Dear Doctor,

Welcome to the fall edition of HEPDATES, Gilead Science medical newsletter, sharing the recent clinical and scientific updates of treatments’ portfolio for hepatitis C and B infection.

Thinking on your patients’ needs, we gathered recent clinical data that may interest you and includes:

Hope you will enjoy!

Clinical interventions and use of resources for the management of adverse effects associated with multiple drug interactions in the hepatitis C population.

Turnes J, et al. EASL 2024 Poster #THU-410

This retrospective, observational study describes the real-life impact of potential multiple drug-drug interactions (DDIs) of 1,620 patients with chronic hepatitis C (CHC) treated with pan-genotypic direct-acting antivirals (DAAs) in a Spanish database (2017-2020).

Patients with CHC often have multiple comorbidities linked to comedication intake. DAAs share pharmacokinetic pathways with many comedications and hence increased the risk for potential adverse effects (AEs) associated to DDIs as previous studies have already reported.

The aim of this study was to evaluate the clinical interventions and resources utilization to manage AEs in patients with multiple-DDIs treated with the two major DAAs regimens, 730 treated with SOF/VEL (Sofosbuvir/Velpatasvir) and 890 with GLE/PIB (Glecaprevir/Pibrentasvir), as well as to analyze the medical specialties that reported AEs.

27% (444/1,620) of patients in the overall population showed3 1 potential DDI. 78% (1,256/1,620) of patients had3 2 comedications prescribed, of whom 10% (123/1,256) with3 2 comedications were at risk of multiple DDIs with DAAs (52 with SOF/VEL and 71 with GLE/PIB). 18 AEs were reported, of which 16 occurred in patients with potential multiple DDIs. All AEs required clinical interventions or use of resources for their management. The most frequent interventions were discontinuation of comedication or DAAs and reduction of comedication dose, being more frequent in the group treated with GLE/PIB, since this group presented approximately 3 times more AEs then the group treated with SOF/VEL (18.3% GLE/PIB [13/71] vs 5.8% SOF/VEL [3/52]; p<0.05). There were 3 cases of DAAs discontinuation in patients treated with GLE/PIB (2 associated with atorvastatin, and 1 with quetiapine). 1 case in the group treated with SOF/VEL (associated with carvedilol). All dose reductions were reported in the GLE/PIB group. AEs were reported mostly by primary care physicians (62.5%).

The investigators concluded that there is an elevated risk of AEs in hepatitis C patients with potential multiple-DDIs treated with DAAs, particularly with cardiovascular and nervous system comedication, and especially with DAAs containing protease inhibitor. These AEs may require clinical interventions and the use of resources for their clinical management.

†Multiple DDIs were defined as ≥2 comedications, each with a DDI with DAA treatment.

96-Week results of ALLIANCE, a Phase 3, randomized, double-blind study comparing BIC/FTC/TAF versus DTG + FTC/TDF in Treatment-Naive Patients with both HIV-1 and Hepatitis B coinfection.

1Avihingsanon A, et al. AIDS 2022 Oral OALBX0105   2Avihingsanon A, et al. The Lancet HIV vol.10, E640-E652, Oct 2023

TDF & TAF are a guideline recommended treatment for HIV-1/HBV coinfected patients. The ALLIANCE study is the first prospective, Ph3 clinical study of BIC/FTC/TAF vs DTG+FTC/TAF showing superiority in achieving HBV DNA <29 IU/mL (63% vs. 43%) with noninferiority of HIV-1 RNA<50 c/mL (95% vs. 91%) at the 48-week primary analysis1. The HIV-1 & HBV suppression rates were maintained at the 96-week follow-up, with significantly higher rates for HBeAg loss and seroconversion with BIC/FTC/TAF than with DTG+FTC/TDF as well as other markers of Anti-HBV activity (ALT normalization, HBsAg loss and seroconversion)2. These results demonstrate the clinical benefit of BIC/FTC/TAF as a Single-Tablet Regimen (STR) for treatment HIV-1 and HBV coinfection.

The ALLIANCE study is an ongoing randomized, double-blind, multicenter, Phase 3 study (N=243) of B/F/TAF, a single-tablet regimen (STR) recommended for treatment of HIV-15 as an initial treatment for adults with HIV-1/HBV co-infection.

In the primary endpoint at 48-weeks B/F/TAF demonstrated superiority vs. DTG+F/TDF (63% vs. 43%) in achieving HBV DNA <29 IU/mL, and noninferiority to DTG+F/TDF (95% vs. 91%) HIV-1 RNA<50 c/mL6.

In the prespecified secondary analysis at 96-weeks, B/F/TAF maintained high rates of HIV-1 and HBV viral suppression. Rates of HBeAg loss and seroconversion were significantly higher with B/F/TAF than with DTG+F/TDF as well as other markers of Anti-HBV activity (ALT normalization, HBsAg loss and seroconversion) which trended toward improvement with B/F/TAF through 96 weeks.

These results, combined with the improvements in renal and bone health biomarkers7-8 , show the clinical benefit of the STR B/F/TAF for adults co-infected with HIV-1 and HBV as an initial antiviral therapy.

Link for the full article: ALLIANCE 96-week results

  1. WHO
  2. EACS Guidelines v12.0 Oct 2023
  3. DHHS Guidelines Sep 2022 HIV/HBV co-infection
  4. Gandhi RT, et al. JAMA 2023:329:63-84
  5. The Israeli MoH approved PI for at Biktarvy
  6. Avihingsanon A, et al. AIDS 2022 Oral OALBX0105
  7. Buti M, et al. Lancet Gastroenterol Hepatol. 2016;1:196-206
  8. Chan HLY, et al. Lancet Gastroenterol Hepatol. 2016;1:185-195

ATTENTION Trial: Multinational randomized trial to investigate the efficacy of Tenofovir Alafenamide in reducing adverse clinical events in chronic Hepatitis B patients who are beyond treatment indications by current guidelines: first interim analysis.

Lim YS, et al. EASL 2024 Oral #OS-121

There is lack of robust evidence regarding the efficacy of early antiviral therapy in reducing adverse events among non-cirrhotic hepatitis B (CHB) patients with significant viremia but with no remarkable alanine aminotransferase (ALT) level elevation.

The ATTENTION trial is an ongoing, randomized, open-label, multicenter, phase 4 study, which enrolled 780 participants at 22 sites in Korea and Taiwan, with average age of ~53 years, median HBV-DNA levels between 4-8 log10 IU/mL, ALT levels <70 U/L for males, and <50 U/L for females and no cirrhosis. Participant randomized at 1:1 ratio to receive Tenofovir Alafenamide 25 mg/day (TAF) or no antiviral treatment (Observation).

The trial is planned for 8-year follow up and now we have the results of the first interim analysis which planned for year 4 (from 2019 to 2023).

*HCC, death, transplant, and decompensation (Child-Pugh score ≥7, ascites, or varices); †Normal ALT: ≤25 IU/L (females) and ≤35 IU/L (males). ALT, alanine aminotransferase; CHB, chronic hepatitis B, TAF tenofovir alafenamide.

A substantial proportion of patients with chronic hepatitis B (CHB) do not fall into any of the defined phases and are considered to be in the “grey zone”.  Most of the current clinical practice guidelines have no recommendations for antiviral treatment for them and define only the CHB patients who are clearly need the antiviral treatment as those with elevated ALT (approximately  ~33% of patients are eligible) 1-5.

In most of the cases, changes in HBV DNA levels (viremia) precede the ALT elevation, so the “grey zone” CHB patients with significant hepatitis B virus levels (>2000 IU/mL) and persistently normal alanine aminotransferase (ALT) levels have a significantly high risk of hepatic inflammation, fibrosis, and hepatocellular carcinoma.

The ATTENTION is an ongoing, RCT , open-label, multicenter trial which evaluating impact of treatment with TAF on reducing risk of negative clinical outcomes in non-cirrhotic, grey zone CHB patients. The study setting includes 10 sites in Korea and 12 sites in Taiwan and planned to be 8 years follow-up.  The primary endpoint is defined as composite clinical event of hepatocellular carcinoma (HCC), death, liver transplantation, or hepatic decompensation.

Participant randomized to receive Tenofovir Alafenamide 25 mg/day (TAF group, n=369) or no antiviral treatment (Observation group, n=365). For the first interim analysis at year 4, a total of 11 primary clinical events occurred: 2 in TAF group (both HCC) and 9 in the observation group (7 HCC, 1 death, 1 hepatic decompensation), corresponding to incidence rates of 0.33 and 1.57 per person-years, respectively.

Preliminary findings suggest that early initiation of TAF may significantly reduce the risk of liver-related adverse clinical events in non-cirrhotic CHB patients with significant viremia, but without elevated ALT levels. These results highlight the potential benefit of proactive antiviral therapy in these patients.  

  1. EASL 2017 Clinical Practice Guidelines Hepatitis B: J Hepatol. 2017;67:370–98.
  2. AASLD 2018 Hepatitis B guidance: Terrault NA, et al. 2018;67:1560–99.
  3. Cui F, et al. Lancet Gastroenterol Hepatol. 2023;8(4):332-
  4. Lim YS, et al. Aliment Pharmacol Ther. 2022;56(3):519-
  5. Lee CH, et al. Clin Mol Hepatol. 2023;29(3):779-
  6. Lim YS, et al. Grey Zone of hepatitis B virus infection, review SJ Gastro. 30(2):p 76-82, Apr 2024.

Hope you enjoyed this edition of HepDates, Hepatology newsletter for health care providers.

For any questions or more information please contact me:

Shimrit Refaeli
Shimrit.Refaeli@gilead.com

IL-UNB-0704

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