[Feature] Similar efficacy and improved kidney and bone safety markers—the value of TAF in treating chronic hepatitis B

 

The European Association for the Study of the Liver (EASL) released an updated Clinical Practice Guideline on the management of hepatitis B virus (HBV) infection on April 20th, 2017, and in addition to tenofovir disoproxil fumarate (TDF) and entecavir (ETV), tenofovir alafenamide (TAF) was added as a first-line recommended regimen.

 

Since the main goal for chronic hepatitis B (CHB) treatment is to improve survival and quality of life by preventing disease progression and HCC development, the long-term suppression of HBV DNA levels is the main endpoint of current treatment strategies. According to the updated guideline, an optimized safety profile of a long-term nucleos(t)ide analogue (NA) therapy should be used, particularly in an ageing CHB population with increasing comorbidities. The guidelines recommend TAF as a preferred choice for patients at risk of development and/or with underlying renal or bone disease, especially those with previous exposure to nucleoside analogue.

 

TAF has been approved in the U.S., Europe, and Japan, mainly based on two randomized double-blinded, non-inferiority phase 3 studies that had TDF as active control (Studies 108 and 110). The 96-week results of these two studies were also announced on Apr. 20th at this year’s EASL conference. TAF clinical studies are being implemented in China, where it has not approved. Next, we will introduce you to clinical study data recently presented at leading scientific congresses for liver disease, including AASLD and EASL.

 

The burden of the chronic hepatitis B disease and the current recommended therapies

 

Currently there are about 240 million chronic HBV infected patients globally, and if not treated, about 1/4 of them will die from cirrhosis, liver failure, and hepatocellular cancer (HCC). Each year, there are about 650 thousand people die from Hepatitis B and its related complications. Our country has about 93 million people with chronic HBV infection, and among them about 20 million are chronic hepatitis B (CHB) patients.

 

It is a common view that the goal of treating CHB is to reduce liver cell inflammatory necrosis and liver fibrosis, delay and reduce the incidence of liver failure, decompensated cirrhosis, HCC, and other complications, in order to improve patients’ quality of life and their survival rate. To achieve the above goal, we need to maximize the inhibition of HBV duplication on the long-term. When treating naive patients with NA, we should first consider the drugs that are highly potent and with a high barrier to resistance, such as TDF, EVT, and TAF that has been listed into EASL guideline recently.

 

Regarding TDF, the 8-year intention-to-treat data shows that the HBV DNA is lower than the detection limit (<69 IUs/mL) for 58% of the HBeAg-positive patients and 75% of the HBeAg-negative patients, and according to on-treatment data, 98% HBeAg-positive patients and 99.6% HBeAg-negative patients have reached virological response after 8-year treatment of TDF and no drug resistance is found. The overall tolerance and safety profile of TDF is very good. However, by the end of the 8th year, 2.2% subjects had serum creatinine ≥0.5 mg/dL from the baseline and 1.7% had transient hypophosphatemia.

 

Although there were kidney and bone related problems happened to several patients during TDF treatment, according to analysis, many incidence might be associated with improper clinical practices as well as failure to adhere to recommended dosing guidelines and other precautions listed in the product label. For instance, the lack of detailed assessment of patient’s disease history and treatment history prior to their treatment, the lack of understanding of patient’s kidney and bone conditions as well as related risk factors, and the dosage was not adjusted according to indicators such as the estimated infiltration rate of glomerulus during treatment.

 

Meanwhile, complications will develop as chronic Hepatitis B patients grow older. A cohort study that enrolled 1334 chronic Hepatitis B patients indicates that the prevalence rate of CKD is 7.2% in all patients, while for patients aged over 65, the CKD rate is 14% and hypertension/diabetes complication rate has reached to 25%. In addition, chronic Hepatitis B patients require long-term and even infinite treatments, so they would require continually improved safety profile for DAA drugs.

 

The 96-week data showing anti-virus potency of TAF and its improved kidney and bone safety markers

 

Both TAF and TDF are the prodrug of Tenofovir (the difference between the two is shown in Figure 1). TAF is more stable in plasma with a half-life of 90 min (the half-life of TDF is 0.4 min), and can deliver TFV to hepatocytes more effectively comparing to TDF. In hepatocytes, TAF is broken down into active metabolite, Tenofovir Diphosphate. To produce the same concentration of the active metabolite, the dosage needed for TAF is only about 1/10 of that needed for TDF (25 mg versus 300 mg), resulting an 89% reduction of TFV exposure in the blood system.

 

Figure 1. Introduction of tenofovir alafenamide（TAF）

 

The study designs of study 108 and 110 are the same. The former enrolled 425 HBeAg-negative patients and the latter enrolled 873 HBeAg-positive patients. The patients randomly received treatment with TAF (25mg, QD) or TDF (300mg, QD) at a ratio of 2:1. At this year’s conference, professor Brunetto from University of Pisa in Italy and professor Agarwal from King's College London School of Medicine in UK respectively reported the efficacy and safety of the TAF 96-week treatment for HBeAg-negative patients and HBeAg-positive patients (abstract’s serial numbers: PS-042 and FRI-153).

 

Sustained efficacy of TAF in treating CHB for 96 weeks

 

The previous 48-week data shows that TAF’s anti-virus efficacy is comparable to that of TDF. After 48 weeks of treatment, the percentage of HBeAg-negative patients whose HBV DNA level is <29 IU/ml is 94.0% and 92.9% in the TAF group and the TDF group respectively, and the response rate of the HBeAg-positive patients is 63.9% and 66.8% (P=0.25) in the TAF group and the TDF group respectively.

 

After 96 weeks of treatment, the virologic response rate of the HBeAg-negative patients is 90% and 91% in the TAF group and the TDF group respectively (the difference after calibration is 0.6%, p=0.84); the virologic response rate of the HBeAg-positive patients is 73% and 75% in the TAF group and the TDF group respectively (the difference after calibration is 2.2%, p=0.47). The virologic response data of the two groups is shown in Figure 2.

 

Figure 2. The SVR of TAF and TDF Treating Chronic Hepatitis B Patients for 48 weeks and 96 weeks (HBV<29 IU/mL)

 

There are more patients whose serum ALT level is back to normal in the TAF group than that in the TDF group – according the research standard, the percentage of patients with ALT back to normal in 96 weeks is 81% versus 71% (P=0.035) among the HBeAg-negative patients and 75% versus 68% (P=0.017) among the HBeAg-positive patients. HBeAg clearance rates are similar in both groups. In the TAF group, 1 HBeAg-negative patient showed HBeAg clearance and had seroconversion after 80 weeks of treatment.

 

Improved safety markers for bone and kidney during 96 weeks of TAF treatment for CHB

 

The previous 48-week data shows that bone and kidney safety markers were improved for TAF as compared to TDF, and this improvement lasts to the 96th week of the treatment. Compared to TDF, the decline of bone mineral density (BMD) of the hip joint and spine from the baseline was smaller, the decline of eGFR was smaller, and the change in the markers of kidney tubules was also smaller for patients in TAF 96 weeks of treatment group (see chart 1). The adverse rates are similar for both groups, the withdrawal rate due to adverse events and the incident rate of level 3-4 severe adverse events are low. According to the product instruction of TAF, common adverse events (incident rate ≥5%) including headache, abdominal pain, fatigue, cough, nausea, back pain.

 

Figure 3. The BMD Changes of Spine and Hip during TAF and TDF Treatment

 

(Above: HBeAg-negative patients, Blow: HBeAg-positive patients; The BMD decrease is smaller in TAF group, and the difference becomes distinct in week-96)

 

The data of bone and kidney safety is improved after using TAF to replace TDF

 

At the EASL conference, Professor Henry Chan from Chinese University of Hong Kong reported the change of kidney and bone parameters and the retainment of virus inhibition for patients in the above two studies to whom TAF was used to replace TDF after the double-blinded 24 weeks treatment (abstract serial number: PS-041). As of the time when this analysis was conducted, 200 HBeAg-negative patients and 340 HBeAg-positive patients completed 96 weeks of treatment and TAF was used to replace TDF for open-label treatment.

 

The result shows that, after using TAF to replace TDF for 24 weeks of treatment (n=117), the creatinine clearance of the patients was significantly improved, with an average increase of 2.43ml/min (P=0.02), and the creatinine clearance of the patients who previously receiving TAF treatment remained stable (Figure 4). Similarly, after using TAF to replace TDF for 24 weeks, patient’s BMD was also significantly improved, with p <0.001 comparing to 96 weeks (Figure 5), and the BMD of those previously receiving TAF treatment remained stable. In terms of virologic control, both groups demonstrated sustained strong virologic inhibition - the percentage was 97%-99% for HBeAg-negative patients and 80%-83% for HBeAg-positive patients.

 

Figure 4. The change of creatinine clearance rate in 24 weeks after switching TDF to TAF

 

Figure 5. The change of BMD in 24 weeks after switching TDF to TAF

 

Conclusion

 

While maintaining virologic inhibition, TAF demonstrated a higher ALT recovery rate, a higher HBeAg seroconversion rate, as well as a less impact on kidney and bone safety markers. In addition, after using TAF to replace TDF for 24 weeks of treatment, patients’ BMD and creatinine clearance showed improvement in clinical trials. Additional long-term data is anticipated in the future which may provide further information on how best to achieve long-term safety management. We are expecting to see more TAF data in naive patients as well as previously treated patients in the future, to help us designing a more effective and safer clinical practice strategy.