Infection with HIV and HBV often coexist in the same patient as the two viruses share similar modes of transmission. Around 10% of HIV patients are co-infected with HBV. With early diagnosis of HIV infection and effective anti-retroviral treatment leading to improved survival of patients with HIV infection, Hepatitis B related liver disease is emerging as a significant health problem in this group of patients.
Acute Hepatitis B tends to become chronic more often in HIV patients (80% vs 10% in HIV uninfected) indicating an immune dysfunction and defective clearance of the virus. Protection against HBV infection should be provided to HIV patients by effective use of Hepatitis B vaccine. Higher and frequent doses may be required in HIV patients as their immune response rates are poor.
The response to treatment of CHB with Interferon-alpha in HIV patients is around 0-10%, much less than what is achieved in non-HIV patients. Considering the cost, adverse effects and the poor response with Interferon-alpha, there is lack of optimism vis-a-vis its use in HIV patients.
The nucleoside analogue, Lamivudine, has shown promise in this group of patients. Lamivudine is useful in suppressing replication of both HIV and HBV. It has been found to be effective in suppressing HBV replication in 96% of HIV patients with chronic Hepatitis B infection. This was associated with clinical, biochemical and histological improvement in liver function. The dose of Lamivudine required in this special group is higher (300 mg/day), and the duration of treatment is long (until HBe sero-conversion and disappearance of HBV-DNA from blood). Besides, rebound viral replication on discontinuation of treatment and the development of YMDD mutants while on prolonged treatment are major concerns at the moment.
|How to cite this article:
Choudhuri G. Treatment of chronic hepatitis B in HIV patients. Hep B Annual 2004;1:217-28
Chronic hepatitis B (CHB) infection occurs frequently in patients infected with the Human Immunodeficiency virus (HIV). The two viruses, Hepatitis B virus (HBV) and HIV, share the same modes of transmission, are present in the same body fluids and have similar high risk groups. Further, they are endemic in the same geographic regions. Before the isolation of the HIV in the late seventies and early eighties, the AIDS epidemic had been linked to HBV, due to the very high prevalence of markers of HBV infection.
The markedly shortened survival of patients with full-blown AIDS did not justify greater attention to co-infection with HBV a decade or two ago. In recent times, on account of a large number of individuals being detected to have infection with HIV while they are still asymptomatic, together with their improved survival with anti-HIV drug therapy, chronic infection with HBV is emerging as a significant health problem in HIV infected subjects. The epidemiologic, clinical and virological patterns of co-infection with these two viruses and their interaction are now being increasingly recognized, and therapeutic strategies being explored.
How common is the problem?
The prevalence rate of HBsAg is 5% in the global population. Of persons infected with HIV as many as 10% may show evidence of HBV infection., There seems to be considerable variation in the prevalence rate of HBV infection in HIV infected subjects, perhaps reflecting geographical or ethnic differences. A recent study from the USA reported a rate of 23.7%, while another earlier study had shown evidence of HBV infection in as high as 80% of those infected with HIV.
The mode of infection with HIV seems to influence the rate of HBV co-infection. Those at highest risk are intravenous drug users (IVDU). In fact the risk of co-infection with HBV in HIV infected IVDUs is ten times greater than those patients who contracted their HIV infection from infected transfusions.
Influence of HIV on HBV infection
In patients already infected with HIV, acute HBV infection progresses more frequently to chronicity. Among homosexuals for example, acute HBV infection becomes chronic in 20% in those who are HIV infected compared to 6% in those who are not infected with HIV., The prevalence of chronic HBsAg carriage increases from 5% in HIV un-infected homosexuals to 12% in those who are HIV infected; the corresponding figures for IVDUs are 3% in HIV antibody-negative and 89% in HIV antibody-positive subjects. These observations point towards a defective immune clearance of HBV in patients infected with HIV. This dysfunction seems to occur even in those with early HIV infection much before an overt immunodeficiency state is reached.
Prevention of HBV infection in HIV infected patients
Effective vaccines, prepared from plasma or recombinant technology, have proved extremely useful in preventing HBV infection in groups at high risk of contracting the infection. HBV infection is effectively prevented in HIV infected patients once protective titers of anti-HBs antibody are achieved. Patients with HIV infection however have lower response rates to vaccination than the general population., The response rate falls markedly and becomes negligible when the CD4+ cell count starts declining.
In spite of these limitations, HBV vaccination remains a useful strategy for preventing infection with HBV in HIV antibody-positive subjects as well as in those at high risk of contracting either or both of these viral infections, such as homosexuals, commercial sex workers and IVDUs. A modified schedule of vaccination using higher dose of the vaccine and increased number of injections may be required to achieve protective immunity. Also, frequent boosters may be required to maintain the anti-HBs antibody titers above the protective levels in these patients. Once adequate levels of antibody are achieved, protection against HBV infection seems to be quite effective.
Treatment of HBV infection in HIV infected patients
Interferon-alpha (IFN) is a cytokine that has antiviral and immuno-modulatory properties and has been in use for the treatment of CHB infection. Several trials have reported benefit with the use of recombinant IFN-alpha in reducing necro-inflammation of the liver as well as suppressing and clearing the viral infection. Till recently, IFN was in fact the only approved drug for this condition. One third to half of the patients treated with IFN have been reported to show response to this drug.
The response to IFN of patients with CHB co-infected with HIV has however been poor. In a study on 41 patients with CHB, none of those who were sero-positive for HIV cleared HBV-DNA. The response rate was a dismal 8% in another study. Somewhat encouraging results were reported from two other studies. In one study on 5 co-infected patients with CD4+ count of about 500/mm 3sub and CDC stages II or III treated with interferon 5MU 3 times a week for 6 months, anti-HBe seroconversion occurred in 2, anti-HBs sero-conversion was observed in one while HBV-DNA disappeared in one. There was documented histological improvement as well. In another recent controlled trial, alpha-interferon was given in the dose of 6 MU 3 times a week for 6 months to 25 patients of CHB co-infected with HIV who had mean CD4+ count of 480 (234)/mm. 3sub Nine (36%) lost HBV-DNA and were considered responders. Antibody to HBe however developed in only one while HBsAg disappeared in another. The HBV-DNA loss observed in the anti-HIV positive patients was 2.15 times more with IFN treatment compared to those who did not receive the drug (36% vs 16.7%). Interestingly, HBV-DNA loss was not found to correlate with the patient's immune status as the 9 responders had a lower mean CD4+ count (283/mm 3) than non-responders (454/mm).
Interferon injections do seem to suppress HBV replication in HIV positive patients with CHB although the response rates remain low. The decision to treat CHB aggressively with IFN in this setting will probably be influenced by the relative stages of the 2 diseases and the expected duration of survival. Interferon therapy is expensive and is also associated with significant side effects. Since AIDS predominates as the cause of death of patients with co-infection, some workers argue that the target of treatment should be HIV rather than HBV.
Mode of action
Lamivudine, the (-) enantiomer of 2'-deoxy-3'thiacytidine, an inhibitor of HIV types 1 and 2 reverse transcriptase, has anti-retroviral activity in HIV infected patients. This drug has also been found to be a potent selective inhibitor of a reverse transcriptase enzyme of HBV that is necessary for its replication. Experimental studies both on HBV transfected cell lines and in chimpanzees have demonstrated the ability of Lamivudine in inhibiting viral replication. Several large clinical studies of Lamivudine on patients with CHB have shown effective inhibition of viral replication as well as clinical and histological improvement of the liver disease., Lamivudine, even when given for long periods, was well tolerated and had a very low incidence of adverse effects.
HBV replication requires synthesis of an RNA intermediate that serves as a template for reverse transcription. These RNA molecules are transcribed from a fully double stranded HBV-DNA template (covalently closed circular DNA), which is believed to persist indefinitely in the nuclei of infected cells. The 5' triphosphate derivative of lamivudine competitively blocks the reverse transcriptase activity of HBV and acts as a chain terminator.
Chronic HBV infection is sustained by multiple copies of covalently closed circular DNA (cccDNA) in the nucleus. The pool of cccDNA is maintained by an intracellular conversion pathway to ensure that a stable number of copies of cccDNA exist in equilibrium. Inhibition of HBV replication by lamivudine may result in a decline in the total HBV load through 2 mechanisms: a combination of diminished production of viable virus (permitting new cells to remain uninfected) with hepatocyte turnover, resulting in a decrease in the number of copies of cccDNA within the infected hepatocyte through inhibition of production of replicative intermediates.
Lamivudine was tried in 40 consecutive patients infected with both HIV and HBV in the dose of 600 mg/day or 600 mg/day followed by 300 mg/day as therapy for HIV disease. All patients had progressive HIV disease and HBsAg in the serum for at least one year prior to starting treatment. HBV replication was inhibited as early as after 2 months of starting therapy in 86% of patients. After 6 months of treatment, 96.3% had lost serum HBV-DNA, the rate of loss being much higher than that reported with IFN-alpha in similar patients. Lamivudine was also effective in patients in whom HBV-DNA had not previously cleared from serum after IFN-alpha therapy.
Response to Lamivudine in HIV infected patients may depend on the rate of HBV replication. While serum HBV-DNA levels fell significantly in 96.3% of those with high HBV replication (serum HBV-DNA concentrations >5pg/mL) after 12 months of treatment, 11.5% still had detectable HBV-DNA in their serum. On the other hand, 100% of those with initially low HBV replication (HBV-DNA concentration <5pg/mL) had undetectable HBV-DNA in their blood after one year of treatment.
Long-term suppression of HBV replication leads to HBeAg seroconversion and possibly long term "cure" in HIV un-infected CHB patients in around 20% per year. The only major concern with prolonged usage of the drug has been the development of YMDD mutants in as high as 32%. Exacerbations of chronic active hepatitis B in HIV infected patients following development of resistance to or withdrawal of Lamivudine have been reported.,, Data on long-term viral clearance in HIV infected patients is presently scanty, and the duration of suppressive therapy has not yet been defined.
Several other nucleoside analogues, such as Famcilovir and Adefovir Dipivoxil are in the phase of evaluation for chronic hepatitis B infection. Till such time, the role of Lamivudine in treating CHB in HIV infected patients needs further studies by large multi-centric trials especially with regard to dose, duration and expected outcome.
Suggested approach in India
Asian AIDS has few special features that need to be kept in mind when deciding treatment. The incubation period as well as the survival time after the first clinical manifestation is short. The disease tends to progress more quickly than the Western variety. Most infections are acquired by heterosexual contact; intravenous drug use is an important factor only in the North East. Also most patients do not come from affluent homes, do not have adequate health insurance or reimbursement support, and cannot hope to avail expensive treatment free of charge from government hospitals for indefinite periods.
When HIV infection is detected and the patient is un-infected with HBV, adequate doses and number of vaccination for HBV should be offered to achieve protective levels of anti-HBs antibody. Needless to add, this should also be prescribed to high risk groups who are still negative for HIV-antibody such as IVDU, commercial sex workers, homosexuals and those in need of frequent transfusion of blood or blood products.
Co-infection with HBV infection has been shown to be a significant cause of morbidity and liver enzyme elevation in HIV patients. If HIV infection is detected early before clinical disease has ensued or CD4+ count has declined, and the patient has co-infection with HBV infection with evidence of ongoing viral replication (detectable HBeAg or HBV-DNA in the serum) and liver inflammation (elevated ALT), anti-viral treatment for HBV should be considered. If there are no constraints on finance, an initial trial of Interferon-alpha in high dose and possibly on a daily injection regime may be tried first. As very high initial HBV-DNA concentrations are often associated with failure to IFN therapy, such patients may be spared the expense and side effects of IFN therapy. Disappearance of HBeAg and HBV-DNA and the appearance of anti-HBe antibody should be considered the virological end points.
Most patients with HIV and HBV infections will probably do better with oral treatment with Lamivudine. This nucleoside analogue can be used in a wide range of clinical situations: early HIV infection or full blown AIDS, high or low HBV replicative states (high or low levels of HBV-DNA concentrations in serum) and naοve patients or those who have failed interferon therapy. While the normal recommended dose of Lamivudine for HIV un-infected patients is 100 mg/day, those with co-infection with HIV require higher doses: 300 mg daily. The duration of treatment is however long, usually one year or more. Successful virological end point should be development of antibody to HBeAg along with clearance of HBeAg and HBV-DNA from the blood. Withdrawal of Lamivudine before complete viral eradication may result in rebound increase in ALT and viremia, while long term usage may be associated with development of YMDD mutant viral forms whose clinical significance has not yet been adequately studied. Since Lamivudine is a component of anti-HIV treatment as well, its use for treating co-infection with HBV seems an easier and more justifiable choice to suppress HBV replication.
Algorithm for management of HBV infection in HIV patients
- Evaluation of a HIV patient should include
a. ALT estimation
especially if the patient is in good general condition and has been an IVDU.
- If HBsAg is positive and ALT is elevated, HBeAg should be tested to determine the replicative status of HBV.
- If the patient tests positive for HBeAg and is being considered for interferon therapy, quantitative HBV-DNA estimation should be done. If the viral load is high ( > 5 pg/mL) then he is likely to be a poor responder to IFN therapy and should be considered for lamivudine treatment
- Patients with replicative HBV ( HBeAg +) and
a. Liver cirrhosis and decompensation
b. High HBV DNA load
c. Financial constraints
Are best treated with Lamivudine in a dose of 300 mg/day for long periods. Lamivudine, used in the drug regime for HIV, suppresses HBV replication as well, providing a dual benefit.
- Periodic evaluation should include assessment of liver functions (3 monthly) and response to therapy (HBeAg/Anti-HBe every 6 months).
- HBV infection is twice as common in HIV patients (10%) as in the normal population (5%)
- Infection with HBV tends to become chronic in HIV patients (80%) far more often than in HIV uninfected subjects (10%)
- With early detection of HIV infection and prolonged survival made possible with effective anti-retroviral therapy, co-infection with HBV has emerged as a significant cause of morbidity
- Oral lamivudine is the drug of choice for treatment of HBV co-infection in HIV patients.
- The dose in this setting is higher (300mg/day)
- Lamivudine has been shown to suppress HBV replication effectively in HIV patients
- Lamivudine is safe and needs to be continued for long periods till HBeAg seroconversion has occurred.
|Lunel-fabiani F. Interactions between Human Immunodeficiency Virus and Hepatitis Viruses B, C and D. In Sarin SK and Hess G (Eds). Transfusion Associated Hepatitis, CBS Publishers, New Delhi, 1998; pp 282-294.
|Hadler JC, Judson FN, O'Malley PM. Outcome of hepatitis B virus infection in homosexual men and its relation to prior immunodeficiency virus infection. J Infect Dis 19991;63:454-9.
|McNair ANB, Main J, Thomas HC. Interactions of the human immunodeficiency virus and the hepatotropic viruses. Sem Liv Dis 1992;12:188-96.
|Benhamou Y, Katlama C, Lunel F, et al. Effects of Lamivudine on replication of Hepatitis B virus in HIV-infected men. Ann Intern Med 1996:125:705-12. [PUBMED] [FULLTEXT]
|Holland CA, Ma Y, Moscicki B, et al. Seroprevalence and risk factors of hepatitis B, hepatitis C, and cytomegalovirus among HIV-infected and high risk uninfected adolescents: findings of the REACH Study. Sex Transm Dis 2000;27:296-303. [PUBMED] [FULLTEXT]
|Monno L, Angarano G, Lo Caputo S. Unfavourable outcome of acute hepatitis B in anti-HIV positive drug addicts. In Zuckerman AJ ed. Viral Hepatitis and Liver Disease. New York: AR Liss,1988;205-6.
|Bodsworth N, Donovan B, Nightingale BN. The effect of concurrent human immunodeficiency virus infection on chronic hepatitis B:a study of 150 homosexual men. J Infect Dis 1989;160:577-82. [PUBMED]
|McDonald JA, Harris S, Waters JA, et al. Effect of human immunodeficiency virus (HIV) infection on chronic hepatitis B hepatic antigen display. J Hepatol 1988;4:337-42.
|Ockenga J, Stoll M, Tillman HL, et al. Coinfection of hepatitis B and C in HIV-infected patients (English abstract). Wien Med Wochenschr 1997;147(19-20):439-42.
|Mai ML, Yim C, O'Rourke K, et al. The interaction of human immunodeficiency virus infection and hepatitis B virus infection in infected homosexual men. J Clin Gastroenterol 1996;22:299-304.
|Koblin BA, Taylor PE, Rubenstein P, et al. Effect of duration of Hepatitis B infection on the association between human immunodeficiency virus type-1 and hepatitis B replication. Hepatology 1992;15:590-2.
|Ho D. Viral count in HIV infection. Science 1996; 272:1124-5.
|Gesemann M, Sheiermann N, Brokemeyre N. Clinical evaluation of a recombinant hepatitis B vaccine in HIV infected vs uninfected persons. In Zuckerman AJ (Ed). Viral Hepatitis and Liver Disease. New York: AR Liss, 1988;1076-8.
|McDonald JA, Caruso L, Karayiannis P, et al. Diminished responsiveness of male homosexual chronic hepatitis B carriers with HTLV-III antibodies to recombinant alpha-interferon. Hepatology 1987;7:719-23. [PUBMED]
|Wong DK, Yim C, Naylor CD, et al. Interferon treatment of chronic hepatitis B: randomized trial in a predominantly homosexual male population. Gastroenterology 1995;108:165-71. [PUBMED] [FULLTEXT]
|DiMartino V, Lunel F, Cadranel JC, et al. Long term effects of interferon in five HIV poitive patients with chronic hepatitis B. J Viral hepatitis 1996;3:253-66.
|Zylbergberg H, Jiang J, Pialoux G, et al. Alpha-interferon for chronic active hepatitis B in human immunodeficiency virus-infected patients. Gastroenterol Clin Biol 1996; 20:968-71.
|Lai CL, Chien RN, Leung NW, et al. A one-year trial of Lamivudine for chronic hepatitis B. N Engl J Med 1998;339:61-8. [PUBMED] [FULLTEXT]
|Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256-63. [PUBMED] [FULLTEXT]
|Beesen M, Ives D, Condreay L, et al. Chronic active hepatitis B exacerbations in human immunodeficiency virus-infected patients following development of resistance to or withdrawal of Lamivudine. Clinical Infectious Diseases 1999;28:1032-5.
|Altfeld M, Rockstroh JK, Addo M, et al. Reactivation of hepatitis B in a long-term anti-HBs-positive patient with AIDS following Lamivudine withdrawal. J Hepatol 1998;29:306-9. [PUBMED] [FULLTEXT]
|Gisolf EH, Dreezen C, Danner SA, et al. and the Prometheus study group. Risk factors for hepatotoxicity in HIV-1-infected patients receiving Ritonavir and Saquinavir with or without Stavudine. Clinical Infectious Diseases 2000;31:1234-9. [PUBMED] [FULLTEXT]
Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226 014
Source of Support: None, Conflict of Interest: None
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