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Hepatitis C virus (HCV) disease progression in people who inject drugs (PWID): A systematic review and meta-analysis - IDUs are not engaged in care resulting in increased infectiousness/costs/disease progression
 
 
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HCV in IDUs: engage in care & treat
 
"Policy: Based on our synthesis of fibrosis progression, PWID on average will reach METAVIR stage F3 26-38 years after HCV infection, and will develop cirrhosis within 34-46 years. As in other populations where carcinogenic viruses are endemic, PWID are infected at an early age and thus may develop HCC in mid- to late-adulthood, leading to losses of individuals in their most productive period of life (Yang & Roberts, 2010). The prognosis following diagnosis with HCC is extremely poor, and the median length of survival is 12-15 months (Yip et al., 2014).......Our results also demonstrate that attempts to manage HCV-related costs by delaying treatment with the new regimens until patients develop advanced disease will result in a period of infectiousness that persists for an average of three to four decades. The impact of such restrictions on any proposed HCV eradication efforts will certainly be deleterious, resulting in increased costs to care for ill patients and delaying the achievement of HCV control. A Markov model of treatment with new agents demonstrated that liver disease complications were three times higher post-treatment in patients with cirrhosis compared to those with less advanced disease (Younossi & Henry, 2014)......However, just as new HCV treatments may not be implemented at public health scale to control HCV in PWID, the implementation of HCV prevention strategies lags far behind knowledge. Policy decisions regarding HCV treatment for PWID historically have been influenced by the perception that these patients will not adhere to treatment and will become re-infected (again, despite knowledge to the contrary) (de Vos and Kretzschmar, 2014, Harris and Rhodes, 2013). Progress toward elimination of HCV infection as a source of cirrhosis, liver failure and cancer will certainly require directly addressing the persistent stigmatization of drug use and drug users."
 
from Jules: addressing the potential for re-infection with education & programs is better health policy than not treating these patients, as the authors say not treating PWIDs results in increased rates of transmission in society, prevents elimination of the HCV epidemic which we now have the treatments to eliminate, and not treating these PWIDs put patients in a position, as the authors also say just above, to be at risk for advanced doses - HCC, fibrosis, cirrhosis - this increases public health costs & endangers the health & mortality of the patients.
 
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Article in Press
 
Hepatitis C virus (HCV) disease progression in people who inject drugs (PWID): A systematic review and meta-analysis
 
International Journal of Drug Policy July 24 2015
 
Daniel J. Smith a,*, Joan Combellick a, Ashly E. Jordan a,b, Holly Hagan a,b a College of Nursing, New York University, NY, NY, USA b Center for Drug Use and HIV Research, New York University, NY, NY, USA
 
Received: January 13, 2015; Received in revised form: May 27, 2015; Accepted: July 7, 2015; Published Online: July 24, 2015 Publication stage: In Press Corrected Proof
 
Highlights
 
· Early engagement in HCV needs to be a policy priority to address HCV as a source of serious disease in PWID.
 
· The natural history of HCV among PWID was explored through systematic review and data synthesis.
 
· Few people who inject drugs are engaged in needed care for chronic HCV infection.
 
· PWID infected with HCV will develop liver sequelae in mid- to late-adulthood if left untreated.
 
Abstract
 
Background

 
Understanding HCV disease progression rates among people who inject drugs (PWID) is important to setting policy to expand access to detection, diagnosis and treatment, and in forecasting the burden of disease. In this paper we synthesize existing data on the natural history of HCV among PWID, including fibrosis progression rates (FPR) and the incidence of compensated cirrhosis (CC), decompensated cirrhosis (DC), and hepatocellular carcinoma (HCC).
 
Methods
 
We conducted electronic and manual searches for published and unpublished literature. Reports were eligible if they (i) included participants who were chronically infected with HCV and reported current or previous injection drug use; (ii) presented original data on disease progression in a study sample comprised of at least 90% PWID; (iii) published between January 1, 1990, and December 31, 2013; and (iv) included data from upper-middle- or high-income countries. Quality ratings were assigned using an adaptation of the Quality In Prognosis Studies (QUIPS) tool. We estimated pooled FPRs using the stage-constant and stage-specific methods, and pooled incidence rates of CC, DC, and HCC.
 
Results
 
Twenty-one reports met the study inclusion criteria. Based on random-effect models, the pooled stage-constant FPR was 0.117 METAVIR units per year (95% CI, 0.099-0.135), and the stage-specific FPRs were F0 -> F1, 0.128 (95% CI 0.080, 0.176); F1 -> F2, 0.059 (95% CI 0.035, 0.082); F2 -> F3, 0.078 (95% CI 0.056, 0.100); and F3 -> F4, 0.116 (95% CI 0.070, 0.161). The pooled incidence rates of CC, DC, and HCC were 6.6 (95% CI 4.8, 8.4), 1.1 (95% CI 0.8, 1.4), and 0.3 (95% CI -0.1, 0.6) events per 1000 person-years, respectively. Following the stage-constant estimate, average time to cirrhosis is 34 years post-infection, and time to METAVIR stage F3 is 26 years; using the stage-specific estimates, time to cirrhosis is 46 years and time to F3 is 38 years.
 
Conclusion
 
Left untreated, PWID with chronic HCV infection will develop liver sequelae (including HCC) in mid- to late-adulthood. Delaying treatment with the new drug regimens until advanced fibrosis develops prolongs the period of infectiousness to perhaps thirty years. Scaling up of effective HCV prevention and early engagement in care and treatment will facilitate the elimination HCV as a source of serious disease in PWID.
 
Introduction
 
Hepatitis C virus (HCV) infection is a chronic blood-borne viral infection that is of global importance (Averhoff et al., 2012, Nelson et al., 2011). Approximately 160 million people, or 2-3% of the world's population, have chronic HCV; chronic HCV accounts for one-quarter of cases of cirrhosis and hepatocellular carcinoma (HCC) (Averhoff et al., 2012, Lavanchy, 2011, Nelson et al., 2011, World Health Organization, 2014). The vast majority of incident and prevalent HCV infections in the world are related to unsafe medical and illicit drug injections (Colvin & Mitchell, 2010). In most high-income countries, the primary route of HCV transmission is due to drug injection. HCV is concentrated in people who inject drugs (PWID) in these countries (Aceijas and Rhodes, 2007, Nelson et al., 2011), and approximately 50-80% of PWID are chronically infected (Nelson et al., 2011, Wiessing et al., 2014).
 
Viral and host factors hinder the detection, diagnosis and treatment of HCV in PWID (Hagan, 2011). Acute infection is typically asymptomatic and chronically infected individuals may not develop significant sequelae for decades after initial infection (Grebely et al., 2012). If left untreated, chronic liver disease will occur in 60-70%, cirrhosis in 5-20%, and 1-5% will die from decompensated cirrhosis or HCC (Rein et al., 2011). It has been estimated that fewer than 5% of PWID have received treatment for chronic HCV (Adeyemi et al., 2004, Grebely et al., 2009).
 
New HCV treatments feature shorter drug regimens with manageable side effects, and are highly likely to result in cure (Kohli, Shaffer, Sherman, & Kottilil, 2014). However these options are expensive and treatment eligibility guidelines may explicitly exclude active drug users (Fralick, 2014, Harris and Rhodes, 2013;Robaeys et al., 2013, World Health Organization, 2014). Many US states' public insurance programs (e.g., Medicaid) have restricted coverage of these new treatments to those with more advanced disease, i.e., METAVIR fibrosis stages 3 or 4, which may delay treatment for years; this restriction will disproportionately affect PWID and other low-income patients (Viohl & Associates, 2014). These restrictions also are in conflict with new HCV treatment guidelines from the American Association for the Study of Liver Disease (2015)), which state explicitly that active injection drug users should be prioritized for treatment in part because of the risk of transmission to susceptible injection partners.
 
Understanding HCV disease progression rates among PWID is important to setting policy to expand access to detection, diagnosis and treatment, and in forecasting the burden of disease. In this paper we synthesize existing data on the natural history of HCV among PWID, including fibrosis progression rates and the incidence of compensated cirrhosis (CC), decompensated cirrhosis (DC), and HCC. Prior systematic reviews of HCV disease progression in PWID did not explicitly exclude studies of HIV-HCV co-infected patients. Because the majority of PWID with HCV are mono-infected, it is important to characterize this group separately. Estimates from the analysis will be used to inform simulations of the impact and cost-effectiveness of HCV management among PWID. This systematic review and meta-analysis and related simulations are conducted as part of the HCV Synthesis Project (see Hagan et al., 2014, Jordan et al., 2014), which is funded to develop guidance and recommendations for HCV control strategies for the US.
 
Discussion
 
This systematic review synthesized the available data on the progression of fibrosis and the incidence of severe hepatic sequelae in PWID with chronic HCV infection. Random-effects estimation generated a stage-constant FPR of 0.117 and stage-specific FPRs of 0.128 (F0 -> F1), 0.059 (F1 -> F2), 0.078 (F2 -> F3), and 0.116 (F3 -> F4). The stage-constant rate (0.117) is within the range (and near the midpoint) of other stage-constant estimates from samples of HIV-negative patients with HCV infection due to other exposures (range 0.07, 0.151) (Bochud et al., 2009, Bonacini et al., 2001;Mathurin et al., 1998, Mohsen et al., 2003, Rodríguez-Torres et al., 2006, Souza et al., 2008).
 
Likewise, based on a progression rate of 0.117, the estimated time to cirrhosis of 34 years is near the midpoint of the time-to-event range (22, 57) in the other patient groups. Although there is wide variance in the estimates of fibrosis progression and the associated times to event, the stage-constant rate of the present meta-analysis lies near the centers of the distributions. Similarly, the stage-specific rates we derived—0.128 (F0 -> F1), 0.059 (F1 -> F2), 0.078 (F2 -> F3), and 0.116 (F3 -> F4)—are consistent with the rates of Thein et al. (2008)), who also examined fibrosis progression among PWID: 0.116 (F0 -> F1), 0.085 (F1 -> F2), 0.085 (F2 -> F3), and 0.130 (F3 -> F4). With the exception of the transition from F1 -> F2, our estimates deviate slightly from Thein et al.; this is demonstrated in the comparison of between-stage duration and overall time to CC. We estimate the occurrence of compensated cirrhosis at 46 years post-infection, and Thein et al. provide an estimate of 40 years. One explanation for the difference in rates is the moderation effect of HIV co-infection, which was prevalent in higher proportions in the PWID samples of Thein et al.
 
Limitations
 
There are several limitations to our study. Our inclusion criteria restricted the size of the dataset and limited generalizability to upper-middle and high-income countries. Also, the study-level estimates for the included reports were calculated using estimators that rely on cohort-level data rather than participant-level data, which was generally unavailable. Furthermore, our linear FPR was based on the assumption of stage-constant disease progression, and recent literature suggests that the course of disease may actually vary across fibrosis stages (Bochud et al., 2009, Sweeting et al., 2006, Thein et al., 2008, Yi et al., 2004), as suggested by the MML estimates we provided. However, because the lack of required data in some of the reports precluded calculation of stage-specific rates for all included literature that examined fibrosis progression, our MML estimation must be viewed with caution.
 
This analysis is further limited by the shortcomings of the contributing reports. First, reports varied in methodology, particularly the definition of chronic infection, the approximation of date of infection, and recruitment location. The potential inclusion of RNA-negative participants and the use of date of first injection as a time point for infection would underestimate rates of fibrosis progression and incidence of severe liver outcomes. On the other hand, many of the included studies recruited participants from hospitals, especially liver units, and this may overestimate progression to serious sequelae. This concern arises from studies of other conditions showing that patients who are experiencing symptoms (and have more advanced disease) are more likely to be found in specialty clinics (Ness et al., 2009, Wilfley et al., 2001).
 
Additionally, there was not enough information in the reports on factors that are known to influence the rate of progression (e.g., alcohol consumption), and thus we could not examine whether these factors explained variability. Furthermore, some extracted data, particularly those measuring baseline covariates, introduced the possibility of misclassification, wherein the reported sample characteristics may not accurately represent PWID after losses to follow-up. More consistent characterization and improved reporting of participants with respect to these prognostic factors in future studies will allow for more informative syntheses of disease progression rates.
 
Policy and research implications
 
Based on our synthesis of fibrosis progression, PWID on average will reach METAVIR stage F3 26-38 years after HCV infection, and will develop cirrhosis within 34-46 years. As in other populations where carcinogenic viruses are endemic, PWID are infected at an early age and thus may develop HCC in mid- to late-adulthood, leading to losses of individuals in their most productive period of life (Yang & Roberts, 2010). The prognosis following diagnosis with HCC is extremely poor, and the median length of survival is 12-15 months (Yip et al., 2014).
 
It is clear that there is a need for more literature describing the impact of alcohol consumption and other factors on disease development in PWID, particularly in view of the likelihood that new HCV treatments will not be made available on a public health scale and that other measures to reduce disease development will remain important. Consistent reporting of excess or problem drinking using standard measures, such as the Alcohol Use Disorders Identification Test (AUDIT) (Babor, Higgins-Biddle, Saunders, & Monteiro, 2001), will permit comparing and pooling of data across studies. Our review showed that the number of studies of the natural history of HCV in PWID is relatively small, so standard reporting of drinking and other patient characteristics is particularly important to advancing our understanding of the role of these factors.
 
Our results also demonstrate that attempts to manage HCV-related costs by delaying treatment with the new regimens until patients develop advanced disease will result in a period of infectiousness that persists for an average of three to four decades. The impact of such restrictions on any proposed HCV eradication efforts will certainly be deleterious, resulting in increased costs to care for ill patients and delaying the achievement of HCV control. A Markov model of treatment with new agents demonstrated that liver disease complications were three times higher post-treatment in patients with cirrhosis compared to those with less advanced disease (Younossi & Henry, 2014).
 
One of the main goals in synthesizing data on disease progression rates is to inform our (and others') modeling of the impact of various combinations of prevention and treatment interventions on HCV disease burden and its associated costs to society and individual patients, so as to influence policy decisions regarding the allocation of public health resources. Recent evidence shows that combination prevention (opiate substitution treatment and syringe access) may reduce HCV incidence in PWID by 75-80% (Hagan et al., 2011, Turner et al., 2011).
 
However, just as new HCV treatments may not be implemented at public health scale to control HCV in PWID, the implementation of HCV prevention strategies lags far behind knowledge. Policy decisions regarding HCV treatment for PWID historically have been influenced by the perception that these patients will not adhere to treatment and will become re-infected (again, despite knowledge to the contrary) (de Vos and Kretzschmar, 2014, Harris and Rhodes, 2013). Progress toward elimination of HCV infection as a source of cirrhosis, liver failure and cancer will certainly require directly addressing the persistent stigmatization of drug use and drug users.
 
Results
 
Overview of included reports

 
As presented in Fig. 1, 21 unique reports were included in this review. Table 1, Table 2 present the pooled estimates and characteristics of the included reports for each of the four main outcomes of interest: FPR (10 reports), CC (15 reports), DC (4 reports), and HCC (5 reports). The geographic scope of the data focused largely on Europe where 11 reports (52%) originated; a smaller percentage represented data from the United States (5; 24%) and Australia (5; 24%). A total of 8502 unique PWID contributing 145,228.6 person-years (PYs) of observation for the study of four major HCV-related outcomes were included in this review. Among the 8495 PWID for which data on duration of infection was available, the estimated mean disease duration was 15.0 years (median 14.1; range 5.6, 26.0; 20 reports); in 7177 PWID, the estimated age of infection was 20.8 years (median 21.1; range 15.8, 23.0; 17 reports).
 
Across the included reports, very few participant characteristics were consistently measured and presented. Sex and age were described most frequently; 19 reports (90%) summarized the sex distribution, and 14 reports (67%) provided a mean or median estimate of age at enrollment. Despite its critical role in the progression of liver disease, alcohol consumption among participants was given in only 13 reports (62%), measurement of alcohol use varied widely, and few reports specifically assessed problem or excess drinking.
 
Pooled estimates
 
In Table 1, Table 2, Table 3, Table 4, Table 5, both fixed-effect and random-effects meta-analysis results are presented. We discuss below only the random-effects estimates.
 
Fibrosis progression rate
 
A total of 2607 participants representing 41,119 PYs and 3775 cumulative METAVIR units contributed to the study of FPR in 10 reports. Among 2361 PWID in 9 of the remaining 10 reports, the estimated mean duration of infection was 15.2 years (median 14.6; range 5.6, 26.0) and the estimated mean age of infection was 20.7 years (median 21.0; range 15.8, 23.0).
 
Linear estimation
 
In the 10 reports, the pooled stage-constant estimate of fibrosis progression (F0 -> F4), described in Table 1, was 0.117 units per year (range 0.070, 0.232). Using this estimate, time to CC was 34 years for an individual with chronic HCV.
 
Nonlinear estimation
 
MML estimation was performed for 6 of the 10 reports containing sufficient data on the fibrosis staging distribution and person-time of the sample. Table 3 presents the pooled stage-specific transition rates among this subset; the FPRs were the following: F0 -> F1, 0.128 (CI 0.080, 0.176); F1 -> F2, 0.059 (CI 0.035, 0.082); F2 -> F3, 0.078 (CI 0.056, 0.100); and F3 -> F4, 0.116 (CI 0.070, 0.161). Based on this progression sequence, time to CC was 46 years.
 
Cirrhosis
 
In aggregate, 4340 participants contributing 66,256 PYs were examined in the 15 reports characterizing CC. Among these participants the estimated mean disease duration was 15.4 years (median 14.6; range 7.8, 26.0); from 12 reports examining 3022 PWID, the estimated mean age of infection was 20.5 years (median 21.0; range 15.8, 22.0). The pooled incidence rate was 6.6 events per 1000 PYs (95% CI 4.8, 8.4).
 
Decompensated cirrhosis
 
Within the four reports investigating DC, there were 2003 participants who provided 41,311 PYs of observation. The estimated mean duration of infection was 18.3 years (median 17.7; range 12.0, 26.0; 4 reports), and the estimated mean age of infection was 19.9 years (median 20.9; range 15.8, 22.0; 4 reports). The pooled incidence was 1.1 events per 1000 PYs (95% CI 0.8, 1.4).
 
Hepatocellular carcinoma
 
HCC was examined in five reports representing 80,096 PYs and 4506 participants. In these reports, the estimated mean disease duration was 16.9 years (median 18.0; range 12.0, 19.0); from the four reports that assessed 4432 PWID, the estimated mean age of infection was 20.4 years (median 20.3; range 19.0, 22.0). Most of these reports presented data from cohorts prior to 2001. The pooled incidence rate was 0.3 events per 1000 PYs (95% CI -0.1, 0.6).
 
Quality ratings
 
Mean quality scores, ranging from 0 (low) to 2 (high), by outcome for the reports on FPR, CC, DC, and HCC were 1.5, 1.3, 1.8, and 1.8, respectively. Using random-effects modeling, we conducted subgroup analysis of the quality ratings for the reports examining fibrosis progression; reports were stratified by quality score and pooled stage-constant estimates were calculated. Referring to Table 4, the results suggest a negative correlation between report quality and fibrosis progression—that is, in higher quality reports, the FPR is slower (low 0.164, n studies = 3; moderate N/A, n = 0; high 0.107, n = 7). The variance across the pooled estimates translates to a range for time to cirrhosis of 24-37 years.
 
Of the study design issues accounted for in the quality ratings instrument, we were particularly interested in selection bias, defined for our purposes as the likelihood that observed disease progression was related to the setting or method for recruiting participants. The overall rating for selection bias was 1.4. This mean score corresponds to the lower rating applied to reports that sampled from liver or unidentified units in hospitals, wherein the population is believed to be composed disproportionately of individuals with more severe hepatic conditions.
 
Table 4 presents additional analysis of report-level data and fibrosis progression. The pooled stage-constant FPR was 0.112 for those reports in which recruitment exclusively occurred in liver clinics (n = 5) compared to 0.125 for reports that recruited across multiple clinics or non-clinical settings (n = 5); the difference in time to CC was approximately 4 years (36 vs. 32 years). In comparing the chain of stage-specific rates in Table 4, CC occurs at 42 years post-infection among samples exclusively drawn from liver clinics (n = 4) and at 69 years for samples recruited in all other settings (n = 2).
 
Heterogeneity
 
Tests for heterogeneity, detailed in Table 1, Table 2, Table 3, revealed significant variability across the reports contributing to four of the eight outcomes. Among the meta-analysis estimates affected by heterogeneity, the Q-statistic was associated with a p-value less than 0.05, and the I2 values suggested moderate to high inconsistency. However, there was no strong evidence to suggest the influence of heterogeneity in the estimation of four outcomes: the stage-specific progression from F2 -> F3 and F3 -> F4, and the incidence of DC and HCC. The p-values for all Q-statistics were greater than 0.10, and I2 values were below 23%.
 
Meta-regression
 
We performed a random-effects meta-regression to examine the influence of report and participant characteristics on fibrosis progression and incidence of CC. Both stage-constant and stage-specific rates were used as dependent variables. In a univariate regression, quality rating (coeff. -0.029; 95% CI -0.055, -0.004; p = 0.026) was associated with a slower stage-constant FPR. However, there was no evidence of an effect of quality rating on stage-specific fibrosis progression or incidence of CC. (Results are not shown.) The results of a multivariate analysis are presented in Table 5. Across all three outcome variables, there was no evidence to suggest the influence of age at infection, duration of infection, male sex, or recruitment from clinical settings.
 
 
 
 
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