Thai patients enrolled in STACCATO with HIV/hepatitis B virus (HBV) co-infection and tenofovir/emtricitabine-based antiretroviral therapy (ART) were randomly assigned to continuous treatment or CD4 cell count-guided interruptions. HBV replication was suppressed below detection in 15/16 patients. Structured treatment interruption increased transaminases and HBV viraemia in five of six patients; one flare was severe. Conversion to anti-hepatitis Be occurred with continuous treatment only. Tenofovir/emtricitabine-containing ART is highly effective in controlling chronic HIV/HBV co-infection but treatment should not be interrupted.
aHIV-NAT, The Thai Red Cross AIDS Research Center, Bangkok, Thailand
bOutpatient Clinic of Internal Medicine and Division of Infectious Diseases, University Hospital, Basel, Switzerland
cNational Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
dKhon Kaen University, Khon Kaen, Thailand
eBamrasnaradura Institute, Nonthaburi, Thailand
fSanpatong Hospital, Chiang Mai, Thailand
gDivision des Maladies Infectieuses, Geneva University Hospital, Geneva, Switzerland.
Received 11 June, 2007
Revised 25 September, 2007
Accepted 4 October, 2007
The management of chronic hepatitis B virus (HBV)/HIV co-infection has to consider both infections. Scheduled treatment interruption (STI) of HIV therapy potentially reduces side effects and costs and increases comfort and quality of life by decreasing overall drug exposure. A reason for concern in patients with HIV/HBV co-infection undergoing STI is the occurrence of severe and in some cases lethal acute hepatitis after interrupting HBV treatment, described in 19–50% of patients [1–5]. Tenofovir and emtricitabine have shown potent and sustained activity against hepatitis B [6–12], and the combination of both drugs may be even more beneficial. Both drugs are active against HIV and are an appealing option to treat patients with HBV/HIV co-infection. STACCATO was a large multinational trial investigating CD4 cell count-guided STI. In Thailand, where HIV/HBV co-infection is frequent , patients enrolled in the STACCATO study were treated with antiretroviral therapy (ART) containing tenofovir/emtricitabine. This offered a unique opportunity to study the effect of this drug combination on patients with HIV/HBV co-infection, and their reaction to treatment interruptions.
STACCATO was a randomized trial of continuous versus CD4 cell count-guided treatment with a threshold CD4 cell count of 350 cells/μl .
Thai patients with HIV/HBV co-infection who started tenofovir/emtricitabine-containing ART underwent repeated plasma sampling for liver enzymes and hepatitis B viral load on weeks 4, 8, 12 and every 12 weeks thereafter up to the end of STACCATO. A complete hepatitis B serology was performed at the initiation of tenofovir/emtricitabine and at week 48. HIV viral load and CD4 cell counts were assessed according to the STACCATO protocol . Patients off therapy who had transaminases five or more times the upper limit or normal (ULN) or bilirubinemia more than 2.5 times the ULN were treated again immediately with tenofovir/emtricitabine-containing ART. The study was performed in accordance with the approval of the local ethical committee.
For HBV, viral load and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) time-weighted average changes were calculated from baseline to week 48. An intention-to-treat approach (including all subjects) was used. Last values were carried forward when data were missing. Average change in time-weighted HBV viral load, AST and ALT were compared using a paired t-test. Statistical analyses were performed using STATA version 8.2 (STATA Corp., College Station, Texas, USA). Statistical significance was taken as a two-sided P value of less than 0.05.
The HBV viral load in serum was measured using the commercial quantitative polymerase chain reaction assay the Cobas Amplicor Monitor Test (Roche Diagnostic Systems, Inc., Branchburg, New Jersey, USA). For serological testing the commercial enzyme-linked immunosorbent assay Mini VIDAS Instrument was used (Biomerieux Co., Marcy l'Etoile, France).
Among the 362 Thai patients included in the STACCATO trial, 16 had a detectable hepatitis B surface antigen and a negative hepatits C serology when tenofovir/emtricitabine was started. Baseline characteristics are shown in Table 1. Six patients were treated within the continuous arm, 10 in the CD4 cell count-guided arm: six of them underwent one to two (mean 1.3) on–off cycles. Transaminases at baseline were normal in eight patients; six patients had an elevation of twice the ULN, two patients an elevation of more than three times the ULN. Seven patients had a positive hepatitis Be (HBe) antigen. Median follow-up time was 69 weeks (48–96). At week 48 one patient in the continuation arm became negative for HBe antigen and developed HBe antibodies, one lost his hepatitis B surface (HBs) antigen but did not develop HBs antibodies. This patient had HBV viraemia below the detection limit at inclusion. The combination of tenofovir/emtricitabine suppressed HBV replication below the detection limit in 15 of 16 patients after 4–24 weeks. One patient interrupted therapy when HBV viraemia was 4062 copies/ml, dropping from 108 after 24 weeks. Continuous treatment reduced AST (−17.8, 47.5) and ALT (−31.3, 47.8; P = 0.2). After STI, the median increase in log HBV load was 2.52 (0.49–4.70), ALT 13 (10–130), and AST 7 (−11–350). Immediate reinitiation of therapy was necessary because of a flare of hepatitis with AST reaching 408 U/l, ALT 218 U/l, bilirubin 23.1 μmol/l, and viral load log 7.61 copies/ml. In the other patients ALT (U/l)/HBV load (log copies/ml) rose to: 38/8; 29/3.79; 26/3.3; 41/5.36; 26/4.96; 20/5.48; and 43/6.22. All responded completely to re-treatment. The mean (SD) of time-weighted average area under the curve at week 48 was calculated for the HBV load, AST and ALT. Continuous treatment led to a stronger decrease in AST [−17.8 (47.5) versus 1.1 (6.3), P = 0.350], ALT [−31.3 (47.8) versus 0.8 (11.1), P = 0.11], and log HBV load [−1.4 (2.1) versus −0.5 (1.8), P = 0.381].
The combination of tenofovir/emtricitabine completely suppressed HBV replication in 15 of the 16 patients. In one patient, treatment was interrupted before HBV viraemia was below the detection limit. Complete suppression would probably have been achieved without STI. The control of HBV lasted until the end of follow-up (maximum 96 weeks). The excellent virological response to tenofovir/emtricitabine-based ART was paralleled by a decrease in transaminases. As most patients had normal transaminases at baseline, this decrease did not reach statistical significance. Patients in the STI arm had a worse control of HBV and consecutively higher transaminase levels. This is problematical for various reasons [15–17]. Treatment interruptions may compromise the outcome by permitting HBV replication. After 48 weeks one patient seroconverted from HBe antigen to HBe antibodies, one other patient lost his HBs antigen (core only). Both were on continuous treatment. So far HBe seroconverison has been described exclusively in HIV-infected patients with active ART in the range of 12–25% [2–5,16]. Most elevations of liver enzymes were asymptomatic, not severe, and all responded well to re-treatment. One patient, however, required immediate intervention because of a flare of hepatitis as defined by the protocol. Although manageable with tenofovir/emtricitabine-containing ART such an event is alarming.
Tenofovir/emtricitabine-containing ART is highly effective in controlling both chronic HBV and HIV infections. It is an ideal combination to treat HIV/HBV-co-infected patients and has been recommended previously . Treatment interruptions in HBV/HIV-co-infected patients may induce progression and flares of hepatitis B even with careful monitoring. This is in addition to potential disadvantages regarding HIV infection [17,18]. ART with drugs active against HBV in HIV/HBV-co-infected patients should not be interrupted.
The Staccato Hepatitis B Study Group
The HIV Netherlands Australia Thailand Research Collaboration, Bangkok, Thailand: Praphan Phanuphak, Sukontha Saenawat, Saijai Wicharuk, Siriporn Nonenoy, Natnipa Wannachai, Sineenart Chautrakarn, Theshinee Chuenyam, Patcharee Pararit, Bunruan Sopa, Naphassanant Loapraynak and Sasiwimol Ubolyam.
Bamrasnaradura Institute, Nonthaburi, Thailand: Sirirat Liganonsakul Suchittra Putthawong, Wattana Sanchiem, Pongpan Boonchoo, Malee Suannum.
Khon Kaen University, Khon Kaen, Thailand: Parichat Bunyaprawit, Ratthanant Kaewmarg.
Sanpatong Hospital, Chiang Mai, Thailand: Phitsanu Raksakulkarn, Yaowaluk Penglimoon.
Sponsorship: Roche provided financial support for this substudy. The Swiss HIV Cohort Study provided logistic support for STACCATO. The antiretroviral drugs were provided at no cost by Roche (saquinavir), Abbott (ritonavir) and Gilead (tenofovir). Bristol Myers Squibb provided stavudine and didanosine at a reduced price.
Part of the data has been presented as a late breaker at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, USA, 17–20 September 2007.
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