Antiviral Therapy 13:895–900
Original article Efficacy and safety of adefovir dipivoxil plus pegylated interferon-α2a for the treatment of lamivudine-resistant hepatitis B virus infection in HIV-infected patients Patrick Ingiliz1*, Marc-Antoine Valantin2, Vincent Thibault 3, Claudine Duvivier 2, Stephanie Dominguez 2, Christine Katlama2, Thierry Poynard1 and Yves Benhamou1 Hepatology Department, Pitié-Salpêtrière Hospital, Paris, France Infectious Disease Department, Pitié-Salpêtrière Hospital, Paris, France 3 Virology Laboratory, Pitié-Salpêtrière Hospital, Paris, France 1 2
*Corresponding author: E-mail:
[email protected]
Background: Up to 10% of the HIV-positive population is coinfected with hepatitis B virus (HBV). Generally, combined treatment includes agents against both viruses, such as lamivudine (3TC). However, HBV resistance to 3TC is high. Adefovir dipivoxil (ADV) has shown its efficacy for treating 3TC-resistant (3TC-R) HBV in HIV-coinfected patients. ADV combined with pegylated interferon (PEG-IFN) has never been evaluated in this population. Methods: HIV–HBV-coinfected patients with positive HBV e antigen (HBeAg), documented 3TC‑R HBV mutation and antiretroviral treatment including 3TC were selected and received ADV (10 mg daily) and PEG-IFN-α2a (180 µg weekly) for 48 weeks. Results: Of 18 eligible patients (n=16 [89%] male, mean ±sd age 40.45 ±4.82 years), 17 were treated
for 48 weeks. One stopped IFN treatment because of adverse events and continued ADV only. The median (interquartile range) HBV DNA at baseline was 8.0 (5.30– 8.97) log10 copies/ml and the median (95% confidence interval [CI]) decrease after 48 and 72 weeks was 3.6 (4.9– 2.4) and 1.4 (‑5.0– 2.2) log10 copies/ ml, respectively. None of the patients became HBeAgnegative. Median (95% CI) decrease of serum alanine aminotransferase was 27.8 (‑66.2–10.5) IU/ml after 48 weeks and 93.0 (‑80.0– 26.1) IU/ml after 72 weeks. Conclusions: ADV and PEG-IFN is safe and effective for treating 3TC‑R HBV in HIV patients. However, on‑ treatment response was not maintained off therapy and did not lead to HBV seroconversion. The combination had no effect on HIV disease progression.
Introduction With more than 400 million people worldwide who are chronically infected and accounting for an estimated one million deaths annually, hepatitis B virus (HBV) infection poses a serious global health problem [1]. The incidence of HBV in HIV-infected individuals varies from 5–10% in Europe and the United States [2,3] and up to 20–30% in Asia and parts of subSaharan Africa [4,5]. High levels of HBV replication or HBV e antigen (HBeAg) seropositivity is common in HIV–HBV-coinfected individuals. These two conditions might be predictive of a poor survival. Progression to cirrhosis, liver decompensation, hepatocellular carcinoma and liver-related mortality might be higher in HIV–HBV-coinfected patients compared with HBV-monoinfected patients [6]. © 2008 International Medical Press 1359-6535
Ingiliz.indd 895
Five drugs have been approved for the treatment of chronic hepatitis B (CHB). These include pegylated interferon-α2a (PEG-IFN-α2a; 180 µg weekly for 48 weeks), lamivudine (3TC; 100 mg daily), adefovir dipivoxil (ADV; 10 mg daily), entecavir (0.5 or 1 mg daily) and telbivudine (600 mg daily). In addition, tenofovir disoproxil fumarate (TDF; 300 mg daily), an anti-HIV nucleotide analogue, has demonstrated its safety and efficacy against HBV [7,8] and was approved recently. Because 3TC is effective against both HBV and HIV, it has almost always been included as a single anti-HBV agent in the antiretroviral regimen of patients coinfected with HIV and HBV. However, up to 90% of HIV–HBVcoinfected patients treated with 3TC monotherapy are at risk of developing HBV resistance to 3TC after 4 years of 895
20/10/08 13:41:51
P Ingiliz et al.
therapy [9]. Prior to the availability of TDF, treatment of 3TC-resistant (3TC‑R) HBV in HIV-coinfected patients was limited. ADV is active against wild-type and 3TC‑R HBV [10–12] in both HBV–HIV-coinfected and HBVmonoinfected patients. In 3TC‑R HIV–HBV-coinfected patients the long term use of ADV added to an antiretroviral regimen including 3TC showed a continuous serum HBV DNA decline over 3 years of therapy [13]. Moreover, no ADV resistance was identified after 3 years and tolerability was excellent. PEG-IFN has been associated with higher HBeAg seroconversion rates in HBV-monoinfected patients compared with 3TC monotherapy [14]. No such data exist in 3TC‑R patients. As previously shown, HBV genotype in HIV-infected patients is predominantly A [15] and is associated with a greater efficacy of PEG-IFN therapy compared with genotype D in HBV-monoinfected patients [14]. Therefore, PEGIFN could be an interesting treatment alternative in this population [15]. Moreover, the combination of 3TC and PEG-IFN resulted in higher rates of HBeAg and HBV s antigen (HBsAg) seroconversion, virological suppression and biochemical response among patients with HBeAg-positive CHB than 3TC alone [14]. The combination of PEG-IFN with an oral antiHBV drug might be attractive and could be used as a first-line therapy in HBeAg-positive patients because of a potent higher rate of HBeAg seroconversion and subsequent limited duration of therapy. New therapeutic strategies in difficult-to-treat HIV coinfection, including those patients with HBV 3TC-R mutations and without indication for antiretroviral treatment are therefore important to develop. In this study we explored the efficacy and safety of a combination therapy with ADV and PEG-IFN in 3TC-R HBV–HIV-coinfected patients.
Methods Study design This pilot, open-label study was conducted to evaluate the efficacy and safety of a combination therapy of ADV with PEG-IFN-α2a for the treatment of 3TC-R HBV in HIV-coinfected patients. Those with proven HBV DNA polymerase mutations that conferred HBV resistance to 3TC received ADV 10 mg daily (taken orally) and PEG-IFN 180 µg weekly for 48 weeks. ADV plus PEGIFN were added to the pre-existing antiretroviral regimen that contained 3TC. Safety visits were held every 4 weeks to monitor haematological parameters, liver function, renal function and physical or psychological symptoms. Changes in serum HBV DNA, HIV RNA and CD4+ T-cell count were assessed every 12 weeks. After the 48-week treatment course, patients were followed up for 24 weeks. 896
Ingiliz.indd 896
The primary study endpoint was the rate of HBeAg seroconversion to anti-HBe. Secondary objectives assessed the change in serum HBV DNA from baseline to week 48, alanine aminotransferase (ALT) flares (defined as rise in ALT levels according to the baseline levels) and changes in creatinine levels. The study protocol and amendments were approved by the local institutional review board and ethics committees and all patients gave written informed consent.
Patients All patients were HIV–HBV-coinfected. Inclusion criteria were age >18 years, HIV plasma load 200 cells/µl, stable antiretroviral therapy that included 3TC (150 mg twice daily) for at least 3 months prior to baseline, confirmed infection with 3TC-R HBV as defined by the presence of a 3TC-R mutation in the polymerase encoding gene, baseline HBV DNA >5 log10 copies/ml (Cobas Amplicor HBV Monitor 2.0, Roche; LLQ 2.3 log10 copies/ml), serum HBeAgpositive and HBV e antibody (HBeAb)-negative (AxSYM, Abbott Diagnostics, Les Ulis, France), availability and willingness to provide written informed consent. Exclusion criteria were use of ADV in the 24 weeks prior to baseline, use of PEG-IFN in the 24 weeks prior to baseline, coinfection with HCV or hepatitis delta virus, new AIDS-defining event diagnosed within 4 weeks prior to baseline, treatment with immunomodulator drugs (IFNs, IL2 or corticosteroids) in the 4 weeks prior to baseline, anti-HBV therapy (IFN-α, famciclovir, TDF, foscarnet, ganciclovir or lobucavir) in the 12 weeks prior to baseline, history of clinically significant renal dysfunction within the 12 months prior to baseline, severe hepatic dysfunction or decompensated cirrhosis (Child–Pugh score >5), history of hepatic encephalopathy, history of variceal bleeding, ascites, sonographic suspicion of hepatocellular carcinoma or alpha foeto protein >50 ng/ ml, concomitant therapy with aminoglycosides, amphotericin B, cidofovir, cis-platinum, intravenous pentamidine, vancomycin, systemic chemotherapeutic agents, d‑carnitine and d‑l-carnitine, pregnancy or breastfeeding and history of autoimmune hepatitis.
Viral parameters HBV serum markers (HBeAg and anti-HBeAb) were determined by Abbott’s AxSYM test (Abbott Diagnostics). Serum HBV DNA was measured by PCR (Cobas Amplicor HBV Monitor 2.0, Roche; LLQ 2.3 log10 copies/ml). Serum was diluted to allow quantification of samples above the upper limit of quantification (200,000 copies/ml). HIV RNA was assessed by a commercial assay (Amplicor HIV-1 Monitor 1.5, Roche; LLQ 2.3 log10 copies/ml). HBV 3TC-R mutations were detected using a © 2008 International Medical Press
20/10/08 13:41:51
Adefovir plus pegylated interferon in HIV–HBV-coinfected patients
Results Baseline characteristics Table 1 summarizes the baseline characteristics of the 18 HIV–HBV-coinfected patients included in the study. In total, 16 patients were male with a mean age of 40.45 ±4.82 years. The main risk factor for viral infections was sexual transmission in 17 cases (94%) and intravenous drug use in one case (6%). The median duration of HIV infection was 10.4 years (95% CI 8.96–14.31). All patients were on a stable antiretroviral treatment consisting of two nucleoside analogues including 3TC and one protease inhibitor. Antiretroviral therapy remained unchanged in all patients throughout the study period. The median HIV viral load was 2.52 log10 copies/ml (interquartile range [IQR] 2.00–2.89) and the median CD4+ T-cell count was 441 cells/mm3 (IQR 299–557). The median HBV viral load at baseline was 8.0 log10 copies/ml (IQR 5.30–8.97). All patients showed 3TC-R mutations as defined by the detection of at least one amino acid change at position rtM204. The distribution of mutations included rtL180M and rtM204V in 16 patients and rtL180M and rtM204V/l in two patients. The median ALT level at baseline was 78 IU/l (IQR 60–121) and two patients had normal ALT. The median creatinine level was 86.5 µmol/l (IQR 76–94).
Safety
Antiviral Therapy 13.7
Ingiliz.indd 897
Efficacy One study endpoint was to assess the HBeAg or HBsAg seroconversion rate of treatment with PEG-IFN and
Table 1. Main baseline characteristics of the 18 HIV–HBV-coinfected patients with lamivudine-resistant HBV Characteristic
Value
Male, n (%) Mean age, years (±sd) Caucasian, n (%) Risk factors for HIV Sex, n (%) Intravenous drug use, n (%) Median HIV duration, years (95% CI) Median HIV viral load, log10 copies/ml (95% CI) Median CD4+ T-cell count, cells/mm3 (95% CI) Median HBV viral load, log10 copies/ml (95% CI) Median ALT level, IU/l (95% CI)
16 (89) 40.45 ±4.82 16 (89) 17 (94.4) 1 (5.6) 10.4 (8.96–14.31) 2.52 (2.3–2.8) 441 (298–544) 8.0 (5.3–8.97) 78 (60–118)
ALT, alainine aminotransferase; CI, confidence interval; HBV, hepatitis B virus.
Figure 1. Changes in median ALT and median creatinine levels during treatment and follow-up of 17 HIV–HBV-coinfected patients treated with ADV and PEG-IFN
ADV + PEG-IFN Follow-up 200 170 Median serum ALT 180 Median serum creatinine 160 140 89 86.5 84 84 83 87.5 81 82 79 120 100 80 82 79 60 78 60.5 67 40 52 47 35 20 0 0 4 8 12 24 36 48 60 72
150
100
50
Serum creatinine, µmol/l
A total of 17 patients completed the 48-week treatment course with PEG-IFN 180 mg weekly (subcutaneous) and ADV 10 mg daily (oral). One patient discontinued prematurely at week 4 because of asthenia and continued on ADV only. This patient was excluded from the efficacy analysis. There were no serious adverse events reported. All 17 remaining patients complained about mild asthenia from week 2, which was attributed to IFN therapy, but no significant mood changes were reported. One patient had erythema at the injection site during the first 4 weeks of treatment. No patient had liver decompensation. Platelet count and neutrophil count dropped slightly during treatment and returned to baseline in the follow-up period. Dose reduction of PEG-IFN and growth factor use were not needed in any of the patients. No changes in serum creatinine levels were observed in this study (Figure 1). An ALT flare was observed at week 4. ALT reached a median level of 170 IU/l (IQR 65–194) and then
returned to normal levels during the follow-up period. ALT flares were not associated with liver decompensation or alteration of liver synthesis tests (bilirubin and prothrombine time). At week 72, the median ALT level was 35 IU/l (IQR 28–52) and 6 of 17 patients (35%) had ALT levels below the upper limit of the normal range compared with two patients at baseline (Figure 1). Three patients flared after cessation of treatment but had normalized ALT levels at week 72. There was no evidence of loss of HIV control during the study. The CD4+ T-cell count dropped non-significantly on treatment and returned to baseline off therapy.
Serum ALT, IU/l
first generation line probe assay as previously described [16]. 3TC-R was defined by the detection of at least one amino acid change at position rtM204. Variables were expressed as mean (±sd) or medians (95% confidence interval [CI]) as appropriate. Twosided P-values 30% in HBV-monoinfected patients [14], especially in patients with HBV genotype A, a low viral load and increased transaminase levels. Response rates in the HIV setting have not yet been investigated. Almost all the studies conducted on HIV–HBV-coinfected patients concluded that there was a reduced response to standard IFN-α2a compared with HBV-monoinfected patients [17–22]. However, endpoints were heterogenous and the numbers of patients included were small. Furthermore, these studies were performed in immunosuppressed patients not receiving potent anti-HIV 898
Ingiliz.indd 898
Figure 2. Changes in median HBV DNA during treatment and follow-up of 17 HIV–HBV-coinfected patients treated with ADV and PEG-IFN
9 HBV DNA, log10 copies/ml
ADV in HIV–HBV-coinfected patients with 3TC‑R HBV. Unfortunately, none of the 17 patients who completed the 48-week treatment course had HBeAg or HBsAg seroconversion at the end of treatment or at the end of the 24-week follow-up period. Figure 2 shows the changes in HBV DNA during treatment and follow-up. There was a significant ontreatment reduction from baseline in HBV viral load of 4.35 log10 copies/ml to 3.65 log10 copies/ml (95% CI 2.49–4.30) at week 48 (P=0.001). However, at the end of the follow-up period HBV DNA returned to pretreatment levels with a median of 7.3 log10 copies/ml (IQR 4.76–9.57). Two patients had undetectable HBV DNA under the LLQ of 2.3 log10 copies/ml by week 48, one by week 60 and none at the end of follow-up (week 72). No on‑treatment serum HBV DNA breakthrough (1 log10 copies/ml increase from nadir) was observed.
Follow-up
ADV + PEG-IFN 8
8
7.3
7
HBV DNA
6
5.3
5.06
5
4.3
4.3 3.65
4 3
LLQ
2 1 0
0
12
24
32 Weeks
48
60
72
ADV, adefovir dipivoxil; HBV, heptatitis B virus; LLQ, lower limit of quantification; PEG-IFN, pegylated interferon.
therapy. Although anticipated, the antiviral activity of PEG-IFN in 3TC-R HBV is yet unknown. The most beneficial effect expected of IFN treatment in HBV, namely HBeAg seroconversion to anti-HBe, was not observed in this study. HBeAg seroconversion is a key objective of therapy in HBeAg-positive patients with CHB because it is associated with improved long-term clinical outcomes (such as improved liver histology and increased complication-free and overall survival) [23,24]. A previous study [14] showed that the combination of 3TC and PEG-IFN leads to higher rates of HBeAg seroconversion and HBV DNA suppression than 3TC monotherapy in HBeAg-positive HBV-monoinfected patients, but did not show higher rates compared with PEG-IFN alone. We presumed an additional effect in our population that was not observed. Our results are comparable to those observed in ADV monotherapy in HIV–HBVcoinfected patients, and a beneficial effect of the addition of PEG-IFN treatment could not be described. The immunological effect of PEG-IFN that could play a role in HBeAg seroconversion was not observed and might be impaired in HIV patients (although their immune system has been stabilized by HIV treatment) compared with the non-HIV population. However, no strong conclusion can be formulated from the results of our study because there was no control arm and, more importantly, the number of included patients was small. Although needed, larger trials could be difficult to carry out in developed countries as almost all HIV–HBV-coinfected patients have TDF plus 3TC or emtricitabine included in their antiretroviral regimen, which is one of the most effective © 2008 International Medical Press
20/10/08 13:41:54
Adefovir plus pegylated interferon in HIV–HBV-coinfected patients
anti-HBV regimens currently available. Nevertheless our study indicates the antiviral efficacy and tolerability of a combination therapy including an oral anti-HBV agent with PEG-IFN. Encouraging results on the tolerability of PEG-IFNbased therapy in HIV–HBV-coinfected patients were observed. The most common side effect associated with IFN was asthenia, resulting in a withdrawal of PEG-IFN in only one case. Haematological changes were mild and growth factor use was not necessary during the study period. PEG-IFN had no effect on HIV disease and changes in CD4+ T-cell count were moderate and transient. There was no evidence of loss of antiretroviral efficacy over the study period and all patients remained on their pretreatment regimen. Furthermore, no modification of any of the antiretrovirals was needed throughout the study period. The tolerability results are encouraging, taking into account a possible longer duration (for example, 96 weeks) of PEG-IFN treatment that might be needed in HIV– HBVcoinfected individuals. A substantial reduction of serum ALT levels compared with baseline was observed. Initial and transient ALT flares were not associated with liver decompensation or liver function test alteration. Interestingly, reduced serum ALT level was maintained off therapy. The choice of anti-HBV treatment in HIV–HBVcoinfected patients is usually based on the indication for an antiretroviral treatment. Because TDF has proven its non-inferiority to ADV for the treatment of HBV in HIV-coinfected patients [7], it would be the drug of first choice in combination with 3TC in coinfected patients with high serum HBV DNA who need antiretroviral therapy [25]. In contrast, agents with activity against both HIV and HBV should be avoided when therapy is only needed for HBV because of concerns over the development of HIV drug resistance [26]. As concerns have been raised over the use of entecavir in untreated HIV patients because of the possible emergence of 3TC‑R HIV [27] and the reduced efficacy in 3TC‑R HBV, ADV might play an important role in this setting. A theoretical risk for developing mutation K65R has not been demonstrated [26], but all patients in our study were on suppressive highly active antiretroviral therapy regimens. PEG-IFN, as an effective and safe agent, should still be taken into consideration [25]. In conclusion, ADV plus PEG-IFN is safe and effective for the treatment of 3TC-R HBV in HIVcoinfected patients. However, on-treatment response is not maintained off therapy and did not lead to HBV seroconversion. The combination has no effect on HIV disease progression. Studies are needed to assess the role of PEG-IFN for the treatment of HBV in HIVcoinfected patients. Antiviral Therapy 13.7
Ingiliz.indd 899
Acknowledgements This study received an unrestricted grant from Gilead Sciences (Paris, France) and Roche Products (Paris, France).
Disclosure statement The authors declare no competing interests.
References 1. 2.
3.
4. 5.
6. 7.
8.
9.
10.
11. 12.
13. 14.
15. 16.
Lai CL, Ratziu V, Poynard T. Viral hepatitis B. Lancet 2003; 362:2089–2094. Solomon L, Flynn C, Muck K, Vertefeuille J. Prevalence of HIV, syphilis, hepatitis B, and hepatitis C among entrants to Maryland correctional facilities. J Urban Health 2004; 81:25–37. Goedert JJ and the Second Multicenter Hemophilia Cohort Study. Prevalence of conditions associated with human immunodeficiency and hepatitis virus infections among persons with haemophilia, 2001–2003. Haemophilia 2005; 11:516–528. Thio CL. Hepatitis B in the human immunodeficiency virus-infected patient: epidemiology, natural history, and treatment. Semin Liver Dis 2003; 23:125–136. Uneke CJ, Ogbu O, Inyama PU, Anyanwu GI, Njoku MO, Idoko JH. Prevalence of hepatitis‑B surface antigen among blood donors and human immunodeficiency virus-infected patients in Jos, Nigeria. Mem Inst Oswaldo Cruz 2005; 100:13–16. Colin JF, Cazals-Hatem D, Loriot MA, et al. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology 1999; 29:1306–1310. Peters MG, Andersen J, Lynch P, et al. ACTG Protocol A5127 Team. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology 2006; 44:1110–1116. van Boemmel F, De Man RA, Erhardt A, et al. First multicenter evaluation of the efficacy of tenofovir in nucleos(t)ide analog experienced patients with HBV monoinfection. Hepatology 2007; 46:270A. Benhamou Y, Bochet M, Thibault V, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology 1999; 30:1302–1306. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003; 348:800–807. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003; 348:808–816. Peters MG, Hann Hw H, Martin P, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 2004; 126:91–101. Benhamou Y, Thibault V, Vig P, et al. Safety and efficacy of adefovir dipivoxil in patients infected with lamivudineresistant hepatitis B and HIV-1. J Hepatol 2006; 44:62–67. Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study Group. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005; 352:2682–2695. Lacombe K, Massari V, Girard PM, et al. Major role of hepatitis B genotypes in liver fibrosis during coinfection with HIV. AIDS 2006; 20: 419–427. Stuyver L, Van Geyt C, de Gendt S, et al. Line probe assay for monitoring drug resistance in hepatitis B virus-infected patients during antiviral therapy. J Clin Microbiol 2000; 38:702–707. 899
20/10/08 13:41:54
P Ingiliz et al.
17. Wong DK, Cheung AM, O’Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A metaanalysis. Ann Intern Med 1993; 119:312–323. 18. McDonald JA, Caruso L, Karayannis P, et al. Diminished responsiveness of male homosexual chronic hepatitis B virus carriers with HTLV III antibodies to recombinant alpha interferon. Hepatology 1987; 7:719–723. 19. Brook MG, Karayiannis P, Thomas HC. Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors. Hepatology 1989; 10:761–763. 20. Scully LJ, Lever AM, Yap I, Pignatelli M, Thomas HC. Identification of factors influencing response rate to antiviral therapy of chronic hepatitis B virus infection. A review of the efficacy of adenine arabinoside and lymphoblastoid interferon in the Royal Free Hospital studies. J Hepatol 1986; 3 Suppl 2:S291–S299. 21. Marcellin P, Boyer N, Colin JF, et al. Recombinant alpha interferon for chronic hepatitis B in anti-HIV positive patients receiving zidovudine. Gut 1993; 34 Suppl 2:S106.
22. Zylberberg H, Jiang J, Pialoux G, et al. Alpha-interferon for chronic active hepatitis B in human immunodeficiency virus-infected patients. Gastroenterol Clin Biol 1996; 20:968–971. 23. Fattovich G, Rugge M, Brollo L, et al. Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B. Hepatology 1986; 6:167–172. 24. Lai CL, Chien RN, Leung NW, et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998; 339:61–68. 25. Alberti A, Clumeck N, Collins S, et al. ECC Jury. Short statement of the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV co‑infected patients. J Hepatol 2005; 42:615–624. 26. Soriano V, Puoti M, Bonacini M, et al. Care of patients with chronic hepatitis B and HIV coinfection: recommendations from an HIV-HBV International Panel. AIDS 2005; 19:221–240. 27. McMahon MA, Jilek BL, Brennan TP, et al. The HBV drug entecavir - effects on HIV-1 replication and resistance. N Engl J Med 2007; 356:2614–2621.
Accepted for publication 8 July 2008
900
Ingiliz.indd 900
© 2008 International Medical Press
20/10/08 13:41:54
