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Tenofovir-Based HBV Treatment Cuts HCC Risk After Several Years
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EASL Congress 2024, June 5-8, 2004, Milan
Mark Mascolini
Through up to 8 years of tenofovir-based therapy in four phase 3 trials, hepatocellular carcinoma (HCC) developed 46 of 2273 people (2%) with chronic HBV infection-a rate lower than predicted by the model [1]. Modeling indicated that most people classified at low or medium risk for HCC when the trials began remained at low risk or improved from medium to low risk through follow-up. But most participants initially ranked at high risk for HCC moved into a lower risk category by week 384. Tenofovir-based therapies would appear to trim HCC risk because uncontrolled HBV infection boosts HCC risk.
Prior modeling by some of the US, European, and Asian researchers who conducted this new study used a validated risk prediction model to analyze HCC risk in people who took tenofovir disoproxil fumarate (TDF) for up to 5 years [2]. The REACH-B model (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B) estimates new diagnoses (incidence) of HCC for up to 10 years while factoring in age, sex, alanine aminotransferase (ALT), hepatitis B e antigen status, and HBV DNA level.
After 384 weeks of follow-up in 634 TDF-treated people with chronic HBV infection, 14 HCC cases emerged, 4 in the first year of therapy [2]. Those numbers yielded an incidence of 0.37% per year-0.28% in people without cirrhosis and 0.65% in people with cirrhosis. Among TDF-treated people without cirrhosis, HCC incidence after 384 weeks was 60% lower than the model predicted (standardized incidence ratio [SIR] 0.40, 95% confidence interval [CI] 0.199 to 0.795, statistically significant at P = 0.009). In people with cirrhosis, HCC incidence through 384 weeks of TDF was 0.51 (95% CI 0.231-1.144, not statistically significant).
The new analysis pooled data from four phase 3 randomized trials of TDF. Studies 102 [3], 103 [4], 108 [5], and 110 [6]. Studies 102 and 103 compared TDF with adefovir, while studies 108 and 110 compared TDF with TAF. Cumulative HCC incidence in studies 102 and 103 was 3.8% in the TDF arms and 1.9% in the adefovir-to-TDF switch arms. In studies 108 and 110 HCC incidence was 1.3% in the TAF arms and 2.2% in the TDF-to-TAF switch arms. Overall HCC incidence in these four studies was 2.0% (46 of 2273 people). Cumulative HCC incidence came to 3.1% (20 of 641 people) in studies 102 and 103 and 1.6% (26 of 1632 people) in studies 108 and 110.
Compared with people who never got HCC, at the baseline visit those in whom HCC developed were older (median 52 vs 39, P < 0.0001), included a higher proportion of men (87% vs 67%, P = 0.0046), were more likely to be HBeAg-negative (61% vs 42%, P = 0.0113), but had a lower median HBV DNA (6.5 vs 7.2 log10 IU/mL, P = 0.0228) and a lower ALT (75 vs 88 U/L, P = 0.0547).
The REACH-B model predicted 119 HCC cases, but only 46 cases developed in these TDF trial participants to yield an SIR of 0.39 (95% CI 0.29 to 0.52). That meant people in the TDF studies had about a 60% lower HCC incidence.
In studies 102 and 103, overall SIR favored TDF or adefovir followed by TDF (0.65, 95% CI 0.42 to 1.01), a result just a hair short of statistical significance (P = 0.0528). Compared with people taking TDF throughout the study (SIR 0.79, 95% CI 0.49 to 1.29, P = 0.3530), those switching from adefovir to TDF had a lower HCC incidence than the model predicted (SIR 0.37, 95% CI 0.14 to 1.00, P = 0.0501).
In studies 108 and 110, people taking TDF or TAF had about a 70% lower-than-expected HCC incidence (SIR 0.29, 95% CI 0.20 to 0.43, P < 0.0001). In the TAF-only arm, SIR was better (0.25, 95% CI 0.15 to 0.42, P < 0.0001) than in people switching from TDF to TAF (0.37, 95% CI 0.21 to 0.66, P = 0.0006), though both comparisons were statistically significant.
Through 384 weeks of follow-up, observed HCC incidence proved significantly lower than REACH-B-predicted cases in people with baseline cirrhosis (0.50, 95% CI 0.31 to 0.83, P = 0.0063) and also in people without baseline cirrhosis (0.35, 95% CI 0.25 to 0.50, P < 0.0001). The curve graphing observed HCC cases in people enrolled in these four trials split from the curve showing predicted cases more quickly in people without cirrhosis (about week 96) than in people with cirrhosis (about week 240).
Multivariate Cox regression analysis identified three predictors of higher HCC risk and three predictors of lower risk:
Higher risk of HCC
- Male sex, adjusted hazard ratio (aHR) 4.561, 95% CI 1.742 to 11.942, P = 0.0020
- Older age per year, aHR 1.074, 95% CI 1.041 to 1.108, P < 0.0001
- ALT not returned to normal at week 24, aHR 2.237, 95% CI 1.113 to 4.494, P = 0.0238
Lower risk of HCC
- Lower baseline ALT per U/L, aHR 0.994, 95% CI 0.988 to 0.999, P = 0.0232
- Lower baseline platelet count x 10,000/uL, aHR 0.985, 95% CI 0.979 to 0.992, P < 0.0001
- Lower baseline albumin per g/L, aHR 0.974, 95% CI 0.957 to 0.990, P = 0.0020
Pooled analysis of the four trials with the aMAP (age-male-ALBI-platelets) model and the mPAGE-B (modified platelet age gender-HBV) model determined that most people with low or medium HCC risk at baseline either stayed in those risk categories or slipped to a lower risk group by week 384. Among people with a high baseline HCC risk, most improved to medium or low risk by week 384.
The researchers proposed that "long-term antiviral treatment significantly reduces the risk of HCC in patients with hepatitis B."
References
1. Kim WR, Lim YS, Janssen HLA, et al. Tenofovir-based antiviral therapy reduces long term incidence of hepatocellular carcinoma in chronic hepatitis B patients. EASL Congress 2024, June 5-8, 2004, Milan. Abstract WED-397.
2. Kim WR, Loomba R, Berg T, et al. Impact of long-term tenofovir disoproxil fumarate on incidence of hepatocellular carcinoma in patients with chronic hepatitis B. Cancer. 2015;121:3631-8. doi: 10.1002/cncr.29537.
https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.29537
3. ClinicalTrials.gov. A study to compare tenofovir disoproxil fumarate versus adefovir dipivoxil for the treatment of HBeAg-negative chronic hepatitis B. ClinicalTrials.gov ID NCT00117676.
4. ClinicalTrials.gov. A study to compare tenofovir disoproxil fumarate versus adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. ClinicalTrials.gov ID NCT00116805.
5. ClinicalTrials.gov. Study to compare tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF) in participants with chronic hepatitis B infection who are negative for hepatitis B e antigen. ClinicalTrials.gov ID NCT01940341.
6. ClinicalTrials.gov. Study to compare tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF) in participants with chronic hepatitis B infection who are positive for hepatitis B e antigen. ClinicalTrials.gov ID NCT01940471.
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