% were PWID), pooled SVR was 56% (95% confidence interval CI, 50%–61%) for all genotypes, 37% (95% CI, 26%–48%) for genotypes 1/4, and 67% (95% CI, 56%–78%) for genotypes 2/3. Pooled 80/80/80 adherence was 82% (95% CI, 74%–89%) across 2 studies, and pooled treatment discontinuation was 22% (95% CI, 16%–27%) across 4 studies. Across 5 studies (comprising 131 drug users) examining reinfection, pooled risk was 2.4 (95% CI, .9–6.1) per 100 person-years. Conclusions. HCV treatment outcomes are acceptable in PWID, supporting treatment guidelines. The pooled estimate of HCV reinfection risk was low, but there was considerable uncertainty around this estimate. Further studies on the risk of reinfection are needed to assess the long-term effectiveness of HCV treatment in PWID.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Government policy has precipitated recent changes in the provision of harm reduction interventions - injecting equipment provision (IEP) and opiate substitution therapy (OST) - for people who inject ...drugs (PWID) in Scotland. We sought to examine the potential impact of these changes on hepatitis C virus (HCV) transmission among PWID.
We used a framework to triangulate different types of evidence: 'group-level/ecological' and 'individual-level'. Evidence was primarily generated from bio-behavioural cross-sectional surveys of PWID, undertaken during 2008-2012. Individuals in the window period (1-2 months) where the virus is present, but antibodies have not yet been formed, were considered to have recent infection. The survey data were supplemented with service data on the provision of injecting equipment and OST. Ecological analyses examined changes in intervention provision, self-reported intervention uptake, self-reported risk behaviour and HCV incidence; individual-level analyses investigated relationships within the pooled survey data. Nearly 8,000 PWID were recruited in the surveys. We observed a decline in HCV incidence, per 100 person-years, from 13.6 (95% CI: 8.1-20.1) in 2008-09 to 7.3 (3.0-12.9) in 2011-12; a period during which increases in the coverage of OST and IEP, and decreases in the frequency of injecting and sharing of injecting equipment, were observed. Individual-level evidence demonstrated that combined high coverage of needles/syringes and OST were associated with reduced risk of recent HCV in analyses that were unweighted (AOR 0.29, 95%CI 0.11-0.74) and weighted for frequency of injecting (AORw 0.05, 95%CI 0.01-0.18). We estimate the combination of harm reduction interventions may have averted 1400 new HCV infections during 2008-2012.
This is the first study to demonstrate that impressive reductions in HCV incidence can be achieved among PWID over a relatively short time period through high coverage of a combination of interventions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Needle and syringe programmes (NSP) aim to reduce the risk of HIV by providing people who inject drugs (PWID) with sterile injecting equipment. A recent review of reviews (ROR) concluded that there ...was only tentative evidence to support the effectiveness of NSP in reducing HIV. We carried out a systematic review and meta-analysis to assess the association between NSP and HIV transmission.
Relevant primary articles presenting data on the risk of HIV transmission associated with NSP were identified in two stages: (i) from reviews identified in two published RORs (covering the period 1980-2008); and (ii) a literature search of CINAHL, Cochrane Library, EMBASE, MEDLINE and PsychINFO for primary articles published since the most recent high quality review (covering the period 2008-12). Study results were synthesized using random-effects meta-analysis.
There were 12 studies comprising at least 12 000 person-years of follow-up. Exposure to NSP was associated with a reduction in HIV transmission: pooled effect size 0·66 95% confidence interval (CI) 0·43, 1·01 across all studies, and 0·42 (95% CI 0·22, 0·81) across six higher quality studies (according to the Newcastle-Ottawa tool).
There is evidence to support the effectiveness of NSP in reducing the transmission of HIV among PWID, although it is likely that other harm reduction interventions have also contributed to the observed reduction in HIV risk. NSP should be considered as just one component of a programme of interventions to reduce both injecting risk and other types of HIV risk behaviour.
Substantial reductions in hepatitis C virus (HCV) prevalence among people who inject drugs (PWID) cannot be achieved by harm reduction interventions such as needle exchange and opiate substitution ...therapy (OST) alone. Current HCV treatment is arduous and uptake is low, but new highly effective and tolerable interferon‐free direct‐acting antiviral (DAA) treatments could facilitate increased uptake. We projected the potential impact of DAA treatments on PWID HCV prevalence in three settings. A dynamic HCV transmission model was parameterized to three chronic HCV prevalence settings: Edinburgh, UK (25%); Melbourne, Australia (50%); and Vancouver, Canada (65%). Using realistic scenarios of future DAAs (90% sustained viral response, 12 weeks duration, available 2015), we projected the treatment rates required to reduce chronic HCV prevalence by half or three‐quarters within 15 years. Current HCV treatment rates may have a minimal impact on prevalence in Melbourne and Vancouver (<2% relative reductions) but could reduce prevalence by 26% in 15 years in Edinburgh. Prevalence could halve within 15 years with treatment scale‐up to 15, 40, or 76 per 1,000 PWID annually in Edinburgh, Melbourne, or Vancouver, respectively (2‐, 13‐, and 15‐fold increases, respectively). Scale‐up to 22, 54, or 98 per 1,000 PWID annually could reduce prevalence by three‐quarters within 15 years. Less impact occurs with delayed scale‐up, higher baseline prevalence, or shorter average injecting duration. Results are insensitive to risk heterogeneity or restricting treatment to PWID on OST. At existing HCV drug costs, halving chronic prevalence would require annual treatment budgets of US $3.2 million in Edinburgh and approximately $50 million in Melbourne and Vancouver. Conclusion: Interferon‐free DAAs could enable increased HCV treatment uptake among PWID, which could have a major preventative impact. However, treatment costs may limit scale‐up, and should be addressed. (Hepatology 2013;58:1598–1609)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Sustained viral response (SVR) is the optimal outcome of hepatitis C virus (HCV) therapy, yet more detailed data are required to confirm its clinical value. Individuals receiving treatment in ...1996‐2011 were identified using the Scottish HCV clinical database. We sourced data on 10 clinical events: liver, nonliver, and all‐cause mortality; first hospitalisation for severe liver morbidity (SLM); cardiovascular disease (CVD); respiratory disorders; neoplasms; alcohol‐intoxication; drug intoxication; and violence‐related injury (note: the latter three events were selected a priori to gauge ongoing chaotic lifestyle behaviours). We determined the association between SVR attainment and each outcome event, in terms of the relative hazard reduction and absolute risk reduction (ARR). We tested for an interaction between SVR and liver disease severity (mild vs. nonmild), defining mild disease as an aspartate aminotransferase‐to‐platelet ratio index (APRI) <0.7. Our cohort comprised 3,385 patients (mean age: 41.6 years), followed‐up for a median 5.3 years (interquartile range: 3.3‐8.2). SVR was associated with a reduced risk of liver mortality (adjusted hazard ratio AHR: 0.24; P < 0.001), nonliver mortality (AHR, 0.68; P = 0.026), all‐cause mortality (AHR, 0.49; P < 0.001), SLM (AHR, 0.21; P < 0.001), CVD (AHR, 0.70; P = 0.001), alcohol intoxication (AHR, 0.52; P = 0.003), and violence‐related injury (AHR, 0.51; P = 0.002). After 7.5 years, SVR was associated with significant ARRs for liver mortality, all‐cause mortality, SLM, and CVD (each 3.0%‐4.7%). However, we detected a strong interaction, in that ARRs were considerably higher for individuals with nonmild disease than for individuals with mild disease. Conclusions: The conclusions are 3‐fold: (1) Overall, SVR is associated with reduced hazard for a range of hepatic and nonhepatic events; (2) an association between SVR and behavioral events is consistent with SVR patients leading healthier lives; and (3) the short‐term value of SVR is greatest for those with nonmild disease. (Hepatology 2015;62:355–364
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict ...the HCC development for patients with chronic hepatitis.
A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686).
We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin–bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82–0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0–0.8%, 1.5–4.8%, and 8.1–19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7–100% and a negative predictive value of 99.3–100%. The cut-off value of 60 resulted in a specificity of 56.6–95.8% and a positive predictive value of 6.6–15.7%.
This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide.
In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin–bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.
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•In total, 17,374 patients with viral and non-viral hepatitis from 11 global prospective cohorts/trials were studied.•An HCC risk score (called the aMAP score, ranging from 0 to 100), which involves only age, male, albumin–bilirubin and platelet data, was developed and validated.•The aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk irrespective of aetiology and ethnicity.•Patients with aMAP score <50, accounting for 44% of overall population, had an HCC incidence of <0.2% per year.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The expense of new therapies for HCV infection may force health systems to prioritise the treatment of certain patient groups over others. Our objective was to forecast the population impact of ...possible prioritisation strategies for the resource-rich setting of Scotland.
We created a dynamic Markov simulation model to reflect the HCV-infected population in Scotland. We determined trends in key outcomes (e.g., incident cases of chronic infection and severe liver morbidity (SLM)) until the year 2030, according to treatment strategies involving prioritising, either: (A) persons with moderate/advanced fibrosis or (B) persons who inject drugs (PWID).
Continuing to treat the same number of patients with the same characteristics will give rise to a fall in incident infection (from 600 cases in 2015 to 440 in 2030) and a fall in SLM (from 195 cases in 2015 to 145 in 2030). Doubling treatment-uptake and prioritising PWID will reduce incident infection to negligible levels (<50 cases per year) by 2025, while SLM will stabilise (at 70-75 cases per year) in 2028. Alternatively, doubling the number of patients treated, but, instead, prioritising persons with moderate/advanced fibrosis will reduce incident infection less favourably (only to 280 cases in 2030), but SLM will stabilise by 2023 (i.e., earlier than any competing strategy).
Prioritising treatment uptake among PWID will substantially impact incident transmission, however, this approach foregoes the optimal impact on SLM. Conversely, targeting those with moderate/advanced fibrosis has the greatest impact on SLM but is suboptimal in terms of averting incident infection.
In resource‐rich countries, chronic hepatitis C (CHC) infection is associated with a sizeable excess mortality risk. The extent to which this is due to (1) the biological sequelae of CHC infection ...versus (2) a high concomitant burden of health risk behaviors (HRBs) is unclear. We used data from the 1999‐2010 U.S. National Health and Nutritional Examination Surveys (NHANES), which include detailed information on HRBs and CHC infection status. We calculated the prevalence of the five major HRBs—alcohol use; cigarette smoking, physical inactivity, unhealthy diet, and illicit drug use—according to CHC after adjusting for sociodemographic differences. Mortality status after survey interview was ascertained by linkage to the U.S. National Death Index. To assess the contribution of HRBs to the excess mortality risk, we determined the all‐cause mortality rate ratio (MRR) for individuals with CHC relative to individuals without, and then calculated the attenuation in this MRR following adjustment for HRBs. This analysis included 27,468 adult participants of NHANES of which 363 tested positive for CHC. All HRBs were markedly more prevalent among individuals with CHC versus individuals without. CHC was associated with a 2.4‐fold higher mortality rate after adjustment for sociodemographic factors (MRR, 2.36; 95% CI, 1.60‐3.49). Subsequent adjustment for all five HRBs attenuated this ratio by 50.7% to MRR 1.67 (95% CI, 1.14‐2.44). Higher levels of attenuation (69.1%) were observed among individuals aged 45‐70 years, who form the target demographic for U.S. birth cohort screening. Conclusion: At least half the excess mortality risk for individuals with CHC in the United States may be attributed to HRBs rather than CHC. The remedial response to hepatitis C must not neglect action on HRBs if it is to fully resolve the high mortality problem in this population. (Hepatology 2018;67:97‐107).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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