Faydra I. Lieveld

Natural history and treatment of HCV/HIV coinfection: Is it time to change paradigms?

Evidence over the past decades have shown that HIV/HCV coinfected patients did not respond as well to HCV therapy as HCV mono-infected patients. However, these paradigms are being recently reassessed with the improvements of care for HIV and HCV patients. This article reviews these original paradigms and how the new data is impacting upon them. Treatment efficacy now appears comparable for HIV/HCV coinfected and HCV mono-infected patients, while liver fibrosis progression is increasingly similar in optimally managed patients. Additional importance of therapy is directed to drug-drug interactions and the impact of HCV reinfection, as well as the possibility of transmitted drug resistance.

The hepatitis C virus nonstructural protein 3 Q80K polymorphism is frequently detected and transmitted among HIV-infected MSM in the Netherlands.

Objectives: The Q80K polymorphism is a naturally occurring resistance-associated variant in the hepatitis C virus (HCV) nonstructural protein 3 (NS3) region and is likely transmissible between hosts. This study describes the Q80K origin and prevalence among HCV risk groups in the Netherlands and examines whether Q80K is linked to specific transmission networks. Design and methods: Stored blood samples from HCV genotype 1a-infected patients were used for PCR and sequencing to reconstruct the NS3 maximum likelihood phylogeny. The most recent common ancestor was estimated with a coalescent-based model within a Bayesian statistical framework. Results: Study participants (n = 150) were either MSM (39%), people who inject drugs (17%), or patients with other (15%) or unknown/unreported (29%) risk behavior. Overall 45% was coinfected with HIV. Q80K was present in 36% (95% confidence interval 28–44%) of patients throughout the sample collection period (2000–2015) and was most prevalent in MSM (52%, 95% confidence interval 38–65%). Five MSM-specific transmission clusters were identified, of which three exclusively contained sequences with Q80K. The HCV-1a most recent common ancestor in the Netherlands was estimated in 1914 (95% higher posterior density 1879–1944) and Q80K originated in 1957 (95% higher posterior density 1942–1970) within HCV-1a clade I. All Q80K lineages could be traced back to this single origin. Conclusion: Q80K is a highly stable and transmissible resistance-associated variant and was present in a large part of Dutch HIV-coinfected MSM. The introduction and expansion of Q80K variants in this key population suggest a founder effect, potentially jeopardizing future treatment with simeprevir.

Real life adherence of chronic hepatitis B patients to entecavir treatment

BACKGROUND Real-life prospective data on adherence to nucleos(t)ide analogues in chronic hepatitis B patients are scarce. AIMS We investigated adherence to entecavir in relation to virological response. METHODS In this prospective study, we provided 100 consecutive chronic hepatitis B patients with a medication dispenser that monitored entecavir intake during 16 weeks therapy. Hepatitis B virus (HBV) DNA was measured at baseline and after 16 weeks. Beliefs about medicines were evaluated using a questionnaire. RESULTS Adherence over 16 weeks averaged 85 ± 17%, with 70% of patients exhibiting good (i.e. ≥ 80%) adherence. Patients with poor (i.e. <80%) adherence were significantly younger (p=0.01), with more often indifferent attitudes towards entecavir (p=0.03) Viral breakthrough did not occur during the study. Adherence in patients with HBV DNA after 16 weeks > 20 IU/mL (n=18) and ≤ 20 IU/mL (n=81) averaged 83% and 91% respectively (p=0.19). In multivariate analysis, adherence was not a significant predictor of HBV DNA negativity (adjusted OR 1.02; p=0.34), after adjustment for duration of entecavir treatment (p<0.001) and HBe-status (p=0.001). CONCLUSIONS 70% of chronic hepatitis B patients exhibited good adherence to entecavir, with younger age and an indifferent attitude being risk factors for poor adherence. Poor adherence was not an independent predictor of virological response.

Resistance-associated polymorphisms in Dutch hepatitis c genotype 1a patients with and without HIV infection

BACKGROUND AND AIM Resistance-associated variants (RAVs) on the NS3 region of the hepatitis C virus (HCV) may be relevant for antiviral therapy, but data in human immunodeficiency virus (HIV) coinfected patients are scarce. We assessed frequencies of NS3 RAVs in patients infected with HCV genotype 1a with or without HIV coinfection. MATERIAL AND METHODS HCV NS3 amino acids 1-181 were sequenced by the Sanger method and analyzed for RAVs. RAVs and their distribution between HCV genotype 1a clade I and II viruses were compared between HIV-infected versus HIV-uninfected patients. RESULTS 148 samples were available (n = 68 HIV and n = 80 non-HIV). Relative frequency of clade I and clade II was significantly different between HIV (85% and 15%) and non-HIV groups (49% and 51%). Overall, HIV infected patients exhibited significantly lower prevalence of RAVs than HIV-uninfected patients (62% vs. 79%, p = 0.03). However, Q80K prevalence was significantly higher in HIV-infected subjects (50% vs. 24%, p = 0.001), whereas prevalence of S122D/G/N/S (2% vs. 16%, p = 0.002) and N174G/N/S (10% vs. 55%, p < 0.0001) polymorphisms were significantly lower. Q80K was found exclusively in clade I viruses. S122 (3% vs. 22%, p=0.001) and N174 (13% vs. 75%, p<0.0001) polymorphisms had significantly lower prevalence in clade I than clade II viruses. CONCLUSIONS In the Netherlands, prevalence of clade I viruses and Q80K was significantly higher in HCV genotype 1a infected patients with HIV coinfection than in those without HIV coinfection. Prevalence of N174 and S122 polymorphisms was significantly higher in clade II than clade I viruses.

Impact of transient elastography on clinical decision-making in patients with chronic viral hepatitis

Abstract Objective. Transient elastography is a noninvasive tool to quantify liver fibrosis by liver stiffness measurements (LSMs). Previous studies have extensively evaluated the accuracy of LSMs compared to liver biopsy. In this retrospective study we explore potential impact of LSMs on clinical decisions in chronic viral hepatitis. Material and methods. LSM-based medical advice whether to start antiviral treatment and/or surveillance for hepatocellular carcinoma (HCC) and clinical follow-up after LSMs were analyzed in 349 patients. Results. In 20% of 184 hepatitis B virus (HBV)-infected patients and 38% of 165 hepatitis C virus (HCV)-infected patients, significant fibrosis (≥F2) was detected. In 5% (n = 7) of the 129 untreated HBV patients and in 12% (n = 19) of the HCV-infected patients, antiviral treatment was recommended solely based on LSMs. Advice for surveillance for HCC was in 40 patients based solely on LSMs (11% of all patients). Furthermore, 95% of 19 non-viremic HCV-patients (after spontaneous clearance or sustained viral response) could be discharged due to favorable LSMs (≤F2). Medical advice was followed by the treating physician in the majority of cases. However, in only 47% of 51 HCV-infected patients with advice to start treatment, this was followed in clinical practice. Conclusions. Transient elastography has a major impact on clinical practice, both as an indication to start or postpone antiviral treatment, to start surveillance for HCC, and to discharge HCV patients from follow-up after viral clearance and favorable LSMs. Medical advice to start antiviral treatment is followed in the large majority of HBV patients, but in only half of HCV patients.

Adherence to ribavirin in chronic hepatitis C patients on antiviral treatment: Results from a randomized controlled trial using real-time medication monitoring.

BACKGROUND AND OBJECTIVE Adherence is essential in antiviral therapy for chronic hepatitis C. We investigated the effect of real-time medication monitoring on adherence to ribavirin. METHODS In this randomized controlled trial, patients in the intervention group received a medication dispenser that monitored ribavirin intake real-time during 24 weeks PEG-interferon/ribavirin±boceprevir or telaprevir. Patients in the control group received standard-of-care. Adherence was also measured by pill count. RESULTS Seventy-two patients were assigned to either intervention (n=35) or control groups (n=37). Median adherence by pill count was 96% (range: 43%-100%) with 30 (94%) of patients exhibiting≥80% adherence. Perfect adherence (i.e. 100%) was similar in intervention and control groups: 22 (85%) vs. 15 (75%) (P=0.47). Adherences by real-time medication monitoring and by pill count did not correlate (R=0.19, P=0.36). No predictors of poor adherence could be identified. Ribavirin trough levels after 8 weeks (median: 2.4 vs. 2.7mg/L, P=0.30) and 24 weeks (median: 3.0 vs. 3.0mg/L, P=0.69), and virological responses did not differ between intervention and control groups. CONCLUSIONS Adherence to ribavirin during PEG-interferon containing therapy in chronic hepatitis C is high. Real-time medication monitoring did not influence adherence to ribavirin, plasma ribavirin levels or virological responses.

Ribavirin steady-state plasma level is a predictor of sustained virological response in hepatitis C–infected patients treated with direct-acting antivirals

In the era of highly effective direct‐acting antivirals (DAAs) for treatment of patients with chronic hepatitis C virus (HCV) infection, ribavirin (RBV) is still considered beneficial in certain patients.

Adherence to ursodeoxycholic acid therapy in patients with cholestatic and autoimmune liver disease

BACKGROUND Ursodeoxycholic acid (UDCA) is used for treatment of cholestatic liver diseases and may improve long-term outcome. Although treatment with this hydrophilic bile acid is virtually without side effects, medication adherence might be suboptimal due to patient misconceptions, compromising clinical outcome. Our aim was to evaluate adherence to UDCA in relation to patient beliefs about medicine and to identify potential predictors of poor adherence. METHODS Prospective open-label study recruiting patients in treatment with UDCA from April 2016 to March 2017. Adherence was assessed both by the Sensemedic dispenser and by patient-reported adherence, during 12 weeks. Good adherence was defined as ≥ 80% intake. Quality of life (by SF-36) and beliefs about medicine (by BMQ) were also assessed. RESULTS A total of 75 patients were enrolled (32% primary biliary cholangitis, 31% autoimmune hepatitis, 29% primary sclerosing cholangitis and 8% other conditions). Average adherence according to the medication dispenser was 92 ± 16% (range: 17-100). Eighty-nine percent of the patients exhibited good adherence and 11% poor adherence. According to the BMQ, 42% of all patients were accepting, 50% ambivalent, 8% indifferent and 0% skeptical to UDCA treatment. Poor adherence was associated with young age (P = 0.029) and male gender (P = 0.021). CONCLUSIONS Despite the excellent safety profile of UDCA, still a significant number of patients are poorly adherent. Young age and male sex are associated with poor adherence. Efforts should be made to identify patients with poor adherence and to improve their compliance to therapy.

Overcoming Outpatient Loss to Follow-up as a Barrier to Efficiently Instituting Hepatitis B Liver-related Care

Clinical Infectious Diseases 2017;64(2):232–33 Also, frequently no information beyond histopathology is available because no cultures from the biopsy material were sent due to low suspicion of an infection. The recently released, comprehensive Coccidioidomycosis guidelines [3] do not directly address what strategy or strategies are to be considered in this situation. Realizing the available quality of evidence is very low, I suggest that these asymptomatic patients be treated with an oral azole-based regimen for at least 3 months followed by close monitoring. For patients with high risk for an opportunistic mold infection, such as hematologic malignancy or allogeneic transplant, perhaps a mold-active azole is preferable to fluconazole, especially in the setting of a cavitating Coccidioidal nodule, where secondary colonization by another mold (eg, Aspergillus) could occur. I offer the following rationale for supporting a trial of “preemptive” azole treatment. First, there is, although unmeasured, risk for progression or dissemination of this occult lung infection in the setting of subsequent immune impairment [2, 4], and there are no clinical or immunogenetic predictors to prognosticate this event. Second, the possibility of extrapulmonary Coccidioidal lesions beyond the dominant Coccidioidal nodule exists; therefore, the burden of fungal disease might be underestimated by conventional computerized tomography of the lung. As Coccidioidal lesions are F-Fluorodeoxyglucose-avid [5] and in view of the well-known poor sensitivity of Coccidioides serology in immunosuppressed patients [2], positron emission tomography /computed tomography as a baseline to look for the extent of lung involvement and to evaluate for cryptogenic disseminated diseases [6] could be informative in selected cases. Third, as pulmonary Coccidioidal lung nodules simulate cancer [1, 2], it would be important in a patient with underlying cancer and an asymptomatic pulmonary Coccidioidal nodule to eradicate these nodules with antifungals. This can facilitate the downstream differential diagnosis in case the patient subsequently develops new pulmonary lesions. In view of the availability of oral azoles that have excellent efficacy and long-term safety, the benefit of treating preemptively far outweighs the risk. Finally, surgical resection can be an alternative modality in selected patients with solitary culture-proven Coccidioidal cavitating lung nodule, if no further chemotherapy is planned and azole treatment is not feasible or is undesirable. Again, more studies are needed in order to validate this proposed strategy. I thank Galgiani et al for their significant contribution with their guidelines to the clinical management of a complex disease.

Patients’ misconceptions about surveillance for hepatocellular carcinoma: Education is needed

of performed surveillance tests), only lower education level was an independent predictor of misconception. Second, patients largely underestimate HCC-related mortality rates. Nearly 50% of patients think that curative treatment is still possible in P40% of HCC cases detected without surveillance (Fig. 1F). Furthermore, many patients believed that surveillance reduces the risk of HCC deaths by P70% (Fig. 1G). Unfortunately,