Abstract
Introduction: With the advent of direct-acting antiviral (DAA) therapy for HCV, the cure is achieved at similar rates among HIV–HCV coinfected patients as in HCV mono-infected patients. The present study evaluates host plasma metabolites as putative indicators in predicting the treatment response in baseline HIV–HCV patients. Methods: Non-cirrhotic HIV–HCV (N = 43) coinfected patients were treated with sofosbuvir and daclatasvir for 12 weeks. Plasma metabolite profiling of pre- and post-therapy was analyzed in 20/43 patients. Of the 20 selected, 10 (50%) attained the sustained viral response [(SVR) (responders)] as defined by the absence of HCV RNA at 12 weeks after the treatment, and 10 (50%) did not attain the cure for HCV (nonresponders). Results: A total of 563 features were annotated (metabolomic/spectral databases). Before therapy, 39 metabolites differentiated (FC ±1.5, p < 0.05) nonresponders from responders. Of these, 20 upregulated and 19 downregulated were associated with tryptophan metabolism, nicotinamide metabolism, and others. Post therapy, 62 plasma metabolites (12 upregulated and 50 downregulated, FC±1.5, p < 0.05) differentiated nonresponders from responders and highlighted a significant increase in the steroid and histidine metabolism and significant decrease in tryptophan metabolism and ascorbate and pyruvate metabolism in the nonresponders. Based on random forest and multivariate linear regression analysis, the baseline level of N-acetylspermidine (FC > 2, AUC = 0.940, Bfactor = −0.267) and 2-acetolactate (FC > 2, AUC = 0.880, Bfactor = −0.713) significantly differentiated between nonresponders from responders in HIV–HCV coinfected patients and was able to predict the failure of treatment response. Conclusion: Increased baseline levels of N-acetylspermidine and 2-acetolactate levels are associated with the likeliness of failure to attain the cure for HCV in HIV–HCV coinfected patients.
Highlights
With the advent of direct-acting antiviral (DAA) therapy for hepatitis c virus (HCV), the cure is achieved at similar rates among human immunodeficiency virus (HIV)–HCV coinfected patients as in HCV mono-infected patients
Based on random forest and multivariate linear regression analysis, the baseline level of N-acetylspermidine (FC > 2, area under the ROC curve (AUC) 0.940, Bfactor −0.267) and 2-acetolactate (FC > 2, AUC 0.880, Bfactor −0.713) significantly differentiated between nonresponders from responders in HIV–HCV coinfected patients and was able to predict the failure of treatment response
Increased baseline levels of N-acetylspermidine and 2-acetolactate levels are associated with the likeliness of failure to attain the cure for HCV in HIV–HCV coinfected patients
Summary
With the advent of direct-acting antiviral (DAA) therapy for HCV, the cure is achieved at similar rates among HIV–HCV coinfected patients as in HCV mono-infected patients. Pegylated interferon (PEG-IFN) and ribavirin (RBV) were used to treat chronic HCV infection, but a low SVR attainment rate was the primary concern (Palumbo, 2011). This led to the discovery of direct-acting antivirals (DAAs). In 2011, first DAAs, telaprevir and boceprevir, were approved to treat HCV genotype-1 infection (Murphy et al, 2014) These drugs were NS3/4A protease inhibitors and showed improved SVR rates to 75–80% when administered together with PEG-IFN and RBV. In 2014, new DAAs were approved belonging to different classes such as NS3/4A protease inhibitors, NS5A replication complex inhibitors, nucleoside, and non-nucleoside polymerase inhibitors Their fixed dosage compensation was equilibrated, increasing the SVR attainment rate to 90% (Bailly et al, 2015). There is an HIV–HCV population that includes DAA nonresponders, and these patients still have a higher mortality rate (Patel et al, 2020)
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