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The Impact of Direct-acting Antiviral Therapy on End Stage Liver Disease Among Individuals with Chronic Hepatitis C and Substance Use Disorders
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Hepatology - 05 February 2021 - Haesuk Park1, Xinyi Jiang1, Hyun Jin Song1, Vincent Lo Re III2, Lindsey M. Childs-Kean3, Wei-Hsuan
Lo-Ciganic1, Robert L. Cook4, David R. Nelson4
In conclusion, despite the availability of effective all-oral DAA therapies, the rate of DAA prescribed treatment is much lower among HCV patients with an SUD compared to HCV patients without an SUD. The incidence rates for DCC and HCC were higher for those with an SUD compared to those without an SUD, but treatment with DAA therapy was significantly associated with a decreased risk for DCC and HCC. Our findings suggest that all those with HCV and an SUD should receive DAA treatment, and it is important to develop strategies that complement the initiation of DAA treatment and treatment of SUD, especially for those with an alcohol use disorder. .....Among the HCV patients with an SUD, 24% initiated DAA therapy, which is significantly lower compared to the initiation rate of 34% of HCV patients without an SUD
Abstract
To evaluate the impact of direct-acting antivirals (DAAs) on decompensated cirrhosis (DCC) and hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) and substance use disorder (SUD) compared to those without an SUD. This retrospective cohort study used the MarketScan database (2013-2018) to identify 29 228 patients with chronic HCV, where 22% (n=6385) had ≥1 SUD diagnosis. The inverse probability of treatment weighted (IPTW) multivariable Cox proportional hazard models were used to compare the risk of developing DCC and HCC. Among the non-cirrhotics, treatment reduced the DCC risk among SUD (aHR 0.13; 95% CI, 0.06-0.30) and non-SUD (aHR 0.11; 95% CI, 0.07-0.18) while the risk for HCC was not reduced for the SUD group (aHR 0.91; 95% CI, 0.33-2.48). For those with cirrhosis, compared to untreated patients, treatment reduced the HCC risk among SUD (aHR, 0.33; 95% CI, 0.13-0.88) and non-SUD (aHR, 0.40; 95% CI, 0.25-0.65) while the risk for DCC was not reduced for the SUD group (aHR, 0.64; 95% CI, 0.37-1.13). Among untreated patients with cirrhosis, the SUD group had a higher risk of DCC (aHR, 1.52; 95% CI, 1.03-2.24) and HCC (aHR, 1.69; 95% CI, 1.05-2.72) compared to non-SUD group.
Conclusions: Among the HCV SUD group, DAA treatment reduced the risk of DCC but not HCC for the non-cirrhotics while DAA treatment reduced the risk of HCC but not DCC for those with cirrhosis. Among the non-treated, patients with an SUD had a significantly higher risk of DCC and HCC compared to those without an SUD. Thus, DAA treatment should be considered for all HCV patients with an SUD while also addressing the SUD.
Of the HCV patients with an SUD, 57% had a diagnosis of opioid use disorder, 61% had a diagnosis of other drug-related disorders (22% with cocaine and heroin, 15% with sedatives, 11% with stimulants, 21% with cannabis), and 48% had a diagnosis of alcohol use disorder. Approximately one-third of the individuals with an SUD received some form of
medication for opioid use disorder or alcohol use disorder during the one year before and six months after their first HCV diagnosis. After we applied IPTW weighting, in the SUD and non-SUD cohort patients in the DAA and non-DAA groups achieved an acceptable balance (with standardized difference of each covariate <0.1).
Patient Characteristics
Of 29 228 patients newly diagnosed with HCV, 22% (n = 6385) had an SUD while 78% (n = 22 843) did not (Figure 1). HCV patients with an SUD were more likely to be younger (40% vs. 6% aged 18- 35 years) at the time of the HCV diagnosis, male (63% vs. 58%), and to have ALD (4.6% vs. 0.7%) compared to HCV patients in the non-SUD group (P-values <0.001) (Supplemental Table 2). Among the HCV patients with an SUD, 24% initiated DAA therapy, which is significantly lower compared to the initiation rate of 34% of HCV patients without an SUD (Table 1). Table 1 summarizes the patient characteristics between the treated and untreated groups, categorized by the presence of an SUD prior to the index date. Of the HCV patients with an SUD, 57% had a diagnosis of opioid use disorder, 61% had a diagnosis of other drug-related disorders (22% with cocaine and heroin, 15% with sedatives, 11% with stimulants, 21% with cannabis), and 48% had a diagnosis of alcohol use disorder. Approximately one-third of the individuals with an SUD received some form of medication for opioid use disorder or alcohol use disorder during the one year before and six months after their first HCV diagnosis. After we applied IPTW weighting, in the SUD and non-SUD cohort patients in the DAA and non-DAA groups achieved an acceptable balance (with standardized difference of each covariate <0.1).
DISCUSSION
This retrospective cohort study provides U.S. population-based evidence for the effects of all-oral DAA therapy on the incidence of DCC and HCC among a specific but growing population of HCV- infected patients—those with an SUD. Despite the National Viral Hepatitis Action Plan that prioritizes efforts to focus on improving access to care and treatment among HCV patients with an SUD, (31) less than one-fourth of HCV patients with an SUD initiated DAA therapy.
For both groups of patients, those with and without an SUD, treatment with DAAs resulted in a lower incidence of DCC and HCC when compared to no treatment; this finding further confirms the recommendations of the current treatment guidelines which suggest that HCV antiviral therapy is feasible in patients with an SUD and should be provided as indicated to avoid the development of liver complications. (32) These results continue to be very encouraging because they help confirm prior studies which showed that SUD patients treated for HCV can achieve similar adherence and SVR rates (10-14) as non-SUD patients, countering arguments that have been commonly used to limit treatment access in the SUD patient population. (33, 34)
In fact, we found that those with an SUD who were not treated had a significantly higher risk of developing DCC while those with an SUD and cirrhosis had a significantly higher risk for developing both DCC and HCC compared to those untreated without an SUD. Such a finding suggests that having an SUD may confer a more rapid progression to end stage liver disease especially if one has been diagnosed with ALD or uses alcohol with opioids or other drugs (polysubstance use disorder), most likely due to the synergic hepatotoxic effect of HCV and alcohol. (35) This suggestion becomes more apparent when we see that the DAA-treated non-SUD group received benefits against DCC and HCC regardless of their cirrhosis status. Therefore, we suggest that patients with HCV who also have ALD or use alcohol with other drugs are a group of patients at a particularly high risk for liver related adverse outcomes even with DAA treatment, a finding that was recently reported from a large Australian study. (36) As such, strategies must be developed that combine DAA therapy with the management of alcohol use disorder especially as some studies have suggested that patients with an alcohol use disorder and HCV are more likely to participate in risky drinking behaviors since to them severe liver-related outcomes appear to be inevitable. (37, 38)
Another factor associated with the development of DCC or HCC among those with HCV and an SUD was the presence of CKD in which one was over two times more likely to be diagnosed. This finding is most likely due to the known association of renal failure in patients with advanced liver disease and HCV. (39, 40) However, the presence of CKD does highlight the need to find, diagnose, and treat HCV before liver disease progresses to a point where other organ failure occurs. (39)
The reasons chronic HCV patients with SUD did not receive treatment may include insurance company restrictions (19), provider bias or lack of knowledge that new HCV medications do not have a negative impact on SUD, or a failure to follow up by the patients for HCV evaluation visits. Therefore, we think addressing the above barriers to treatment outside of health insurance is going to be key to meeting the U.S. Action Plan for Viral Hepatitis (31) as well as the World Health Organization’s goal of elimination of HCV by 2030, (41) especially for those with SUD-a group whose incidence of HCV is growing.
The goals of HCV treatment are to not only prevent the complications of liver disease, but also to prevent transmission of HCV. (42) Thus, DAA treatment is a key component in preventing HCV transmission especially among intravenous SUD patients. (43) It is noteworthy to mention that among newly diagnosed HCV patients aged 18-35 years, almost 66% of patients had at least one SUD diagnosis, which is significantly higher when compared to all other age groups. The substantially high proportion of SUD in young HCV patients is reflective of the recent changes in the demographics of HCV patients as a result of the opioid epidemic and the increase in injectable drug use. (4) Although those who were younger (18 to 35 years old) were less likely to develop DCC or HCC, this result highlights the need to follow the new CDC and the United States Preventive Services Task Force recommendation to screen for HCV more frequently among those with high-risk behaviors so that treatment with DAAs, if indicated, can be initiated before further liver damage is incurred. (7, 8)
Our study has several strengths. This retrospective, IPTW weighted cohort analysis is, to the best of our knowledge, one of the first population-based studies to report a reduced risk of developing DCC and HCC associated with DAA therapy among HCV patients with SUD compared to those without. This study has a large sample size and our cohort was representative of the general, insured population in the U.S. This study also has methodological strengths as it employed a prescription time-distribution matching to adjust time to initiate HCV treatment after diagnosis and the use of IPTW propensity scores to balance the characteristics of the treated and untreated groups.
There are also limitations to this study as this was an analysis of administrative claims data using ICD-9-CM and ICD-10-CM codes, which lacks laboratory results, so we were unable to report SVR and viral load to assess for reinfection, which could potentially have affected our outcomes of DCC or HCC. In addition, although a prior study has validated the use of billing ICD-9-CM and ICD-10-CM codes for the diagnosis of SUD definition (23) and this approach is commonly used in retrospective claims data analyses, some individuals with SUD remain unrecognized and underdiagnosed in routine practice. Thus, we may have underestimated the risk of DCC or HCC in the untreated patients with SUD. Although the methods we used to identify patients with cirrhosis and outcomes (DCC and HCC) have been validated and are highly accurate, (25, 28, 44) it is possible that incomplete, missing, or miscoded claims may impact the study findings; however, coding errors are likely distributed evenly between the treated and untreated patients. This study is also limited by its design as a retrospective cohort study; however, prospective studies comparing the effects of DAA therapy with no treatment would be unethical as DAAs have been shown to be highly efficacious. Another limitation is that we were only able to identify individuals who engaged the system, so our findings cannot be generalized to HCV patients with an SUD who do not have health insurance or Medicaid. As many state Medicaid programs still restrict access to DAA therapies for illicit drug or alcohol users, it is important to evaluate the risk of end-stage liver disease among Medicaid HCV patients with an SUD. In addition, patient mortality status is not fully captured in the claims database. A potential bias due to the competing risk of death may exist. We also were not able to differentiate between individuals with former and current SUDs as well as those who lived in rural versus urban areas. Finally, although we used the first five years of data after the approval of all-oral DAAs, we have a relatively short follow-up, which did not allow us to explore the long-term effect of all-oral DAAs.
In conclusion, despite the availability of effective all-oral DAA therapies, the rate of DAA prescribed treatment is much lower among HCV patients with an SUD compared to HCV patients without an SUD. The incidence rates for DCC and HCC were higher for those with an SUD compared to those without an SUD, but treatment with DAA therapy was significantly associated with a decreased risk for DCC and HCC. Our findings suggest that all those with HCV and an SUD should receive DAA treatment, and it is important to develop strategies that complement the initiation of DAA treatment and treatment of SUD, especially for those with an alcohol use disorder.
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