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VIENNA -- A combination therapy with nucleoside/nucleotide analogues plus a novel core protein inhibitor was associated with a significant reduction in the decline of hepatitis B (HBV) DNA and HBV RNA compared with nucleoside/nucleotide monotherapy, a researcher said here.

In treatment-naive, viremic patients with chronic HBV infection, treatment with entecavir (Baraclude) plus novel core protein inhibitor, ABI-H0731 (731), was associated with significant declines in both HBV DNA, as well as HBV RNA compared to entecavir alone, reported Jacob Lalezari, MD, of Quest Clinical Research in San Francisco.

Moreover, in patients with chronic HBV who were virally suppressed on current standard-of-care therapy, adding ABI-H0731 was associated with further declines in HBV RNA. And they proved this by creating an assay that measured declines in viremia below detection of 2-5 IU/mL.

Could the results of this small late-breaking trial be a small, promising step towards a cure for HBV? Lalezari expressed cautious optimism during a press conference at the European Association for the Study of the Liver (EASL) annual meeting.

"One of the messages from this conference is that cure is not possible as long as there is residual virus present. To go further and start talking about cure rates, we need to prevent new reservoir virus from being generated; we need to eliminate residual virus that remains...we expect once DNA and RNA are cleared, viral antigens will follow," he said.

EASL press conference moderator Francesco Negro, MD, of the University Hospital of Geneva, called the approach "extremely promising...and extremely logical. Under the threshold, viremia is very interesting, I've never seen that data before," he told MedPage Today.

Lalezari explained that current standard-of-care therapy for HBV is effective at reducing HBV DNA, but where it falls short is that "it doesn't eliminate the virus to zero," and residual viremia generates new reservoir virus.

The core protein inhibitors are different, he said, because they act at multiple steps of the viral life cycle. Most importantly, they appear to block the formation of covalently closed circular (ccc)DNA, which is "a key step necessary to get to a cure."

This was an interim analysis of two phase IIa studies -- one with treatment-experienced patients with chronic HBV who were virally suppressed on nucleoside/nucleotide analogue therapy, and one with treatment-naive HBV e antigen (HBeAg)-positive patients. After 24 weeks of treatment, patients could roll over into an open-label study to get both drugs together for <1 year, Lalezari said.

In Study 202, 25 HBeAg-positive viremic patients were randomized 1:1 to receive entecavir or entecavir plus core protein inhibitor, 731. Primary endpoint was a log10 decline in HBV DNA at weeks 12 and 24. At the time of analysis, 24 patients had crossed the week 12 threshold and 12 were at week 24.

Overall, patients on the combination therapy experienced greater log10 declines in HBV DNA versus patients on entecavir alone at week 12 (-4.54 vs -3.29, respectively, P<0.011) and week 24 (-5.94 vs -3.99, respectively, P<0.005). But patients on the combination regimen also experienced significant declines in HBV RNA at both time points.

In Study 201, 47 HBeAg-positive patients and 26 HBeAg-negative patients were randomized 3:2 to receive standard of care nucleoside/nucleotide analogue therapy or current therapy plus 731. At the time of analysis, 65 patients had crossed the week 12 threshold and 11 were at week 24. Primary endpoint was a log10 decline at week 24 of hepatitis B s antigen (HBsAg) or HBeAg.

At week 24, patients on the combination therapy experienced significantly larger declines in HBV RNA compared to those on monotherapy (-2.20 vs -0.15, P=0.012).

Researchers then examined a subgroup of patients in study 201 who entered the study with viremia <20 IU/mL, and developed a semi-quantitative assay for a level of detection of 2-5 IU/mL. They looked at serial samples of these patients, and found that in five of six patients, detectable virus had declined to below the level of detection of the assay, at weeks 8-16 compared to zero patients on monotherapy.

"This work is completely novel -- no one has ever shown that you can move residual virus ... past the level of current detection," Lalezari said. "This confirms what's being more broadly understood at this meeting -- that patients on a 'Nuc' monotherapy have ongoing viremia, which explains why we don't get a cure with the current drugs because we're not actually getting rid of the virus."

The therapy was also safe, he noted, with treatment-emergent adverse events (such as rash) generally mild or moderate and transient.

But Lalezari also said that this was an interim analysis, and the manufacturer is actually developing more potent compounds, "because it gives patients a little bit of wiggle room in terms of compliance."

Negro told MedPage Today this study appeared to be a "proof-of concept," and "it is something they want to study in more detail."

"I don't understand that [decision]," he said, when asked if he was surprised that this compound was not moving into phase III trials.

Lalezari said that the mood in the HBV space may be shifting from a cure that could take years to one that might take around 6 months -- a "finite process" rather than "an indefinite process with no end in sight."

"It might not be [hepatitis C virus], where you stop viral replication, and 8 weeks later, patients have cleared out all virus, but this isn't HIV either," he said.

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