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The Long Term Use of Tenofovir Disoproxil in HIV-HBV Co-Infection Induces a Marked Decrease in Liver Fibrosis
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Reported by Jules Levin
CROI 2009 Montreal Feb 8-12
K Lacombe,1,2 A Boyd,1 J. Guechot,3 D Wendum,4 JM Molina,5 L Serfaty,6 C Lascoux-Combe,7 P Bonnard,8,1 P Miailhes,9 and PM Girard1,2
1INSERM, Paris and UMR-S707, Universite Pierre et Marie Curie-Paris 6, France; 2Service de Maladies Infectieuses et Tropicales, Hopital Saint-Antoine, AP-HP, Paris, France;
3Service de biochimie, Hopital Saint-Antoine, AP-HP, Paris; 4Service d'anatomie pathologique, Hopital Saint-Antoine, AP-HP, Paris, France; 5Service de Maladies infectieuses, Hopital Saint-Louis, AP-HP, Paris, France;
6Service d'hepatology, Hopital Saint-Antoine, AP-HP, Paris, France; 7Service de Medecine interne, Hopital Saint-Louis, AP-HP, Paris, France;
8Service de maladies infectieuses et tropicales, Hopital Saint-Antoine, AP-HP, Paris, France; 9Hospices Civils de Lyon, Hotel Dieu, Service d'hepatologie et de gastroenterologie, 69002 Lyon, France
AUTHOR CONCLUSIONS
TDF induced a significant decrease in fibrosis level after mean treatment duration of 29.6 months
This decrease is particularly strong in patients with extensive fibrosis and cirrhosis
Activity also markedly decreased while a normalisation of transaminases was noted over time
Our findings suggest that a long and extensive use of TDF in HIV-HBV infected patients might help to prevent end-stage liver disease in this population, by slowing or reversing the liver fibrosis process
INTRODUCTION
Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue licensed in 2001 for HIV infection and in 2008 for HBV infection within the US and EU
Its chemical structure and activity on HBV replication in vitro has made this drug an attractive candidate for inclusion in HAART regimens of HIV-HBV co-infected patients
TDF showed potent and sustained activity on HBV viral load in HIV-infected patients, either treatment-naive1,2 or infected with LAM-resistant strains and pre-core mutants3,4,5
Recent clinical trials have confirmed strong anti-HBV activity in HBV mono-infected patients6
However, data regarding TDF activity on liver fi brosis and activity are scarce and non-existant in the context of HIV
OBJECTIVES
To describe the changes in liver fi brosis in HIV-HBV co-infected patients during treatment with TDF by means of biochemical markers acting as surrogate markers of liver fi brosis
To determine the difference in liver fibrosis changes according to fibrosis stages
To report the changes of liver fibrosis and activity in patients treated with TDF and undergoing liver biopsy
130 co-infected patients [mean age years (SD): 40.9 (7.7)] were treated with TDF and followed for a median of 29.5 months (IQR 16.7)
At baseline, 45 patients presented with Fibrometer stage F0-F1, 29 with stage F2, and 56 patients with stage F3-F4
The majority of patients were exposed to lamivudine before inclusion [mean duration: 28.6 months, SD (30.0)], and 76% were still co-treated with lamivudine/ emtricitabine during follow-up
Transaminases significantly decreased over time [mean ALT/AST (SD) at baseline, 24 months, and 36 months: 76(90) / 57(46), 47(40)/41(30), and 39(29) / 33(15), p=0.002/<0.0001]
Among patients with F3-F4 baseline fibrosis stages, there was a steep decline in fibrosis score at 12 months [adj DAVG=-0.126 (unadj DAVG= -0.139); 95% CI: -0.209, -0.044; p=0.003) followed by a slow and stable decline at 24
and 36 months of treatment [adj DAVG=-0.149 (unadj DAVG=-0.166); 95% CI: -0.250, -0.049; p=0.004 and adj DAVG=-0.171 (unadj=-0.169); 95% CI: -0.329, -0.013; p=0.03 respectively]
Patients with F0-F1 and F2 baseline fibrosis remained consistently stable over follow-up [adj DAVG at 36-months: 0.072 (unadj DAVG=0.068); 95% CI: -0.039, 0.182; p=0.2 and -0.012 (unadj DAVG=-0.064); 95% CI (-0.148, 0.124); p=0.9 respectively]
Change in Fibrosis Evaluated in Liver Biopsies
Among 38 pairs of biopsies:
-- A decrease of at least 1 point in fi brosis stage was observed in 9 patients
(1 to F2, 8 to F0-F1)
-- 4 progressed from F2 to F3-F4
-- 25 remained stable (8 F0-F1, 6 F2, 11 F3-F4)
-- Activity score decreased from A2-A3 to A0-A1 in 10 patients, increased from
A0-A1 to A2-A3 in 2 patients and remained stable (20 A0-A1 and 6 A2-A3) in 26 patients
REFERENCES
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2. Lewin SR, Ribeiro RM, Avihingsanon A, Bowden S, Matthews G, Marks P, Locarnini SA, Ruxrungtham K, Perelson AS, Dore GJ. Viral dynamics of hepatitis B virus DNA in human immunodefi ciency virus-1-hepatitis B virus coinfected individuals: Similar effectiveness of lamivudine, tenofovir, or combination therapy. Hepatology. 2008 Nov
25. [Epub ahead of print]
3. Peters MG, Andersen J, Lynch P, Liu T, Alston-Smith B, Brosgart CL, Jacobson JM, Johnson VA, Pollard RB, Rooney JF, Sherman KE, Swindells S & Polsky B. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology 2006; 44:1110-1116.
4. Lacombe K, Gozlan J, Boelle PY, Serfaty L, Zoulim F, Valleron AJ & Girard PM. Long-term hepatitis B virus dynamics in HIV-hepatitis B virus-co-infected patients treated with tenofovir disoproxil fumarate. AIDS 2005; 19:907-915.
5. Lacombe K, Gozlan J, Boyd A, Boelle PY, Bonnard P, Molina JM, Miailhes P, Lascoux-Combe C, Serfaty L, Zoulim F, Girard PM. Comparison of the antiviral activity of adefovir and tenofovir on hepatitis B virus in HIV-HBVcoinfected patients. Antivir Ther. 2008;13(5):705-13.
6. Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Washington MK, Sorbel J, Anderson J, Snow-Lampart A, Mondou E, Quinn J, Rousseau F. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008 Dec 4;359(23):2442-55.
7. Cales P, Oberti F, Michalak S, Hubert-Fouchard I, Rousselet MC, Konate A, et al. A novel panel of blood markers to assess the degree of liver fi brosis. Hepatology 2005 Dec;42(6):1373-1381.
8. Bottero J, Lacombe K, Guechot J, Serfaty L, Miailhes P, Bonnard P, Wendum D, Molina JM, Lascoux-Combe C,
Girard PM. Performance of eleven biomarkers for liver fi brosis assessment in HIV-hepatitis B virus co-infected patients. J Hepatol, on press.
9. EASL International Consensus Conference on Hepatitis B. J Hepatol 2003,39:S5-23.
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