Tuberculosis Research Centre, Chetput, Chennai - 600031
Background: Tuberculosis (TB) and hepatitis are the two common
co-infections in patients infected with human immunodeficiency virus (HIV).
Anti-tuberculosis treatment (ATT) may have an effect on the liver enzymes in
these co-infected HIV patients. Aims: To determine the prevalence of
Hepatitis B and C virus coinfection in HIV infected patients in Tamilnadu
and assess effects of anti-tuberculosis drugs on their liver function.
Settings: HIV positive subjects referred to the Tuberculosis Research
Centre, Chennai Materials and Methods: All HIV infected patients
referred to the Tuberculosis Research centre, from March 2000 to May 2004,
were screened for Hepatitis B surface antigen (HBsAg) & Hepatitis C virus (HCV)
antibodies by enzyme linked immunoabsorbent assay (ELISA). HIV infection was
confirmed using two rapid tests and one ELISA. Patients were given either
short- course anti-tuberculosis treatment or preventive therapy for
tuberculosis, depending on the presence or absence of active TB, if their
baseline liver functions were within normal limits. None of these patients
were on antiretroviral therapy during the study period. Statistical
Analysis: Paired t-test was used to find the significance between
baseline and end of treatment liver enzymes levels, while logistic
regression was done for assessing various associations. Results: Of
the 951 HIV-infected patients, 61 patients (6.4%) were HBsAg positive, 20
(2.1%) had demonstrable anti HCV antibodies in their blood. Serial
estimation of liver enzymes in 140 HIV patients (81 being co-infected with
either HBV or HCV) showed that 95% did not develop any liver toxicity while
they were on anti-tuberculosis treatment or prophylaxis. Conclusions:
The prevalence of hepatitis B and C coinfection was fairly high in this
largely heterosexually infected population supporting the use of more
careful screening for these viruses in HIV positive persons in this region.
Anti-tuberculosis therapy as well as TB preventive therapy can be safely
employed in HIV and hepatitis coinfected patients, if baseline liver
function tests are within normal limits.
Keywords: HIV, Hepatitis B, Hepatitis C, antituberculosis therapy
|How to cite this article:
Padmapriyadarsini C, Chandrabose J, Victor L, Hanna LE, Arunkumar N,
Swaminathan S. Hepatitis B or hepatitis C co-infection in individuals
infected with human immunodeficiency virus and effect of
anti-tuberculosis drugs on liver function. J Postgrad Med 2006;52:92-96
Tuberculosis and viral hepatitis are two of the commonest co-infections,
seen among HIV-positive patients worldwide. Infection with hepatitis B (HBV)
and hepatitis C viruses (HCV) are especially common and more significant in
HIV patients. Though there is some data on the prevalence of these
infections in the general population in India,
there is limited information from HIV infected individuals.,
The main mode of spread of HIV in India is heterosexual, with blood products
and intravenous drug use accounting for less than 5% of the infections.
Tuberculosis (TB) is the commonest opportunistic infection in HIV-infected
patients in India and most of the drugs used in anti-tuberculosis treatment
(ATT) cause varying degrees of hepatotoxicity. Fatal hepatotoxicity although
rare, has been reported. One
study has demonstrated that in patients with pre-existing liver injury due
to hepatitis C virus, the relative risk of developing drug-induced hepatitis
was increased 14.4 fold ( P <0.002).
However, the impact of anti tuberculosis treatment on the liver enzymes in
patients co-infected with HIV and hepatitis in India has not been described.
We therefore sought to determine: (i) the prevalence of hepatitis B and C
infection in patients infected with HIV in Tamilnadu, and (ii) the risk of
hepatotoxicity with antituberculosis drugs in these coinfected patients.
Materials and Methods
The study was undertaken after the protocol was approved by the
Institutional Ethics committee. A retrospective review of case records of
all the HIV seropositive patients, enrolled in 2 controlled clinical trials,
between March 2000 and May 2004, namely chemotherapy for TB in HIV positive
patients and the other chemoprophylaxis for TB in HIV positive individuals
was carried out after obtaining consent from these subjects. For all
clinical trials in our institution, the case records of all trial
participants are stored in safe lockers/cupboards for a minimum of 7 years
after the end of a trial. All case records had details of clinical history
(including history of intravenous drug use, other risk behavior), physical
examination findings and laboratory investigation results. The latter
included complete blood counts, liver function tests (Serum bilirubin,
Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) Alkaline
phosphatase, total protein, serum albumin and globulin) and renal function
tests measured by clinical autoanalyser, (Model: ACE, Schiapparelli
Biosystems. INC, Netherlands). All serum samples were screened for hepatitis
B surface antigen (HBsAg) by ELISA (Hepalisa, J. Mitra & Co. Ltd/Biotech
INC, India), and for anti-HCV antibodies by ELISA (Micro Lisa, J. Mitra &
Co. Ltd/Biotech INC, India) and the cut off values were calculated as per
the manufacturer's instructions manual. Any value above the cut off was
taken as positive for HBsAg/ HCV. Positive results on ELISA were confirmed
by a second test (Hepacard for Hepatitis B and RIBA assay for hepatitis C
from Biotech INC, India). HIV infection was confirmed using a combination of
two rapid tests namely Combaids (Span Diagnostics, India) and Tridot (J.
Mitra & Co.Ltd/Biotech INC, India) and one ELISA (Lab systems, U.K.) as per
the guidelines of National AIDS control organization (NACO). Pre-test
counseling was done and informed consent obtained from the patient before
performing an HIV test.
Tuberculosis was diagnosed on the basis of sputum smear and culture results
for M. tuberculosis with clinical and radiographic evidence of tuberculosis.
Patients with bacteriologic or radiographic evidence of tuberculosis were
started on anti-tuberculosis treatment (ATT) with a directly observed short
course (DOTS) intermittent regimen with isoniazid (H), rifampicin (R),
ethambutol (E) and pyrazinamide (Z) as per the Revised National Tuberculosis
Control Programme (RNTCP) guidelines,
(2EHRZ 3 /4RH 3 or 2SEHRZ 3 /1EHRZ 3
/5EHR 3 ). They were monitored clinically every month and liver
function tests were done at second month, at the end of treatment and at any
time, in case of suspected toxicity. Patients who were asymptomatic and had
no evidence of active TB were enrolled into a randomized trial of preventive
therapy for TB with either Isoniazid (300 mg) daily or Ethambutol (800 mg)
and Isoniazid (300 mg) daily. They were monitored clinically once a month
and liver function tests performed once in 6 months, unless they developed
symptoms suggestive of hepatotoxicity. Patients with a history of seizures,
pregnancy, jaundice in the recent past, those who were seriously ill and
those with abnormal liver function tests (i.e. AST or ALT >2 times ULN i.e.
> 80 i.u) at the initial assessment period, were excluded from the clinical
trial. Due to the non-availability of free antiretroviral drugs at that
time, none of the patients in this study were on anti-retroviral drugs.
The characteristics of HIV positive patients with hepatitis co-infection
and those without co-infection were compared. With categorical variables the
chi-square test was applied. Paired t-test was used to test the difference
between zero and six month levels of liver enzymes. 95% confidence intervals
were constructed for AST and ALT. To find out the association between the
enzymes (AST and ALT) with other variables namely age, sex, alcoholism and
coinfection, logistic regression was used. Statistical analysis was
performed using SPSS 10.0.
Of the 951 HIV infected patients (286 with TB, 473 without TB and 192
who were not enrolled into the trials), 81 patients were co-infected with
hepatitis and HIV (61 were HBsAg positive in addition to being HIV positive,
20 were HCV and HIV positive; 4 amongst HIV Infected patients were positive
for both HBV and HCV tests). There were 62 males and 19 females, their age
ranging from 20 to 40 years. Sixty seven were infected through sexual
transmission, while intra-venous drug abuse was responsible for transmission
in 13. One subject acquired infection through blood transfusion. The
baseline characteristics of these co-infected patients are shown in
[Table - 1]. Among the dually infected patients, 22 patients received
ATT as per RNTCP guidelines and 59 patients received prophylaxis for TB.
The baseline values of liver enzymes along with serum bilirubin of all the
co-infected patients are shown in
[Table - 2] along with values for the age, sex and socio-economically
matched HIV positive controls, without hepatitis virus co-infection. Among
the latter group, 20 patients received anti-tuberculosis drugs for TB and 78
were on prophylaxis for TB.
Serial estimation of hepatic enzymes (ALT, AST, SAP) in 74 patients while
they were on ATT, showed that only 8 patients with HBV, 2 patients with HCV
and 6 patients with HIV had more than two-fold elevations in the enzyme
levels from the upper limit of normal, which did not require discontinuation
of anti tuberculosis drugs
[Figure - 1][Figure
- 2]. Two percent of patients had a greater than three-fold elevation in
AST and 5% of patients in ALT.
[Table - 3] shows the enzyme levels at the baseline and at 6-months
after introduction of ATT in patients, in whom paired data were available.
Paired t-test was done to detect a significant change in levels between zero
and six months in relation to hepatitis infection and anti-TB drugs and did
not show any significant change in the levels of liver enzymes in
co-infected patients. Logistic regression analysis done among these
co-infected patients did not show any significant association between liver
enzymes and coinfection status, age, sex, alcoholism or route of
Two patients, who were negative for hepatitis serology before the initiation
of ATT, subsequently developed acute hepatitis B, a few months after
starting antituberculosis therapy. One patient developed jaundice, with a
serum bilirubin of 8.5 mgs%, ALT of 900 I.U. and AST of 725 I.U, after 14
months of isoniazid (INH) therapy. The other patient developed jaundice with
a serum bilirubin of 6.0 mgs%, ALT of 1725 I.U. and AST of 600 I.U., during
the fourth month of ATT (while on rifampicin and isoniazid thrice weekly).
In these two patients, antituberculosis drugs were withheld, till the liver
enzymes returned to normal and they improved symptomatically. Anti-TB
therapy was successfully restarted in both without further problems.
Co-infection with Hepatitis B virus (HBV) or Hepatitis C virus (HCV), in HIV
infected patients complicates the clinical course, management and may also
adversely affect therapy for HIV infection. The prevalence of hepatitis
co-infection with HIV varies widely across different studies, mainly due to
the variation in the distribution of risk factors, geographic location etc
of the study population. In a study from Maharashtra,
among 110 HIV seropositive patients, 30.4% and 7.27% of patients were
positive for HBV and HCV respectively. A study from Manipur,
reported a very high prevalence of HBV (100%) and HCV (92%) infection,
amongst HIV seropositive intravenous drug users.
A cluster survey conducted in three randomly selected districts of Tamilnadu
showed that the overall community prevalence of HIV and hepatitis B in
Tamilnadu was 1.8% and 5.3% respectively.
Another study reported a
seroprevalence of HIV/HBV coinfection of 4% and HIV/HCV of 3%. Our study
documents a hepatitis B infection rate of 6.4% in HIV positive individuals,
which is slightly higher than that seen in the general population and
hepatitis C virus infection of 2.1%. While in most patients in the HIV
positive group, transmission was by the sexual route, 10% of HBV and 30% of
HCV coinfected patients had history of IV drug use.
Serial estimation of Alanine aminotransferase (ALT) is an inexpensive and
non-invasive means of assessing liver disease as it reflects the activity of
hepatotropic viruses and status of liver during therapy with various
hepatotoxic drugs. A substantial proportion of our patients had normal ALT
and AST levels. The hepatitis B coinfected group had higher baseline AST
values and marginally higher ALT values than the HIV group. During serial
estimation while on ATT, majority of coinfected patients had normal ALT, if
they had normal liver function at baseline. Studies have shown that the risk
of isoniazid associated hepatotoxicity increases with age,
and with daily alcohol consumption.
A previous study from TRC, Chennai in HIV negative patients on a daily dose
of isoniazid and rifampicin for pulmonary tuberculosis, has shown a
hepatotoxicity of 2-8% (drug dose based on body weight).
In the present study an increase in hepatic transaminase values to more than
2 times the upper limit of normal (> 80 IU) occurred in 11.3% of HIV
infected, 24% of HBV and 20% of HCV co infected patients who received
concurrent ATT either as preventive regimen or as treatment regimen for TB.
However, this required alteration/interruption of therapy in only 2 cases.
Further, there was a statistically significant increase in serum bilirubin
and alkaline phosphatase levels at 6 months compared to baseline, only in
the HIV group but this was not clinically significant. HIV infection is
known to cause a rise in alkaline phosphatase levels, and this has been
linked to progression of the disease. While studies, in which transaminase
levels were monitored regularly, regardless of symptoms, have shown an
elevated transaminase levels in 10-22% of patients receiving isoniazid at
least once during the course of therapy,,
other studies have shown higher incidence of hepatotoxicity and appearance
of cutaneous rash with pyrazinamide than with other first line anti TB
From a clinical perspective, the most important aspect is the incidence of
discontinuation of INH therapy due to hepatotoxicity. In previous studies on
INH preventive therapy, the rates of discontinuation of such therapy,
because of hepatotoxicity, ranged from 0.1% to 10%.,
Although the height at which asymptomatic elevations of aminotransferase
enzymes should necessitate discontinuance of INH is arbitrary, five times
the baseline level is accepted as a reasonable cutoff.
Most of the participants in this study, whose hepatic transaminase levels
were elevated, were asymptomatic and did not necessitate discontinuation of
INH therapy, except two patients, who developed acute hepatitis B infection.
Our study has its share of limitations. This was a retrospective analysis of
case records. There could have been a selection bias of the sample as very
ill and moribund patients with abnormal baseline liver enzymes were excluded
from these clinical trials. Secondly, LFT was monitored only once in 6
months in patients on TB chemoprophylaxis and at the second and sixth month
for patients on chemotherapy for TB. This infrequent monitoring could have
missed a few short lasting episodes of liver enzyme elevations. Moreover, at
the time of this study, HIV negative group was not available. Hence the
effect of HIV itself on liver enzymes could not be studied. Further, our
data may have underestimated the true prevalence of HCV among HIV positive
patients as at least 4% of HIV-HCV co-infected patients have no detectable
antibodies in the presence of HCV viremia.,
Another difficult issue associated with serological testing for HBV is that
some individuals test positive only for antibodies to hepatitis B core
antigen (anti HBc). However
other potential hepatotoxic exposures were not quantified.
In summary, our study documents fairly high rates of hepatitis B and C
coinfection among HIV infected persons suggesting more careful screening for
these viruses in HIV positive persons. Further, we have shown that anti TB
therapy as well as TB preventive therapy can be safely employed in patients
coinfected with hepatitis viruses, if baseline liver function tests are
within normal limits and they are closely monitored, though these findings
must be confirmed in larger studies of co-infected individuals. Future
research questions that need to be addressed include the impact of HAART and
anti-TB drug interactions in these dually infected patients.
We would like to acknowledge gratefully the help rendered by Superintendent,
Govt. hospital of Thoracic Medicine, Chennai, Director, Institute of
Venereology, Govt. General Hospital, Chennai and Professor, Dept. of Chest
Diseases, Govt. Rajaji Hospital, Madurai.
||Thomas K, Thyagarajan SP, Jeyaseelan L, Varghese JC, Krishnamurthy
P, Lakshmibai, et al . Community prevalence of sexually
transmitted disease and human immunodeficiency virus infection in
Tamilnadu, India:A probability proportional to size cluster survey. Nat
Med J India 2002;15:135-40.
||Tankhiwale SS, Khadase RK, Jalgoankar SV. Seroprevalence of anti-HCV
and hepatitis B surface antigen in HIV infected patients. Ind J Med
||Saha MK, Chakrabarti S, Panda S, Naik TN, Manna B, Chatterjee A,
et al . Prevalence of HCV and HBV infection among HIV seropositive
intravenous drug users and their non-injecting wives in Manipur, India.
Ind J Med Res 2000;111:37-9.
||Salpeter SR. Fatal isoniazid induced hepatitis:its risk during
chemoprophylaxis. West J Med 1993;159:560-4. [PUBMED] [FULLTEXT]
||Ungo JR, Jone D, Ashkin D, Hollender ES, Bernestein D, Albanese AP,
et al . Antituberculosis drug induced hepatotoxicity:the role of
hepatitis C virus and the human immunodeficiency virus. Am J Respir Care
||RNTCP guidelines 2002. Central TB division, Directorate General of
Health Services, Ministry of Health and family welfare, New Delhi.
||Rogers MC, Kumarasamy N, Chaguturu SK, Flanigan TP, Mayer KH,
Balakrishnan P, et al . Hepatitis B, Hepatitis C and HIV
coinfection in Chennai, India. XI CROI, San Fransico, February 2004,
Abstract No. 796.
||Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with
isoniazid preventive therapy:a 7-year survey from a public health
tuberculosis clinic. JAMA 1999;281:1014-8. [PUBMED] [FULLTEXT]
||Parthasarathy R, Sarma GR, Janardhanam B, Ramachandran P, Shantha T,
Sivasubramanian S, et al . Hepatic Toxicity in South Indian
patients during treatment of Tuberculosis with Short-Course Regimens
containing Isoniazid, Rifampicin and Pyrazinamide. Tubercle.
||Byrd RB, Horn BR, Solomon DA, Griggs GA. Toxic effects of isoniazid
in tuberculosis chemoprophylaxis:role of biochemical monitoring in 1000
patients. JAMA 1979;241;1239-41.
||Yee D, Valiquette C, Pelletier M, Parisien L, Rocher I, Menzies D.
Incidence of serious side effects from first line antituberculosis drugs
among patients treated for active tuberculosis. Am J Respir Crit Case
||Sadaphal P, Astemborski J, Graham NMH, Sheely L, Bonds M, Madison A
et al. INH preventive therapy, HCV infection and hepatotoxicity Among
IDU infected with Mycobacterium tuberculosis. Clin Inf Dis
||Barber PG, Goldman WM, Stahl AJ, Avicolli. Antitubercular drugs.
In:Lutwick LI, editor. Tuberculosis A clinical Handbook. Chapman & Hall;
1995. P. 252-94.
||Bonacinin M, Liu HJ, Hollinger FB. Effect of co-existing HIV-1
infection on the diagnosis and evaluation of hepatitis C virus. JAIDS
2001;26 : 340-4.
||Mohsen AH, Easterbrook P., Taylor CB, Norris S. Hepatitis C and HIV-
1 co infection. Gut 2002;51:601-8.
||Gandhi RT, Wurcel A, Lee H, McGovern B, Boczanowski M, Gerwin R,
et al . Isolated antibody to Hepatitis B core antigen in human
immunodeficiency virus type-1 infected individuals. Clin Infect Dis