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  • Although low baseline virus load

    2018-10-29

    Although low baseline virus load is considered one of the predictive factors for SVR12, many other host, virus and drug related factors are also important and can sometimes affect the virus response to treatment regardless of baseline virus load. The significant existence of Resistance Associated Substitutions (RASs) is an example of an unpredictable virus related factor that can affect the response rate and it is still not routinely tested for on a wide scale (Di Maio et al., 2017). We had suggested in a previous study report (Yakoot et al., 2016), that the speed of virus response during the first 2weeks of therapy could be regarded as an efficacy marker with a high positive predictability for sustained virologic response. It combines the measured displacement (reduction) of the virus load divided by the time which is another independent factor for response (Pineda et al., 2017; Sulkowski et al., 2016); (Speed (v)=Displacement of virus load (d)/Time(t)). The very rapid virologic response (vRVR), defined as undetectable serum HCV RNA level at week 2 of therapy, was found, in our study to be a good positive predictor for SVR12 to dual therapy with sofosbuvir and ribavirin in patients with chronic HCV genotype-4. It had a high positive predictive value (PPV) of 100% (95% CI, 90.8–100%) and a high sensitivity of 82.6% (CI, 68.6–92.2%) but with low negative predictive value (Yakoot et al., 2016). We suggested that achieving a vRVR could be used as a prudent objective qualifier to shorten duration of therapy. It objectively demonstrates that the treatment has been working against at least insignificant drug resistance and maintained for a period of at least 6weeks after reaching viral negativity in the serum. This, in our assumption, might be enough time for the complete eradication of the virus from all liver liquiritin and other hidden potential reservoirs such as platelets and mononuclear cells in blood or RES (ex: spleen) that could probably be the potential initiators for relapse. Our new suggestion of tailoring the duration of therapy according to achieving a vRVR can be regarded as a positive response guided therapy. This is totally different from the previously implemented negative response guided therapy, in the pre- directly acting antiviral drugs (DAAs) era. Because now with the lower failure rates (>90% success rates), achieved with DAAs, the early viral response kinetics (i.e. time to viral negativity) became strong positive predictors for treatment success but weak negative predictors for treatment failure (Maasoumy et al., 2016). All non-cirrhotic patients are being treated with a fixed 12weeks protocol according to the Egyptian and EASL guidelines. We have observed during our real life practice that the success rate is very high reaching above 95% and the majority of patients respond very early during the first 2weeks of treatment (vRVR) and remain with undetectable HCV RNA in serum till the end of the 12weeks post-treatment follow up period (SVR12). Also, we have noticed in many incidents that non-cirrhotic patients, who for any reason, interrupted treatment at as early as 8weeks did not relapse. This observation has lead us to further study our above mentioned suggestion that the vRVR might be used as a prudent qualifier to shorten the duration of therapy in this setting to 8weeks as it allows a period of at least 6weeks on observably working treatment after reaching undetectable HCV RNA level in serum. We planned this research to study whether the proportion of SVR12 in the response tailored duration (test group) is non-inferior to that in the recommended fixed 12weeks duration (reference group). So we tested the null hypothesis of inferiority of a protocol tailored according to vRVR of 8/12weeks versus the recommended fixed 12weeks course of dual SOF/DCV treatment in non-cirrhotic Egyptian chronic HCV genotype-4 patients.
    Methods
    Results A hundred twenty eligible patients were included to be treated with dual SOF/DCV and randomized for either a fixed 12weeks duration group (reference group: n=60 patients) or a response tailored 8/12weeks durations group (test group: n=60 patients). During the whole period of the study, only 1 patient dropped-out from each group. Both were lost to follow-up after the 4th week\'s visit. One of them achieved vRVR at week 2 and the other became negative at week 4 of treatment. Their results have been included in the intention to treat analysis (ITT) as not achieving SVR12. We also conducted a per-protocol efficacy analysis in which we excluded these 2 patients from analysis and included only those who completed the full protocol (Flowchart: Fig. 1).