Treatment Switch for Hep B Patients With Renal, Bone Risk

Laird Harrison

April 18, 2019

SAN DIEGO — Patients with hepatitis B at particular risk for bone and renal harm from tenofovir disoproxil fumarate (TDF; Viread, Gilead Sciences) might benefit from a switch to tenofovir alafenamide (TAF; Vemlidy, Gilead Sciences), according to specialists.

"If you have someone at high risk for renal or bone toxicity, or you notice that they're experiencing decline, then by switching to the other form of tenofovir, you may see some improvement," said Nancy Reau, MD, from the Rush University Medical Center in Chicago.

However, TAF is not without risks, Reau pointed out, and switching drugs "can be difficult" in practice.

In a pooled analysis of 26 treatment-naïve and antiretroviral switch trials, researchers found better bone and renal biomarkers and fewer renal adverse events in patients taking TAF than in those taking TDF (AIDS. Published online March 29, 2019).

The efficacy and safety results of switching from one drug to the other will be discussed at the upcoming Digestive Disease Week (DDW) 2019 meeting, along with news of multiple drugs in the pipeline for hepatitis B.

Tenofovir, a nucleotide analogue reverse transcriptase inhibitor, works by interfering with hepatitis B DNA polymerase, an enzyme essential for the replication of the virus.

TDF, an ester prodrug of tenofovir, swiftly became a first-line treatment after it was approved for chronic hepatitis B infection by the US Food and Drug Administration (FDA) in 2008. It had been approved for HIV-1 in 2001.

However, TDF comes with some risks.

Challenges With TDF

The label includes a warning about renal impairment, including cases of "acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia)."

The label also warns that clinical trials showed cases of osteomalacia associated with proximal renal tubulopathy, as well as decreased bone mineral density.

In response to these safety issues, Gilead Sciences developed TAF, a phosphonate prodrug of tenofovir, which has more potent antiviral activity than TDF and better distribution to lymphoid tissues. TAF, which can be taken at lower doses than TDF (25 mg vs 300 mg daily), was approved for the treatment of chronic hepatitis B in 2016.

In clinical trials of TAF, there have been no cases of Fanconi syndrome or proximal renal tubulopathy, and decreases in bone mineral density were slightly less than with TDF, according to Gilead.

In one recent study, hip and spine bone mineral density increased significantly from baseline to week 12 in 75 people with chronic hepatitis B who switched from TDF to TAF (J Viral Hepat. Published online December 21, 2018). In addition, the patients experienced a decrease in the ratio of urinary beta-2-microglobulin to creatinine and in the ratio of retinol-binding protein to creatinine.

"No one is going to say that it will heal your bones or kidneys, but if you're concerned about drug-related toxicity, switching from one to the other seems to offer improvement," Reau told Medscape Medical News.

However, some concerns about the switch have cropped up. HIV-positive patients showed signs of increased cardiovascular risk after switching from TDF to TAF, according to a study presented at the HIV Drug Therapy 2018 meeting in Glasgow (abstract P187).

What to Watch for with TAF

One of the studies slated for presentation at next month's DDW meeting will report on 48-week safety and efficacy data after a switch between the two drugs.

And more dramatic improvements in chronic hepatitis B care might be on the horizon. "There is drug development in nearly every aspect of the replication cycle," said Reau.

An overview of these developments will be presented at the upcoming meeting by Norah Terrault, MD, MPH, from the Keck School of Medicine at the University of Southern California in Los Angeles.

Powerful antiviral medications have made it possible to cure hepatitis C, and many patients with hepatitis B are wondering when their turn will come, Terrault told Medscape Medical News.

But hepatitis B poses different challenges. Most notably, it becomes integrated into the DNA of the host. With the current drugs, including tenofovir, only a partial cure is achieved; the virus is not detectable in serum after completion of a finite course of treatment, but hepatitis B surface antigen (HBsAg) is still detectable.

HBsAg disappears in about 1% to 3% of patients, and the prognosis in these patients improves. However, Terrault explained, fragments of the virus DNA remain in cell nuclei. Researchers refer to this outcome as a functional cure.

Current therapies are not able to eliminate those traces of the virus, a goal that researchers refer to as a "sterilizing cure," said Terrault.

Still, a functional cure is a worthwhile intermediate step. "People have to understand that loss of surface antigen is a very good outcome," she said. "Studies show that if you achieve a functional cure before cirrhosis, the survival and risk of cancer is no different than in people who don't have hepatitis B."

Whether any of the drugs in the pipeline will lead to a high rate of functional cure, or a sterilizing cure, remains to be seen. None of the research has progressed beyond phase 2 trials, she noted.

But Terrault said she is encouraged by the amount of research in the field. "It's exciting," she said.

Reau reports relationships with AbbVie, Gilead, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, and Intercept. Terrault reports a relationship with Gilead .

Digestive Disease Week (DDW) 2019.

Follow Medscape Gastroenterology on Twitter @MedscapeGastro and Laird Harrison @LairdH

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