S U M M E R 2 0 0 9 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E 10 BIOLOGY Hepatitis B is a DNA virus classified as a hepadnavirus, which replicates in the liver but is found in other sites of the body.7 A simplified version of the very complicated HBV life cycle begins with the DNA virus entering into the hepatocyte’s nucleus, which then produces and releases RNA into the cell’s cytoplasm. A nucleoside reverse tran- scriptase enzyme is necessary to revert into DNA strand for viral packaging and release from the hepatocyte for further infection. Hence the effectiveness of the nucle- oside reverse transcriptase inhibitors (NRTIs) in the use of both HIV and hepatitis B treatment (Fig. 1). As with HIV, HBV has a high mutation rate. The reverse transcriptase enzyme lacks the proof-reading function that is seen with most DNA polymerases. There are three important clinical mutations in the HB virus: tryosine- methionine-aspartate-aspartate mutant (more com- monly known as the YMDD mutant), N236T mutant pre- core mutants, and core promoter mutants. The first two are important for nucleoside reverse transcriptase drug resistance and the last one is important in diagnosis and prognosis of HBV infection. These mutants will be de- scribed in more detail further on.8 HBV is classified into eight different genotypes using al- phabetical nomenclature (A - H). The different genotypes are represented in different geographical locations, and genotype can influence both the prognosis of clinical disease and treatment response rates. In South Africa the common genotypes seen are A1 and E. In Asia B and C genotypes are seen. Genotype C has been noted not to respond as well to interferon treatment as genotypes HEPATITIS B AND HIV CO-INFECTION IN SOUTH AFRICA: JUST TREAT IT! CLINICAL Cynthia S Firnhaber1,2, MD Prue Ive1, FCP (SA) 1Clinical HIV Research Unit, University of the Witwatersrand, Johannesburg 2Right to Care, Johannesburg There are an estimated 350 million hepatitis B carriers worldwide. The prevalence of mono-infection with hepatitis B in South Africa has been estimated at approximately 10% for the rural population and 1% in urban areas.1,2 The transmission routes of hepatitis B and HIV are similar, but hepatitis B is more efficient. Co-infection with HIV and hepatitis B is therefore not unusual. Recent studies have shown that the prevalence of HIV/HBV co-infection (using HBV surface antigen (HBsAg) as a marker for HBV) in South Africa ranges from 4.8% to 17%, depending on the population studied.3-5 The guidelines for the South African HIV Comprehensive Care, Management and Treatment (CCMT) programme do not include viral hepatitis studies.6 Hepatitis B serology is usually done only if serum aminotransferases are evalu- ated in the absence of another known cause (e.g. tuberculosis and concomitant medications). The clinical sequelae of HIV/HBV co-infection are multiple and can cause an increase in morbidity and mortality. Awareness of HBV/HIV co-infection with appropriate diagnosis and management is imperative for improved care of our HIV patients. Fig.1. Simplified life cycle comparison of HBV and HIV– use of reverse transcriptase enzyme in viral reproduction. hepatitus b.indd 10 3/16/09 2:16:16 PM T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E S U M M E R 2 0 0 9 11 A and D. C has also been reported to have an increased tendency to be associated with liver failure and hepato- cellular carcinoma.8-10 TRANSMISSION Transmission of HBV follows the same blood/body fluid patterns of HIV, but is much more efficient. For example, the rate of HIV transmission from a needle stick is 0.03%, whereas the rate of transmission of hepatitis B can be as high as 30%. Serum but also semen and saliva are effective infectious agents.7,11 Horizontal transmission due to close contact between young children is a major modality of HBV spread in southern Africa.12,13 Perinatal transmission is very important in Asia and is thought to occur mainly during delivery and not during breast- feeding.7 Most of these data come from the literature on HBV mono-infection. HIV-related immunosuppres- sion increases the viral replication and viral load of HBV. HIV/HBV co-infected people have higher HBV viral loads, so co-infection would be likely to make transmission of HBV more efficient.14 SEROLOGY AND DIAGNOSIS The diagnosis of hepatitis B disease is complicated, and multiple laboratory evaluations of serology, HBV viral load, hepatic transaminase levels and/or histological studies are often required. Serological markers have been the standard method of diagnosis of HBV infec- tion for more than 30 years and have been the cause of great confusion among many an intern over this time. The traditional interpretation of serological markers is as follows: n Anti-HBs – antibody to hepatitis surface antigen con- fers immunity (either through the vaccine or through exposure). Anti-HBs alone is seen with immunity ac- quired through vaccination. Anti-HBs + anti-HBc is usually seen with immunity acquired through HBV infection. n HBsAg – hepatitis B surface antigen (infectious agent) is the first serological marker to appear after infection, and persistence for more than 6 months indicates chronic HBV infection. n Anti-HBc – antibody to the hepatitis core antigen becomes positive when exposed to hepatitis B virus. n HBeAg – e antigen represents active replication of hepatitis B (it can be viewed as a poor man’s HBV viral load). n Anti-HBeAg – antibody of e antigen indicates that HBV replication is not occurring and has been con- sidered an end-point of HBV treatment. PRECORE AND PROMOTER MuTANTS These mutations occur in the wild-type hepatitis B rep- licating virus in the precore and/or promoter regions of the virus. In these regions there are mutations leading to changes in the DNA code which form stop codons in the templates, preventing HBeAg production. A replicat- ing HBV that should be producing the e antigen there- fore cannot do so, and is called HBeAg-negative chronic hepatitis B.8 With the wider availability of sensitive molecular bio- logical techniques for detecting HBV DNA in serum and liver tissue, increased attention is being paid to occult (silent) HBV infection. Occult HBV DNA is defined as DNA found in liver or serum in HBsAg-negative patients, and detection of two regions of the hepatitis virus DNA via PCR is required for an infection to be considered occult. The clinical importance of occult HBV infection is un- clear and debated. In a co-infected HIV/occult hepati- tis B cohort in Philadelphia, no significant increase in liver transaminases was seen after controlling for con- founders such as alcohol exposure and hepatitis C. 15 An Italian cohort found an increased frequency of elevated liver transaminases in HIV-seropositive patients who were co-infected with occult hepatitis B. There was a statistically significant increase in hepatitis flares during highly active antiretroviral therapy (HAART). In addition, with the discontinuation of lamivudine in these co-in- fected patients, there were hepatic exacerbations (de- fined as greater than twofold increase in transaminases from basesline) when compared with HIV-seropositive patients who did not have occult HBV DNA (64.7% v. 24.6%, p<0.005).16 If occult HBV DNA in HIV is found to be clinically significant, the greater prevalence of HIV/HBV co-infection will have significant consequences for the antiretroviral (ARV) treatment programme in re- source-poor settings such as southern Africa. Depart- ment of Health and Human Services (DHHS) guidelines and World Health Organization (WHO) recommenda- tions for the treatment of HBV include the use of more than one medication active against HBV in combination therapy for HIV infection.17 As mentioned above, diagnosis of chronic hepatitis B may need a variety of testing for accuracy, and serologi- cal studies alone may not be adequate. HBV PCR is not readily available in South Africa and is very expensive, but could be considered if there is concern about possi- ble occult infection or HBeAg-negative chronic hepatitis B. Raised levels on liver function tests can be helpful, but ‘normal’ liver function test results do not rule out chronic hepatitis B infection.18 CLINICAL COMPLICATIONS Of HIV/HBV CO- INfECTION As with most co-infections with HIV, there are interac- tions between the viruses that can affect the clinical course. HIV increases the risk of an acute hepatitis B in- fection progressing to a chronic active infection (defined as positive HBsAg for over 6 months) by at least three- fold. These co-infected individuals will have significantly higher HBV viral loads, and HIV-infected individuals will have a higher risk of reactivating the latent HBV infec- hepatitus b.indd 11 3/16/09 2:16:18 PM S U M M E R 2 0 0 9 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E 12 tion. Occult hepatitis B infection is also seen more com- monly in HIV-positive individuals and co-infection may escape diagnosis, especially in resource-limited coun- tries where it is not possible to measure the HBV DNA viral load. Clinically these viral interactions lead to an increased risk of hepatic cirrhosis caused by hepatitis B and of hepatic-related deaths in HIV patients (hepato- cellular carcinoma and cirrhosis) if not treated.14 Hepatitis B per se does not interfere with the disease course of HIV, as CD4 immune reconstitution and viral load suppression in patients on HAART are similar to those in hepatitis B-negative patients. However, HBV co-infection can increase complications with treat- ment of HIV patients with HAART or other concomitant medications. A retrospective study in miners in South Africa showed that hepatotoxicity was more likely to occur with HAART initiation if the baseline HBV DNA was above 1×104 copies/ml, and a higher proportion of these patients had hepatotoxicity 12 weeks after initi- ating HAART.19 The HIV/HBV-co-infected patients who had the highest degree of hepatotoxicity were taking HAART and antituberculosis treatment. Patients who were HBsAg positive had 100% increase in hepato- toxicity (0.11 to 0.22 proportion of patients) compared with patients on TB medication without HBsAg during the first 6 months of TB/ARV treatment.3 These hepatic exacerbations can be related to several mechanisms: direct drug-related liver damage, seroconversion from HBeAg or HBsAg positivity, immune reconstitution in patients with HBsAg, and an HBV viral load rebound after effective ARV therapy (tenofovir/lamivudine) for HIV/hepatitis B is withdrawn. Co-infected patients can also be at increased risk of hepatic steatosis and lactic acidosis from ARVs.12,14 Careful observation is needed in the co-infected patient if anti-hepatitis B antiretroviral drugs are removed. Sig- nificant hepatic exacerbations (alanine aminotransferase >200 U/l) were reported in 4% of a European HIV/HBV- co-infected cohort, and 1/147 deaths from fulminant hepatic failure (0.7%) occurred. Hepatitis exacerba- tions were seen about 5 - 8 weeks after removal of the antiretroviral agent. Re-institution of the agent in these situations is the treatment of choice.20 CLINICAL fOLLOW-uP HBV viral load is the major factor that determines pro- gression to liver cirrhosis, hepatocellular carcinoma and death in patients with chronic hepatitis B. However, serum hepatitis B DNA is costly and not routinely per- formed in South Africa, especially in the public sector. The degree of liver fibrosis is also important in determin- ing prognosis and treatment decisions. As in mono-in- fections, the patient with hepatic cirrhosis carries a high risk of developing hepatocellular carcinoma. Liver biopsy has been used to stage fibrosis, but more recently new non-invasive methods such as elastometry and serum biochemical indices have been used. Neither of these methods is well validated in co-infected patients.21 In the South African public sector context HBV/HIV co- infected patients should have liver function tests 1, 3 and 6 months after initiation of HAART, and close moni- toring should be performed with any change or discon- tinuation of HAART. Education regarding transmission of hepatitis B (including condom use), avoidance of alco- hol and herbal medications is needed. All concomitant medications should be reviewed for hepatic toxicity and if possible switched to a less hepatotoxic drug. Partners of HBV-infected HIV patients should be evaluated for HBV. If seronegative, they should be vaccinated. Serum HBeAg and anti-HBe can be used as a limited surrogate marker for HBV DNA replication, and a clinical history and examination, measurement of the serum albumin, prothrombin time and platelet count, and an abdomi- nal ultrasound scan can be done to evaluate for liver cirrhosis.14,22 TREATMENT Treatment for HBV in HIV-seropositive patients is usu- ally not curative because viral reserves are not eradi- cated. Treatment is done to reduce the HBV DNA viral load with the goal of preventing or reducing the risk of liver disease progression, cirrhosis and hepatocellular carcinoma. There are several drugs available for treat- ment of hepatitis B mono-infection: interferon-alpha, lamivudine, adefovir, tenofovir, emotricitabine, entecavir, telbivudine and interferon.8,14 In public sector CCMT sites in South Africa only lami- vudine and tenofovir are available for treatment. As the majority of people in South Africa come in for evaluation of their HIV late in the disease (the average CD4 count on initiation at the Helen Joseph clinic is approximate- ly 90 cells/µl), most will need treatment for their HIV. DHHS guidelines recommend treatment for HBV when the viral load is >20 000 IU/ml in HBeAg-positive pa- tients and 2 000 copies/ml in HBeAg-negative patients.14 However, since HBV DNA is not readily available, the clinician should just treat for both infections. Patients who need treatment for HBV infection should also be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against HBV including dual therapy for hepatitis B to prevent resistance: for exam- ple, tenofovir plus either emtricitabine or lamivudine. Monotherapy with lamivudine for hepatitis B in co-in- fected patients will result in resistance in 60 - 80% of patients within 12 months. If tenofovir cannot be used, another agent with anti-HBV activity should technically be used in combination with lamivudine or emtricitabine for treatment of HBV infection. However, in the public health sector other drugs are not available.17 Hepatitis B infection in HIV-seropositive patients may respond poorly to interferon-alpha, and this drug should not be used in any patient with cirrhosis as it can trigger fulmi- nant liver failure. When patients have failed the first-line therapy for HIV with treatment containing lamivudine, hepatitus b.indd 12 3/16/09 2:16:20 PM S U M M E R 2 0 0 9 T H E S O U T H E R N A F R I C A N J O U R N A L O F H I V M E D I C I N E 14 it is recommended that lamivudine be included in the second-line therapy.8,14 In instances when HIV treatment is not an option or is not desirable, pegylated interferon-alpha (excluding cirrhosis) may be used for the treatment of HBV infec- tion, as it does not lead to the emergence of HIV or HBV resistance. Adefovir dipivoxil is active against HBV but not against HIV at the 10 mg dose; however, there is a theoretical risk of development of HIV resistance, as it has anti-HIV activity at higher doses and is related to tenofovir. Adefovir is not available in the public sector.17 VACCINATION Benjamin Franklin’s ‘An ounce of prevention is worth a pound of cure’ could not have been more prophetic than in the situation of HIV/HBV. With the addition of the hepatitis B vaccination to the Expanded Programme on Immunization (EPI) in 1995 for all infants at 6, 10 and 14 weeks, HBV/HIV coinfection will begin to decrease.13 For those who were born before 1995, vaccination is imper- ative for prevention. In those already infected with HIV, the vaccine is not as effective. With a CD4 count >500 cells/µl the response rate is 87%, and with a count of 200 - 500 cells/µl it falls to 33%. Vaccination is recom- mended when the CD4 count is above 350 cells/µl. How- ever, vaccination should not be delayed if the CD4 count is low, as there are some patients who do respond with lower CD4 counts. Vaccination response rates improve when the HIV viral load is suppressed to <50 copies/µl on HAART. Doubling the dose of the vaccine from 20 µg to 40 µg per injection or adding a fourth immunisation also helps response rate.22 CONCLuSION Hepatitis B co-infection is prevalent in our population and can make HAART more complicated. However, most of our patients tolerated HAART without difficulty, and with close monitoring the simple combination of teno- fovir/lamivudine with efavirenz is very effective in treat- ing both HIV and hepatitis B and should be considered first-line therapy in these patients. REFERENCES 1. Kramvis A, Kew MC. Epidemiology of hepatitis B virus and its genotypes in Africa, and the clinical associations of the genotypes. Hepatol Res 2007; 37: 9-9. 2. Shisana O, Rehle T, Simbayi L, et al. South African National HIV Prevalence, HIV Incidence, Behaviour and Communication Survey, 2005. Cape Town: HSRC Press, 2005. 3. Hoffmann C, Charalambous S, Thio C, et al. Hepatotoxicity in an African antiretroviral therapy cohort: the effect of tuberculosis and hepatitis B. AIDS 2007; 21: 1301-1308. 4. Lodenyo H, Schoub B, Ally R, Kairu S, et al. Hepatitis B and C virus infections and liver function in AIDS patients at Chris Hani Baragwanath Hospital, Johannesburg. East Afr Med J 2000; 77(1): 13-15. 5. Firnhaber C, Reyneke A, Schulze D, et al. The prevalence of hepatitis B co-infection in a South African (SA) urban government HIV Clinic. S Afr Med J 2008; 98: 541- 544. 6. Tshabalala-Msimang ME, MBewu A, Simelela N, et al. Operational Plan for Comprehensive HIV and AIDS Care, Management and Treatment For South Africa. 19 November 2003. 7. Dienstag JL. Acute viral hepatitis. In: Fauci A, Braunwald E, Kasper D, et al., eds. Harrison’s Principles of Internal Medicine. 17th ed. New York: McGraw-Hill, 2008: 1932-1949. 8. Keeffe, E, Dieterich D, Han H, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol 2004; 2(2): 87-106. 9. Owiredu WK, Kramvis A, Kew MC. Molecular analysis of hepatitis B virus genomes isolated from black African patients with fulminant hepatitis. Br J Med Virol 2001; 65(3): 485-492. 10. Kimbi GC, Kramvis A, Kew MC. Distinctive sequence characteristics of subgenotype A1 isolates of hepatitis B virus from South Africa. J Gen Virol May (85) 2004 1211- 1120. 11. Management of Disease Control and Prevention: Updated US Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR Morb Mortal Wkly Rep 2005; 54: 1-11. 12. DiBisceglie AM, Kew MC, Dusheiko GM, et al. Prevalence of hepatitis B virus infection among black children in Soweto. BMJ 1986; 292: 1440-1442. 13. Burnett RJ, Francois G, Kew MC, et al. Hepatitis B virus and human immunodeficiency virus co-infection in sub-Saharan Africa: a call for further investigation. Liver Int 2005; 25(2): 201-213. 14. Thio C. Hepatitis B virus infection in HIV-infected persons. Current Hepatitis Reports 2004; 3: 91-97. 15. Lo Re V 3rd, Frank I, Gross R, et al. Prevalence, risk factors, and outcomes for occult hepatitis B virus infection among HIV-infected patients. J Acquir Immune Defic Syndr 2007; 44(3): 315-320. 16. Filippini P, Coppola N, Pisapia R, et al. Impact of occult hepatitis B virus infection in HIV patients naïve for antiretroviral therapy. AIDS 2006; 20: 1253-1260. 17. DHHS Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents, November 2008. http://AIDSinfo.nih.gov/guidelines (accessed 13 February 2009. 18. Bhattacharya D, Katzenstein D, Wong A, et al. Alanine aminotransferase levels are not significantly elevated in patients with HIV/HBV co-infection and lamivudine resistance. Int J STD AIDS 2008; 19(11): 780-781. 19. Hoffmann C, Charalambous S, Martin D, et al. Hepatitis B virus infection and response to antiretroviral therapy (ART) in a South Africa ART program. Clin Infect Dis 2008; 47: 1479-1485. 20. Bellini C, Keisen O, Chave JP, et al. Liver enzyme elevation after lamivudine withdrawal in HIV-hepatitis B virus co-infected patients: The Swiss HIV Cohort Study. HIV Med 2009; 10(1): 12-18. 21. Soriano V, Puoti M, Peters M, et al. Care of HIV patients with chronic hepatitis B: Updated recommendations from the HIV-hepatitis B virus international panel. AIDS 2008; 22(12): 1399-1410. 22. DHHS Guidelines for Prevention and Treatment of Opportunistic Infections in HIV- infected Adults and Adolescents, June 2008. http://AIDSinfo.nih.gov (accessed 13 February 2009). hepatitus b.indd 14 3/16/09 2:16:21 PM