Effectiveness and safety of Tenofovir disoproxil fumarate in field practice: a multicenter European cohort study of 737 patients with chronic hepatitis B
Reported by Jules Levin
AASLD Nov 2 2010 Boston
P. Lampertico1; M. Vigan˛1; C. Yurdaydin2; R. Idilman2; M. Buti3; R. Esteban3; G. V. Papatheodoridis4; G. Pinzello5; M. Vinci5; E. Minola6; F. Suter16; P. Del Poggio7; M. Andreoletti8; S. Fagiuoli9; A. Colombo10; A. Salmi11; T. Santantonio12; C. Magni13; G. A. Gubertini13; F. Fumagalli Maldini14; N. M. Terreni15; F. Facchetti1; R. Soffredini1; M. Colombo1
1. 1st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, UniversitÓ degli Studi di Milano, Milano, Italy.
2. Gastroenterology Division, University of Ankara Medical School, Ankara, Turkey.
3. Hospital General Universitario Valle Hberon and Ciberehd , Barcelona, Spain.
4. 2nd Dept. of Internal Medicine, Hippokration Hospital, Athens, Athens, Greece.
5. SC Epatologia e Gastroenterologia, Ospedale Niguarda CÓ Granda, Milano, Italy.
6. Servizio Malattie Epatiche e Infettive, Humanitas Gavazzeni, Bergamo, Italy.
7. UO Epatologia, Ospedale di Treviglio, Treviglio, Italy.
8. S.C. Medicina Generale, Ospedale "A.Manzoni", Lecco, Italy.
9. Gastroenterology Unit, Liver and Lung Transplantation Center, Ospedali Riuniti di Bergamo, Bergamo, Italy.
10. UnitÓ operativa di Medicina, Servizio di Epatologia, Ospedale Sant' Anna, Como, Italy.
11. UnitÓ Operativa di Gastroenterologia, Fondazione Poliambulanza, Ospedale S.Orsola, Brescia, Italy.
12. Clinic of Infectious Diseases, UniversitÓ di Foggia, Foggia, Italy.
13. I and II Div. Infectious Diseases, Ospedale Luigi Sacco, Milano, Italy.
14. Liver Center, Clinica Medica, Azienda Ospedaliera S. Gerardo, UniversitÓ Milano Bicocca, Monza, Italy.
15. UO Gastroenterologia, Ospedale Valduce, Como, Italy.
16. Infectious Diseases, Ospedali Riuniti di Bergamo, Begamo, Italy.
Background and Aim. Registration studies showed Tenofovir disoproxil fumarate (TDF) to be an effective therapy for both NUC na´ve and NUC resistant patients with chronic hepatitis B, but its effectiveness and safety in field practice is only partially established.
Methods: 737 patients on either mono or combo therapy with TDF were enrolled in a retrospective/prospective cohort study conducted in 17 Centers. Included were all patients with chronic hepatitis B starting TDF in each center, with the exclusion of HIV co-infected ones. Median follow-up was 16 months (range 0-52). Virological response was defined as undetectable HBV DNA by sensitive assays; safety analysis focused on renal and tubular function.
Results. Baseline features were: median age 56 years, 75% males, 77% HBeAg negative, 42% with cirrhosis, 9% with HCC, 30% with previous IFN treatment, 47 % with concomitant disease/medications, 71% NUC experienced or resistant and 29% NUC-na´ve patients.
TDF was given as a monotherapy in 27% of the patients and in combination, with lamivudine in most of the cases, in 72%. 14% of the patients started on reduced TDF dose because of reduced creatinine clearance. In NUC na´ve patients, with a median baseline viremia of 5.9 log IU/ml (1.6 - >9), virological response rates were 37%, 66%, 72% and 89% at 12, 24, 36, 48 weeks with time to PCR negativity being significantly affected by baseline viral load. At 48 weeks, 17 patients had a partial virological response with a median 2.5 log IU/ml (1.3-5.4) residual viremia.
In NUC-experienced or resistant patients, viremia remained undetectable in those who switched from ADV to TDF whereas it became undetectable in 74% of those with baseline ongoing HBV replication (median HBV DNA 4.1 log IU/ml, range 1->9 log), independently of the treatment strategy.
In pooled safety assessment, a greater than 0.3 or 0.5 mg/dl increase of serum creatinine in the last visit versus baseline occurred in 3% and <1% of the patients, respectively. Blood phosphorus levels dropped below 2.3 mg/dl in 8% of the patients and urinary phosphate absorption, as assessed by estimated TmPI/GFR, decreased below 0.7 mmol/L in 37%: most of these patients had long-term previous exposure to ADV. Overall, TDF dose was reduced in 6% of the patients because of worsened creatinine clearance: most of these patients were older than 60 years, with previous exposure to ADV and with concomitant potentially nephrotoxic diseases/medications.
Conclusions. TDF suppressed HBV replication in most NUC-na´ve and NUC-experienced or resistant patients in field practice. Few patients showed an impaired renal and tubular function of multifactorial origin.
AASLD: HBV New Target for HIV Drug
By Michael Smith, North American Correspondent, MedPage Today
Published: October 31, 2010
* Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
* Explain to interested patients that the nucleotide analogue reverse transcriptase inhibitor (NRTI) tenofovir, a drug used to treat HIV infection, was found to be safe and effective for treating hepatitis B virus infection.
* Note that successful treatment was especially useful among hep B patients not previously exposed to an NRTI -- with a response rate of 80% at 48 weeks.
BOSTON -- A drug widely used to treat HIV infection -- tenofovir (Viread) -- may become a "new friend" for physicians treating chronic hepatitis B, researchers reported here.
A multicenter European cohort study using the nucleotide analogue reverse transcriptase inhibitor (NRTI) tenofovir found that the drug appears to be safe and effective for treating hepatitis B, according to Pietro Lampertico, MD, of the University of Milan, and colleagues.
It was especially useful among hep B patients not previously exposed to an NRTI, Lampertico told the annual meeting of the American Association for the Study of Liver Diseases.
Lampertico was reporting interim results of a planned five-year analysis of 737 chronic hepatitis B patients treated with tenofovir at 17 European centers.
"We think it is very important to generate data about early clinical practice" because patients in clinical trials are often not representative of all patients with the disease, Lampertico told MedPage Today.
Tenofovir was approved in 2008 both in Europe and the U.S. for treating hepatitis B, but it has long been a mainstay of therapy for HIV. "It's an old friend for those in HIV, but it's a new friend for us," Lampertico said.
To see how well the drug performs in the real world of clinical practice, Lampertico and colleagues studied all patients -- except those with HIV coinfection -- who were put on the drug in each of the 17 centers. The main outcomes of the analysis were undetectable hepatitis B DNA and renal and tubular function.
The patients were stratified according to their previous exposure to NRTIs -- 71% were previously exposed and 29% were NTRI-naive, Lampertico reported.
Median follow-up was 16 months -- but in some cases it was as long as 52 months.
In the NRTI-naive patients, response rates rose over time, reaching 89% at 48 weeks, Lampertico reported. On the other hand, he said, the time to a response was significantly affected (at P<0.0001) by baseline viral load and some patients with extremely high viremia at the start of treatment did not achieve a response.
Indeed, at 48 weeks, 17 patients still had only a partial response, with a median residual viral load of 2.5 log10 international units per mL of serum.
In the previously treated patients, Lampertico said, those who had undetectable viremia on their previous regimen -- most on adefovir (Hepsera) -- continued to have undetectable viremia on tenofovir. Among those who had developed resistance on their previous regimen, 74% became undetectable on tenofovir.
The proportion of patients with impaired renal or tubular function was relatively small, Lampertico said, but those with previous exposure to adefovir were more likely to have low blood phosphorous levels and urinary phosphate absorption.
About 6% of patients had their tenofovir dose reduced because of reduced creatinine clearance, Lampertico said, but most of them were over 60, had previous exposure to adefovir, and had comorbid conditions with the potential to affect kidney function.
"There's a very good safety performance in naive patients," he said, "but in the experienced patients, we may see a few problems."
But he cautioned that the results -- while encouraging -- are provisional and may change as the study continues.
The analysis is "confirmatory and reassuring" that tenofovir works well in clinical practice, not just in trials, according to Arun Sanyal, MD, of Virginia Commonwealth University Medical Center in Richmond, Va. Sanyal, president of the AASLD, was not part of the study.
"People are very interested in knowing what the gap is between outcomes in clinical trials and in real life," he told MedPage Today. "Clearly, it's a good antiviral agent."
But Sanyal added that the safety signal for tenofovir-exposed patients seen by Lampertico and colleagues needs more analysis. "We need more focused studies using state-of-the-art measures of renal injury," he said. That's an "important future direction," he concluded.
The study had no external support.
Lampertico reported financial links with Gilead, Roche, Bristol-Myers Squibb, and Novartis.
Sanyal reported financial links with Takeda, Salix, Ikaria, Exhalenz, Bayer Onyx, Norgine, Gore, Gilead, Intercept, Roche and Astellas.
Primary source: American Association for the Study of Liver Diseases
Lampertico P, et al "Effectiveness and safety of tenofovir disoproxil fumarate in field practice: a multicenter European cohort study of 737 patients with chronic hepatitis B" AASLD 2010; Abstract 369.