Long-term clinical, histological and virological outcomes after sustained virologic response in patients with chronic hepatitis C

Successful antiviral treatment of chronic hepatitis C (HCV), resulting in Sustained Virologic Response (SVR) has been shown to reduce the risk for liver related complications, hepatocellular carcinoma (HCC) and death. Several studies have also shown that liver histology improves after achieved SVR. In a small sub-set of patients, however, liver fibrosis will persist and sometimes even progress to cirrhosis after SVR. Furthermore, a risk to develop HCC seems to remain many years after SVR has been achieved. The aim of this thesis was to study the long-term effect of sustained virologic response on clinical, histological and virological outcomes, and to identify risk factors associated with persisting advanced fibrosis and a continued risk to develop HCC after SVR. In study I we investigated the effect of antiviral treatment on liver-related complications, HCC and death. We included 351 patients with HCV related cirrhosis in a prospective cohort study. Mean follow-up time was 5.3 years. The risk to develop liver-related complications, HCC, and liver-related and all-cause mortality was 0.9, 1.0, 0.7 and 1.9 per 100 person years for patients with achieved SVR, compared to 4.9, 4.0, 4.5 and 5.1 per 100 person years for patients never treated for HCV. In study II we investigated the prevalence and clinical implications of occult hepatitis C. In a cross-sectional study, 54 patients with all stages of pre-treatment liver fibrosis and SVR 5-20 years prior to inclusion were tested for HCV RNA using a highly sensitive method. Three patients (6%) tested positive for HCV RNA in peripheral blood mononuclear cells (PBMCs), but this did not correlate to clinical, histological or immunological evidence of persisting liver disease. In study III we investigated the long-term risk and risk factors for the development of HCC after achieved SVR. In this cohort study we included 399 patients with SVR and pre-treatment advanced fibrosis or cirrhosis. Median follow-up time was 7.8 years. The incidence rate of HCC was 0.15 and 0.95 per 100 person years for patients with advanced fibrosis and cirrhosis respectively. The main risk factor for the development of HCC was pre-treatment cirrhosis, low serum albumin and diabetes mellitus. The risk to develop HCC diminished with longer follow-up time. In study IV we investigated fibrosis regression and risk factors for persisting advanced fibrosis after achieved SVR. In a cross-sectional study 269 patients were examined with transient elastography. Median follow-up time was 7.7 years. A majority of patients regressed to a lower fibrosis stage at follow-up, but 24% had persisting advanced fibrosis. This proportion, however, diminished over time. Risk factors associated with persisting advanced fibrosis were pre-treatment cirrhosis, higher age and high body mass index. Our studies have contributed to the growing evidence of the positive effects of SVR in chronic HCV. With long follow-up time, we were also able to show that disease regression continues over time. We identified established cirrhosis and co-morbidity with metabolic disease as important risk factors for persisting advanced fibrosis and a continued risk to develop HCC after SVR has been achieved

Nitric oxide dosed in short bursts at high concentrations may protect against Covid 19.

It has long been suggested that NO may inhibit an early stage in viral replication. Furthermore, in vitro tests have shown that NO inhibits the replication cycle of severe acute respiratory syndrome coronavirus. Despite smoking being listed as a risk factor to contract Covid-19, only a low proportion of the smokers suffered from SARS-corona infection in China 2003, and from Covid-19 in China, Europe and the US. We hypothesize, that the intermittent bursts of high NO concentration in cigarette smoke may be a mechanism in protecting against the virus. Mainstream smoke from cigarettes contains NO at peak concentrations of between about 250 ppm and 1350 ppm in each puff as compared to medicinal use of no more than 80 to a maximum of 160 ppm. The diffusion of NO through the cell wall to reach the virus should be significantly more effective at the very high NO concentration in the smoke, according to classic laws of physics. The only oxide of nitrogen in the mainstream smoke is NO, and the NO2 concentration that is inhaled is very low or undetectable, and methemoglobin levels are lower in smokers than non-smokers, reasonably explained by the breaths of air in between the puffs that wash out the NO. Specialized iNO machines can now be developed to provide the drug intermittently in short bursts at high concentration dose, which would then provide both a preventative drug for those at high risk, as well as an effective treatment, without the health hazards associated with smoking

Efficacy of Routine Fecal Microbiota Transplantation for Treatment of Recurrent Clostridium difficile Infection: A Retrospective Cohort Study

Background. Patients with recurrent Clostridium difficile infections (CDIs) constitute an increasing treatment problem. Fecal microbiota transplantation (FMT) has shown promising results of treating recurrent CDI, where treatment with antibiotics fails repeatedly. Our study describes retrospective cohort treated with FMT at two major hospitals in Stockholm. Methods. Medical records of all patients with recurrent CDI treated with FMT during the period 2013–2017 were reviewed. We evaluated cure of CDI-related diarrhea without relapse 10 weeks after FMT. Results. 47 patients were included. One treatment cured 25 patients (53%), and more than one treatment cured 32 patients (68%). Treatment outcome did not vary significantly with treatment with fresh donor feces or frozen fecal culture, days of use of antibiotics or days of hospitalization prior to CDI, and renal function or time from the first CDI to therapy. Treatment failure was associated with a significantly lower Karnofsky performance status score (70 points vs 90, p=0.02). Conclusion. Fecal instillation, for the treatment of relapsing CDI, is a promising approach, with 68% success rate reported in this study. The success rate of FMT is high, regardless of multiple comorbidities, extended use of antibiotics, or long time hospitalization. Although generally FMT is performed with fresh donor feces, our data show that the usage of frozen fecal culture could be an effective treatment alternative in recurrent CDI

A Risk for Hepatocellular Carcinoma Persists Long-term After Sustained Virologic Response in Patients With Hepatitis C-Associated Liver Cirrhosis

Background. The long-term effect of sustained virologic response (SVR) to antiviral therapy on the risk of developing hepatocellular carcinoma (HCC), liver complications, liver-related death, and overall death in hepatitis C virus (HCV)-infected patients with liver cirrhosis is not fully known. Methods. These risks were evaluated during long-term follow-up in 351 patients with HCV-related cirrhosis. One hundred ten patients with SVR, 193 with non-SVR, and 48 who were untreated were included in a multicenter cohort that was initiated in 2001 and prospectively followed up for a mean of 5.3 (SD, 2.8) years. Complementary follow-up data from national registries were used to minimize the loss of patients during follow-up. Results. Six patients with SVR developed HCC at 0.04, 0.64, 2.4, 7.4, 7.4, and 7.6 years, respectively, after achieving SVR. The incidences of HCC, any liver complication, liver-related death, and overall death per 100 person-years were significantly lower in SVR time with 1.0, 0.9, 0.7, and 1.9, compared to 2.3, 3.2, 3.0, and 4.1 in non-SVR and 4.0, 4.9, 4.5, and 5.1 in untreated time. The long-term consequences did not decline significantly after >3 years versus during the first 3 years of follow-up. Conclusions. The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk of developing HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed