Tenofovir (Viread) Produces Good HBV Suppression in Chronic Hepatitis B Patients with Resistance to Adefovir (Hepsera)

		SUMMARY: Nucleoside/nucleotide analogs are highly effective against HBV, but the virus can evolve to become resistant to the drugs, especially when used as monotherapy. Tenofovir (Viread) -- an HIV drug recently approved for treatment of chronic hepatitis B -- was shown to be effective over the long term in patients who had developed resistance to adefovir (Hepsera), according to 2 studies presented this month at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009) last in Boston.

By Liz Highleyman

In the OptiB trial, M. Levrero colleagues from Italy (abstract 489) evaluated response to tenofovir in chronic hepatitis B patients with suboptimal response to adefovir alone (monotherapy) or adefovir plus lamivudine (Epivir-HBV).

A total of 91 patients were screened for the study, and 85 were enrolled. About 82% were men, the mean age was 55 years, 41% were hepatitis B "e" antigen (HBeAg) positive, and 44% had liver cirrhosis.

A majority (about 56%) had baseline lamivudine-resistance mutations, including rtL180M, rtL180M + rtM204V/I, and rtM204I. Nearly half (47%) had mutations conferring resistance to adefovir -- a nucleotide analog like tenofovir -- including rtA181V, rtN236, rtA181T/V + rtN236T, and rtI233V. About 10% had entecavir (Baraclude) resistance mutations. One 3 patients had wild-type, or non-mutated, virus.

About 15 participants switched to 300 mg/day tenofovir from adefovir monotherapy and 85% switched from adefovir/lamivudine combination therapy to a tenofovir/lamivudine combination. The median duration of prior adefovir use was 29 months.

At 24 weeks of treatment, HBV DNA fell by a median 1.97 log10 UI/ml, and 60% achieved viral load levels < 69 UI/ml. According to baseline genotypic resistance analysis, 59% of patients had suboptimal response to adefovir without adefovir resistance mutations, and 41% had adefovir genotypic resistance.

Five participants who were HBV DNA positive at week 24 reached levels < 69 UI/ml by week 48. Overall, 75% achieved HBV DNA <69 UI/mL at week 48. Percenatges of patients reaching HBV DNA levels < 12 UI/ml were 31% by week 12, 44% by week 24, and 52% by week 48.

The proportion of patients reaching undetectable HBV DNA at week 24 was not correlated with baseline viremia levels, HBeAg status, HBV genotype, or the presence of baseline adefovir or lamivudine resistance mutations. No instances of virological breakthrough were observed between weeks 24 and 48.

Tenofovir was generally well tolerated, with no clinically significant side effects related to tenofovir. Creatiinine levels (a measure of kidney function) remained stable overall, though 1 person experienced a sharp increased in creatinine levels and a decrease in creatinine clearance while using NSAIDs and dropped out of the study.

"[Tenofovir] shows significant antiviral activity against HBV in patients who have failed lamivudine and are sub-optimal responders to [adefovir]," the investigators concludes. "The probability of achieving HBV DNA suppression during [tenofovir] treatment was slightly reduced but not significantly different in patients with or without genotypic resistance to [adefovir] at baseline."

Study 2

In a related study, N. Sarin and colleagues from Toronto (abstract 454) also looked at response to tenofovir in patients with pre-existing nucleoside/nucleotide resistance by means of a retrospective database review of 130 chronic hepatitis B patients seen at a single center through May 2009,

In this study, 45% were HBeAg positive, 57% had cirrhosis, and 17% were HIV/HBV coinfected. Most (84%) took combination therapy, either tenofovir/lamivudine or tenofovir/emtricitabine (the drugs in the Truvada coformulation), but 16% used tenofovir monotherapy.

After 1 year on tenofovir, 87% achieved HBV DNA < 60 IU/mL. Of the 14 with HBV DNA >60 IU/mL at this point, 4 were had a history of non-adherence. The remaining 10 patients with persistent viremia had higher HBV viral load before starting tenofovir (6.2 log IU/mL).

None of these 10 experienced virological rebound. Three patients subsequently achieved HBV DNA < 60 IU/mL -- after 15-27 months -- while 6 continued to experience a downward trend in their viral load and 1 maintained stable viremia. A majority (4 of 7) patients with persistent viremia were HIV positive.

A total of 58 patients were initially switched to adefovir after developing lamivudine resistance. Of this group, 13 subsequently developed adefovir resistance as well. Upon switching to tenofovir, most (11 of 13) achieved HBV DNA < 60 IU/mL by 1 year and 2 continued a downward trend.

The remaining 45 switched to tenofovir due to incomplete viral suppression after more than 1 year on adefovir. Within this group, 42 achieved HBV DNA < 60 IU/mL by 1 year, 2 did so after more than 1 year (15-23 months) on tenofovir, and 1 was non-adherent.

Based on these findings, the researchers concluded, "[Tenofovir] is extremely effective and should be considered first-line therapy for nucleoside-resistant chronic hepatitis B."

Study 3

Finally, W. Alazawi and colleagues in the U.K. asked, "Is substituting tenofovir for adefovir worthwhile?" At their center in London, they introduced combination therapy with lamivudine plus adefovir in 2006, and decided to switch all patients receiving adefovir to tenofovir in 2007.

The analysis included 51 patients on tenofovir: 16 started first-line combination therapy, 16 had tenofovir added to lamivudine monotherapy, and 19 switched from adefovir/lamivudine to tenofovir/lamivudine.

Independent of treatment strategy, complete response rates (defined as at least 3 log IU/ml drop in HBV DNA during the first month of therapy) were significantly greater for patients receiving tenofovir. Virological breakthrough was not seen in any patients taking tenofovir during a mean treatment duration of 211 days, but was seen in 5 of the 30 patients receiving adefovir/lamivudine. Among 18 patients switched from adefovir/lamivudine to tenofovir/lamivudine, 7 achieved undetectable HBV DNA shortly after changing therapy, 6 did so after a longer delay. Four patients experienced virological breakthrough, but 3 of these ultimately reached undetectable levels.

"In patients receiving lamivudine + adefovir who have detectable viremia there is a further reduction in viral load if adefovir is changed to [tenofovir]," the researchers concluded. "In patients receiving lamivudine + adefovir who relapse, switching adefovir to [tenofovir] improves viremia."

11/24/09

References

M Levrero, L Cimino, P Lampertico, and others. Tenofovir DF (TDF) for chronic hepatitis B patients with suboptimal response to adefovir (ADV) or ADV/LAM treatment: interim analysis of the multicenter prospective open label study OptiB. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 489

N Sarin, C Yim, JJ Feld, and others. Tenofovir is effective salvage therapy for nucleoside-resistant Hepatitis B. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 454.

W Alazawi, R Cottle, V Ross, and others. Substitution of adefovir for tenofovir in patients with chronic HBV receiving combination therapy who have incomplete control or virological breakthrough - is it worthwhile? 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 415.