Title: Antiviral chemotherapy for chronic hepatitis B infection: lessons learned from treating HIV-infected patients
Abstract: After years of modest treatment success with the use of interferon alpha, antiviral chemotherapy for chronic hepatitis B virus (HBV) infection with nucleoside analogues now provides an alternative means for interrupting the progression of disease and even conceivably eradicating the virus from the infected host. Three factors have converged to provide important advances in anti-hepadnaviral chemotherapy:1.(i) improved understanding of the immunopathogenesis of HBV infection;2.(ii) the availability of standardised, reliable quantitative assays for serum HBV DNA; and3.(iii) the range and type of potent anti-hepadnaviral drugs. Almost identical statements were made about therapeutic options for the human immunodeficiency virus (HIV) over 2 years ago (1.Richman DD HIV therapeutics.Science. 1996; 272: 1886-1888Crossref PubMed Scopus (71) Google Scholar). Since then, confidence and optimism regarding the likelihood of suppressing and even eliminating HIV from infected individuals has waxed and waned. However, extremely important lessons have been learned from the HIV experience, and these are likely to have a significant impact on the treatment of HBV infection. Several reviews describing antiviral agents active against the HBV have recently been published (2.Nicoll A Locarnini S Review: present and future directions in the treatment of chronic hepatitis B infection.J Gastroenterol Hepatol. 1997; 12: 843-854Crossref PubMed Scopus (36) Google Scholar, 3.Zoulim F Trepo C Review: drug therapy for chronic hepatitis B: antiviral efficacy and influence of hepatitis B virus polymerase mutations on the outcome of therapy.J Hepatol. 1998; 29: 151-168Abstract Full Text PDF PubMed Scopus (103) Google Scholar, 4.Bartholomeusz, A, Schinazi, RF and Locarnini, SA, Significance of mutations in the hepatitis B vírus polymerase selected by nucleoside analogues and implications for controlling chronic disease, Viral Hep Rev, in press.Google Scholar) and this material will not be re-presented here. The focus and purpose of this review is to compare and contrast key virological, pathogenetic and chemotherapeutic issues in the treatment of these two viral infections so that new paradigms for managing chronic hepatitis B infection may be developed. Understanding of the pathogenesis of HIV-AIDS has advanced considerably in the last few years (5.Feinberg MB Changing the natural history of HIV disease.Lancet. 1996; 348: 239-246Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). The damage inflicted by HIV-1 is mainly brought about by active viral replication (1.Richman DD HIV therapeutics.Science. 1996; 272: 1886-1888Crossref PubMed Scopus (71) Google Scholar, 5.Feinberg MB Changing the natural history of HIV disease.Lancet. 1996; 348: 239-246Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). An individual's risk for disease progression can now be assessed early in the course of the infection and the efficacy of antiviral therapies can now be determined rapidly and accurately. This has been due mainly to the advent of sensitive and reliable laboratory testing such as quantitative polymerase chain reaction (PCR) assays for monitoring HIV replication in vivo (5.Feinberg MB Changing the natural history of HIV disease.Lancet. 1996; 348: 239-246Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). Also, combinations of potent antiviral drugs have reduced the rate of emergence of resistance, the main reason for therapeutic failure, and have permitted the development of rational approaches to block and possibly eliminate HIV-1 from an infected person (1.Richman DD HIV therapeutics.Science. 1996; 272: 1886-1888Crossref PubMed Scopus (71) Google Scholar, 5.Feinberg MB Changing the natural history of HIV disease.Lancet. 1996; 348: 239-246Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). The clinically latent period characteristic of HIV infection is in reality virologically dynamic. Nearly 1010 HIV virions are produced per day in some patients (6.Wei X Ghosh SK Taylor ME Johnson VA Emini EA Deutsch P et al.Viral dynamics in human immunodeficiency virus type 1 infection.Nature. 1995; 373: 117-122Crossref PubMed Scopus (2905) Google Scholar). A cycle of infection, destruction and reinfection of CD4+ T-lymphocytes sustains high-level virus replication (6.Wei X Ghosh SK Taylor ME Johnson VA Emini EA Deutsch P et al.Viral dynamics in human immunodeficiency virus type 1 infection.Nature. 1995; 373: 117-122Crossref PubMed Scopus (2905) Google Scholar, 7.Ho DD Neumann AU Perelson AS Chen W Leonard JM Markowitz M Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.Nature. 1995; 373: 123-126Crossref PubMed Scopus (3777) Google Scholar). The majority of circulating virus (more than 99%) is derived from these cells (Fig. 1). The remainder is produced from latently infected, long-lived cells which become activated (7.Ho DD Neumann AU Perelson AS Chen W Leonard JM Markowitz M Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.Nature. 1995; 373: 123-126Crossref PubMed Scopus (3777) Google Scholar). Substantial numbers of HIV species containing pre-existing drug resistance mutations are present within this rapidly replicating pool of virus. These strains are thought to arise as a result of the error-proneness of the HIV reverse transcriptase (RT). Conservatively, one error occurs in every 10 000 nucleotides transcribed, and this is not corrected by exonucleolytic proof reading (8.Roberts JD Bebenek K Kunkel TA The accuracy of reverse transcriptase from HIV-1.Science. 1988; 242: 1171-1173Crossref PubMed Scopus (724) Google Scholar). As a result, a large number of HIV quasispecies exist in each individual. Some of these mutants have the potential to replicate in the presence of antiretroviral drug pressure, and it is recognised that HIV strains containing amino acid changes known to be associated with phenotypic resistance to protease inhibitors exist in patients who have never been treated with this class of drug (9.Kozal MJ Shah N Shen N Yang R Fucini R Merigan TC et al.Extensive polymorphisms observed in HIV-1 clade B protease gene using high-density oligonucleotide arrays.Nat Med. 1996; 2: 753-759Crossref PubMed Scopus (457) Google Scholar). Because they represent only a fraction of the number of wild-type viruses present (10.Coffin JM HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy.Science. 1995; 267: 483-489Crossref PubMed Scopus (1678) Google Scholar), such mutants are normally likely to be at a replicative disadvantage compared to wild-type virus. However, when a drug is used for the first time, they will be rapidly selected, despite their relatively reduced replicative fitness. This is a form of Darwinian evolution; mutations providing a survival advantage result in selection of populations acquiring and retaining that mutation. In contrast to HIV, the pathogenesis of liver tissue injury in chronic hepatitis B infection, although closely related to ongoing active viral replication (11.Chisari FV Ferrari C Hepatitis B virus immunopathogenesis.Ann Rev Immunol. 1995; 13: 29-60Crossref PubMed Scopus (1459) Google Scholar) is determined primarily by the host's immune responses (12.Weissberg JI Andres LL Smith CI Weick S Nicholas Je Garcia G et al.Survival in chronic hepatitis B: an analysis of 397 patients.Ann Intern Med. 1984; 101: 613-616Crossref PubMed Scopus (234) Google Scholar, 13.Hoofnagle JH The treatment of chronic viral hepatitis.Drug Ther. 1997; 336: 347-356Google Scholar). Under most conditions HBV is not directly cytopathic, and the lesion of chronic liver disease results from an inadequate or inappropriate host immune response directed at virus-infected hepatocytes (11.Chisari FV Ferrari C Hepatitis B virus immunopathogenesis.Ann Rev Immunol. 1995; 13: 29-60Crossref PubMed Scopus (1459) Google Scholar). The major cytotoxic T-cell response to HBV appears to be directed to key epitopes within the hepatitis B viral core (HBcAg) and hepatitis B e antigen (HBeAg) (14.Milich DR Jones JE Hughes JL Price J Paney AK McLachlan A Function of the secreted hepatitis B e antigen to induce immunological tolerance in utero?.Proc Natl Acad Sci USA. 1990; 87: 6599-6603Crossref PubMed Scopus (502) Google Scholar, 15.Milich DR Influence of T-helper cell subsets and cross regulation in hepatitis B virus infection.J Viral Hepat. 1997; 4: 48-59Crossref PubMed Scopus (49) Google Scholar). This activity has been identified as an important determinant of viral clearance and cell damage. The HBeAg is a toleragen (14.Milich DR Jones JE Hughes JL Price J Paney AK McLachlan A Function of the secreted hepatitis B e antigen to induce immunological tolerance in utero?.Proc Natl Acad Sci USA. 1990; 87: 6599-6603Crossref PubMed Scopus (502) Google Scholar) and the aim of removing the toleragenic effect of circulating serum HBeAg by chemosuppression in order to induce endogenous immuno-elimination may prove a useful strategy for future management of chronic hepatitis B. Furthermore, Milich (15.Milich DR Influence of T-helper cell subsets and cross regulation in hepatitis B virus infection.J Viral Hepat. 1997; 4: 48-59Crossref PubMed Scopus (49) Google Scholar) has proposed that the induction or maintenance of the chronic carrier state may be the result of an imbalance in the TH1 and TH2 cytokine responses specific to the HBcAg and HBeAg. A predominance of HBV-specific TH2-type cytokine responses during chronic infection would favour antibody production, whereas a predominance of TH1-type cytokine responses in acute infection would favour a cell-mediated immune response. Milich (15.Milich DR Influence of T-helper cell subsets and cross regulation in hepatitis B virus infection.J Viral Hepat. 1997; 4: 48-59Crossref PubMed Scopus (49) Google Scholar) has further suggested that a cytokine-focused therapy designed to shift a TH2-type cytokine response toward a TH1-type response may be beneficial in the treatment of chronic infection. The effects of cytokines such as interleukin 2 (a TH1-type cytokine) on the viral life-cycle as well as on the host's immune response clearly require further exploration (16.Guidotti LG Guilot S Chisari FV Interleukin-2 and alpha/beta interferon down-regulate hepatitis B virus gene expression in vivo by tumour necrosis factor-dependent and independent pathways.J Virol. 1994; 68: 1265-1270PubMed Google Scholar). Clinical trials with highly active antiretroviral therapy (HAART) have shown that long-term suppression of HIV replication, indicated by plasma HIV RNA levels falling below the limits of detection, is now possible. Although HAART has not yet been shown to eliminate the virus from the body, since integrated HIV proviral DNA in activated, long-lived, memory CD4− T-lymphocytes is able to direct virus production, the viruses detected have a wild-type drug resistance profile (17.Finzi D Hermankova M Pierson T Carruth LM Buck C Chaisson RE et al.Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.Science. 1997; 278: 1295-1300Crossref PubMed Scopus (2438) Google Scholar, 18.Wong JK Hezareh M Gunthard HF Havlir DV Ignacio CC Spina CA et al.Recovery of replication-competent HIV despite prolonged suppression of plasma viremia.Science. 1997; 278: 1291-1295Crossref PubMed Scopus (1768) Google Scholar). We can therefore be confident that the use of HAART can lead to the suppression of HIV replication and prevent resistance developing in some individuals. Nevertheless, as many as 50% of treated individuals do not achieve complete viral suppression (19.Kaufman D Pantaleo G Sudre P Telenti A CD4-cell count in HIV-1-infected individuals remaining viraemic with highly active antiretroviral therapy (HAART).Lancet. 1998; 351: 723-724Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar). Many such patients have received prior antiretroviral drug therapy, and have received HAART outside of clinical trials, where compliance with a complex drug regimen is often less stringently monitored. These individuals are at risk for developing resistance. Interferon alpha therapy, the only licensed treatment for chronic hepatitis B in most countries, has proven moderately effective but is often limited by dose-dependent side-effects (20.Lok ASF Treament of chronic hepatitis B.J Viral Hepat. 1994; 1: 105-124Crossref PubMed Scopus (66) Google Scholar, 21.Carithers RL Effect of interferon on hepatitis B.Lancet. 1998; 351: 157Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). Most importantly, the majority of patients receiving interferon alpha will not clear the infection and will remain at risk for developing progressive liver disease including cirrhosis and hepatocellular carcinoma (HCC) (22.Hoofnagle JH DiBisceglie AM The treatment of chronic viral hepatitis.N Engl J Med. 1997; 336: 347-356Crossref PubMed Scopus (987) Google Scholar). Similar clinical efficacy has been described with a second cytokine, thymosin α-1, but unlike interferon-alpha, treatment with this agent is not associated with serious adverse events (23.Andreone P Cursaro C Gramenzi A Zavaglia C Rezakovic I Altomare E et al.A randomized controlled trial of thymosin-α1, versus interferon alfa treatment in patients with hepatitis Be antigen antibody- and hepatitis B virus DNA-positive chronic hepatitis B.Hepatology. 1996; 24: 774-777PubMed Google Scholar, 24.Chien R-N Liaw Y-F Chen T-C Yeh C-T Sheen I-S Efficacy of thymosin-α1 in patients with chronic hepatitis B: a randomised controlled trial.Hepatology. 1998; 27: 1383-1387Crossref PubMed Scopus (133) Google Scholar). Clinical trials with the nucleoside analogues lamivudine (25.Dienstag J Perillo R Schiff E Bartholomew M Vicary C Rubin M A preliminary trial of lamivudine for chronic hepatitis B infection.N Engl J Med. 1995; 333: 1657-1661Crossref PubMed Scopus (819) Google Scholar), famciclovir (26.Trepo C Jezek P Atkinson G Boon R Efficacy of famciclovir in chronic hepatitis B: results of a dose finding study.Hepatology. 1996; 24 ([abstract]): 1881AGoogle Scholar), adefovir (27.Gilson R Chopra K Murray-Lyon I Newell A Nelson M Tedder R et al.A placebo-controlled phase I/II study of Adefovir Dipivoxil (bis-POM PMEA) in patients with chronic hepatitis B infection.Hepatology. 1996; 24 ([abstract]): 281AGoogle Scholar) and lobucavir (28.Bloomer J Chan R Sherman M Ingraham P DeHertogh D the -008 study group.A preliminary study of lobucavir for chronic hepatitis B.Hepatology. 1997; 26 ([abstract]): 428AGoogle Scholar) have been undertaken and show promising results in terms of maximal chemosuppression of viral load and association with minimal adverse side effects. However, monotherapy with this group of agents has failed to clear viral infection, and at least three challenges to the development of future effective therapy for chronic hepatitis B can now be defined:1.(i) the persistence of viral covalently closed circular (CCC) DNA;2.(ii) the role of extra-hepatocyte reservoirs; and3.(iii) the emergence of drug-resistance. During initial infection of the hepatocyte, the viral genomic DNA is converted to a minichromosome that functions as the transcriptional template of the virus. It is within this viral minichromosome that the viral DNA exists as a supercoiled or CCC DNA molecule (29.Newbold JE Xin H Tencza M Sherman G Dean J Bowden S et al.The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral minichromosomes.J Virol. 1995; 69: 3350-3357PubMed Google Scholar). A major reason for the relapse seen after completion of antiviral therapy for hepatitis B infection was recognised more than 13 years ago by Omata and colleagues (30.Yokosuka O Omata A Imazeki F Okuda K Summers J Changes of hepatitis B virus DNA in liver and serum caused by recombinant leukocyte interferon treatment: analysis of intrahepatic replicative hepatitis B virus DNA.Hepatology. 1985; 5: 728-734Crossref PubMed Scopus (87) Google Scholar) who demonstrated that this CCC DNA form of the viral DNA was not eliminated by treatment with interferon-α. Similarly, hepadnaviral CCC DNA is also unaffected by nucleoside analogue therapy (31.Dean J Bowden S Locarnini S Reversion of duck hepatitis B virus DNA in vivo following cessation of treatment with the nucleoside analogue ganciclovir.Antiviral Res. 1995; 27: 171-178Crossref PubMed Scopus (24) Google Scholar, 32.Moraleda G Saputelli J Aldrich CE Averett D Condreay L Mason WS Lack of effect of antiviral therapy in nondividing hepatocyte cultures on the closed circular DNA of woodchuck hepatitis virus.J Virol. 1997; 71: 9392-9399PubMed Google Scholar) despite the reduction or elimination of all other viral DNA forms in the liver (reviewed in 33). A likely reason for this failure could be a long intrahepatic half-life of viral CCC DNA, which under normal circumstances may be as stable as host-cell DNA. Although, in vitro studies have determined a relatively short half-life of 3–5 days for duck HBV CCC DNA (34.Civitico G Locarnini S The half-life of duck hepatitis B virus supercoiled DNA in congenitally infected primary hepatocyte cultures.Virology. 1994; 203: 81-89Crossref PubMed Scopus (62) Google Scholar), the heterogeneity of the viral CCC DNA topoisomers (29.Newbold JE Xin H Tencza M Sherman G Dean J Bowden S et al.The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral minichromosomes.J Virol. 1995; 69: 3350-3357PubMed Google Scholar) makes interpretation of these data difficult. Several studies have shown that long-term antiviral treatments have failed to eliminate viral CCC DNAs, which continue to persist and maintain their functionality in infected cells (35.Mason WS Cullen J Saputelli J Wu T-T Liu C London WT et al.Characterization of the antiviral effects of 2′-carbodeoxy-guanosine in ducks chronically infected with duck hepatitis B virus.Hepatology. 1994; 19: 398-411Crossref PubMed Scopus (58) Google Scholar, 36.Luscombe C Pedersen J Uren E Locarnini S Long-term ganciclovir chemotherapy for congenital duck hepatitis B virus infection in vivo: effect on intrahepatic viral DNA, RNA, and protein expression.Hepatology. 1996; 24: 766-773PubMed Google Scholar). Only famciclovir-penciclovir has demonstrated consistent and significant inhibition, but not elimination, of viral CCC DNA (37.Lin E Luscombe C Wang Y Shaw T Locarnini S The guanine nucleoside analogue penciclovir is active against chronic duck hepatitis B virus infection in vivo.Antimicrob Agents Chemother. 1996; 40: 413-418PubMed Google Scholar, 38.Lin E Luscombe C Colledge D Wang YY Locarnini SA Long-term therapy with the guanine nucleoside analog penciclovir controls chronic duck hepatitis B virus infection in vivo.Antimicrob Agents Chemother. 1998; 42: 2132-2137PubMed Google Scholar). Thus, the eradication of chronic HBV infection requires either the permanent inactivation of the viral CCC DNA species (33.Locarnini S Civitico GM Newbold JE Hepatitis B: new approaches for antiviral chemotherapy.Antiviral Chem Chemother. 1996; 7: 53-64Crossref Scopus (18) Google Scholar) or the elimination of each infected cell (39.Averett DR Mason WS Evaluation of drugs for antiviral activity against hepatitis B virus.Viral Hepatitis Reviews. 1995; 1: 129-142Google Scholar). HIV (40.Luciw P Human immunodeficiency viruses and their replication.in: Fields BN Knipe DM Howley PM Fields Virology, 3rd ed. Lippincott-Raven, Philadelphia1996: 2703-2738Google Scholar) and HBV (41.Ganem D Hepadnaviridae: the viruses and their replication.in: Fields BN Knipe DM Howley PM Fields Virology, 3rd ed. Lippincott-Raven, Philadelphia1996: 2703-2738Google Scholar) copy their genomes by reverse transcription, and it has been estimated that each undergoes approximately 3×10−5 mutations per nucleotide per replication cycle (42.Mansby LM Temin HM Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase.J Virol. 1995; 69: 5087-5094PubMed Google Scholar). The HBV has its genome organised into four open reading frames (ORF) with the polymerase gene overlapping the other three ORFs (41.Ganem D Hepadnaviridae: the viruses and their replication.in: Fields BN Knipe DM Howley PM Fields Virology, 3rd ed. Lippincott-Raven, Philadelphia1996: 2703-2738Google Scholar). Thus, a mutation in one ORF can affect the amino-acid sequence in another ORF (43.Locarnini S Hepatitis B virus surface antigen and polymerase gene variants: potential virological and clinical significance.Hepatology. 1998; 27: 294-297Crossref PubMed Scopus (75) Google Scholar), thereby restricting the number of viable mutants so generated. In HIV, the genome is linear and non-overlapping but splicing is required to produce mRNA for the envelope and regulatory proteins (40.Luciw P Human immunodeficiency viruses and their replication.in: Fields BN Knipe DM Howley PM Fields Virology, 3rd ed. Lippincott-Raven, Philadelphia1996: 2703-2738Google Scholar). In the HIV-infected patient, the concentration of virus in blood is less than in lymphoid tissues and almost certainly reflects spillover from replication in that tissue. This large amount of virus turns over rapidly, with a virion half-life of hours in blood (see Fig. 1). Within a year after infection, each infected individual establishes a“set-point” or steady-state level of HIV RNA, which is usually between 102 and 106 copies/ml of plasma. This virus load largely determines the rate at which CD4 cells are subsequently lost (1.Richman DD HIV therapeutics.Science. 1996; 272: 1886-1888Crossref PubMed Scopus (71) Google Scholar, 44.Perelson AS Neumann AU Markowitz M Leonard JM Ho DD HIV-1 dynamics in vivo: virion clearance rate, infected cell life span, and viral generation time.Science. 1996; 271: 1582-1585Crossref PubMed Scopus (2791) Google Scholar). The set-point is a dynamic equilibrium of viral clearance (by the infected host's natural defences) and virus production. The half-life of most infected CD4 cells is approximately 1.5 days and 109 CD4HIV-infected cells are destroyed, and new cells generated, each day (Fig. 1) (5.Feinberg MB Changing the natural history of HIV disease.Lancet. 1996; 348: 239-246Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 44.Perelson AS Neumann AU Markowitz M Leonard JM Ho DD HIV-1 dynamics in vivo: virion clearance rate, infected cell life span, and viral generation time.Science. 1996; 271: 1582-1585Crossref PubMed Scopus (2791) Google Scholar). The level of HIV replication, measurable as plasma HIV RNA, therefore drives the rate of immune destruction and can be used to predict the natural history of the disease (45.Mellors JW Riaaldo C Gupta P White RM Todd JA Kingsley LA Prognosis in HIV-1 infection predicted by the quantity of virus in plasma.Science. 1996; 272: 1167-1170Crossref PubMed Scopus (2307) Google Scholar). The major benefit of antiretroviral therapy in HIV-infected patients is the associated drop in plasma HIV-RNA, or alteration of the virological set-point downwards (45.Mellors JW Riaaldo C Gupta P White RM Todd JA Kingsley LA Prognosis in HIV-1 infection predicted by the quantity of virus in plasma.Science. 1996; 272: 1167-1170Crossref PubMed Scopus (2307) Google Scholar). Similar kinetic studies have been performed in chronic hepatitis B infection and have shown that the half-life of HBV in plasma is 24 h, the total daily production of virus is 1011 virus particles and the overall total viral load is 2×1011 (46.Nowak MA Bouhoeffer S Hill AM Boehme R Thomas HC McDade H Viral dynamics in hepatitis B virus infection.Proc Natl Acad Sci USA. 1996; 93: 4398-4402Crossref PubMed Scopus (834) Google Scholar). The similarities to HIV infection are obvious. The half-life of infected hepatocytes has been calculated to be 10–100 days, depending on the degree of necro-inflammatory activity within the liver with a daily turnover of infected hepatocytes of 1–7% (46.Nowak MA Bouhoeffer S Hill AM Boehme R Thomas HC McDade H Viral dynamics in hepatitis B virus infection.Proc Natl Acad Sci USA. 1996; 93: 4398-4402Crossref PubMed Scopus (834) Google Scholar). Based on this model, it has been predicted that in the active phase of chronic hepatitis B infection, 12 months treatment with lamivudine should reduce the total body viral burden by a factor of about 1011, that is, virtual elimination of HBV (46.Nowak MA Bouhoeffer S Hill AM Boehme R Thomas HC McDade H Viral dynamics in hepatitis B virus infection.Proc Natl Acad Sci USA. 1996; 93: 4398-4402Crossref PubMed Scopus (834) Google Scholar). More recently, a short-term clinical trial using lamivudine to treat chronically infected individuals has suggested a half-life for serum HBV of 2–3 days (47.Zeuzem S deMan RA Honkoop P Roth WK Scham SW Schmidt JM Dynamics of hepatitis B virus infection in vivo.J Hepatol. 1997; 27: 431-436Abstract Full Text PDF PubMed Scopus (103) Google Scholar) (see Fig. 2). This longer half-life significantly extends the duration of antiviral monotherapy required to eliminate HBV if the“active phase” disease model of Nowak and colleagues (46.Nowak MA Bouhoeffer S Hill AM Boehme R Thomas HC McDade H Viral dynamics in hepatitis B virus infection.Proc Natl Acad Sci USA. 1996; 93: 4398-4402Crossref PubMed Scopus (834) Google Scholar) is accepted. In both cases, high viral turnover combined with relatively high mutation rate and low to moderate cell turnover contributes to the generation of substantial viral genome diversity. Many factors are associated with the development of antiviral drug resistance. The virus itself, the drugs, and characteristics of the infected patient are all involved. Factors associated with HIV resistance include the kinetics of its production and clearance, and the inherent error-proneness of its RT. In addition, HIV possesses a structurally flexible protease and can alter the conformation of its substrates when under drug pressure. The potency of antiretroviral drug combinations, their pharmacokinetic properties (including their ability to reach reservoirs of HIV infection in sites such as the CNS), the likelihood of cross-resistance developing to other drugs and the prior antiretroviral drug experience of the treated individual are also important. Finally, whether the patient remains compliant in taking a large number of drugs, often at inconvenient times, also influences the development of resistance. Most, if not all, of these factors are likely to be relevant to the development of drug resistance by HBV. In clinical trials of HIV drugs, most of the antiviral activity resulting from monotherapy is largely reversed within 4 weeks after the initiation of therapy. This reversal is associated with the emergence of drug-resistant mutants (48.Schuurman R Nijhuis M van Leeuwen R Schipper P de Jong D Collis P et al.Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug resistant virus populations in persons treated with lamivudine (3TC).J Infect Dis. 1995; 171: 1411-1419Crossref PubMed Scopus (464) Google Scholar, 49.Wainberg MA Salomon H Gu Z Montaner JS Cooley TP MacCaffey R et al.Development of HIV-1 resistance to (–) 2′-deoxy-3′-thiacytidine in patients with AIDS or advanced AIDS-related complex.AIDS. 1995; 9: 351-357PubMed Google Scholar). These observations provide compelling evidence for a relationship between the loss of antiviral drug activity and the emergence of drug resistance, and they are consistent with the existence of drug-resistant subpopulations in patients before treatment (50.Najera I Holguin A Quinones-Mateu ME Monoz-Fernandez MA Najera R Lopez-Galindez C et al.Pol gene quasispecies of human immunodeficiency virus mutations associated with drug resistance in virus from patients undergoing no drug therapy.J Virol. 1995; 69: 23-31Crossref PubMed Google Scholar). From the virus perspective, these mutations are rarely without cost. Compromises of replicative fitness appear to occur with most mutations in HIV (10.Coffin JM HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy.Science. 1995; 267: 483-489Crossref PubMed Scopus (1678) Google Scholar) and HBV (51.Melegari M Scaglioni PP Wands JR Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective.Hepatology. 1998; 27: 628-633Crossref PubMed Scopus (339) Google Scholar). However, in HIV a compromising mutation survives under the pressure of selection by, for example, protease inhibitors, by a second compensatory mutation that partly restores the original levels of viral replication (52.Ho DD Toyoshima T Mo H Kempf DJ Norbeck D Chen CM et al.Characterisation of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor.J Virol. 1994; 68: 2016-2020Crossref PubMed Google Scholar). A similar scenario probably operates in HBV. The swarm of genetic variants in any patient is a mixture of viruses with varying replication capacities and selective advantages under the changing conditions of host cell type, immune response or pressure from drug treatment. The fitness of the predominant population (master sequence) changes in response to changing selection pressures (53.Holland JJ De La Torre JC Steinhauer DA RNA virus populations as quasispecies.Curr Top Microbiol Immunol. 1992; 176: 1-20Crossref PubMed Scopus (434) Google Scholar). Therapeutic strategies can only address these dynamics by suppressing virus replication to such a degree that the emergence of variants is prevented (54.Havlir DV Richman DD Viral dynamics of HIV: implications for drug development and therapeutie strategies.Ann Intern Med. 1996; 124: 984-994Crossref PubMed Scopus (
Publication Year: 1999
Publication Date: 1999-03-01
Language: en
Type: review
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 68
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