Health inequalities in the management of chronic hepatitis B virus infection in patients from sub-Saharan Africa in high-income countries.

Chronic hepatitis B virus disproportionately affects migrant communities in high-income countries, reflecting increased migration from sub-Saharan Africa. Chronic hepatitis B virus is endemic in sub-Saharan Africa, yet the natural history of chronic infection experienced by patients remains incompletely understood, with evidence of variability across genotypes and regions within sub-Saharan Africa. Clinical guidelines recommending treatment thresholds are not specific to sub-Saharan African patients and are based on natural history studies from Western Pacific Asian countries. Access to standard of care treatment is available for sub-Saharan African people with chronic hepatitis B virus infection in high-income countries; however, the evidence base for these treatments was not established in this cohort and areas of uncertainty remain, particularly regarding HCC surveillance and treatment discontinuation. Participation in phase III clinical trials for chronic hepatitis B therapies is almost non-existent amongst sub-Saharan African patients, even when residing in high-income countries that participate in multicentre trials. Engagement with sub-Saharan African patients with chronic hepatitis B in high-income countries is challenging because of the stigma associated with the diagnosis, absence of routine screening systems and the complexities involved in navigating the healthcare system. Nonetheless, improved engagement is critical if we are to achieve global hepatitis B virus elimination.

Hepatitis B virus infection combined with nonalcoholic fatty liver disease: Interaction and prognosis.

Hepatitis B virus (HBV) infection is still one kind of the infectious diseases that seriously threaten human health. Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. HBV infection complicated with NAFLD is increasingly common. This review mainly describes the interaction between HBV infection and NAFLD, the interaction between steatosis and antiviral drugs, and the prognosis of HBV infection complicated with NAFLD. Most studies suggest that HBV infection may reduce the incidence of NAFLD. NAFLD can promote the spontaneous clearance of hepatitis B surface antigen (HBsAg), but whether it affects antiviral efficacy has been reported inconsistently. HBV infection combined with NAFLD can promote the progression of liver fibrosis, especially in patients with severe steatosis. The outcome of HBV infection combined with NAFLD predisposing to the progression of HCC remains controversial.

A Prospective Five-Year Follow-up After peg-Interferon Plus Nucleotide Analogue Treatment or no Treatment in HBeAg Negative Chronic Hepatitis B Patients.

Background: Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however benefit from treatment by achieving a functional cure, defined by HBsAg-loss and undetectable HBV DNA. This study evaluated the long-term effect of combination treatment with peg-interferon-alpha-2a (peg-IFN) and adefovir or tenofovir compared to no treatment in these patients. Methods: HBeAg-negative CHB patients with HBV-DNA levels < 20,000 IU/mL (n = 151) were previously randomised 1:1:1 for peg-IFN 180 µg/week plus either adefovir 10 mg/day or tenofovir 245 mg/day, or no treatment and treated for 48 weeks in an open-label study. In this prospective long-term follow-up study, patients were monitored yearly up to five years after end of treatment (week 308). The primary outcome was sustained HBsAg-loss and secondary outcome the dynamics of HBsAg and HBV-DNA levels over time. Results: Of the 131 followed patients, the HBsAg-status was known for 118 patients after five-year follow-up. HBsAg-loss occurred similarly (P = 0.703) in all arms: 8/43 (18.6%) peg-IFN + adefovir, 4/34 (11.7%) peg-IFN + tenofovir, and 6/41 (14.6%) among the untreated patients. The time to HBsAg-loss did not differ between groups (P = 0.641). Low baseline HBsAg levels and genotype A were independently associated with HBsAg-loss irrespective of allocation. HBsAg and HBV-DNA levels declined similarly during follow-up in all patient groups. Conclusions: This prospective randomised controlled study showed that HBsAg-loss overtime was not influenced by treatment with a combination of nucleotide analogue and Peg-IFN. Low baseline HBsAg levels can predict HBsAg-loss irrespective of treatment allocation.

Approved HIV reverse transcriptase inhibitors in the past decade.

HIV reverse transcriptase (RT) inhibitors are the important components of highly active antiretroviral therapies (HAARTs) for anti-HIV treatment and pre-exposure prophylaxis in clinical practice. Many RT inhibitors and their combination regimens have been approved in the past ten years, but a review on their drug discovery, pharmacology, and clinical efficacy is lacking. Here, we provide a comprehensive review of RT inhibitors (tenofovir alafenamide, rilpivirine, doravirine, dapivirine, azvudine and elsulfavirine) approved in the past decade, regarding their drug discovery, pharmacology, and clinical efficacy in randomized controlled trials. Novel RT inhibitors such as islatravir, MK-8504, MK-8507, MK8583, IQP-0528, and MIV-150 will be also highlighted. Future development may focus on the new generation of novel antiretroviral inhibitors with higher bioavailability, longer elimination half-life, more favorable side-effect profiles, fewer drug-drug interactions, and higher activities against circulating drug-resistant strains.

Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs? An in vitro and in vivo DMPK assessment.

Remdesivir (RDV) is the only US Food and Drug Administration (FDA)-approved drug for treating COVID-19. However, RDV can only be given by intravenous route, and there is a pressing medical need for oral antivirals. Significant evidence suggests that the role of the parent nucleoside GS-441524 in the clinical outcomes of RDV could be largely underestimated. We performed an in vitro and in vivo drug metabolism and pharmacokinetics (DMPK) assessment to examine the potential of RDV, and particularly GS-441524, as oral drugs. In our in vitro assessments, RDV exhibited prohibitively low stability in human liver microsomes (HLMs, t 1/2 = âˆ¼1 min), with the primary CYP-mediated metabolism being the mono-oxidation likely on the phosphoramidate moiety. This observation is poorly aligned with any potential oral use of RDV, though in the presence of cobicistat, the microsomal stability was drastically boosted to the level observed without enzyme cofactor NADPH. Conversely, GS-441524 showed excellent metabolic stability in human plasma and HLMs. In further in vivo studies in CD-1 mice, GS-441524 displayed a favorable oral bioavailability of 57%. Importantly, GS-441524 produced adequate drug exposure in the mice plasma and lung, and was effectively converted to the active triphosphate, suggesting that it could be a promising oral antiviral drug for treating COVID-19.

Entecavir is Safe and Effective in Long Term for the Treatment of Hepatitis B in Immunocompromised Children.

OBJECTIVE: Hepatitis B infection is common in patients with cancer, and prompt treatment is necessary; otherwise, it can result in life-threatening complications. The objective of this study was to assess the long-term safety and efficacy of entecavir in immunocompromised children with hepatitis B. METHODS: This single-center prospective study was conducted on children with different malignancies referred to our department with evidence of hepatitis B infection. Only those children were included in the study who had HBsAg positive and alanine aminotransferase (ALT) more than 2 times the upper limit of normal and whose hepatitis B virus (HBV) DNA was more than 20,000IU/ml. These children were put on entecavir and prospectively observed upto 192 weeks. Primary efficacy end point was the proportion of patients who achieved undetectable HBV DNA at 48 weeks of treatment. Other efficacy end points were the proportion of patients with HBeAg seroconversion, undetectable HBV DNA, and ALT normalization at weeks 48 and 96 weeks. RESULTS: A total of 41 children met the inclusion criteria, of which 5 children died because of malignancy and 5 were lost to follow-up. Mean log DNA was 7.67 at the start which after starting entecavir reduced to 4.1, 2.8, 1.19, 1.09, and 0.84 at 12, 24, 48, 72, and 96 weeks, respectively (P value < 0.0001). Mean ALT decreased from 332.5 which reduced to 190, 115, 63, and 46 at 4, 12, 24, and 48 weeks, respectively (P < 0.0001). 67.7% achieved the primary outcome and had undetectable DNA at 48 weeks which increased to 26 (83.9%) at 96 weeks. At 48 weeks, 80.6% patients achieved ALT normalization. Thirty percent developed HBeAg seroconversion. Two patients developed virological breakthrough, one at 96 weeks and another at 192 weeks. No significant adverse effects were observed. CONCLUSION: Entecavir is safe and effective in long term for the treatment of hepatitis B in immunocompromised children.

Clinical Profile and Efficacy of Antivirals in Hepatitis B Virus Reactivation, in Patients With Cancer Receiving Chemotherapy.

BACKGROUND/PURPOSE: Hepatitis B virus reactivation (HBVR) is common in patients withcancer. The aim of the present study was to find out clinical profile of patients with cancer receiving chemotherapy with HBVR and to study the efficacy of entecavir (ETV) and tenofovir in the treatment of HBVR. METHODS: This is a prospective study in which all consecutive patients with cancer with evidence of HBVR were included. HBVR was defined as: New onset transaminitis with alanine aminotransferase (ALT) >3 times upper limit of normal and >10 fold increase in HBV DNA levels from baseline levels or detection of HBV DNA ≥100,000 IU/ml in patients with no baseline HBV DNA. Patients with HBVR were put on ETV or tenofovir and were closely monitored for efficacy and safety for minimum of 1 year. RESULTS: Of 204 Hepatitis B surface antigen (HBsAg)-positive patients with different cancers, 92 met the inclusion criteria. Of 92, 46 received ETV 0.5 mg/day and 46 received tenofovir disoproxil fumarate (TDF) 300 mg/day. At 6 months, there was 4.7 log reduction in HBV DNA level in the ETV group and 5.2 log reduction in the TDF group (P = 0.029). Proportion of patients with undetectable HBV DNA (75.7% vs 87.5%), ALT normalization (89.2% Vs 87.5%), HBsAg negativity (25% vs 28.1%), and seroconversion (2.8% vs 3.1%) at 1 year were almost similar in both groups with P value > 0.05 for all efficacy end points. There was no HBVR-related mortality in any group. CONCLUSION: Both ETV and tenofovir are very effective in the treatment of HBVR and reduce the liver-related mortality and morbidity in such patients.

Indian National Association for the Study of the Liver-Federation of Obstetric and Gynaecological Societies of India Position Statement on Management of Liver Diseases in Pregnancy.

Liver diseases occurring during pregnancy can be serious and can progress rapidly, affecting outcomes for both the mother and fetus. They are a common cause of concern to an obstetrician and an important reason for referral to a hepatologist, gastroenterologist, or physician. Liver diseases during pregnancy can be divided into disorders unique to pregnancy, those coincidental with pregnancy, and preexisting liver diseases exacerbated by pregnancy. A rapid differential diagnosis between liver diseases related or unrelated to pregnancy is required so that specialist and urgent management of these conditions can be carried out. Specific Indian guidelines for the management of these patients are lacking. The Indian National Association for the Study of the Liver (INASL) in association with the Federation of Obstetric and Gynaecological Societies of India (FOGSI) had set up a taskforce for development of consensus guidelines for management of patients with liver diseases during pregnancy, relevant to India. For development of these guidelines, a two-day roundtable meeting was held on 26-27 May 2018 in New Delhi, to discuss, debate, and finalize the consensus statements. Only those statements that were unanimously approved by most members of the taskforce were accepted. The primary objective of this review is to present the consensus statements approved jointly by the INASL and FOGSI for diagnosing and managing pregnant women with liver diseases. This article provides an overview of liver diseases occurring in pregnancy, an update on the key mechanisms involved in its pathogenesis, and the recommended treatment options.

INASL Guidelines on Management of Hepatitis B Virus Infection in Patients receiving Chemotherapy, Biologicals, Immunosupressants, or Corticosteroids.

Hepatitis B Virus (HBV) reactivation in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids is emerging to be an important cause of morbidity and mortality in patients with current or prior exposure to HBV infection. These patients suffer a dual onslaught of illness: one from the primary disease for which they are receiving the culprit drug that led to HBV reactivation, and the other from HBV reactivation itself. The HBV reactivation not only leads to a compromised liver function, which may culminate into hepatic failure; it also adversely impacts the treatment outcome of the primary illness. Hence, identification of patients at risk of reactivation before starting these drugs, and starting treatment aimed at prevention of HBV reactivation is the best strategy of managing these patients. There are no Indian guidelines on management of HBV infection in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids for the treatment of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions, or solid-organ or bone marrow transplantation. The Indian National Association for Study of the Liver (INASL) had set up a taskforce on HBV in 2016, with a mandate to develop consensus guidelines for management of various aspects of HBV infection, relevant to India. In 2017 the taskforce had published the first INASL guidelines on management of HBV infection in India. In the present guidelines, which are in continuation with the previous guidelines, the issues on management of HBV infection in patients receiving chemotherapy, biologicals, immunosupressants, or corticosteroids are addressed.

INASL Position Statements on Prevention, Diagnosis and Management of Hepatitis B Virus Infection in India: The Andaman Statements.

Hepatitis B Virus (HBV) infection is one of the major causes of morbidity, mortality and healthcare expenditure in India. There are no Indian consensus guidelines on prevention, diagnosis and management of HBV infection. The Indian National Association for Study of the Liver (INASL) set up a taskforce on HBV in 2016, with a mandate to develop consensus guidelines for diagnosis and management of HBV infection, relevant to disease patterns and clinical practices in India. The taskforce first identified contentious issues on various aspects of HBV management, which were allotted to individual members of the taskforce who reviewed them in detail. A 2-day round table discussion was held on 11th and 12th February 2017 at Port Blair, Andaman & Nicobar Islands, to discuss, debate, and finalize the consensus statements. The members of the taskforce reviewed and discussed the existing literature threadbare at this meeting and formulated the 'INASL position statements' on each of the issues. The evidence and recommendations in these guidelines have been graded according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) system with minor modifications. The strength of recommendations (strong: 1, weak: 2) thus reflects the quality (grade) of underlying evidence (A, B, C, D). We present here the INASL position statements on prevention, diagnosis and management of HBV in India.

Tenofovir alafenamide (TAF) as the successor of tenofovir disoproxil fumarate (TDF).

Tenofovir alafenamide (TAF) can be considered a new prodrug of tenofovir (TFV), as successor of tenofovir disoproxil fumarate (TDF). It is in vivo as potent against human immunodeficiency virus (HIV) at a 30-fold lower dose (10mg) than TDF (300mg). TAF has been approved in November 2015 (in the US and EU), as a single-tablet regimen (STR) containing 150mg elvitegravir (E), 150mg cobicistat (C), 200mg emtricitabine [(-)FTC] (F) and 10mg TAF, marketed as Genvoya®, on 01 March 2016 in the US as an STR containing 25mg rilpivirine (R), 200mg F and 25mg TAF, marketed as Odefsey®, and on 4 April 2016 in the US, as an STR containing 200mg F and 25mg TAF, marketed as Descovy®, for the treatment of HIV infections. STR combinations containing TAF and emtricitabine could be paired with a range of third agents, for example, darunavir and cobicistat. TAF has a much lower risk of kidney toxicity or bone density changes than TDF, and also offers long-term potential in the pre-exposure prophylaxis (PrEP) of HIV infections. TAF is specifically accumulated in lymphatic tissue, and in the liver, and hence also holds great potential for the treatment of hepatitis B virus (HBV) infections. Akin to TDF, TAF is converted intracellularly to TFV. Its active diphosphate metabolite (TFVpp) is targeted at the RNA-dependent DNA polymerase (reverse transcriptase) of either HIV or HBV.