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2007
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2006
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2005
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Jan-Christian Wasmuth and Jurgen Rockstroh

Introduction

The hepatitis B virus is one of the most common human pathogens worldwide. Up to 95 % of all HIV-infected patients have been infected with hepatitis B, and approximately 10-15 % have chronic hepatitis B, with considerable variation among geographical regions and risk groups. It is estimated that around 100,000 HIV-infected patients in the USA suffer from chronic hepatitis B. Sexual transmission is the most frequent route of contraction. Transmission via the bloodstream is more probable than for HIV: following a needlestick injury contaminated with HBV-infected blood, the risk of infection is around 30% (HCV approx. 2-8 %; HIV approx. 0.3 %). Primary HBV infection leads to chronic hepatitis in 2-5 % of immunocompetent adults, whereas HIV-infected patients experience chronification about five times more often. A possible reason for this is the HIV-associated immunosuppression, whereas virus-specific factors such as the extent of HBV viremia and genotype seem to be not so relevant. Hepatitis B and HIV share several common features, although hepatitis B is a double-stranded DNA virus. After entering the hepatocyte, viral DNA is integrated into the host genome. Viral RNA is translated by HBV reverse polymerase into new viral DNA and transcribed into viral proteins. Reverse transcription may be inhibited by nucleos(t)ides reverse transcriptase inhibitors. Integration of the virus into the host genome of hepatocytes and CD4+ T-cells prevents its eradication. The diagnosis of HBV is established as in patients without HIV infection. Table 1 summarizes the interpretation of serological test results. Screening HIV-infected patients for HBV starts with HBsAg, anti-HBs, and anti-HBc. If a positive HBsAg is found, testing for HBeAg, anti-HBe, and HBV DNA should follow. There is debate about a so-called occult infection due to immune escape. This means patients lack HBsAg, but are positive for HBV DNA. Recent studies have not found evidence of such occult infection and the prevalence and impact in coinfection remains unclear.

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Table 1: Interpretation of serological test results for HBV Interpretation HBsAg anti-HBs anti-HBc HBeAg anti-HBe HBV-DNA No prior contact with HBV - - - - - - Acute infection + - + (IgM) + - + Past infection with immunity - + + (IgG) - + - Chronic hepatitis B + - + (IgG) + - + Occult infection1 - - + (IgG) - - + Pre-core mutant + - + (IgG) - + + Inactive carrier state + - + (IgG) - + - Immunity after vaccination - + - - - - 1 Controversial. See text above. In general, patients with chronic hepatitis B should be screened for hepatocellular carcinoma (HCC) every 6 to 12 months. Serum alpha fetoprotein and an ultrasound of the liver should be performed. This recommendation is independent of apparent cirrhosis, as 10 to 30 % of patients who develop HCC do not have pre-existing cirrhosis. Course of hepatitis B with concurrent HIV infection In HIV-infected patients, chronic hepatitis B has an unfavorable course compared with monoinfected patients, and the risk of liver-associated mortality is significantly increased (about 15 times). Following the decrease in HIV mortality, an increase of liver-associated mortality has been observed (Thio 2002, Konopnicki 2005). In addition to increasing mortality, HIV coinfection accelerates the progression of hepatitis B and increases the risk of cirrhosis. Despite the worsening described, initially the clinical course is usually more benign in HIV-positive patients, although viral replication is increased. This seems contradictory at first, but can be explained by the impairment of cellular immunity, which may lead to an increase in viral replication, but at the same time also reduces hepatocyte damage. Therefore, transaminases in HBV/HIV-coinfected patients are frequently only mildly increased. In contrast, HBV DNA, as a marker for viral replication, is higher than in immunocompetent patients. Accordingly, despite less inflammatory activity, liver fibrosis and cirrhosis are more common. This phenomenon has also been described in other immunocompromised patient populations (e.g. organ transplant recipients). There is a direct correlation between the extent of immunosuppression and the control of viral replication of HBV: Even in cases with apparently resolved hepatitis B (anti-HBe positive, HBV DNA negative), increasing deterioration of the immune system may result in reactivation of the HBV infection. Notably, some cases of reactivation of hepatitis B have been described following immune reconstitution after initiation of HAART. In contrast to the unfavorable course of hepatitis B, the course of HIV-infection is not altered significantly by coinfection. However, HAART-related hepatotoxicity develops about three times more frequently in patients with chronic hepatitis B. Whether or not the prognosis of HBV/HIV-infected patients is changed by HAART and HBV-effective therapies, remains to be seen. HBV-associated mortality seems to decrease, if HBV can be controlled effectively (e.g. French GERMIVIC-cohort). Prevention All patients infected with HIV but with negative hepatitis B serology should be vaccinated! The vaccine may, however, be less effective due to immunosuppression. Approximately 30 % of HIV-infected patients have a primary non-response (only 2.5 % in immunocompetent individuals). This is particularly true for patients with CD4+ T-cell counts less than 500/µl whose response rate is only 33 %. Therefore, a conventional dose is administered to patients with CD4+ T-cell counts greater than 500/µl (20 µg at months 0, 1, and 12), whereas an intensive schedule is recommended for patients with CD4+ T-cell counts less than 500/µl (20 µg at months 0, 1, 2, and the last dose between month 6 and 12). In case of non-response (checked 12 weeks after each cycle), vaccination is repeated at double the dose in four steps (40 µg at months 0, 1, 2, and 6-12). Patients with CD4+ T-cell counts less than 200/µl, who are not on HAART, should receive HAART first and HBV immunization thereafter. Loss of protective immunity is seen in up to 30 % during each year following seroconversion. Therefore, anti-HBs should be monitored once a year and consideration should be given to booster doses if anti-HBs-antibody levels are less than 100 IU/l. HIV patients, who are not adequately immunized against HBV, should be screened yearly to look for newly acquired infection. HIV/HBV-coinfected patients who are seronegative for hepatitis A should be vaccinated against hepatitis A (months 0, and 6), as there is an increased rate of severe or fulminant hepatitis in case of acute hepatitis A. Patients who are susceptible to both hepatitis A and B can be vaccinated with a bivalent vaccine (months 0, 1, and 6). Following immunization, patients should be counseled about common measures to prevent further transmission and transmission of other viruses such as hepatitis C (safer-sex practices, avoidance of needle-sharing and others). They should be educated about strategies to prevent progression of liver disease such as avoidance of alcohol consumption, tobacco use (controversial), or herbal supplements, many of which are hepatotoxic. The application of hepatotoxic drugs (e.g. anti-tuberculous agents) should be carried out cautiously. Newborns of mothers with chronic hepatitis B should receive hepatitis B-immunoglobulin and active immunization. Treatment Treatment of chronic hepatitis B is problematic in coinfected patients because of the impaired immune function. As HBV persists in infected cells even after successful treatment, eradication of HBV seems not possible with current treatment strategies. Similar, development of protective anti-HBs-antibodies with subsequent loss of HBsAg is difficult to achieve. Current treatment goals are seroconversion from HBeAg to anti-HBe, a complete suppression of HBV DNA, normalization of transaminases, improvement of liver histology, and prevention of hepatocellular carcinoma. Other benefits of HBV therapy include the reduction in the risk of transmission and possibly in the risk of HAART-induced hepatotoxicity. Drugs with HBV activity HBV can be treated with nucleoside analogues, nucleotide analogues, and interferon (see table 2). Some nucleos(t)ides are effective against HIV also. Therefore, HBV-medication will be part of the HIV combination therapy in most circumstances, unless there is no need for HAART. 3TC, FTC, tenofovir and probably entecavir are effective against both HIV and HBV. Adefovir and telbivudin are effective against HBV only. Interferon is almost irrelevant in the setting of HBV/HIV coinfection in contrast to HBV monoinfection where it is regarded standard treatment. Antiviral potency can be graded as follows (measured as reduction in HBV-replication after one year): entecavir > telbivudin > tenofovir > 3TC > adefovir > FTC. Entecavir allows a 7 log reduction in HBV replication, tenofovir about 6 log, 3TC 5 log, and FTC 3 log. At the moment treatment recommendations do not take into account these possible differences in potency. It is not clear yet, whether these differences are of clinical relevance. Development of resistance is a matter of concern. Monotherapy with 3TC selects a mutation in the YMDD-motif of the polymerase gene in about 20% of patients per year (production of HBeAg may stop in case of such mutation similar to a pre-core-mutant). There might be cross resistance between 3TC, FTC, entecavir and telbivudin, that can be overcome partly by increase of dosing (e.g. entecavir dose will be higher, if the patient has been treated with 3TC in the past). Adefovir and tenofovir are nucleotide analogues with different mechanisms of resistance, and therefore will be effective after failure of nucleoside analogues in most instances. Tenofovir seems to be active even after failure of adefovir. In the light of the lesson learned from HIV and the high resistance rate of HBV on lamivudine therapy, combination of at least two drugs seems prudent in order to avoid development of resistance. Small series found no resistance development, if a nucleoside and nucleotide analogue were combined. However, there is no proof for better efficacy for this approach. At present, combination therapy with one nucleoside and one nucleotide analog should be preferred to monotherapy if feasible. Optimal treatment duration is not clear. As eradication is not realistic, a lifelong suppression of HBV is the more realistic scenario similar to HIV treatment. HIV/HBV coinfection will require continuous treatment of HIV anyway, so drugs effective against HBV will be integrated into the HAART. A clinical picture of acute hepatitis may develop if HBV treatment is discontinued. This may result even in fatal liver failure. Any interruption of treatment must be thoroughly balanced in HBV/HIV-coinfected patients. In case of loss of effectiveness the treatment may be discontinued without any precautions. No clinical deterioration has to be expected. In case of renal insufficiency all nucleos(t)ide analogues have to be dose adjusted. Interferon might be the treatment of choice in a certain subgroup of patients. These have no need for HAART and positive predictive factors for response to interferon: high CD4-count, HBeAg positive, elevated ALT, low HBV-DNA. Treatment with interferon is limited due to its toxicity (see section on hepatitis C, and section on drugs). Inteferon is contraindicated in patients with decompensated liver disease. In case of advanced liver disease it should be used only with great caution. Finally, liver transplantation may be an option for selected patients who have cirrhosis and/or develop hepatocellular carcinoma. Table 2: Current therapeutic options for chronic hepatis B in HIV/HBV-coinfected patients Drug Dose Duration Adefovir 10 mg QD Minimum of 12 months, possibly lifelong FTC, Emtricitabin 200 mg QD Undefined Entecavir 0,5 mg (if 3TC naive) 1 mg (if 3TC experienced) Undefined 3TC, Lamivudin 300 mg QD1 Minimum of 12 months in HBeAg+ patients and 6 months after HBeAg seroconversion Indefinite in HBeAg- patients Telbivudin2 600 mg QD Undefined Tenofovir 300 mg QD Undefined Interferon-a 5 MU per day or 10 MU 3 x / week 4-6 months in HBeAg+ patients 12 months in HBeAg- patients Pegylated Interferon PegasysÒ 180 µg 1 x / week PEG-IntronÒ 1,5 µg/kg 1 x / week Only Pegasys is licensed of hepatitis B in monoinfected patients. Here legth of therapy is 12 months 1Zeffix, the lower dose, should not be used in HIV-coinfection.2Telbivudin has been licensed in the States in October 2006. Licensing in Europe is still pending. Treatment guidelines In principle, due to accelerated progression and increased mortality in coinfection, treatment possibilities should be examined for every patient. Treatment is recommended if (Alberti 2005, Soriano 2005, Brook 2005): § ALT is consistently > 2-fold above the norm (high pre-treatment ALT values correlate with better treatment responses to interferon and lamivudine); § HBeAg is positive; § HBV DNA > 20,000 IU/mL, if HbeAg+ > 2,000 IU/mL, if HbeAg- (the optimal threshold is unknown; 20,000 IU correspond to approximately 105 copies/ml depending on the assay used) § Significant inflammation or liver fibrosis has been detected bioptically. Currently, the indication for HBV therapy is based on serological markers alone. To determine the extent of liver fibrosis several non-invasive methods are available now. Of special interest is the Fibroscan™ system that measures liver stiffness as a correlate of liver fibrosis. Grading of fibrosis probably will gain more importance in the near future. The impact of liver biopsy will decrease. Liver biopsy is recommended particularly for patients with the inactive carrier state (positive for HBsAg, but no other marker of replication). There are several histological classifications used. In Europe the METAVIR-Score is used most often. It distinguishes five stages of fibrosis (0 = no fibrosis, 1 = portal fibrosis without septa, 2 = few septa, 3 = numerous septa without cirrhosis, 4 = cirrhosis). Hepatitis activity is graded according to the intensity of necroinflammatory lesions (A0 = no activity, A1 = mild activity, A2 = moderate activity, A3 = severe activity). The following non-binding treatment recommendations may be suggested, but need to be confirmed in further studies (figures 1 and 2). An effective treatment of HIV infection must not be put at risk. Accordingly, 3TC, FTC, tenofovir and entecavir (see below), which are effective against both HIV and HBV, have to be combined with other substances effective against HIV in order to ensure an adequate HAART. On the other hand, adefovir and telbivudin are not effective for treatment of HIV and must not be considered as part of the HAART regimen. Figure 1: Treatment recommendations for HIV-HBV coinfected patients without indication for HAART (modified after Alberti 2005) * HBV-DNA > 20,000 IU/ml in HBeAg+ patients; > 2,000 IU/ml in HBeAg- patients ** Metavir < A2 and/or < F2; ***Metavir = A2 and/or F2 (for Metavir-Score refer to text) +IFN and PEG-IFN are preferred in HBeAg positive patients Monitoring means: transaminases every 3 months, INR/HBV-DNA every 6 months The main consideration is the need for HAART: § If there is no need for HAART, the use of drugs without HIV activity seems the best choice (i.e. adefovir, telbivudin or IFN-a; see figure 1). Lamivudine, emtricitabine, and tenofovir should be avoided. Surprisingly, most recently entecavir has been described to be at least partially effective against HIV. This may even lead to selsection of resistance mutations (M184V) (McMahon 2007). Therefore, entecavir should be avoided in HIV-infected patients without indication for HAART. § If the patient is under HAART or needs HAART due to low CD4+ T-cell counts, drugs with both HIV- and HBV-activity should be included in the HAART regimen (see figure 2). In treatment naïve patients who start therapy, the combination of FTC (or 3TC) and tenofovir is preferred as nuke backbone. Figure 2: Treatment recommendations for HIV-HBV coinfected patients with indication for HAART (modified after Alberti 2005) * If compatible with treatment of HIV infection. As an alternative, a substance without HIV-activity may be added (preferably entecavir). A transient elevation of transaminases - which is usually moderate and soon resolves - may be observed after initiation of HBV therapy. It is caused by immunoreconstitution and subsequent increased inflammatory activity. In case of marked and/or ongoing elevation of transaminases, alternative explanations have to be considered (e.g. increasing HBV replication, resistance of HBV, lactic acidosis, hepatotoxicity of antiretroviral drugs, superinfection with hepatitis viruses other than hepatitis B). Initial normalization of ALT and significant reduction of HBV DNA will be achieved in most cases by any anti-HBV agent. ALT levels do not correlate well with inflammatory activity and are influenced by many other factors such as hepatotoxicity of HAART or other drugs, alcohol consumption, and immune reconstitution. Therefore, their value for monitoring treatment is limited. HBeAg seroconversion will occur in as many as 25 % of patients. The most desirable endpoint of HBsAg loss is observed in only 5-10 % of patients within one year of the start of treatment with IFN-a, but occurs less frequently with nucleos(t)ide analogs. As most cases of acute hepatitis B even in HIV-infected patients resolve spontaneously, only supportive treatment is recommended. In addition, data on this situation are sparse (e.g. danger of resistance in case of early therapy with no more options afterwards). References 1. Alberti A, Clumeck N, Collins S, et al. Short statement of the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. J Hepatol 2005; 42:615-624. http://amedeo.com/lit.php?id=15916745 2. Brook MG, Gilson R, Wilkins EL, et al. BHIVA Guidelines on HIV and chronic hepatitis: coinfection with HIV and hepatitis B virus infection. HIV Medicine 2005, 6 Supp. 2:84-95. http://amedeo.com/lit.php?id=16011538 3. Konopnicki D, Mocroft A, de Wit S, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS 2005; 19:593-601. http://amedeo.com/lit.php?id=15802978 4. McMahon M, Jilek B, Brennan T, et al. The Anti-Hepatitis B Drug Entecavir Inhibits HIV-1 Replication and Selects HIV-1 Variants Resistant to Antiretroviral Drugs. Abstract 136 LB, 14th CROI 2007, Los Angeles 5. Soriano V, Puoti M, Bonacini M, et al. Care of patients with chronic hepatitis B and HIV co-infection: recommendations from an HIV-HBV international panel. AIDS 2005, 19:221-240. http://amedeo.com/lit.php?id=15718833 6. Thio CL, Seaberg EC, Skolasky R Jr, et al.; Multicenter AIDS Cohort Study. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet 2002; 360:1921-6. http://amedeo.com/lit.php?id=12493258