| Abstract|| |
Tuberculosis (TB) and Hepatitis B virus (HBV) infections are quite common in the developing world especially South Asia. As both are so common, co-infection is not very uncommonly encountered in clinical practice. However, since anti-tuberculosis therapy (ATT) can be hepatotoxic in around 10% of patients, the occurrence of hepatotoxicity can complicate management especially in the presence of already compromised liver function due to HBV. Therefore, co-infection of TB and HBV is an important public health issue. Unfortunately the regional and National hepatology societies of South Asia have not bothered to provide any guidance in this matter. This article reviews the epidemiology and management of co-infection with Tuberculosis (TB) and Hepatitis B virus (HBV) and the hepatotoxicity due to ATT.
Keywords: Drug induced liver injury, hepatitis B virus, treatment, tuberculosis
|How to cite this article:|
Patel ND, Singh SP. Antituberculosis therapy in patients with hepatitis B viral infection. Hep B Annual 2012;9:16-48
| Introduction|| |
Tuberculosis (TB) and hepatitis B virus (HBV) infections are common in developing countries of south-east Asia, including India. By virtue of commonness, co-infection is not uncommon in clinical practice. Anti-tuberculosis therapy (ATT) can be hepatotoxic in around 10% of the patients, which may be a management issue that is difficult in the presence of already compromised liver functions due to HBV.
Infectious diseases including TB, HBV, and others are the most common causes of mortality (41%) in India. Adverse drug reactions are the sixth most common cause of death in hospitalized patients. Therefore, co-infection of TB and HBV is an important public health issue. This article covers epidemiology and management of co-infection and hepatotoxicity due to ATT.
| Epidemiology of Tuberculosis|| |
Tuberculosis has remained a major health problem in the world. Mycobacterium tuberculosis infects almost one-third of the world's population (around two billion persons), moreso in developing countries. Even in developed countries, there is a resurgence of TB. The reasons are twofold. First, there is an increase in the immunocompromised population secondary to the pandemic of the human immunodeficiency virus (HIV) infection and increased rate of organ transplantation. Second, increased transglobal migration and travel have led to an easy spread of the organism.
Throughout the world, nine million new cases of TB are diagnosed; of which 1.7 million persons succumb to the disease annually. Life-time cumulative risk for active TB is more than 10%. The highest incidence and mortality rates of HIV are seen in sub-Saharan Africa, whereas, the highest incidence and mortality rates of TB are seen in southeast Asia.
India is a country with high prevalence and incidence of TB. The estimated burden of TB in India is around 8.5 million. Average prevalence of all forms of TB is estimated to be 5.05 per 1000 persons and the average annual incidence of smear-positive cases is 84 per 100,000 annually. Also there is a high rate of transmission with the annual risk of infection varying from 1-2.2% in different studies carried out in different parts of the country., Few epidemiologists forecast a 20% rise in incidence in the next 20 years with a cumulative rise of 46 million cases during that period.
| Hepatotoxicity of Anti-Tuberculosis Therapy:|| |
Recommended treatment for TB is a regimen of isoniazid (H), Rifampicin (R), ethambutol (E), and pyrizinamide (Z) for the initial two months followed by 4-10 months of H and R combination. Primary drugs like H, R, and Z are the most potent, but are hepatotoxic also. Most non-hepatotoxic second-line drugs are less effective against TB. Hepatotoxicity is the major side effect of this highly effective ATT. ATT-hepatotoxicity results in significant morbidity and even mortality, due to acute liver failure. Also these events lead to a substantial financial burden because of additional outpatient visits, tests, and additional hospitalization in case of severe reactions. Hepatotoxicity leads to interruption, modification or non-adherence; eventually this results in treatment failure, relapse, and drug-resistance. Modification of therapy results in the use of less effective, second-line drugs, leading to a suboptimal response to the therapy and prolongation of the therapy, with attendant challenges to compliance.
Definition of hepatotoxicity varies from alanine aminotransferase (ALT) > thrice the upper normal limit (X ULN) with symptoms, > 5 X ULN with / without symptoms, to > 10 X ULN in various series.,,,,,,,,,,,,,,,, Different regimens, different study populations, different definitions of hepatotoxicity, different monitoring practices, and different reporting practices are responsible for the variable results in various studies and this makes it difficult to draw any definitive conclusions regarding the risk involved in using any individual regimen. Incidence of ATT-hepatotoxicity with individual drugs is estimated in two studies: (a) 0.6% with H alone, 1.1% with multidrug R-containing regimen without H, 1.6% with multidrug H-containing regimen without R, and 2.6% with HR containing the regimen; and (b) 1.48% for Z, 0.49% for H, and 0.43% for R.
Epidemiology of hepatotoxicity in active TB
Incidence of ATT-hepatotoxicity varies from 2 to 27.7% in various series.,,,,,,,,,,,,,,,, Countrywise reported incidence is as follows: 8% in Nepal, 18.25-36% in Japan,, 14.7-26% in Taiwan,, 13% in Hong Kong, 8-36% in India,, 4.3% in western countries, < 1-3% in US,4% in UK, 2.6-3.3% in Spain, 11% in Germany, and 9.9% in Argentina.,
Risk factors for ATT-hepatotoxicity in various series are: advanced age, female gender, Asian ethnicity, low body mass index (BMI), malnutrition, hypoalbuminemia, abnormal baseline aminotrnaferases, history of hepatitis, alcoholism, HBV, hepatitis C virus infection, concomitant hepatotoxic drugs, HIV infection, low CD4 count, organ transplantation, slow acetylator status, CYP2E1 c1 / c1 genotype, HLA DQB1*0201 genotype, slow acetylator without NAT2*4 allele, and glutathione S-transferase homozygous null genotype.,,,,,,,,,,,,,,,,,,,,,,,,,,,, In an Iranian study, there has been no risk factor identified. The dosing schedule has a controversial role in increasing the risk of hepatotoxicity., Role of Z in hepatotoxicity has remained controversial: A dose of Z, less than 25-30 mg / kg / day, may be safe, but recent reports favor Z to be responsible for hepatotoxicity.,,,,,Globally, the frequency of hepatotoxicity, that is, ALT > 3 x ULN (18.2% vs. 5.8%) and severe hepatotoxicity, that is, ALT > 10 x ULN (6.9% vs. 0.4%) is higher in patients with risk factors than persons without them.
In the Indian series, the risk of ATT-hepatotoxicity is calculated to be 11.5% from four prospective series,,, as compared to 4.28% in a meta-analysis of 14 studies from the west. High incidence of hepatotoxicity in a developing country is thought to be due to viral hepatitis infections, indiscriminate use of drugs, malnutrition, and more advanced TB.,,,, In addition, high incidence of viral hepatitis in TB patients of developing countries results in the misdiagnosis of drug-induced-hepatotoxicity (DIH) if serological tests are not performed during the hepatitis period., In a previous Indian series, 12.9-42.5% of acute hepatitic illness during ATT might be actually due to acute viral hepatitis.,,, Serological tests for viral hepatitis are a must during this period. Later onset of acute hepatitis, higher elevations in aminotransferases, and a longer time for normalization, indicate acute viral hepatitis rather than DIH.,
In the Indian series, the identified risk factors are: advanced age, alcoholism, hypoalbuminemia, malnutrition, slow acetylator status, extensive TB, and glutathione S-transferase homozygous null genotype.,,,
Epidemiology of hepatotoxicity in latent TB infection (LTBI)
Incidence of hepatotoxicity during treatment of LTBI varies according to different regimens: 0.1-5.2% with nine-month H;,,,, 0-0.7% with four-month R;,,, 0% (as safe as H) with three-month HR combination;, 0.9% with three-month H-rifapentine; 7.7-35% (2.8% severe hepatotoxicity) with two-month RZ combination;,,,, 11-14% with H-high-dose Z combination; 2-5% with H or R with low dose Z combination; 50% with ZE combination; and 25-47% with Z-flouroquinolone combination.,
Older age, alcohol consumption, HIV infection, concomitant hepatotoxic drugs, high dose Z, birth in Asia, chronic viral hepatitis, and cirrhosis are risk factors for hepatotoxicity during treatment of LTBI.,,,,,,,
Outcome of hepatotoxicity
There is 6-12% mortality if ATT is continued even after the onset of hepatotoxicity., Evolution to acute liver failure is present in 10% of cases. An overall mortality rate of hepatotoxicity is 0.08% among all cases and 2.4% among cases of severe hepatotoxicity.
| Epidemiology of Hepatitis B Virus Infection|| |
A total of 350 million persons are infected with HBV worldwide, 75% of which reside in Southeast Asia, with prevalence of 5-20% in the general population. In India, HBsAg prevalence in the general population varies from 1.1 to 12.2%, averaging 3.34%; which amounts to around 50 million patients.
| Co-Infection of TB and HBV|| |
As both HBV and TB are highly prevalent in Southeast Asian countries, including India, co-infection is commonly encountered in clinical practice. However, there is sparse data on the prevalence of HBV infection in TB patients: 9% in 752 Thai HIV-infected TB patients; 4.3% in 300 Georgian TB patients; 6.4% in 951 Indian HIV-infected TB patients; 14.6% in Brazilian (35.8% in HIV-infected) TB patients; 61.6% in 356 Russian TB patients; 1.95% in 1637 European TB patients; and 5.7% in 261 Taiwanese TB patients.
Prevalence of LTBI in HBsAg patients is addressed in few series: 53% in 103 HBsAg + / 743 Vietnamese immigrants to USA.
Injection drug abusers, dialysis patients, sex workers, healthcare workers, patients with HIV infection, homeless people, persons in mental hospitals or prisons, and foreign-born persons of countries with highly prevalent HBV / hepatitis C and / or TB are at risk of exposure to both HBV and TB.,,,,, Few studies have looked into suspecting HBV in TB patients. In Thai HIV-infected TB patients, homosexuality was a factor independently associated with HBsAg reactivity, and IV drug abuse was a factor associated with combined HBsAg and anti-HCV reactivity. In Georgian TB patients, 85% of the time HBV serology status can be predicted correctly on the basis of a Questionnaire algorithm, including a history of blood transfusion, IV drug abuse, younger age at sexual debut, and multiple sexual partners.
| Analysis of ATT-Hepatotoxicity in HBV Patients|| |
Data on HBV as a risk factor for ATT-hepatotoxicity
Studies looking into risk factors for ATT-hepatotoxicity, which found HBV to be a risk factor, are summarized in [Table 1]. [Table 2] summarizes the studies on HBV patients who developed hepatotoxicity during ATT, either for TB or LTBI.
|Table 2: Abridged data of anti-tuberculosis therapy-hepatotoxicity in hepatitis B virus patients|
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A major problem in defining ATT-hepatotoxicity (defined on the basis of altered ALT and / or symptoms) in HBV patients is spontaneous flares in the HBV disease, which also result in altered ALT and / or symptoms. Additional tests like HBV DNA and e-antigen serology tests must be done when there is an episode of altered ALT and / or symptoms; to detect reactivation of HBV or serosonversion / seroreversion illnesses. Majority data available on this issue have not looked in to this matter seriously, barring few studies.
Considerable variability in study designs may prevent conclusions from being drawn regarding the potential contribution of hepatitis B infection to drug-induced hepatotoxicity. Most studies agree that hepatitis B co-infection causes more severe hepatitis due to anti-tuberculosis treatment. The natural course of liver chemistry in HBV may be a confounding factor when evaluating for the presence of hepatotoxicity. Transaminases may remain normal or wax and wane over time in a sine-wave pattern or may have spontaneous flares.
Difference in the diagnostic criteria used to define hepatotoxicity, the characteristics and risk factors of the populations studied, the geographical area or the type of monitoring, selected biochemistry taken during follow-up, and selection biases may contribute to such variations.
Difference in severe hepatotoxicity between the preventive therapy for LTBI and curative treatment for TB might reflect a difference in the intake of alcohol, dose of pyrizinamide, immunogenetic differences in the development of ATT hepatotoxicity, and different backgrounds (HIV, hepatitis B, and / or hepatitis C virus infections).
| Monitoring during ATT and Management of ATT-Hepatotoxicity|| |
As hepatotoxicity of ATT is very important, regular monitoring of these patients for detecting early hepatotoxicity is required. [Table 3] summarizes the few available guidelines.
|Table 3: Guidelines on monitoring and action during anti-tuberculosis therapy|
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Other countries follow different monitoring schedules, few of which are written herewith, to show heterogeneity.
France: Weekly laboratory tests in the first two months
Spain: Laboratory test at the second and fourth week and at end of the second and fourth months in high-risk patients with periodical clinical monitoring
Taiwan: Clinical and laboratory every two weeks in the first month and then monthly thereafter
South Korea: Clinical and laboratory every month
Once hepatotoxicity is detected, there can be three actions:
- Stop ATT forever: This will lead to increase in morbidity and mortality due to TB, with subsequently more TB transmission in the community, which is not a good option.
- Stop hepatotoxic drugs and continue modified ATT with non-hepatotoxic drugs: Problem of prolonged therapy due to less effective drugs and other side effects of drugs (ototoxicity–nephrotoxicity of Streptomycin (S) or ophthalmotoxicity of E, etc.).
- Stop drugs, use non-hepatotoxic drugs till normalization of ALT and then reintroduce drugs: seems to be logical if re-exposure to drug is tolerated. When reintroducing ATT, if the drug is found to be causing hepatotoxicity again, then continue further ATT without adding that drug. Reintroduction can be done using three methods:
- Sequential escalating dose reintroduction: Drugs are reintroduced in a phased manner — low dose for the initial three days then full dose of the drug for four days to one week, then subsequently, after documenting normal ALT, the new drug is added in a similar fashion
- Sequential full-dose reintroduction: drugs are reintroduced in a phased manner — full dose of a drug for one week and then another drug is added after documenting normal ALT
- Simultaneous full dose reintroduction: All the drugs are added at a time in full doses, while monitoring closely
Even as initial studies suspected that reintroduction could be risky or life-threatening,, there is now overwhelming evidence in favor of reintroduction of the drugs.,,,,,,,, Different trials have followed different monitoring schedules, different cut-off levels, and different actions on ATT-hepatotoxicity. This is apparent in [Table 4].
| Approach to Management of Co-Infection in HBV Carriers|| |
Most authorities agree that the hepatitis B carrier state requires special attention. All the patients with TB should be screened for HBsAg before starting treatment. Whenever found to be HBsAg positive, the patients must undergo tests to define the stage of HBV disease (i. e. HBeAg, Anti-HBe, HBV DNA) or stage of liver disease (i.e., ALT, AST, bilirubin, SAP, GGTP, protein, PT, USG-abdomen, SOS OGDscopy, SOS liver biopsy).
Recent studies indicate that HBV carriers (defined as HBsAg positive, HBeAg negative, with low HBV DNA levels and persistently normal ALT) are not at increased risk of developing hepatotoxicity, but the severity of hepatotoxicity may be increased. Therefore, frequent clinical and biochemical monitoring of such patients, while on ATT, should be practiced. These patients can be started on standard ATT (HREZRH,,,,,,). The risk of hepatotoxicity must be explained to the patients and counseling regarding symptoms of hepatotoxicity is a must, to identify hepatotoxicity early. Monitoring of such patients should be frequent with clinical as well as biochemical parameters like ALT and bilirubin. In case of development of hepatotoxicity, ATT should be altered in the form of E, ofloxacin / ciprofloxacin / levofloxacin and S. Weekly monitoring of symptoms and ALT / bilirubin should be done. Once they are normalized, sequential full dose / escalating dose reintroduction should be attempted.
| Approach to Management of Co-Infection in HBV Cirrhosis|| |
There is no data on treating TB in HBV cirrhosis, and there is sparse data on treating TB in cirrhosis. There are very few series that have looked into treating these patients [Table 5].
| Management of ATT-Hepatotoxicity during Acute Viral Hepatitis|| |
In case of acute viral hepatitis during ATT, after normalization of ALT, full-dose ATT can be restarted simultaneously.,
| Data on the Use of Antivirals for HBV in ATT-Hepatotoxicity|| |
Antiviral therapy in active HBV disease decreases hepatitic activity and also causes the suppression of HBV DNA (curtail flares due to viral activity). This decreases the chance of occurence of hepatitic illness during ATT. Only a single case report is available on this aspect, where Lamivudine therapy enabled successful reintroduction of INH and RFM.
| Conclusions|| |
Further research is required to exactly define treatment protocols for patients with tuberculosis and hepatitis B. Promising research directions at present are advocating an NAT2 genotype to predict the occurrence of hepatotoxicity or administration of hepatoprotective drugs along with ATT or the role of therapeutic drug monitoring.
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Nikhil D Patel
Jivandeep Hospital, Station Road, Anand - 388001, Gujarat
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]