Hepatitis B Annual

REVIEW ARTICLE
Year
: 2009  |  Volume : 6  |  Issue : 1  |  Page : 41--54

Tenofovir for HBV: The beginning of the end or the end of the beginning?


Naresh Bhat, Amit Yelsangikar 
 Department of Gastroenterology and Liver Diseases, Columbia Asia Referral Hospital, Bangalore - 560 055, India

Correspondence Address:
Naresh Bhat
Department of Gastroenterology and Liver Diseases, Columbia Asia Referral Hospital, Yeshwanthpur, Dr. Rajkumar Road, Malleshwaram West, Bangalore - 560 055
India

Abstract

Patients with Hepatitis B virus infection may present to the treating clinicians at various stages of natural history of hepatitis B infection, including acute viral hepatitis, chronic active hepatitis, incidental hepatitis B s antigen-positive patients and those with decompensated cirrhosis and hepatocellular carcinoma. Management of chronic hepatitis B patients, especially those with e antigen-negative disease poses the biggest challenge today. There are various treatment options available and choosing the correct drug according to the patient profile is important both for optimum response and preventing drug resistance. This article reviews an exciting new molecule tenofovir, which has been approved in August 2008 by the US Food and Drug Administration for treatment of chronic hepatitis B.



How to cite this article:
Bhat N, Yelsangikar A. Tenofovir for HBV: The beginning of the end or the end of the beginning?.Hep B Annual 2009;6:41-54


How to cite this URL:
Bhat N, Yelsangikar A. Tenofovir for HBV: The beginning of the end or the end of the beginning?. Hep B Annual [serial online] 2009 [cited 2022 Jan 29 ];6:41-54
Available from: https://www.hepatitisbannual.org/text.asp?2009/6/1/41/76904


Full Text

 Introduction



Chronic hepatitis B virus (HBV) infection is a major public health problem in India. The carrier rate in India is 3% and it contributes to nearly 10% of the HBV carriers in the world. The World Health Organization classifies India as intermediate prevalence zone with prevalence rates ranging between 2% and 7%. There are 25 million live births each year and nearly 1 million HBV infections are added to the HBV pool yearly, contributing to the ever expanding situation. [1] Treatment options, such as interferon and oral antiviral drugs, are expensive, and in India government funds are not available for treatment of hepatitis B due to low priority. The inherent problems of HBV, such as mutations and drug resistance add to the problem.

 Natural History and Implications in Therapy



In majority of the patients in India, HBV infection is acquired perinatally or in early childhood and the immune system does not recognize the difference between the virus and the host. This results in immunologic tolerance to HBV infection. [2] In this situation, the cellular immune responses to hepatocyte membrane HBV proteins that are associated with acute hepatitis do not occur, and chronic, usually lifelong infection is established in more than 90% of persons who are infected. The immune tolerance phase occurring in the early decades of life is associated with low incidence of HBV-associated liver injury in spite of rapid HBV replication. Male patients of this group have a 40% lifetime risk of death from liver disease. This stage is characterized by hepatitis B e antigen (HBeAg) positivity, high HBV DNA with normal transaminases and liver histology. No medication is effective at this stage of the illness and no treatment is offered. [3]

An immune-clearance phase occurs in the later decades of life with active liver disease. HBeAg becomes negative, anti-HBe antibody becomes positive and HBV DNA is suppressed to low levels. Liver function tests (LFT) show elevation of transaminases to >2 upper limit of normal, and necroinflammatory changes are seen on liver histology. This is the stage of maximum liver damage and long-term prognosis depends on the duration of this stage and degree of liver damage during seroconversion. All treatment modalities are aimed at reducing duration of this stage and restricting liver injury and subsequent fibrosis. Successful antiviral therapy at this juncture delays hepatic fibrosis, reverses cirrhosis, and improves survival. [4]

Low replication phase follows HBeAg seroconversion with normalization of LFTs and liver histology and very low levels of HBV DNA. Anti-HBe antibody is usually positive. These patients generally do not require treatment unless they develop a precore or core promoter gene mutation. This event is characterized by elevated levels of transaminases and necroinflammatory changes on biopsy and is associated with aggressive liver disease and risk of decompensation. [5]

Integrative phase or phase of viral clearance is associated with hepatitis B s antigen (HBsAg) loss and appearance of anti-HB antibody. HBV DNA may become undetectable and the person is declared cured but a low risk of hepatocellular carcinoma (HCC) remains. This seroconversion is associated with good prognosis if it occurs before cirrhosis occurs. Immunosuppression subsequently can cause reactivation of infection. [6]

 HBeAg Status and Implications for Therapy



Chronic HBV-infected patients are divided into 2 categories based on HBeAg status. HBeAg-reactive chronic HBV infection is accompanied by high-level HBV replication. They have elevated transaminases and active inflammation on liver histology. These patients are ideal candidates for interferon therapy. Seroconversion from HBeAg-positive to antibody (anti-HBe)-positive infection is the target endpoint, which is associated with fall in HBV replication and clinical improvement.

Patients with HBeAg negative chronic HBV infection tend to have lower levels of HBV DNA and fluctuating transaminase activity compared with HBeAg-reactive HBV infection. Infection associated with precore mutation causes progressive liver injury. They respond poorly to interferon, and therefore, oral therapy is the treatment of choice in this scenario. [7] In the absence of e antigen, a finite endpoint of treatment is lacking in this subset.

Ideal drug for chronic hepatitis B

An ideal drug for chronic hepatitis B should have the following attributes:



Oral route of administrationRapid and durable suppression of both wildtype and mutant HBV to undetectable levels by polymerase chain reaction (PCR) methodsTo translate HBV DNA suppression into HBeAg and subsequently HBsAg seroconversionFinite duration of treatment No stable drug resistant mutationsGood safety profile with no major adverse effectsInexpensive

Of the currently available drugs, none satisfies the above criteria. Interferon requires parenteral injection and is associated with 20%-60% HBeAg seroconversion rate. Unfortunately, it is very expensive, less effective against HBeAg negative disease, and is associated with significant adverse effects, such as decompensation, bone marrow suppression, and graft dysfunction in organ transplant recipients. Oral antiviral therapy has the disadvantage of prolonged treatment duration and emergence of drug resistance. HBeAg seroconversion is low and HBsAg loss is rare (<2%) with oral drugs when compared with interferon [Table 1]. [7]{Table 1}

 Tenofovir Disoproxil Fumarate



Tenofovir disoproxil fumarate (TDF) is the oral prodrug of tenofovir. It is an acyclic nucleotide analog reverse transcriptase inhibitor structurally similar to adefovir. It has been approved in August 2008 for treatment of chronic hepatitis B by the US Food and Drug Administration.

 Pharmacokinetics and Mechanism of Action



The recommended oral dosage of tenofovir is 300 mg once a day. Bioavailability is increased when it is taken with food. It is metabolized and excreted by the kidneys and the interaction with cytochrome P450 enzymes is low. DNA polymerase is a key enzyme required by HBV for replication. Oral nucleot(s)ide analogs inhibit the action of HBV DNA polymerase. Tenofovir, after activation by diphosphorylation competes with natural triphosphate deoxynucleosides for binding to the active site of HBV polymerase, and its incorporation at the end of the growing DNA terminates chain elongation. Its higher affinity for the viral DNA polymerases than for human cellular DNA polymerases is responsible for minimal interference with human nuclear DNA synthesis, low cytotoxicity, and favorable safety profile. [8]

Efficacy of tenofovir against HBV

Clinical studies have confirmed the efficacy of tenofovir in suppressing HBV replication. Most of the studies demonstrate its excellent activity against HBV in both lamivudine-naive and Lamivudine-resistant patients. [9] In several studies in HBV-infected patients, Tenofovir when given in the dose of 300 mg once daily, resulted in a reduction of 4-6 log 10 copies/mL in serum HBV DNA level from baseline over 48 weeks and in reduction of 5 log 10 copies/mL compared with placebo; HBV DNA was undetectable by PCR assay in 30%-100% of patients after more than 24 weeks treatment. [10]

A large multicenter, phase III, double-blinded study [Table 2] was published by Marcellin et al recently. [11] Patients with HBeAg-negative or HBeAg-positive chronic HBV infection were randomly assigned to receive tenofovir or adefovir once daily for 48 weeks. In the HBeAg-negative group of patients, 18% had previously received lamivudine. At the end of 48 weeks, a significantly higher proportion of patients receiving tenofovir than those receiving adefovir had reached the primary endpoint of HBV DNA < 400 copies/mL and histologic improvement. Viral suppression occurred in more patients receiving tenofovir than those receiving adefovir in both HBeAg-positive and HBeAg-negative groups. Normalization of alanine aminotransferase (ALT) levels and serologic response in the form of loss of hepatitis B surface antigen was significantly more in HBeAg-positive patients treated with tenofovir than those treated with Adefovir. HBV DNA polymerase mutations causing resistance to tenofovir had not developed in any of the patients and the HBV DNA response was independent of previous therapy with Lamivudine. [11] There were similar results in the HBeAg-negative group [Table 3]. [12]

In another study by Heathcote et al [Table 4], after follow up of 72 weeks of tenofovir therapy, more patients who were originally randomized to receive tenofovir had HBV DNA < 400 copies/mL, HBeAg seroconversion, and HBsAg loss. In 78% of those who were switched to tenofovir, after 48 weeks of adefovir therapy and HBV DNA levels above 400 copies/ mL, significant additional viral suppression was seen.{Table 2}{Table 3}{Table 4}

 Tenofovir in Lamivudine/Adefovir-Resistant Infection



In vitro and in vivo studies have shown the excellent efficacy of tenofovir on lamivudine-resistant virus independent of the resistance mutation profile. In 20 patients with chronic HBV infection, who suffered a virologic breakthrough during lamivudine therapy, followed by an incomplete virologic response to 12 months of adefovir treatment, treatment with tenofovir was associated with rapid virologic response. The presence of YMDD mutation had no influence on tenofovir efficacy. [13] In another study, 9 patients with either a virologic breakthrough on adefovir, in the absence of known resistant mutations or with a suboptimal virologic response to adefovir were switched to tenofovir monotherapy. Seven out of 9 had rapid virologic response with undetectable serum HBV DNA within 3-15 months of starting therapy. [14]

In a study from Germany and Netherlands, 121 patients with chronic HBV infection and previous treatment with lamivudine (16), adefovir (9), lamivudine followed by adefovir (72), and adefovir added to lamivudine (21) were analyzed retrospectively. These patients were subsequently switched to tenofovir and 85% had undetectable HBV DNA at the end of 1 year. Rapid virologic response and undetectable HBV DNA was seen in 100% of patients without mutations. On the other hand, in patients with documented YMDD mutation 92% had undetectable HBV DNA after 12 months. Virologic response in adefovir-resistant mutations was seen in 30% of patients, but no virologic breakthrough was seen. [15]

 Tenofovir in HIV/HBV Co-Infection



Tenofovir is an ideal drug for HIV/HBV co-infection due to its good activity against both viruses. The antiviral efficacy of tenofovir for HBV infection is the same in patients with and without HIV co-infection. Compared with adefovir, which lacks anti-HIV activity, TDF is an excellent option for patients with advanced HIV infection in view of good tolerability and reduction in RNA levels. [16] A study from Spain involved HIV/HBV co-infected patients treated with lamivudine (median 84 weeks) and persistently elevated HBV DNA (median 3.73 Χ 10 6 ). HBeAg was positive in 75% of cases and mutations causing resistance to lamivudine were detected in 60% of screened individuals. All patients were treated with 300 mg tenofovir for 24 weeks with no serious adverse effects causing discontinuation of therapy. Virologic response with significant decline in HBV DNA levels was seen in all patients, with a median decrease of 3.78 (0.71-5.22) log 10 copies/mL from baseline to 24 weeks. HBeAg seroconversion and subsequent HBsAg loss was seen in 8% of the study population. [17]

Indications of tenofovir therapy in chronic HBV infection

Tenofovir is indicated for the treatment of patients with lamivudine-resistant HBV infection. It is superior to adefovir and other oral antivirals, such as Entecavir in these patients, and it is safer than adefovir. It is also effective in patients with adefovir resistance when added to lamivudine or Entecavir. Mutants with Entecavir resistance have been successfully treated with TDF. [18] In HIV/HBV co-infection, addition of tenofovir to lamivudine or emtricitabine in patients requiring antiretroviral therapy and in those with lamivudine or emtricitabine resistance is the current treatment of choice. [19] Tenofovir when used alone in HBV monoinfection is characterized by a relative absence of nephrotoxicity and is an optimal drug for posttransplantation HBV prophylaxis. [20] Monotherapy with tenofovir among treatment-naοve patients is a possible option in view of absence of resistance similar to Entecavir.

Combination therapy

Most studies with a combination therapy show no additive antiviral effects, although combination therapy results in reduction of resistance development. Combining a nucleoside analog, such as lamivudine, Entecavir or telbivudine, with a nucleotide analog, such as adefovir or tenofovir, may be ideal. With this combination therapy, one group of agents will remain sensitive to the resistant mutant viruses of the other group. Further trials are required to study this possible benefit. [21]

Drug resistance

Genetic mutations causing resistance to tenofovir are uncommon. Mutations in polymerase-reverse transcriptase associated with either decreased sensitivity to tenofovir or known resistance to antivirals have not been detected in either the HBeAg-negative or -positive patients after 72 weeks of treatment. [12] Tenofovir resistance has been described in only 2 HIV/HBV co-infected patients in addition to lamivudine resistance. Due to conflicting reports on its susceptibility, the clinical significance of this finding needs further clarification. [22] HBV resistance to tenofovir is infrequently found during the first years on therapy, making it an attractive candidate for monotherapy in chronic hepatitis B. Resistance patterns with long-term treatment are not known and will need intensive surveillance and genotyping for mutations

 Safety Profile



The advantage with tenofovir therapy is its excellent safety profile. It is well tolerated in both HBV monoinfection and in HIV/HBV co-infection. Mild to moderate nausea is the most frequent adverse reaction in most clinical trials. Treatment-related ALT flare occurs during first 8 weeks of starting therapy and is associated with decrease in the HBV DNA level and resolution within 4-8 weeks. Flares with ALT levels > 10 times upper limit of normal (grade 4) are associated with HBeAg loss or seroconversion in 63% of patients and rarely in HBsAg loss. [23]

Serious adverse reactions are rare and dose independent, which include pancreatitis, fever, pneumonia, lactic acidosis, and bone abnormalities [Table 5]. Renal toxicity has not been reported in patients with monoinfection with HBV. In the study published in NEJM in Dec 2008, none of the patients who received tenofovir had a confirmed increase from baseline in the serum creatinine level of 0.5 mg/dL or more, or a confirmed calculated creatinine clearance of less than 50 mL/min [Table 6].{Table 5}{Table 6}

Case reports of occurrence of renal insufficiency, tubular dysfunction, Fanconi's syndrome, and diabetes insipidus have been published in HBV/HIV co-infected patients treated with tenofovir. In most cases of nephrotoxicity, patients were either having HIV-related renal dysfunction or were receiving multiple medications, some of which may be nephrotoxic or compete for renal tubular secretion of tenofovir. [24]

In a study in 10,343 HIV patients on tenofovir therapy of at least 4 years duration, the incidence of any type of serious renal adverse event was 0.5%. Spectrum of renal dysfunction included elevations in serum creatinine at or above grade 1 or grade 2 to renal failure (acute and chronic). Other renal events, such as nephritis and proteinuria are rare. [23] Risk factors for nephrotoxicity are sepsis/serious infection, history of renal disease/baseline renal impairment, late-stage HIV, concurrent nephrotoxic drug use, and hypertension.

Tenofovir when used alone in HBV monoinfection has low risk of nephrotoxicity. It can be reduced even further by calculating creatinine clearance through the use of the Cockroft-Gault equation or the Modification of Diet in Renal Disease equation prior to therapy and adjusting the dosage accordingly [Table 6]. [25]

 Conclusion



The future of management of chronic hepatitis B appears to be promising with availability of many therapeutic options currently available, new drugs in development, and development of different on-treatment strategies for optimizing the use of current agents. Among the available nucleoside and nucleotide agents, tenofovir is a potential first-line drug against treatment-naοve HBV, lamivudine-resistant HBV, and HIV/HBV co-infections. Good antiviral efficacy, rapid and durable virologic response, excellent safety, and absence of resistance are its advantages. Further studies are necessary to investigate the incidence of side effects, its efficacy, and resistance patterns in the long term and to prove its potential efficacy other clinical situations. [26]

References

1Chowdhury A, Santra A, Chakravorty R, Banerji A, Pal S, Dhali GK, et al. Community-based epidemiology of hepatitis B virus infection in West Bengal, India: Prevalence of hepatitis B e antigen-negative infection and associated viral variants. J Gastroenterol Hepatol 2005;22:1712-20.
2Thyagarajan SP, Jayaram S, Hari R, Mohan KVK, Murugavel KG. Epidemiology of hepatitis B in India - A comprehensive analysis. In: Sarin SK, Okuda K, Ed. Hepatitis B and C: Carrier to cancer. New Delhi: Elsevier India. 2002:25-39.
3Jonas MM. Treatment of chronic hepatitis in children. J Pediatr Gastroenterol Nutr 2006;43:S56-60.
4Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45:507-39.
5Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2001;34:617-24.
6Yim HJ, Lok AS. Natural history of chronic hepatitis B infection: What we knew in 1981 and what we know in 2005. Hepatology 2006;43:S173-81.
7Dienstag JL. Hepatitis B virus infection. N Engl J Med 2008;359:1486-500.
8De Clercq E. Clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections. Clin Microbiol Rev 2003;16:569-96.
9Wong SN, Lok AS. Tenofovir disoproxil fumarate: Role in hepatitis B treatment. Hepatology 2006;44:309-13.
10Delaney WE 4 th , Ray AS, Yang H, Qi X, Xiong S, Zhu Y, et al. Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob Agents Chemother 2006;50:2471-7.
11Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 2008;359:2442-55.
12Heathcote EJ, George J, Gordon S, Bronowicki JP, Sperl J, Williams R, et al. Tenofovir disoproxil fumarate (TDF) for the treatment of HBeAg-positive chronic hepatitis B: Week 72 TDF data and week 24 adefovir dipivoxil switch data (study 103). J Hepatol 2008;48:S32.
13van Bömmel F, Zöllner B, Möller B, Huppe D, Feucht HH, Wiedenmann B, et al. Is tenofovir effective in treatment of adefovir resistant hepatitis B virus (HBV) infections? Hepatology 2007;44:567A-8A.
14van Bömmel F, Zöllner B, Sarrazin C, Spengler U, Hüppe D, Möller B, et al. Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology 2006;44:318-25.
15Tan J, Degertekin B, Wong SN, Husain M, Oberhelman K, Lok AS. Tenofovir monotherapy is effective in hepatitis B patients with antiviral treatment failure to adefovir in the absence of adefovir-resistant mutations J Hepatol 2008;48:391-8.
16Massard J, Benhamou Y. Treatment of chronic hepatitis B in HIV co-infected patients. Gastroenterol Clin Biol 2008;32:S20-4.
17Núñez M, Pérez-Olmeda M, Díaz B, Ríos P, González-Lahoz J, Soriano V. Activity of tenofovir on hepatitis B virus replication in HIV-co-infected patients failing or partially responding to lamivudine. AIDS 2002;16:2352-4.
18Leemans WF, Niesters HG, van der Eijk AA, Janssen HL, Schalm SW, de Man RA. Selection of an Entecavir-resistant mutant despite prolonged hepatitis B virus DNA suppression, in a chronic hepatitis B patient with preexistent lamivudine resistance: Successful rescue therapy with tenofovir. Eur J Gastroenterol Hepatol 2008;20:773-7.
19Soriano V, Puoti M. Bonacini M, Brook G, Cargnel A, Rockstroh J, Care of patients with chronic hepatitis B and HIV co-infection: Recommendations from an HIV-HBV International Panel. AIDS 2005;19:221-40.
20Taltavull TC, Chahri N, Verdura B, Gornals J, Lopez C, Casanova A, et al. Successful treatment with tenofovir in a child C cirrhotic patient with lamivudine-resistant hepatitis B virus awaiting liver transplantation: Post-transplant results. Transpl Int 2005;18:879-83.
21Marcellin P, Lau GKK, Bonino F, Farci P, Hadziyannis S, Jin R, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:1206-17.
22Reijnders JG, Janssen HL. Potency of tenofovir in chronic hepatitis B: Mono or combination therapy? J Hepatol 2008;48:383-6.
23Nelson MR, Katlama C, Montaner JS, Cooper DA, Gazzard B, Clotet B, et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: The first 4 years. AIDS 2007;21:1273-81.
24Gitman MD, Hirschwerk D, Baskin CH, Singhal PC. Tenofovir-induced kidney injury. Expert Opin Drug Saf 2007;6:155-64.
25Gish RG. Hepatitis B treatment: Current best practices, avoiding resistance. Cleve Clin J Med 2009;76:S14-9.
26Lai CL, Yuen MF. Chronic Hepatitis B - new goals, new treatment. N Engl J Med 2008;359;2488-91.