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Tenofovir is Effective Against HBV in HBV/HIV Coinfection
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Reported by Jules Levin
11th Annual Retrovirus Conference
Feb 8-11, 2004, San Francisco
"Efficacy of Tenofovir Disoproxil Fumarate in Hepatitis B Virus in HIV-co-infected Patients: The TECOVIR Study"
C Piketty*1, I Pellegrin2, C Katlama3, W Rozembaum4, D Neau5, G Le Teuff6, C Tamalet7, A Trylesinski1, H Fleury2, Y Benhamou3, and The Tecovir study group1Hosp Pompidou, Paris, France; 2CHU Bordeaux, France; 3Hosp Pitie Salpetriere, Paris, France; 4Hosp Tenon, Paris, France; 5Hosp Pellegrin, Bordeaux, France; 6Cenbiothech, Dijon, France; and 7CHU Marseille, France
SUMMARY: Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue with dual activity against both HIV and HBV. Small sample sized, pilot open studies have suggested TDF efficacy against wild-type, precore and lamivudine resistant HBV. The objective of this study was to evaluate efficacy of TDF (300 mg once a day), administered as a part of antiretroviral therapy, in a large cohort of HIV/HBV co-infected patients.
HIV/HBV co-infected patients who received TDF for at least 2 weeks and who had stored serum samples at the beginning and during TDF therapy were included. Clinical, biological and virological data were retrospectively recorded. Serum HBV DNA was measured on store samples by the Amplicor Monitor Roche 2.0 (sensitivity 2.3 log10 copies/mL). Baseline was the day of TDF initiation and the end point was the day of the last available stored serum sample during TDF therapy.
A total of 119 patients (mean age 42 yrs) were included. The median follow-up period was 8.0 (1 to 24) months. All the patients but 5 (97%) were receiving lamivudine (150 mg twice daily) at baseline.
Median CD4 count and HIV RNA at baseline were 337 cells/µL and 2.8 (230 copies/ml) log10 copies/mL, respectively. Fifty-two patients (48%) had an HIV RNA <400 copies/mL.
HBeAg and anti-HBe Ab were positive at baseline in 73 patients (68%) and 29 patients (27%), respectively. HBV DNA was detectable at baseline in 88 patients (84%). Of these patients, 83 (95%) were receiving lamivudine at TDF initiation.
After a median period of 9 (1 to 24) months HBV DNA became undetectable in 28 (32%) patients. In this group of patients, the median reduction from baseline of serum HBV DNA (8.0 log10 copies/mL) was -3.8 log10 copies/mL (p <0.0001).
Serum HBeAg became negative in 5 patients after > 6 months of treatment, 3 of them seroconverted to anti-HBe Ab. Serum HBV DNA remained undetectable in the 16 of 17 patients with negative PCR at baseline during TDF therapy (5.0; 1 to 17 months).
The authors concluded that the preliminary results of this cohort study strongly suggest the efficacy of tenofovir for the control of HBV replication in HIV coinfected patients. We observed a favorable safety profile of TDF in this study. TDF was active against HBV exposed to >2.6yrs (median) of 3TC. HIV RNA viral load remained stable in patients with undetectable viral load and in patients with detectable HIV RNA it became below the level of detection (<400 copies/ml) in almost half the patients.
INTRODUCTION
Chronic infection with hepatitis B virus (HBV) affects over 400 million people worldwide. Among HIV-infected individuals , the prevalence of HBV infection is approximately 10 fold higher and is associated with higher risk of cirrhosis and death. Lamivudine (3TC) inhibitis HBV replication in more than 80% of cases in both HIV and non-HIV-infected CHB patients. However, emergence of HBV resistance to 3TC (LAM-R) has been widely observed. HBV resistance to 3TC (lamivudine) has been reported with an incidence of 50% and 90% after 2 and 4 years of therapy, respectively. The clinical consequences of HBV resistance in HIV-positive patients are unknown. However, as observed in HBV mono-infected patients, cases of chronic hepatitis B exacerbation and liver failure have been reported in HIV/AM-R HBV. Until recently, there has not been an effective treatment for LAM-R HBV. We previously reported the safety and efficacy results of 48 weeks of adefovir in co-infected patients with LAM-R HBV.Mean serum HBV DNA decreased from baseline (8.64 log copies/ml( by --4.07 log copies/ml at week 48 associated with improvement of liver lesions and ALT normalization.
Tenofovir (TDF) has recently been shown to have significant activity against both HIV and HBV. TDF is a nucleoside reverse transcriptase inhibitor and has been shown to have potent in vitro activity against both wild-type and 3TC resistant HBV. In treatment experienced HIV-1 infected patients with suboptimal viral suppression, TDF significantly reduced HIV RNA and had a similar safety profile to placebo. The efficacy and safety of TDF have also been proven in antiretroviral-naïve patients with HIV-infection.
TDF is approved for treatment of HIV-1 infection as a once daily 300 mg tablet. In short term small pilot studies, TDF demonstrated anti HBV activity in HIV/HBV coinfected patients. However, a larger patient population and a longer treatment period are necessary to assess the extent and durability of HBV suppression, as well as its long term tolerance profile, the potential emergence of resistance to TDF and the HBeAg seroconversion rate. We retrospectively analyzed efficacy and safety of TDF on HBV replication in HIV-infected patients.
Patients were recruited from 16 Infectious Diseases and/or Internal Medicine Depts in France from January 2001to January 2003.
All the HBV virological tests were run in the same lab on stored serum samples. HBeAg, HBeAb and serum HBV DNA were measured at baseline and at the end of followup. Serum HBV DNA was measured by a polymerase chain reaction (PCR) assay with a 2.3 log copies/ml sensitivity (Amplicor, HBV Monitor Cobas, Roche, Meylan, france). Serum was diluted to allow quantification of sample containing HBV DNA above the upper quantification limit (5.3 log copies/ml).
All the HIV RNA measurements tests were run in the local lab (<1.7 log copies/ml).
Baseline was the day of TDF initiation and the end point was the day of the last available stored serum sample on TDF therapy. The time to negative serum HBV DNA was assessed by means of Kaplan-Meier survival estimates.
RESULTS
A total of 118 patients with HIV and HBV were included in the study. The median followup was 8 months (1-24). During the followup TDF was stopped in 5 patients. One patient was lost to followupduring the study. We observed a favorable safety profile in this population.
BASELINE CHARACTERISTICS:
Median age: 42;
109 men;
43% CDC category C;
median time since first ARV regimen: 7 yrs (0-16);
ARV regimen at baseline: 89% nukes, 27% NNRTIs, 47% PI;
97% had prior 3TC therapy;
median nadir CD4 count: 132;
median CD4 count: 333;
plasma HIV RNA: 2.82 log copies/ml;
48% <400 copies/ml;
25% <50 copies/ml;
13% anti-HCV Ab positive;
median ALT: 51 IU/L;
HBV serological markers: HBeAg+ 66%, HBeAg- 34%; HBeAb+ 28%
Serum HBV DNA:
--detectable- 83% (>2.3 log copies/ml)
--undetectable: <2.3 log copies/ml): 17%
Median HBV DNA in pts with detectable viral load: 8.09 log copies/ml
BASELINE CHARACTERISTICS: HBV REPLICATION AT TDF INITIATION ACCORDING TO 3TC THERAPY AT BASELINE
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3TC (300mg/QD)
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No 3TC
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Total (n=115)
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75%
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26%
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Pts with HBV DNA
>2.3 log copies/ml, n=95
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85%
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77%
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Pts with HBV DNA
<2.3 log copies/ml, n=20
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15%
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23%
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Changes in HBV DNA during TDF Therapy in HIV/HBV Coinfected Patients with Detectable Serum HBV DNA (>2.3 log copies/ml) at Baseline
The total reduction in HBV DNA viral load was --3.94 log copies/ml from baseline (8.09 log copies/ml).
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N
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Followup
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Baseline
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End of Followup
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Change
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p
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Total
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95
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9 mos
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8.09 log
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2.96
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-3.94 log
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<0.001
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HBeAg+
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74
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10 mos
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8.21
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3.21
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-4.39
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<0.001
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HBeAg-
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21
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6 mos
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4.83
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2.30
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-2.53
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<0.001
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Kaplan-Meier Analysis estimates 25 months to reach serum HBV DNA negativity (<2.3 log copies/ml) during TDF therapy in HBV/HIV coinfected patients with detectable DNA.
PERCENTAGE OF PATIENTS WHO REMAIN UNDETECTABLE OR BECAME UNDETECTABLE (HBV DNA <2.3 log copies/ml) FROM BASELINE TO END OF FOLLOWUP (n=115)
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Baseline
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End of Followup <2.3 log c/ml
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End of Followup >2.3 log c/ml
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<2.3 log copies/ml
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95% n=19
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5% n=1
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>2.3 log copies/ml
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32% n=30
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68% n=65
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At the end of followup: 19 pts remained undetectable.
Of patients with detectable serum HBV DNA at baseline 23% of HBeAg+ (n=74) were HBV DNA negative and 62% of HBeAg- (n=21) were HBV DNA negative.
HIV SURROGATE MARKERS EVOLUTION n=109
Median CD4 was 333 at baseline and 374 at the end of followup. Median plasma HIV RNA was 2.82 log copies/ml at baseline and 2.1 at end of followup. Plasma HIV RNA <400 c/ml: 48% at baseline and and 71%a t end of followp. Plasma HIV RNA <50 copies/ml: 25$ at baseline and 48% at end of followup.
For patients who were <50 c/ml at baseline (n=28): 89% were <50 c/ml and 11% >50 c/ml at end of followup. For pts >50 c/ml at baseline (n=81): 33% were <50 c/ml and 66% were >50 c/ml at end of followup.
For pts <400 c/ml at baseline(n=52): 90% <400 c/ml and 10% >50 c/ml at end of followup. For pts >400 c/ml (n=57) at baseline: 52% <400 c/ml and >400 c/ml at at end of followup.
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