Brittany E. Yee

Lower response to simeprevir and sofosbuvir in HCV genotype 1 in routine practice compared with clinical trials

Background High sustained virological response at 12 weeks after end of treatment (SVR12) with 12 weeks of simeprevir and sofosbuvir±ribavirin (SMV+SOF±RBV) has been demonstrated in hepatitis C virus genotype 1 (HCV-1) but is based on limited data. Therefore, we performed a meta-analysis of available data evaluating the effectiveness of SMV+SOF±RBV in HCV-1. Methods We performed a comprehensive literature search in June 2015 to identify randomised controlled trials (RCTs) and observational studies of HCV-1 patients treated with 12 weeks of SMV+SOF±RBV. Original studies with SVR12 data in ≥5 HCV-1 patients were included. We excluded studies on liver transplant recipients and/or patients co-infected with HIV or hepatitis B/D. We estimated pooled effect sizes using a random-effects model and evaluated heterogeneity with Cochrane Q-test, p≤0.10 and I2 statistic ≥50%. Results Pooled SVR12 was 85.6% (CI 81.3% to 89.0%) in 1389 HCV-1 patients from 15 studies. On subgroup analysis, SVR12 was 83.9% (CI 79.4% to 87.5%) in observational studies, which was lower than 93.5% (CI 85.7% to 97.2%) in RCTs. A trend showed SVR12 was higher in mild fibrosis, 93.0% (CI 86.2% to 96.6%) compared with advanced fibrosis, 81.5% (CI 75.7% to 86.1%), OR 2.22 (CI 0.79 to 6.25, p=0.131). There was no significant difference in SVR12 rates between HCV-1a, 89.9% (CI 81.9% to 94.6%) and HCV-1b, 89.0% (CI 78.9% to 94.6%) with OR 1.35 (CI 0.75 to 2.42, p=0.322). The most common pooled side effects were: headache 15.2% (n=55/361), fatigue 12.1% (n=78/646), nausea 9.5% (n=50/527) and rash 9.3% (n=68/728). Conclusions SMV+SOF±RBV is an effective regimen in HCV-1 patients. The SVR12 rate in observational studies was lower than that in RCTs, which may reflect the more diverse patient population in real-world settings.

Tolerability and effectiveness of sofosbuvir and simeprevir in the post-transplant setting: systematic review and meta-analysis.

Background Outcome data on simeprevir and sofosbuvir (SMV+SOF) in patients with liver transplantation (LT) with hepatitis C virus genotype 1 (HCV-1) are limited with individual studies having a small sample size and limited SVR12 (sustained virological response) data. Our goal was to perform a meta-analysis to study the outcome of SMV+SOF±ribavirin (RBV) in recipients with LT. Methods In April 2015, we conducted a literature search for ‘simeprevir’ in MEDLINE/EMBASE and five major liver meetings. We included studies with SVR12 data in ≥5 post-LT mono-infected HCV-1 patients treated with SMV+SOF±RBV. We used random-effects models to estimate effect sizes, and the Cochrane Q-test (p value <0.10) with I2 (>50%) to assess study heterogeneity. Results We included nine studies with a total of 325 patients with post-LT. Studies included mostly men (59–81%). Pooled SVR12 was 88.0% (95% CI 83.4% to 91.5%). In two studies, HCV-1a patients with mild fibrosis (n=108) had an SVR12 rate of 95.0% (95% CI 82.4% to 98.7%), which was significantly higher than that of HCV-1a patients with advanced fibrosis (n=49) with an SVR12 rate of 81.7% (95% CI 69.8% to 89.5%), OR 4.2 (95% CI 1.1 to 16.1, p=0.03). The most common pooled side effects were: fatigue 21% (n=48/237), headache 9% (n=23/254), dermatological symptoms 15% (n=38/254), and gastrointestinal symptoms 6% (12/193). Conclusions SMV+SOF±RBV is safe and effective in recipients with LT with HCV-1 infection.

Extensive pulmonary involvement with raltegravir-induced DRESS syndrome in a postpartum woman with HIV.

An 18-year-old postpartum woman with HIV, on lamivudine–zidovudine, lopinavir–ritonavir and raltegravir, presented with a 1-week history of rash and fevers. Initially admitted to obstetrics and gynaecology service for treatment of possible endometritis, she was transferred to the HIV medicine service for high fever, respiratory distress, hypotension and tachycardia. On admission, she was febrile (102°F) with findings of cervical and submandibular lymphadenopathy, diffuse morbilliform rash, generalised pruritus, facial oedema, and oedematous hands and feet. Consultations to various specialty services were initiated to rule out infectious, dermatological, rheumatological and drug-induced aetiologies. On the fourth day of hospitalisation, laboratory findings of significant eosinophilia and hepatitis (alanine aminotransferase 147 IU/L and aspartate aminotransferase 124 IU/L), in conjunction with the identification of the timing of medication use, led to a diagnosis of DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome secondary to raltegravir. After discontinuing raltegravir and starting prednisone, her DRESS symptoms completely resolved.

Sustained virological response and its treatment predictors in hepatitis C virus genotype 4 compared to genotypes 1, 2, and 3: a meta-analysis.

Background Pegylated interferon and ribavirin (PEG-IFN+RBV) may be more cost-effective than direct-acting antivirals in resource-limited settings. Current literature suggests sustained virological response (SVR) in hepatitis C virus genotype 4 (HCV-4) is similar to genotype 1 (HCV-1), but worse than 2 and 3 (HCV-2/3). However, few studies have compared treatment response between these groups and these have been limited by small sample sizes with heterogeneous designs. We performed a meta-analysis of SVR predictors in HCV-4 versus HCV-1, 2, and 3 patients treated with PEG-IFN+RBV. Methods In November 2013, we searched for ‘genotype 4’ in MEDLINE/EMBASE databases and scientific conferences. We included original articles with ≥25 treatment-naïve HCV-4 and comparisons to HCV-1, 2, and/or 3 patients treated with PEG-IFN+RBV. Random effects modelling was used with heterogeneity defined by Cochrane Q-test (p value<0.10) and I2 statistic (>50%). Results Five studies with 20 014 patients (899 HCV-4; 12 033 HCV-1; and 7082 HCV-2/3 patients) were included. SVR was 53% (CI 43% to 62%) for HCV-4, 44% (CI 40% to 47%) for HCV-1; and 73% (CI 58% to 84%) for HCV-2/3. SVR with EVR (early virological response) was 75% (CI 61% to 86%) in HCV-4; 64% (CI 46% to 79%) in HCV-1; and 85% (CI 71% to 93%) in HCV-2/3. SVR without EVR was 10% (CI 6% to 17%) for HCV-4; 13% (CI 12% to 15%) for HCV-1; and 23% (CI 16% to 33%) for HCV-2/3. Conclusions SVR rates are similar in HCV-4 (∼50%) and HCV-1 (∼40%). Lack of EVR is a good stopping rule for HCV-4 and HCV-1 since only 10% subsequently achieve SVR. In HCV-4 patients with EVR, three-quarters can expect to achieve SVR with PEG-IFN+RBV.

Meta-analysis: Influence of host and viral factors in patients with chronic hepatitis C genotype 4 treated with pegylated interferon and ribavirin

The burden of hepatitis C virus genotype 4 (HCV-4) is high in Africa and East Mediterranean countries. Previous reports estimate sustained virologic response (SVR) rates in HCV-4 to be ∼20–70%. However, many of these studies are limited by different study designs and small sample sizes. Our aim was to evaluate treatment outcome and host/viral factors on SVR in HCV-4 patients treated with pegylated interferon and ribavirin (PEG IFN+RBV) in a systematic and quantitative manner. A comprehensive literature search in MEDLINE and EMBASE for ‘genotype 4’ was conducted in November 2013. Abstracts from American Association for the Study of Liver Diseases, Asian Pacific Study of the Liver, Digestive Disease Week, and European Association for the Study of the Liver in 2012/2013 were reviewed. Inclusion criteria were original studies with at least 25 treatment-naive HCV-4 patients treated with PEG IFN+RBV. Exclusion criteria were coinfection with HIV, hepatitis B virus, or other genotypes. Effect sizes were calculated using random-effects models. Heterogeneity was determined by Cochrane Q-test (P<0.05) and I2 statistic (>50%). We included 51 studies (11 102 HCV-4 patients) in the primary analysis. Pooled SVR was 53% [95% confidence interval (CI): 50–55%] (Q-statistic=269.20, P<0.05; I2=81.43). On subgroup analyses, SVR was significantly associated with lower viral load, odds ratio (OR) 3.05 (CI: 1.80–5.17, P<0.001); mild fibrosis, OR 3.17 (CI: 2.19–4.59, P<0.001); and favorable IL28B polymorphisms, rs12979860 CC versus CT/TT, OR 4.70 (CI: 2.87–7.69, P<0.001), and rs8099917 TT versus GT/GG, OR 5.21 (CI: 2.31–11.73, P<0.001). HCV-4 patients treated with PEG IFN+RBV may expect SVR rates of ∼50%. Lower viral load, mild fibrosis, and favorable IL28B (rs12979860 CC and rs8099917 TT) are positively associated with SVR.

Treatment of Acute Hepatitis C Infection with Pegylated Interferon and Ribavirin in Patients Coinfected with Human Immunodeficiency Virus: A Systematic Review and Meta-Analysis.

Background/Aims: Of the 35 million human immunodeficiency virus (HIV)-positive patients worldwide, 10-40% are coinfected with chronic hepatitis C virus (HCV). Compared to HCV-monoinfected patients, those coinfected experience decreased spontaneous HCV clearance, accelerated liver fibrosis, and a decreased response to anti-HCV therapy. We conducted a meta-analysis to estimate the efficacy of treating acute HCV in HIV-positive patients with peginterferon and ribavirin combination therapy. Methods: Two authors independently searched MEDLINE and EMBASE (2014) for English articles, and reviewed bibliographies and abstracts from major liver and HIV conferences (2011-2013). Original studies featuring at least 10 treatment-naive, HIV-positive adults infected with acute HCV and treated with peginterferon and ribavirin were included. Analyses were calculated using a random-effects model. Heterogeneity was assessed using the Cochrane Q test (p < 0.05) and the I2 statistic (>50%). Results: From 12 studies (450 patients), the pooled sustained virological response (SVR) was 71.4% (95% CI 64.7-77.4; Q statistic = 22.20, p = 0.023, I2 = 50.44). The rapid virological response (RVR; 7 studies, 196 patients) was 47.4% (95% CI 40.6-54.7), and the early virological response (EVR; 9 studies, 283 patients) was 82.8% (95% CI 67.0-92.0). The probability of an SVR was 93.1% (95% CI 84.9-97.0) in those who obtained an RVR (6 studies, 82 patients) and 85.9% (95% CI 78.7-91.0) if an EVR (7 studies, 168 patients) was reached. Conclusion: Peginterferon with ribavirin is an effective option for treating acute HCV in HIV-positive patients, especially if they achieve an RVR or an EVR.

Tu1052 Compared to Non-Asian Patients, Asians With HCV Infection Were Older With Significantly Higher Rates of Co-Morbidities, Cirrhosis, and Liver Cancer but Lower HCV Treatment Rates: Results of a Large U.S. Cohort of 8,559 Patients

BACKGROUND: Infection with HCV is prevalent in many parts of Asia, and most patients acquire the virus through iatrogenic exposure and had no known traditional risk factors. Many would not have met the current CDC or USPTF guidelines for HCV screening and diagnosis. This study seeks to characterize HCV infection in Asian vs. Non-Asian patients. METHODS: We conducted a retrospective study of all patients with HCV diagnosis seen at a U.S. university medical center between 2/1999 and 3/2014. Patients were identified via ICD-9 query with additional clinical and laboratory data obtained from patient medical records. A total of 12,312 patients were identified. Of these, 8,559 had known ethnicity and were included in study analysis: 7,335 Non-Asians (86%) and 1,208 Asians (14%). RESULTS: Compared to non-Asians, Asians were significantly older (mean age=56.7±16.1 vs. 53.5±12.1, p 6M IU/mL). In analysis of available treatment data from 2008 to 2014 (N=5224), treatment rates were low in both groups but significantly lower in Asians compared to Non-Asians (6.9% vs. 7.4%, p<0.0001). CONCLUSION:More than half the Asian patients were found to be outside the birth cohort, being significantly younger or older than their Non-Asian counterparts. Asian patients with CHC had more comorbidities and were much more likely to have advanced disease with HCC, almost double the rates in non-Asians. Asians also had significantly lower HCV treatment rates. Further efforts should be made in screening, diagnoses, and treatment of American Asians for CHC to prevent progression to advanced liver disease and improve health outcomes in this population. HCC screening should be offered to Asians coming from endemic areas with HCV prevalence of 2% or higher.

Re-treatment of patients with chronic hepatitis C virus genotype 4 infection with pegylated interferon and ribavirin: a meta-analysis

Background An estimated 170 million people worldwide are infected with hepatitis C virus (HCV). HCV genotype 4 (HCV-4)—the most prevalent hepatitis C strain in the Middle East and Africa—is difficult to treat, with an estimated sustained virological response (SVR) of 53% when using pegylated interferon and ribavirin (P/R) in treatment-naïve patients with HCV-4 infection. In regions where access to direct-acting antivirals is limited, re-treatment of patients who failed therapy with another course of P/R may be an option if the success rate is acceptable. Objectives We aimed to determine the SVR from retreatment with P/R in treatment-experienced patients with HCV-4 infection. Methods We performed a meta-analysis using MEDLINE and EMBASE searches, and by reviewing article bibliographies and abstracts from recent Liver Society Meetings. Original studies featuring at least 10 adult, treatment-experienced patients with HCV-4 infection failing prior interferon-based therapy and receiving subsequent re-treatment with P/R were included. Results 3 studies were included. Overall pooled SVR was 32.7%, or 41/126 patients. No significant heterogeneity existed among the studies. One study reported higher SVR of 50% in previous relapsers, compared with 23% in previous non-responders. Conclusions As expected, treatment-experienced patients achieved lower rate of SVR compared with previously reported SVR for treatment-naïve patients with HCV-4 infection. The abysmal rate of success from re-treatment with P/R supports the use of direct-acting antivirals whenever re-treatment is considered, even in resource-limited regions.

Strongyloides stercoralis Hyperinfection Syndrome Presenting as Severe, Recurrent Gastrointestinal Bleeding, Leading to a Diagnosis of Cushing Disease

A 50-year-old male immigrant from Ethiopia presented for consultation after 3 years of hematochezia/melena requiring > 25 units of blood transfusions. Physical examination revealed severe proximal muscle wasting and weakness, central obesity, proptosis, and abdominal striae, accompanied by eosinophilia, elevated hemoglobin A1c, elevated 24-hour urinary cortisol, lack of suppression of 8 am cortisol levels by 1 mg dexamethasone, and inappropriately elevated random adrenocorticotropic hormone (ACTH) level. Histopathological examination of gastrointestinal biopsies showed large numbers of Strongyloides stercoralis, indicating Strongyloides hyperinfection. Treatment with 2 days of ivermectin led to resolution of gastrointestinal bleeding. This syndrome was due to chronic immunosuppression from a pituitary ACTH (corticotroph) microadenoma, of which resection led to gradual normalization of urine cortisol, improved glycemic control, resolution of eosinophilia, and no recurrence of infection.