Friday, November 4, 2016

Safe and effective sofosbuvir-based therapy in patients with mental health disease on hepatitis C virus treatment

Safe and effective sofosbuvir-based therapy in patients with mental health disease on hepatitis C virus treatment
Lydia Shuk Yee Tang, Jack Masur, Zayani Sims, Amy Nelson, Anu Osinusi, Anita Kohli, Sarah Kattakuzhy, Michael Polis, Shyam Kottilil

World J Hepatol. Nov 8, 2016; 8(31): 1318-1326
Published online Nov 8, 2016. doi: 10.4254/WJH.v8.i31.1318

Abstract
AIM
To study impact of baseline mental health disease on hepatitis C virus (HCV) treatment; and Beck’s Depression Inventory (BDI) changes with sofosbuvir- and interferon-based therapy.

METHODS
This is a retrospective cohort study of participants from 5 studies enrolled from single center trials conducted at the Clinical Research Center of the National Institutes of Health, Bethesda, MD, United States. All participants were adults with chronic HCV genotype 1 infection and na├»ve to HCV therapy. Two of the studies included HCV mono-infected participants only (SPARE, SYNERGY-A), and 3 included human immunodeficiency virus (HIV)/HCV co-infected participants only (ERADICATE, PFINPK, and ALBIN). Patients were treated for HCV with 3 different regimens: Sofosbuvir and ribavirin in the SPARE trial, ledipasvir and sofosbuvir in SYNERGY-A and ERADICATE trials, and pegylated interferon (IFN) and ribavirin for 48 wk in the PIFNPK and ALBIN trials. Participants with baseline mental health disease (MHD) were identified (defined as either a DSM IV diagnosis of major depression, bipolar disorder, schizophrenia, generalized anxiety, and post-traumatic stress disorder or requiring anti-depressants, antipsychotics, mood stabilizers or psychotropics prescribed by a psychiatrist). For our first aim, we compared sustained virologic response (SVR) and adherence (pill counts, study visits, and in 25 patients, blood levels of the sofosbuvir metabolite, GS-331007) within each study. For our second aim, only patients with HIV coinfection were evaluated. BDI scores were obtained pre-treatment, during treatment, and post-treatment among participants treated with sofosbuvir-based therapy, and compared to scores from participants treated with interferon-based therapy. Statistical differences for both aims were analyzed by Fisher’s Exact, and t-test with significance defined as a P value less than 0.05.

RESULTS
Baseline characteristics did not differ significantly between all participants with and without MHD groups treated with sofosbuvir-based therapy. Among patients treated with sofosbuvir-based therapy, the percentage of patients with MHD who achieved SVR was the same as those without (SPARE: 60.9% of those MHD compared to 67.6% in those without, P = 0.78; SYNERGY-A: 100% of both groups; ERADICATE: 100% compared to 97.1%). There was no statistically significant difference in pill counts, adherence to study visits between groups, nor mean serum concentrations of GS-331007 for each group at week 2 of treatment (P = 0.72). Among patients with HIV co-infection, pre-treatment BDI scores were similar among patients treated with sofosbuvir, and those treated with interferon (sofosbuvir-based 5.24, IFN-based 6.96; P = 0.14); however, a dichotomous effect on was observed during treatment. Among participants treated with directly acting antiviral (DAA)-based therapy, mean BDI scores decreased from 5.24 (pre-treatment) to 3.28 during treatment (1.96 decrease, P = 0.0034) and 2.82 post-treatment. The decrease in mean score from pre- to post-treatment was statistically significant (-2.42, P = 0.0012). Among participants treated with IFN-based therapy, mean BDI score increased from 6.96 at pre-treatment to 9.19 during treatment (an increase of 2.46 points, P = 0.1), and then decreased back to baseline post-treatment (mean BDI score 6.3, P = 0.54). Overall change in mean BDI scores from pre-treatment to during treatment among participants treated with DAA-based and IFN-therapy was statistically significant (-1.96 and +2.23, respectively; P = 0.0032). This change remained statistically significant when analysis was restricted to participants who achieved SVR (-2.0 and +4.36, respectively; P = 0.0004).

CONCLUSION
Sofosbuvir-based therapy is safe and well tolerated in patients with MHD. A decline in BDI associated with sofosbuvir-based HCV treatment suggests additional MHD benefits, although the duration of these effects is unknown.

Core tip: The prevalence of mental health disease (MHD) among patients with chronic hepatitis C virus (HCV) can be high. However, patients with MHD may be marginalized with respect to HCV therapy and MHD is one of the most frequently cited reason for exclusion from HCV therapy. HCV therapy has evolved from interferon-based to directly acting antiviral (DAA)-based therapy with excellent tolerability and efficacy. Our study found that baseline MHD did not impact efficacy nor treatment adherence to sofosbuvir-based therapy. Furthermore, we found that Becks Depression Inventory scores improved with sofosbuvir-based therapy, suggesting that HCV treatment with the newer DAA therapies may have additional mental health benefits.

DISCUSSION ONLY
View Full Text Article - World J Hepatol. Nov 8, 2016; 8(31): 1318-1326
Published online Nov 8, 2016. doi: 10.4254/WJH.v8.i31.1318

Sofosbuvir-based therapy was equally effective among participants with MHD, and among those without MHD. Patients with baseline MHD demonstrated similar levels of adherence with study visits, study drugs, and achieved similar rates of SVR to those who did not have a baseline MHD diagnosis. Furthermore, among participants with HIV/HCV coinfection treated with DAA therapy, we observed a statistically significant improvement in BDI scores during and after the end of treatment time point (post-treatment) compared to baseline (pre-treatment), while participants treated with IFN-based therapy saw no significant change in BDI scores.

In a study of 4084 United States veterans, psychiatric disease was identified as a predictor of non-treatment (odds ratio = 9.45)[29]. Furthermore, due to shared transmission routes, HIV/HCV coinfection can be high among certain cohorts. A cross sectional study of a large cohort of patients with HIV found that 21% were coinfected with HCV. Among these patients with HIV/HCV coinfection, depression severity scores were higher, and antidepressant medications were more often prescribed, compared to patients with HIV mono-infection[30]. Concern for emergent or worsening of neuropsychiatric side effects associated with interferon-based HCV therapy resulted in treatment deferment even for patients with stable MHD[14,31,32]. The treatment of chronic HCV, however, has evolved to interferon-free, all-oral, DAA regimens. Concerns regarding adherence to and subsequent success with DAA regimens among patients with MHD remains to be addressed.

This study has 2 aims: Firstly, to address the impact of baseline MHD on adherence to and subsequent success with DAA regimens among patients with MHD; and secondly, to describe the change in BDI scores among patients treated with a sofosbuvir-based regimen (ledipasvir-sofosbuvir) and compare this to the change among patients treated with IFN-based therapy.

In the current study, we combined results from three studies using interferon-free regimens. We compared the effect of MHD on outcome (SVR) and three modalities of adherence (pill count, study visits and serum levels of GS-331007). The prevalence of MHD among the 3 studies (approximately 35%) was comparable to the baseline prevalence reported in other studies[7,10-14]. This study demonstrates that patients with MHD can achieve SVR at rates comparable to those without MHD. Six patients from SPARE did not complete treatment, 5 of which were identified as suffering from MHD but only one discontinuation from study could be attributed to MHD as determined by evaluation by the principal investigator. This suggests that these interferon-free regimens did not affect adherence and subsequent efficacy of therapy.

For our second aim, we analyzed baseline pre-treatment, during treatment, and post-treatment BDI scores among HIV/HCV coinfected participants treated with a sofosbuvir-based regimen (ledipasvir-sofosbuvir) in the ERADICATE study and coinfected participants treated with IFN-based therapy (PFINPK and ALBIN). Mean changes from baseline to during and to post-treatment were compared within, and between, each treatment group. We demonstrate that despite similar baseline BDI scores in both treatment groups, participants treated with ledipasvir-sofosbuvir saw a decrease in BDI scores during treatment and post-treatment compared to baseline. However, participants treated with IFN-based therapy did not see any change in BDI scores. In fact, when treatment groups were compared to each other and adjusted for participants who achieved SVR, the overall decrease in BDI score from baseline to post-treatment among participants treated with ledipasvir-sofosbuvir was significantly different compared to the overall increase in BDI score among participants treated with IFN-based therapy. It is conceivable that successful treatment of HCV alone should be associated with improvement in mental health. However, our findings suggest that sofosbuvir-based (and possibly any IFN-free) anti-HCV therapy may have additional mental health benefits beyond end of treatment.

This study is strengthened by multiple measures of adherence: Pill counts for all 3 studies; and in SPARE study visits with the additional objective measure of serum levels of the sofosbuvir metabolite GS-331007 at week 2 of therapy. Adherence to oral DAA therapy was high in all 3 studies, regardless of baseline MHD status, with no significant differences in pill counts, study visits, and serum GS-331007 levels between those with and without MHD. Whether the high adherence was a consequence of participant selection and the more intensive adherence interventions and counseling that are inherent to clinical trials, or related to the improved tolerability and ease of administration of the medications cannot be determined.

Limitations of this study include its small sample sizes for the three patient groups analyzed and therefore may not be sufficiently powered to detect differences. This did not allow for addressing the hypothesis that a regimen of fewer pills for shorter duration (1 pill once a day in ERADICATE and SYNERGY-A for 12 wk compared to several pills a day for 24 wk in SPARE) was associated with significantly higher adherence. Furthermore, combining more than one study did result in a non-homogenous study population, most evident in the difference in baseline fibrosis stage among the participants undergoing BDI evaluation. Finally, this study did not include patients with severe, uncontrolled MHD therefore may have been biased towards those who already had a background of good adherence or lower BDI scores.

We hope that these preliminary findings will open the dialogue to further expand eligibility to those with MHD and lead to further, larger studies involving patients with more challenging characteristics: Not just those with baseline MHD, but also those with substance abuse - two diagnoses which are frequently paired[5-8]. Inclusion of these marginalized groups will be necessary if we are to gain an advantage in the battle to eradicate hepatitis C.

In conclusion, our study supports that patients with baseline MHD can be successfully engaged and treated with DAA therapies, and that sofosbuvir-based therapy is associated with improvement in BDI scores.

Continue to full text article - World J Hepatol. Nov 8, 2016; 8(31): 1318-1326

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