Long-Term Therapy With Tenofovir Is Effective for Patients Co-Infected With Human Immunodeficiency Virus and Hepatitis B Virus - pdf attached
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Gastroenterology Article in Press
Received 9 March 2010; accepted 19 August 2010. published online 30 August 2010.
Theodora E.M.S. de Vries-Sluijs, Department of Internal Medicine-Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands
Jurrien G.P. Reijnders, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands,
Bettina E. Hansen, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands, Department of Biostatistics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
Background & Aims:
We investigated the long-term efficacy and renal safety of tenofovir disoproxil fumarate (TDF), administered to patients co-infected with human immunodeficiency virus and hepatitis B virus (HBV) as part of an antiretroviral therapy.
We performed a multicenter, prospective cohort study of 102 patients co-infected with human immunodeficiency virus and HBV who were treated with TDF.
At baseline, 80% of patients had a detectable viral load (HBV DNA > 20 IU/mL). Among patients positive for hepatitis B e antigen (HBeAg) (n = 67), 92% had a virologic response (HBV DNA < 20 IU/mL) after 5 years of treatment. There was no difference between patients with or without lamivudine resistance at baseline (P = .39). Loss rates of HBeAg and hepatitis B s antigen (HBsAg) were 46% and 12%, respectively. Among HBeAg-negative patients (n = 15), 100% had a virologic response after 4 years of treatment and 2 (13%) lost HBsAg. Twenty subjects (20%, all HBeAg-negative) had undetectable HBV DNA at baseline; during a median follow-up period of 52 months (range, 41-63 mo), 19 (95%) maintained a virologic response and 2 (10%) lost HBsAg. Overall, one patient acquired a combination of resistance mutations for anti-HBV drugs and experienced a virologic breakthrough. Three (3%) patients discontinued TDF because of increased serum creatinine levels. The estimated decrease in renal function after 5 years of TDF therapy was 9.8 mL/min/1.73 m2, which was most pronounced shortly after TDF therapy was initiated.
TDF, administered as part of antiretroviral therapy, is a potent anti-HBV agent with a good resistance profile throughout 5 years of therapy. Only small nonprogressive decreases in renal function were observed.
Tenofovir disoproxil fumarate (TDF) was licensed for the treatment of human immunodeficiency virus (HIV) infection in 2001, and since then has played a pivotal role in HIV management. Currently, the combination of TDF and emtricitabine is the most widely prescribed nucleos(t)ide analogue reverse-transcriptase inhibitor backbone in Europe. Because HIV and hepatitis B virus (HBV) share similar routes of transmission, prevalence of HBsAg carriership is more than 5-fold higher among HIV-infected patients compared with the general population.1, 2 Furthermore, HIV/HBV co-infected patients are at increased risk for development of cirrhosis and hepatocellular carcinoma, and have higher overall mortality rates compared with HIV-monoinfected patients.3, 4, 5, 6
The efficacy of TDF in HBV therapy was first described in studies including mainly patients with HIV-1 co-infection.7, 8, 9, 10, 11 Recent data showed the efficacy of TDF in the treatment of chronically HBV-monoinfected patients as well.12 TDF was superior to adefovir dipivoxil in both nucleos(t)ide-naive hepatitis B e antigen (HBeAg)-positive and HBeAg-negative HBV patients, and appeared to be one of the most potent anti-HBV agents so far. Several reports showed that TDF also was effective in the nucleos(t)ide-experienced population, although conflicting results have been presented concerning patients with genotypic resistance to adefovir dipivoxil.13, 14, 15, 16 Moreover, TDF has a good resistance profile, and no convincing proof of HBV-resistant mutants to TDF has been presented so far.17
Long-term therapy is indicated for all HIV/HBV co-infected and most HBV mono-infected patients treated with oral nucleos(t)ide analogues because a sustained response after cessation of therapy is rare.18, 19 However, follow-up evaluation in studies investigating the efficacy of TDF in HIV/HBV co-infected and HBV-monoinfected patients is limited to only 2 years. In addition, there are concerns about the risk of renal toxicity with TDF.20, 21, 22, 23, 24, 25 We investigated the long-term efficacy and renal safety of TDF administered as a part of an antiretroviral therapy in a large cohort of HIV/HBV co-infected patients.
Virologic Response in Patients With Detectable HBV DNA at Baseline
Of 82 patients with detectable HBV DNA at baseline, 67 (82%) subjects were HBeAg-positive at the initiation of TDF, and the mean HBV-DNA level was 7.0 ± 2.1 log10 IU/mL. Fifty (61%) patients were treated previously with LAM for a median duration of 42 months (22-74 mo). TDF was added to LAM therapy as a second anti-HBV drug in 45 (90%) of 50 patients and in 5 patients LAM was reintroduced in combination with TDF. In 33 (66%) subjects LAM-resistant mutations could be detected at the initiation of TDF. During a median follow-up period of 56 months (43-64 mo), 72 (88%) patients achieved virologic response. For HBeAg-positive patients (n = 67), the cumulative probability of achieving virologic response at 1, 2, 3, 4, and 5 years of treatment was 31%, 70%, 83%, 88%, and 92%, respectively (Figure 1). There was no significant difference between patients with or without LAM resistance at baseline (P = .39) (Figure 2). In univariate analysis only HBeAg negativity at baseline showed a trend toward a higher chance of achieving undetectable HBV DNA (P = .09). HBeAg loss and HBsAg loss rates increased to 46% and 12% after 5 years of TDF therapy. For HBeAg-negative patients (n = 15), the cumulative probability of achieving virologic response at 1, 2, 3, and 4 years of treatment was 47%, 85%, 85%, and 100%, respectively (Figure 1). During the follow-up period, 2 (13%) of 15 HBeAg-negative patients achieved HBsAg loss. Of 59 patients with increased ALT levels at baseline, 46 (78%) showed ALT normalization at the end of the follow-up period. Three (4%) patients experienced a virologic breakthrough during the observation period. In 2 subjects no genotypic resistance could be detected; 1 patient showed the combined presence of rtM204I, rtL80I, rtL180M, and rtA181V in the HBV polymerase gene (Figure 3B).
Virologic Response in Patients With Undetectable HBV DNA at Baseline
Twenty patients (100% HBeAg-) had undetectable HBV DNA at baseline. Two patients were treatment-naive; 18 patients were pretreated with LAM for a median duration of 38 months (24-64 mo). In all patients TDF was added as a second anti-HBV drug per internal protocol. During a median follow-up period of 52 months (41-63 mo) 19 (95%) subjects maintained virologic response, and 2 (10%) patients showed HBsAg loss. One (5%) subject experienced a virologic breakthrough after which a hepatocellular carcinoma was diagnosed. No genotypic resistance could be detected.
HBV Resistance Surveillance
During a median follow-up period of 55 months (42-64 mo), 9 of 67 (13%) HBeAg-positive and 1 of 15 (7%) HBeAg-negative patients with a detectable HBV DNA at baseline did not achieve virologic response. Of these 10 subjects, 3 experienced a virologic breakthrough as well. One of 20 patients with undetectable HBV DNA at baseline showed a virologic breakthrough. None of the subjects with a virologic breakthrough showed LAM-resistant mutations at baseline. In 2 patients nonadherence was suspected because a simultaneous rebound HIV RNA was observed. A hepatocellular carcinoma was diagnosed in the other 2 patients, of whom 1 subject also showed multiple anti-HBV drug-resistant mutations (rtM204I, rtL80I, rtL180M, and rtA181V). Of the patients with a detectable viral load at the end of the follow-up period without fulfilling the criteria of virologic breakthrough (n = 7), 4 subjects showed LAM resistance at baseline, and in 1 patient these substitutions persisted throughout the observation period. No therapy-resistant mutations were observed in the other patients at the end of the follow-up period.
Progression of Hepatitis B and Survival
Of the 14 cirrhotic patients at baseline, 3 developed de novo hepatocellular carcinoma after 10-32 months (Figure 3), and 2 subjects developed decompensated liver disease after 42 and 48 months of follow-up evaluation. In total, 4 patients died of hepatocellular carcinoma progression (n = 3) or complications related to end-stage liver disease (n = 1). Of the 88 noncirrhotic patients, none progressed clinically to cirrhosis or developed de novo hepatocellular carcinoma. Three patients died of HBV-unrelated causes.
Entecavir as Rescue Therapy in Patients With Persisting HBV Replication
In 4 patients who showed persistent HBV replication during antiviral therapy, entecavir (ETV) (dosed at 1 mg once daily) was added to the treatment regimen as rescue therapy (Table 2). Patients were compliant with the treatment regimen, which is supported by the undetectable HIV-RNA levels in these 4 patients at the moment ETV was added. The addition of ETV resulted in undetectable HBV DNA in all subjects after 3-15 months of follow-up evaluation; 1 patient also achieved HBeAg loss.
HIV RNA and CD4 Cell Count Changes
At the initiation of TDF, the mean HIV RNA was 2.9 ± 1.6 log10 copies/mL, and 51 patients (50%) showed serum HIV-RNA levels less than 50 copies/mL. At the end of the follow-up period a significantly increased proportion of patients (84%; P < .001) showed undetectable HIV RNA. The median CD4 cell count increased from 293 cells/mm3 (138-470 cells/mm3) at baseline to 455 cells/mm3 (340-643 cells/mm3) at the end of the follow-up period (P < .001).
Two patients (2%) experienced an increase in serum creatinine level greater than 0.5 mg/dL after 5 (peak creatinine level, 1.5 mg/dL; eGFR, 54 mL/min) and 16 (peak creatinine level, 2.2 mg/dL; eGFR, 32 mL/min) months of follow-up evaluation, respectively. In both patients TDF was stopped, after which serum creatinine levels stabilized, but did not return to normal in both patients. In one of these patients this also can be explained by polyarteritis nodosa related to HBV with associated renal insufficiency. In 1 additional subject TDF was discontinued after 45 months because of an increase in serum creatinine of 0.38 mg/dL from baseline. The mean eGFR at baseline was 105 ± 30 mL/min/1.73 m2. The estimated decrease after 5 years of TDF therapy was 9.8 mL/min/1.73 m2 (95% confidence interval, 5.4-14.2 mL/min/1.73 m2). The major part of decline in renal function occurred shortly after initiation of TDF therapy (P = .02), and was observed especially in those subjects with a baseline eGFR greater than 100 mL/min/1.73 m2 (P < .001). The use of ritonavir-boosted protease inhibitors was not related to decline in eGFR (P = .60).
This study assessed the long-term efficacy of TDF administered as part of antiretroviral therapy in a large cohort of HIV/HBV co-infected patients. Previous studies on the efficacy of TDF in both HIV/HBV co-infected and HBV-monoinfected patients were limited by a relatively short follow-up period for up to 2 years.7, 8, 12, 14 In our study, there was a median follow-up period of almost 5 years, and we show a large cohort of HIV/HBV co-infected patients treated with TDF. We showed that after 5 years of follow-up evaluation, approximately 90% of patients achieved undetectable HBV DNA (<20 IU/mL), almost 50% of HBeAg-positive patients showed HBeAg loss, and HBsAg loss was even observed in approximately 10% of subjects. There was no significant difference between patients with or without LAM resistance at baseline. More importantly, only 1 patient showed a combination of known anti-HBV drug-resistant mutations, and experienced a virologic breakthrough thereafter. In 3 patients TDF was discontinued because of increases of serum creatinine levels. The estimated decrease in renal function after 5 years of TDF therapy was approximately 10 mL/min/1.73 m2, and was most pronounced directly after initiation of TDF therapy.
The widespread use of highly active antiretroviral therapy has significantly increased the life expectancy of HIV-infected patients, and liver disease has now emerged as a significant cause of non-acquired immune deficiency syndrome-related death.3, 5 A large prospective cohort study showed active HBV infection to be associated strongly with liver-related mortality.3 Current guidelines therefore recommend inclusion of HBV-active agents within the highly active antiretroviral therapy regimen, and to initiate highly active antiretroviral therapy early if an indication to treat HBV infection exists.30 However, the benefits of long-term treatment may be negated by the development of anti-HBV drug resistance, which can lead to reversion of virologic and histologic improvement. In 2 recently performed randomized clinical trials in HBV-mono-infected patients, TDF resulted in HBV-DNA levels less than 400 copies/mL in 76% and 93% of HBeAg-positive and HBeAg-negative patients, respectively.12 Continued therapy produced additional viral suppression, HBeAg- and HBsAg-loss at weeks 72 and 96, respectively.31, 32 Our study now shows TDF, combined with either LAM or emtricitabine, to be an effective anti-HBV agent through 5 years of therapy with 90% of HIV/HBV co-infected subjects achieving undetectable HBV DNA.
In the phase III trials in HBV-mono-infected patients no evidence of TDF resistance was shown during up to 72 weeks of treatment despite extensive resistance surveillance.17 Until now TDF resistance has been described in only 2 HIV-HBV co-infected patients showing the A194T mutation in addition to LAM resistance,33 yet the association between this mutation and TDF resistance was not confirmed in another study.34 In our study, 4 subjects experienced a virologic breakthrough. In 2 patients this was explained by noncompliance and only 1 patient showed a combination of LAM- and adefovir-resistant mutations in the HBV polymerase gene. The rtA194T mutation was not observed. An interesting phenomenon was that 2 virologic breakthroughs occurred in association with the development of hepatocellular carcinoma. A satisfactory explanation for this relation could not be found. There are many reports that show an association between development of resistance and the risk of hepatocellular carcinoma, which is largely explained by the recurrence of viral replication; only one report noted that significantly more hepatocellular carcinomas were observed shortly after development of LAM resistance.35
The recently published EASL guidelines on the management of hepatitis B state that "in patients receiving entecavir or tenofovir with a partial virologic response at week 48, some experts would suggest adding the other drug in order to prevent resistance in the long term."36 In agreement with the follow-up data of the 2 large phase III trials in HBV-monoinfected patients,12 our study shows that most patients are still able to achieve undetectable HBV DNA in the second year without changing the treatment regimen. Moreover, this report shows that adding ETV to existing TDF therapy still is effective after at least 15 months of treatment, and resulted in undetectable HBV DNA in all patients. Our study therefore suggests that one can probably wait at least 24 months before adding ETV in patients who are viremic on a TDF-containing treatment regimen.
There have been concerns about the risk of renal toxicity with TDF because of an association between related compounds such as adefovir and nephrotoxicity.37, 38 In our study, a small but significant, increase in serum creatinine levels was observed after 5 years of treatment. Yet, only 3% of patients developed serum creatinine increases that necessitated the discontinuation of TDF. Furthermore, serum creatinine increases usually occurred early, which suggests that frequent monitoring of renal function is necessary shortly after initiation of TDF treatment, but that thereafter monitoring probably can be decreased.22 Overall, this study supports the renal safety of TDF as a part of antiretroviral therapy through 5 years of treatment.
To date, no confirmed genotypic substitutions in the HBV polymerase gene associated with decreased sensitivity to TDF have been identified. Although direct sequencing does allow for all mutations to be identified, in vitro phenotypic confirmatory assays are mandatory to detect new substitutions. A limitation of our study, therefore, was that we were only able to search for known anti-HBV drug-resistant mutations. In addition, no liver biopsies were available during follow-up evaluation in all our patients, and abdominal ultrasound was performed only if there was clinical suspicion of progression to cirrhosis, decompensated liver disease, or hepatocellular carcinoma. The frequency of progression of hepatitis B, and, more specifically, the development of cirrhosis and hepatocellular carcinoma, may have been underestimated in our study.
In conclusion, TDF administered as part of antiretroviral therapy was shown to be a potent anti-HBV agent with a good resistance profile throughout 5 years of therapy. The antiviral efficacy of TDF was not influenced by the presence of LAM resistance. Furthermore, this study supports the renal safety of TDF through 5 years of treatment because only a small, nonprogressive decline in renal function was observed. Nevertheless, close monitoring of renal function still is indicated. Adding ETV to the treatment regimen resulted in achievement of undetectable HBV DNA in patients who show persistent HBV replication during a TDF-containing treatment regimen.