Hepatitis B is a viral infection that can cause serious or even fatal damage to the liver. The word hepatitis literally means inflammation of the liver. Hepatitis B is caused by the hepatitis B virus, also known as HBV.

HBV is most common in China, southeast Asia and sub-Saharan Africa, where between 10 and 20% of the population may have been infected with hepatitis B. In western Europe and the United States, 0.1 to 0.2% of the population are infected with the hepatitis B virus.

Hepatitis B is usually transmitted through contact with blood, semen, vaginal fluids or saliva of a hepatitis B virus-infected person. Transmission of hepatitis B virus from mother to infant causes the majority of infections worldwide, but the availability of vaccination has virtually eradicated mother-to-child transmission of hepatitis B virus in developed countries. In western Europe, the United States and Australia, hepatitis B infection occurs predominantly among gay and bisexual men, people who share drug injecting equipment, and healthcare workers. Screening of donated blood has dramatically decreased hepatitis B infection among haemophiliacs and other blood product recipients. The virus is many times more infectious than HIV.

HIV and hepatitis B virus co-infection

Different studies have found varying HIV / hepatitis B co-infection rates. In the EuroSIDA cohort, 9% were infected with both viruses (Konopnicki 2005). Studies of hepatitis B infection in gay men, injecting drug users and people with haemophilia have shown that hepatitis B infection does not hasten HIV disease progression or severity (Gilson 1997; Hadler 1991; Sinicco 1997). However, hepatitis B infection significantly increases the risk of death in people with HIV (Konopnicki 2005). A study of patients in the Multicenter AIDS Cohort found that men who were hepatitis B surface antigen-positive were eight times more likely to die of liver-related causes when compared to men with HIV who did not have hepatitis B (Thio 2002).

Conversely, research shows that being co-infected with HIV does increase the chances that a person exposed to hepatitis B virus will develop chronic hepatitis B. It also accelerates liver disease progression and increases the risk that a co-infected person will develop cirrhosis or hepatocellular carcinoma (liver cancer). HIV co-infection also appears to impair the response to anti-hepatitis B treatment.

Vaccine

There is an effective vaccine against the hepatitis B virus, which is recommended for people at high risk of exposure, including gay men, injecting drug users, health care workers and sex partners and household contacts of people infected with the virus. However, only a small proportion of HIV-positive individuals currently are vaccinated against hepatitis B (Tedaldi 2004).

The vaccine is safe for people with HIV, although compared with HIV-negative people, a higher proportion of HIV-positive people may not develop protective immunity against hepatitis B virus following vaccination, and those who are successfully immunised may be more likely to lose their immunity over time. The United Kingdom currently only targets high risk groups for vaccination, but the Foundation for Liver Research has recommended that the government should meet the demands of the World Health Organization and introduce universal hepatitis B vaccination for infants, as is done in the United States and several European countries.

Symptoms

When someone first becomes infected with the hepatitis B virus, they may develop jaundice (yellowing of the skin and eyes), loss of appetite, pain in the abdomen, malaise, nausea, vomiting, fever, or muscle and joint aches. In some cases, people can develop a form of acute liver failure called fulminant hepatitis, which can be very serious or even fatal. However, many people do not notice any symptoms at all when they become infected.

Active chronic hepatitis B virus infection may also cause ongoing or intermittent symptoms of hepatitis.

Stages of infection

There are four stages of hepatitis B infection:

• Immune tolerance: the hepatitis B virus replicates freely and there are no symptoms of hepatitis. This phase lasts for several weeks when adults become infected and for decades when infants are infected.

• Immune response: the immune system mounts an attack on hepatitis B virus-infected liver cells and starts to clear the virus. This stage may last for as little as three weeks when adults are infected or it may persist for ten or more years in people with chronic infection. Symptoms of hepatitis may occur during this stage. A prolonged period of immune response is associated with a greater risk of cirrhosis or liver cancer.

• Full viral clearance: the immune system has won the battle and active viral replication stops. This is sometimes referred to as seroconversion because the body begins to produce antibodies to the hepatitis B e antigen.

• Immunity: there is a full antibody response to hepatitis B virus antigen and its genetic material usually disappears. A person with full immunity will not become infected with the hepatitis B virus in the future.

Chronic hepatitis B and liver damage

In some people, the hepatitis B virus continues to reproduce in the body long after initial infection. They are sometimes called 'chronic carriers', meaning that they are infectious for life, although they may not experience any symptoms themselves. Approximately 90% of babies exposed to the hepatitis B virus before the age of one year become chronic carriers, compared to 20 to 50% of children aged one to five years at the time of exposure. In contrast, only 5 to 10% of HBV-infected adults go on to develop chronic infection, even though about half develop symptoms of acute infection. People co-infected with HIV are less likely to clear the hepatitis B virus without treatment.

Several factors affect progression to chronic liver inflammation, cirrhosis and liver cancer. These include the state of the immune system, gender, hepatitis C or HIV co-infection, the age of the patient at time of infection, the stage of infection and other genetic and viral factors. Hepatitis B viral genotype C has been associated with greater risk of liver inflammation, cirrhosis and liver cancer than genotype B (Chu and Liaw 2005; Chan 2002; Tsubota 2001; Kao 2002).

Given the many factors that affect hepatitis B progression, estimates of progression rates tend to vary. Approximately 15 to 25% of people with untreated chronic hepatitis B will go on to develop cirrhosis or liver cancer, although this may be lower in women (Dickinson 2001).

HIV-positive people who contract hepatitis B are at higher risk of becoming chronic carriers of the virus and of developing advanced liver damage, as are people who receive immunosuppressive treatments following a transplant (Sinicco 1997).

The liver damage experienced by some people with hepatitis B is caused not by the virus itself, but by the immune system's destruction of infected cells in the liver. Because the immune responses of people with HIV are often impaired, HIV-positive people with chronic hepatitis B virus infection may be less likely to experience liver damage than people with fully functioning immune systems (Perrillo 1986). Conversely, HIV-positive people may have higher levels of hepatitis B virus in their blood due to their weakened immune systems, so HIV-positive carriers of the hepatitis B virus may be more infectious than their HIV-negative counterparts.

Diagnosis and monitoring

Blood tests can detect the presence of hepatitis B virus antigen and antibodies, which show whether an individual has been exposed to the virus. Antigens are foreign proteins or substances in the body, and antibodies are proteins produced by the immune system in response to antigens.

People who have successfully cleared the virus are left with antibodies against it. If fragments of the virus itself, called hepatitis B surface antigen (HBsAg), are found in the blood for more than six months, the person is a chronic carrier and capable of infecting others. People with chronic infection are sometimes also positive for hepatitis B e antigen (HBeAg), which indicates that the virus is actively replicating. However, some people are infected by a mutant precore form of the virus known as HBeAg-negative that does not produce this antigen, and appears to be harder to treat. Some people with chronic hepatitis C may be co-infected with hepatitis B but lack detectable hepatitis B virus surface antigen (Cacciola 1999). In addition, some HIV-positive people, especially if they also have hepatitis C, may not show either HBV surface antigen or surface antibodies, but may still have hepatitis B virus core antibodies, which the immune system produces to fight the virus (Ghandi 2003; Shire 2004). This is called an occult infection, and its clinical significance is not known.

There are also tests that measure hepatitis B virus's genetic material, or DNA, in the blood. These viral load tests may detect DNA even if antibodies and antigens are not detectable. These tests are used to tell how well anti-hepatitis B treatment is working.

After a diagnosis of chronic infection, regular monitoring of the liver is advised. Blood tests including liver function tests should be conducted at least every 6 to 12 months. A liver function test measures levels of particular proteins or enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the blood to determine how well the liver is working. See Liver function in Viral load, CD4 cell counts and other tests: A to Z of medical tests for further details. If a patient already has cirrhosis, a liver ultrasound may be conducted every six months to screen for signs of liver cancer. A liver biopsy may also be performed to determine the extent of liver damage.

United Kingdom guidelines recommend that all HIV-positive patients should be tested for markers of hepatitis B infection within a month of their HIV diagnosis. Those without evidence of infection should be vaccinated against the virus, and should also receive vaccinations for hepatitis A. Liver function should be regularly checked in co-infected people who have had exposure to the hepatitis B virus.

The guidelines also recommend that:

• Babies born to mothers with hepatitis B virus should be vaccinated against the virus at birth and receive post-exposure prophylaxis with injected HBV antibodies or immunoglobulin.

• HIV / hepatitis B virus co-infected patients should be counselled about the potential dangers of alcohol consumption, which can accelerate liver damage, and about ways of reducing the risk of hepatitis B virus transmission. Sexual and household contacts should be tested for HBV, and vaccination is suggested.

• Patients with cirrhosis should be screened for liver cancer, and anti-hepatitis B therapy should be considered for people with active viral replication and raised liver enzyme levels. However, the best time to start therapy has not been determined.

Treatment

The aim of treatment for hepatitis B is to reduce liver inflammation, lower hepatitis B viral load and, ideally, to eradicate the virus and produce antibodies. There are currently four approved treatments for chronic hepatitis B in the European Union, which are effective in about one third of recipients: pegylated interferon alfa 2a (Pegasys), conventional interferon alfa (IntronA / Roferon-A / Viraferon), 3TC (lamivudine, Zeffix) and adefovir (Hepsera).

Conventional interferon alfa is usually given as an injection of 5,000,000 units daily or 10,000,000 units three times per week for four months. It leads to viral clearance in 20 to 40% of recipients, but seems to have little efficacy among Asian people infected during infancy. Other factors that have been associated with a poor response to interferon alfa are male sex, long duration of hepatitis B infection, HIV co-infection, high levels of hepatitis B virus DNA, HBeAg-negative hepatitis B virus, and other viral and host factors. Key side-effects include influenza-like symptoms, aches and pains, depression, bone marrow suppression (causing low white blood cell counts, or neutropenia), and auto-immune responses.

Pegylated interferon alfa, a longer-acting version that is injected less often, was granted European approval for the treatment of chronic hepatitis B in February 2005. The recommended dose is 180µg once weekly for 48 weeks. Studies indicate that pegylated interferon more effectively clears HBV than either conventional interferon alfa or 3TC, or a combination of peginterferon alfa and 3TC (Chan 2005; Berg 2005; Janssen 2005; Lau 2005). In addition, studies have shown that patients can maintain anti-hepatitis B virus responses for over two years after the end of a course of peginterferon alfa (Lau 2006; Marcellin 2006)

3TC inhibits replication of both hepatitis B virus and HIV and is an approved treatment for both infections. It is usually referred to as lamivudine in the context of hepatitis B treatment, but is marketed as Zeffix rather than Epivir. The dose of 3TC for the treatment of hepatitis B virus infection is 100mg taken orally once daily. As a treatment for hepatitis B, 3TC induces viral clearance in about 20 to 30% of people after one year of treatment. The optimal duration of treatment for hepatitis B virus has not been established. Studies have generally treated people for one to two years, but lifelong therapy may be required. Studies show 3TC can reduce the risk of liver failure and liver cancer (Liaw 2004).

People with HIV / hepatitis B virus co-infection who are taking or considering 3TC or the similar drug FTC (emtricitabine, Emtriva) should be aware of the potential for hepatitis flares when they cease taking either drug. One clinical trial found that around 20% of co-infected people who stopped 3TC experienced a rebound in hepatitis B viral load, and 2 to 4% had increased ALT and bilirubin levels, a sign of impaired liver function.

The hepatitis B virus does develop resistance to 3TC, but there is evidence that 3TC-resistant HBV remains sensitive to adefovir and tenofovir (Viread), and to experimental antiviral drugs such as lobucavir, entecavir (Baraclude), clevudine and telbivudine (Delaney 2004; Kioko Ono-Nital 1999; Pessoa 2005). Prolonged use of 3TC leads to resistance in 50% or more of individuals with HBV. See 3TC - key research for further details of research on 3TC and hepatitis B.

Adefovir received European approval as a treatment for hepatitis B in March 2003, following United States endorsement in late 2002. Although it was not approved as an anti-HIV drug due to kidney side-effects at a much higher dose, 10mg adefovir daily is well tolerated and effective against HBV (Benhamou 2001, 2002, 2004; Marcellin 2001, 2005). A key benefit of adefovir is that it is active against HBV that is resistant to 3TC (Westland 2005). However, treating HIV co-infected people with adefovir may not be the best strategy because 10mg of adefovir daily is not active against HIV. Some experts have suggested that tenofovir may be a more attractive option for HIV co-infected people whose HIV has already developed resistance to 3TC, as tenofovir has activity against both HIV and HBV. FTC is also active against both viruses, but may not work against 3TC-resistant HBV. Tenofovir and FTC are not yet approved treatments for hepatitis B.

As in the case of anti-HIV therapy, combining two or more drugs to treat hepatitis B is generally regarded as more effective than the use of a single drug (monotherapy), especially in terms of delaying the development of drug resistance (Lau 2004). However, several studies of the combination of pegylated or conventional interferon alfa plus 3TC failed to show the benefit of either combination over 3TC monotherapy (Berg 2005; Janssen 2005). One study suggested that combining 3TC and HBV vaccination improves response in patients with chronic hepatitis B (Horiike 2005). Combination therapy studies are currently ongoing with the approved treatments and the wide range of experimental agents including tenofovir and entecavir.

United Kingdom guidelines recommend that anti-HIV drugs which have an effect against HBV (3TC, FTC and tenofovir) should only be given as part of a combination anti-HIV treatment regimen or in a clinical trial, and should never be used as HBV monotherapy, because they can cause the emergence of drug-resistant HIV. If a co-infected person is not taking combination anti-HIV therapy, adefovir or pegylated or conventional interferon alfa should be used instead to treat hepatitis B.

Experts recommend that HIV / HBV co-infected individuals with elevated ALT and AST should be considered for hepatitis B treatment. For patients requiring antiretroviral therapy, the suggested first-line regimen is tenofovir plus 3TC or FTC, plus another anti-HIV drug (Soriano 2005). At the First European Consensus Conference on the Treatment of Chronic Hepatitis B and C in HIV Co-infected Patients, held in March 2005, a panel of specialists recommended that individuals whose immune systems have been significantly depressed should receive anti-HIV therapy to increase CD4 cell counts before beginning treatment for HBV, and that the choice of which anti-HIV and anti-HBV regimens to use should be individually tailored (Alberti 2005). Current united States guidelines also recommend using a combination of two NRTIs with anti-HBV activity in HIV co-infected patients to treat HIV to avoid putting patients at risk of the development of resistance in HBV. However, where treatment of HIV, but not HBV is needed, the guidelines recommend using peginterferon alfa, entecavir or low-dose adefovir, as these do not cause resistance in HIV. Use of 3TC, FTC or tenofovir without other anti-HIV drugs is not recommended, as this may cause the development of resistance in HIV.

Experimental treatments

More than 20 agents are being tested as treatments for HBV. Drugs furthest along the development pipeline are Gilead Sciences FTC and tenofovir, which have both already been approved for HIV, Bristol-Myers Squibbs entecavir, Pharmassets clevudine (L-FMAU), Idenixs telbivudine (LdT) and Novartiss famciclovir (Famvir). Famciclovir is already approved for herpes simplex virus.

FTC monotherapy has shown promising results in HIV-negative people with HBV, with 64% of patients taking the 200mg daily dose achieving undetectable HBV at 36 weeks (Rousseau 2001). It also has shown potent activity against both HBV and HIV in co-infected individuals (Harris 2004).

Studies have shown that tenofovir is as or more effective against HBV than adefovir, although HBV can develop resistance to tenofovir (Sheldon 2004; van Bö­­¥l 2004). Further, as suggested above, in the context of HIV co-infection, the use of tenofovir may be a more attractive option than adefovir because tenofovir has activity against both HIV and HBV.

Two small studies of tenofovir in co-infected people found substantial reductions in hepatitis B virus DNA of between 3.4 and 4.6 log₁₀ (Bochet 2002; Cooper 2002). In an open-label study of tenofovir in HIV / hepatitis B co-infected patients, five people seroconverted to HBeAg-negative, indicating hepatitis B viral clearance (Nelson 2003). In this study, previous exposure to 3TC did not affect response to tenofovir. A recent controlled study found that tenofovir is at least as effective as adefovir in controlling HBV in HIV / HBV co-infected patients (Peters 2005).

How co-infected people can get maximal benefit from tenofovir is yet to be established. One consideration is that tenofovir is a useful agent for salvage therapy in HIV treatment, because it is active against virus with a wide range of nucleoside reverse transcriptase inhibitor mutations, including 3TC resistance, so it may not be attractive to use this agent as first-line therapy in co-infected patients, in order to save it if needed later. In addition, as is the case with 3TC, discontinuation of tenofovir can cause severe hepatitis flare-ups.

Entecavir, a polymerase inhibitor, has been shown effective in phase III clinical trials in patients with hepatitis B virus but not HIV and in HIV / hepatitis B co-infected individuals with 3TC-resistant hepatitis B virus (Chang 2004; Pessoa 2005; Sherman 2004). Entecavir does not work against HIV, and therefore does not promote the development of drug-resistant HIV as do 3TC, FTC, and tenofovir. In March 2005, the FDA approved entecavir for the treatment of chronic hepatitis B in both hepatitis B virus monoinfected patients and in HIV co-infected individuals who have previously been treated with 3TC. The drug is under consideration for European approval.

Clevudine, telbivudine and famciclovir have also yielded promising results in some studies to date (Lai 2005; Marcellin 2004; Matthews 2001).

Other drugs in the pipeline include: valtorcitabine (val-LdC); amdoxovir (DAPD); lobucavir; LB80380 (ANA380); pradefovir (a prodrug of adefovir, formerly called remefovir); elvucitabine; penciclovir; racivir; NOV-205; L-3'-FD4C (Pentacept); UT 231-B; DXG; thymosin (Zadaxin); and various therapeutic vaccine candidates.

Antiretroviral therapy

An acute episode of hepatitis may occur in an individual with HIV / hepatitis B virus co-infection who is taking antiretroviral therapy. One study found that such flare-ups are very common among HIV / HBV co-infected people: over two years on HAART, 34% of co-infected people experienced acute hepatitis compared with 18% of people infected with HIV alone (Sheng 2003).

Liver toxicity may be caused by anti-HIV drugs. A number of antiretroviral drugs may cause elevations in liver enzymes, and people with viral hepatitis have an increased risk of liver toxicity. Full-dose ritonavir (Norvir), in particular, is associated with liver side-effects, but the lower dose commonly used to boost other protease inhibitors is less likely to cause toxicity. The non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine (Viramune) can cause a hypersensitivity reaction characterized by liver damage and skin rash. The protease inhibitor lopinavir / ritonavir (Kaletra) has also been linked to severe liver enzyme elevations, especially in people co-infected with hepatitis B or C (Chihrin 2004; Meraviglia 2004). However, other drugs can also trigger liver toxicity including indinavir (Crixivan), sulphur-based antibiotics, ketoconazole (Nizoral), AZT (zidovudine, Retrovir), ddI (didanosine, Videx / VidexEC) and pentamidine (Pentacarinat).

HBV infection itself is a risk factor for the development of liver toxicity in people starting antiretroviral therapy. A major analysis of over 1840 patients enrolled in three major clinical studies found that people with hepatitis B or hepatitis C co-infection were almost five times more likely to suffer severe liver-related adverse reactions to antiretroviral therapy than those with HIV alone (Reisler 2002).

An acute episode of hepatitis B may be the consequence of immune recovery. As HIV treatment improves immune function, this can lead to a form of immune reconstitution syndrome characterised by transient flares of liver inflammation and elevated liver enzymes as the immune system steps up its attack against hepatitis B virus in the liver (Drake 2004). Some individuals who did not have them before may develop antibodies against hepatitis B virus. As a consequence, some experts believe that people with chronic hepatitis B infection who commence antiretroviral therapy should begin treatment for hepatitis B at the same time, in order to reduce the risk that antiretroviral therapy will lead to liver damage. If hepatitis flares up, antiretroviral therapy may need to be suspended temporarily while the hepatitis is addressed.

As noted above, stopping treatment with 3TC, FTC, tenofovir or entecavir can also lead to hepatitis B flare-ups. For this reason, some experts recommend that people should stay on these drugs even after their hepatitis B virus has developed resistance. In July 2004, the FDA mandated a change to the tenofovir label warning that the safety of the drug for the treatment of HIV / hepatitis B co-infection has not been established, and that severe acute exacerbations of hepatitis B had been reported in co-infected individuals who stop taking the drug. A similar warning is in place in the European Union, but tenofovir remains a recommended treatment option for co-infected patients.

Despite the risk of an acute episode of hepatitis and/or elevated liver enzymes, evidence indicates that antiretroviral drugs may be safely used for people with viral hepatitis (Law 2004). However, dose reductions may be warranted due to poor liver function.

Liver transplants

In cases of severe cirrhosis or liver cancer, a liver transplant may be the only treatment option. Liver transplants for HIV-infected patients with end-stage liver disease have not been routinely performed, but some recent studies have shown that transplant outcomes in HIV-positive people with well-controlled HIV disease and CD4 cell counts above 200 cells/mm³ are almost as good as those seen in people without HIV (Neff 2001; Roland 2004). For example, a study with long-term follow-up data found that HIV infection did not, on average, reduce survival twelve months after transplantation (Ragni 2003). It can also be effective in patients with 3TC-resistant HBV^[1].

Following the success of transplants in this patient group, some experts have advocated for a routine approach to liver transplants in HIV-infected patients (Fishman 2003). In 2005, the British HIV Association (BHIVA) and the United Kingdom and Ireland Liver Transplantation Centres issued guidelines recommending that HIV-positive patients with hepatitis B or C should be considered for liver transplants if they have at least a 50% chance of surviving five years or more after receiving a new liver.

Research into conventional and pegylated interferon for hepatitis B

McDonald treated 34 people with HBV, 14 of whom were HIV-positive, with interferon alfa 2a (Roferon-A. No HIV-positive people responded to treatment, compared with 33% of HIV-negative people.

In contrast, Hoofnagle reported a 25% response to therapy among HIV / HBV co-infected people treated with interferon alfa 2b (IntronA / Viraferon).

Chan (2005) compared pegylated interferon alfa 2b (Viraferon-Peg / Peg-Intron) plus 3TC against 3TC monotherapy in 95 patients with chronic HBeAg-positive HBV. After a median follow-up period of about 120 weeks, sustained loss of HBeAg was seen in 63% of the combination arm and 28% of the 3TC monotherapy arm (p = .001).

Berg compared the safety and efficacy of pegylated interferon alfa 2a (Pegasys) 180 micrograms once weekly plus placebo, pegylated interferon plus 3TC, and 3TC alone in 537 patients with HBeAg-negative chronic hepatitis B. After 48 weeks of treatment plus a 24-week follow-up period, about 20% of participants who received pegylated interferon with or without 3TC achieved HBV DNA levels below 400 copies/ml compared with 7% amongst those who received 3TC monotherapy (p < 0.001). The corresponding figures for ALT normalisation were 60% and 44%. The addition of 3TC to pegylated interferon did not improve response rates compared with pegylated interferon alone.

Research into 3TC for hepatitis B

Bellini (2003) used Swiss Cohort data to study the effect of stopping 3TC in 57 HBV/HIV coinfected people who were HbsAg-positive. Over 90 days of follow-up, grade 2 liver elevations developed in 4.5% of cases and grade 4 elevations occurred in 9% of cases, including 2 instances of liver failure.

Kellerman analysed the effect of 3TC in 29,067 individuals receiving antiretroviral therapy in the US. HBV surface antigen was detected in 811 cases. Antiretroviral therapy without 3TC was associated with a relative risk of 0.67 compared to untreated HBV-positive individuals. 3TC treatment of less than 6 months duration was associated with a relative risk of 0.31, 6-24 months a RR of 0.41 and >24 months a RR of 0.26 (non-significant difference).

Kamkamidze treated 6 people with HIV/HCV/HBV coinfection with triple therapy including 3TC. HBV DNA viral load fell by 2.4 log₁₀, 2 individuals became negative for HBsAg and 3 for HBeAg. Moderate normalisation of ALT was reported.

Benhamou (1995) reported that 3TC (300mg twice daily) rendered hepatitis B virus DNA undetectable in 8 out of 9 HIV / HBV co-infected people who had increased HBV DNA serum concentrations at baseline.

Ching-Lung reported a placebo-controlled, double-blind trial of 358 people with HBV. 142 people received 25mg 3TC, 143 people received 100mg 3TC and 73 received placebo. The 100mg dose of 3TC was found to be most effective. Liver inflammation was reduced by two points in 56% of people on 100mg, 49% of people on 25mg, and 25% on placebo. The 100mg dose was associated with reduced development of liver scar tissue. 72% of people on the high dose had ALT normalisation.

In a long-term study by Liaw, HBV-infected patients with advanced fibrosis or cirrhosis who were treated continuously with 3TC for a median of 32.4 months (range 0-42) were significantly less likely to experience hepatic decompensation or develop hepatocellular carcinoma. 3.4% in the 3TC group had increased fibrosis scores, compared with 8.8% in the placebo group (p = 0.02). Patients taking 3TC were about half as likely to reach the endpoints of decompensation, liver cancer, or death than placebo patients (8 vs. 18%; p = 0.001).

Research into adefovir and tenofovir for hepatitis B

Benhamou (2001; 2002; 2004) treated 35 HIV/HBV-coinfected people with adefovir 10mg daily. All were taking 3TC as part of a HAART regimen and all had HBV containing mutations associated with 3TC resistance. After a median time on adefovir of 72 weeks, the mean decrease in HBV DNA viral load was 4.77 log₁₀. 4 of 33 people became HBeAg-negative during treatment, and three developed HBe antibodies. ALT decreased from a mean of 102 IU/L at baseline by 63 IU (p = 0.005) and 17% achieved normal ALT. In 14 people who underwent liver biopsy at baseline and at week 52, median liver necroinflammatory scores decreased. 4 people ceased treatment including 2 who stopped due to adverse events (diabetes and insomnia). Long-term improvement was sustained through 192 weeks.

Marcellin (2001; 2005) conducted a double-blind, randomised study of adefovir (10mg or 30mg daily) in 515 people with chronic HBeAg-positive hepatitis B. 59% were Asian, 74% were male and 24% had previously failed 3TC. After 48 weeks, 12% of adefovir-treated people and 6% of the placebo group became negative for HBeAg. ALT levels fell to normal in 48% of treated and 16% of untreated individuals (p < 0.001). Seroconversion rates increased over time, to 33% at 96 weeks and 46% at 144 weeks.

In a study of 30 treatment-naive HBeAg-positive patients with elevated ALT, Lau showed that the combination of adefovir (10mg daily) plus FTC was more effective against HBV than adefovir monotherapy, producing median HBV DNA reductions of 5.3 log₁₀ and 3.4 log₁₀, respectively, after 48 weeks (p = .13).

Bani-Sadr described 6 HIV/HBV co-infected patients who had wild-type (non-resistant) HBV. All achieved complete and sustained antiviral activity during 96 weeks of therapy with 3TC plus tenofovir.

Nelson reported an open-label study of tenofovir in 20 patients co-infected with HIV and HBV. 15 were 3TC-experienced and 5 were 3TC-naive. HBV DNA viral load fell by an average of 4 log₁₀, and 5 people underwent HBeAg seroconversion over 52 weeks of treatment. ALT fell significantly. There were no significant overall differences between the 3TC-experienced and -naive individuals.

Bochet studied 10 HBV/HIV coinfected people with 3TC-resistant HBV who were treated with tenofovir 300mg once daily in addition to ongoing antiretroviral therapy for HIV infection. 9/10 were HBeAg-positive and one was HBeAg-negative/HBe antibody-positive (presumed precore mutant). Median CD4 cell count was 335 and median baseline ALT was 80.0 IU/L. Median HBV DNA concentration fell by 3.34 log₁₀ at week 12 (p < 0.01). Marcelin reported one-year data: mean reduction of HBV viral load was 4.55 log₁₀ and 3 patients had less than 200 copies/ml, but no one experienced HBeAg loss or seroconversion. Genotyping at 3 months showed no sign of HIV or HBV resistance to tenofovir.

Cooper analysed a subgroup of 14 HIV/HBV coinfected men from Study 907, a randomised, double-blind study of 300mg tenofovir daily in 550 HIV-infected adults. 12 of the subgroup received tenofovir and 2 men were randomised to placebo. Baseline characteristics were: HBeAg+, average HBV DNA 8.74 log copies/ml, average HIV RNA 3.41 log copies/ml, average CD4 cell count 516 and average ALT 71 IU/L. HBV DNA levels fell by an average of 4.63 log₁₀ compared to a mean increase of 1.23 log₁₀ among those on placebo (p = 0.04). Response was not affected by the presence of HBV resistance mutations, which were present in 7 individuals. 2 tenofovir recipients achieved normal ALT and one man achieved HBeAg seroconversion. HIV RNA declined by 0.75 log₁₀ in the tenofovir group compared to no change in the placebo group. No new resistance mutations in the HBV polymerase were detected following treatment.

Van Bö­­¥l assigned 53 chronic hepatitis B patients with high HBV DNA levels and evidence of 3TC resistance to received adefovir (n=18) or tenofovir (n=35). After 48 weeks, all HIV-positive and HIV-negative participants treated with tenofovir showed strong and early suppression of HBV DNA within a few weeks and 100% achieved HBV DNA levels below 100,000 copies/ml, compared with 44% of patients treated with adefovir (p = .001).

Peters randomly assigned 52 HIV / HBV co-infected patients to receive 300mg tenofovir or 10mg adefovir once daily. Participants had well controlled HIV with a median CD4 count above 400 cells/mm³. All were on stable HAART and about 75% had used 3TC. An interim intent-to-treat analysis after a median treatment period of 75 weeks revealed an average time-weighted 4.46 log₁₀ drop in HBV DNA in the tenofovir group vs 3.35 log₁₀ in the adefovir arm. Side-effects and laboratory parameters were similar in both groups. The trial was closed to enrolment after data showed tenofovir was non-inferior to adefovir; the study was not powered to show that tenofovir was superior.

Kioko Ono-Nital reported that 3TC resistant hepatitis B mutants remained sensitive to adefovir and to lobucavir.

Delaney showed that while resistance to 3TC conferred cross-resistance to other L-nucleoside drugs (including FTC, clevudine and telbivudine), 3TC-resistant HBV remained highly sensitive to acyclic phosphonate nucleotides (including adefovir and tenofovir), and partially sensitive to entecavir and DXG.

Research into experimental treatments for hepatitis B

Raffi reported on 52 HBsAg+ people who received FTC through clinical trials of FTC as a treatment for HIV. Among 22 people with baseline HBV viral load of 562,000,000 copies/ml, HBV DNA fell by 2.26 log₁₀ at 12 months and by 2.75 log₁₀ at 4 years. Adverse events included headache, dizziness, nausea, diarrhoea, influenza and liver abnormalities.

Harris reported that FTC has potent activity against HBV and HIV when added to the existing HAART regimen of co-infected people. Analysing data from 39 participants who participated in three studies of FTC for HIV, the researchers found that by week 48, 59% had undetectable HBV viral load and 94% had undetectable HIV RNA.

Rousseau reported results from FTCB-102 - a double-blind, randomised dosing trial of FTC (25 mg, 100 mg or 200 mg once-daily). 98 patients were enrolled, with a mean age of 37 yrs; 70% were male, and 88% were of Asian origin. The median baseline HBV viral load (log₁₀ copies/mL) was 7.57, 7.68, and 7.42 in the 25 mg, 100 mg, and 200 mg cohorts, respectively. Decreases in viral load from baseline at week 36 were 1.7, 3.1 and 3.2 log₁₀ for the 25, 100 and 200 mg groups, respectively. 31%, 24% and 64%, respectively, achieved undetectable HBV DNA.

Chang presented Phase III data on a study (ETV-022) in which 715 treatment-naive HIV-negative HBeAg-positive patients received entecavir or 3TC. After 48 weeks, loss of HBeAg occurred in 21% of entecavir and 18% of 3TC patients. Undetectable HBV DNA (below 400 copies/ml) was achieved in 69% and 38%, respectively, and 72% and 62%, respectively, experienced histological improvement. Side-effect rates were similar in both groups and no entecavir resistance mutations were detected. Sherman conducted a companion study (ETV-026) in which 286 HBeAg-positive patients who were failing 3TC either switched to entecavir or continued on 3TC. After 48 weeks, HBeAg loss occurred in 10% of the entecavir group compared with 3% of the 3TC arm. Undetectable HBV DNA (below 400 copies/ml) was achieved in 21% and 1%, respectively, and 55% and 28%, respectively, experienced histological improvement. Entecavir resistance mutations were rarely observed.

Pessoa conducted a randomised, double-blind study (ETV-038) of entecavir versus placebo in 68 HIV / HBV co-infected patients who experienced recurrence of HBV viral load while receiving a HAART regimen containing 3TC; 88% had HBV with one or more 3TC-resistance mutations. Participants continued HAART and were randomised to add either entecavir (n=51) or placebo (n=17) once daily. In an as-treated analysis after 24 weeks, HBV DNA fell by 3.66 log₁₀ in the entecavir group, but increased by 0.11 log₁₀ in the placebo arm (p < .0001). ALT normalisation was observed in 34% and 8%, respectively (p = .08).

Marcellin (2004) conducted a Phase II dose-escalation study of clevudine in 32 treatment-naive participants (81% male, 81% Asian, 88% HBeAg-positive, none co-infected with HIV or HCV). After 28 days receiving clevudine, median HBV DNA log₁₀ reductions were 2.5 (10mg once daily), 2.7 (50mg), 3.0 (100mg) and 2.6 (200mg). At the end of a six-month follow-up period, the corresponding sustained HBV DNA decreases were 1.2, 1.4, 2.7 and 1.7 log₁₀, respectively. Loss of HBeAg was seen in 22%. Clevudine was well tolerated; six patients experienced transient ALT increases while taking the drug, which was associated with improved HBV suppression.

Lai compared telbivudine (400mg or 600mg daily) plus 3TC against both drugs used as monotherapy in a randomised trial of 104 patients (81% male, more than 80% Asian). After 52 weeks, telbivudine reduced HBV DNA by 6.01 log compared with 4.57 log for 3TC (p < 0.05). Adding 3TC to telbivudine did not provide additional benefit. After 96 weeks, 71% in the telbivudine monotherapy arm, 32% in the 3TC monotherapy arm and 54% in the combination arm achieved undetectable HBV DNA. ALT normalisation was seen in 81%, 47% and 68%, respectively. No serious safety issues were observed.

Matthews treated 8 HIV/HBV co-infected individuals with 3TC plus famciclovir. Seven had previously received 3TC. Median baseline HBV viral load was 9.3 log which fell to 4.5 log after 3 months treatment. At 12 months, median viral load was 7.9 log. The participant who had not previously received 3TC was the only participant who achieved undetectable HBV viral load.

Research into chronic hepatitis B

Thio prospectively followed a cohort of 5293 gay men between January 1984-March 2000, classifying them every 6 months for HIV and HBV infection. 326 (6%) were HBsAg+. Of those with HBV, 213 (65%) were HIV-positive. 47% of the 4967 HBsAg-negative men were HIV-infected. Liver-related mortality (LMR) was more common among HBsAg+ men than HBsAg-negative men (relative risk [RR] 12.7). Of the hepatitis B group, only 1 HIV-negative individual died of liver-related causes compared with 61 liver deaths co-infected men (RR 88.9). Before the introduction of HAART for HIV infection, the LMR among HIV-infected men was 2.5/1000 person-years and rose to 4.0/1000 person-years (RR 1.6, p = 0.16) following the introduction of HAART. In the HAART era, there were no liver-related deaths amongst HIV-negative, HBV-negative men. Among men with HIV infection the LMR was 1.7/1000 person-years (p < 0.001), compared to 0.8 /1000 person-years (p = 0.04) in the HBsAg+ men and 14.2/1000 person-years (p < 0.0001) in the coinfected men. Only 7% of the HIV/HBV coinfected men had hepatitis C antibodies.

Reisler retrospectively analysed 1841 patients who were followed for a 36-month period from September 1999-August 2001. 5.7% were HBsAg+, 17.4% had hepatitis C antibodies (HCV Ab+) and 1% were HIV/HBV or HIV/HCV co-infected. At 30 months, 21% of all patients had experienced a serious event, 4.8% had a liver-related grade IV event, and 6.4% had died. Comparing those with and without viral hepatitis 25% vs 20% (p = 0.004) had any grade IV event; 8% vs 4% (p = 0.0001) had a liver-related grade IV event, and 8% vs 6% (p = 0.004) died. Hepatitis B and/or C were associated with grade IV liver-related events (HR= 4.6; p = 0.0001) and any grade IV event (HR=1.40; p = 0.04).

Barin retrospectively studied hepatitis B reactivation (going from HBV surface antigen-negative to positive) among HIV-infected people at a university hospital between 1990-2001. Prior to the introduction of HAART, 6 cases occurred, associated with low CD4 count. Two cases occurred since that time: one was an untreated person with low CD4 count but the other was a person with a CD4 count of 319 cells/mm³ who was on triple antiretroviral therapy.

Kasolo reported that HIV-infected patients at a hospital in Lusaka, Zambia, were much more likely to be HBsAg+ than HIV-negative patients. Overall prevalence was 25.8%: 31% among the HIV-positive group and 17% among the HIV-negative group.

Hadler reported that there were no significant clinical or biochemical differences in the illness of HIV-positive and HIV-negative people with acute hepatitis B infection, although 21/64 HIV-positive people became chronic carriers (33%), compared with only 14 out of 239 HIV-negative people (6%). This finding has been independently confirmed by Bodsworth and Homann.

Sinicco conducted a prospective study of 347 HIV-infected, AIDS-free patients. At baseline, 229 had evidence of exposure to or chronic infection with HBV. During follow-up, 107 patients had their CD4 count fall to below 200 cells/mm³ and 66 developed AIDS. There was no difference in HIV disease progression between people who had chronic hepatitis B, those who had been exposed to HBV and those who had never had HBV. 15 people were acutely infected with HBV during the study and 40% became chronic carriers.

Gilson reported that there was no evidence of an effect of HBV infection on the speed of HIV progression, but HBV replication was higher among HIV-positive people than HIV-negative people, and HBV infectivity was increased and prolonged.

[REPLACED WITH MORE RECENT EUROSIDA DATA]

Konopnicki reported that amongst the 5,728 participants (out of a total of nearly 10,000) in the EuroSIDA cohort tested for HBV, 9% showed evidence of infection; rates ranged from 18% in Argentina to 6% in Eastern Europe. All-cause and liver-related mortality were significantly higher amongst HBsAg-positive individuals. Liver-related causes accounted for 19% of deaths in co-infected patients compared with 8% in individuals who had only HIV. HIV / HBV co-infected patients were equally likely to respond to HAART and a strong immune response to anti-HIV therapy was associated with reduced risk of death.

Busch reported a study of HCV and HBV serology conducted on 523 HIV patients from Veterans' Affairs. 10% showed hepatitis B surface antigen (HBsAg). Of 226 HBsAg-negative and HBV core antibody positive (anti-HBc+), 8.4% were positive for HBV DNA. 26% of 73 active cases of HBV were HBsAg-negative.

Perrillo (1986) reported that histologically, liver damage is often less severe in HIV-positive people with chronic HBV infection compared with HIV-negative individuals.

Benvegne reported that people infected with HBV and HCV have a greater risk of hepatocellular carcinoma (HCC) compared with people infected with only one of these viruses.

Chu and Liaw followed 202 HBV-infected patients, 150 with genotype B and 52 with genotype C, for a median of about eleven years. They found that 5/150 (3%) with genotype B and 10/52 (19%) with genotype C developed cirrhosis. HBV reactivation was more common among patients with genotype C.

Tsubota followed 26 cirrhotic patients with chronic hepatitis B for a median of 14 years. 4/19 (21%) of patients with HBV genotype B and 5/7 (71%) of patients with HBV genotype C developed HCC. Age over 45 years was the only factor significantly associated with development of HCC by multivariate analysis. Analysis of patients over 45 years showed only genotype was associated with development of HCC.

Chan (2002) studied liver inflammation and scarring of the liver among 55 people with HBeAg-negative chronic HBV infection. Genotype C was associated with greater inflammation but core promoter mutations and precore stop codon mutations were not.

Kao reported higher prevalence of genotype C HBV (50% vs 12%, p = 0.01) among people with multiple episodes of acute exacerbation of hepatitis B without seroconversion among a cohort of 272 Taiwanese people with chronic hepatitis B.

Cacciola found that occult HBV infection (where tests for HBV surface antigen are negative, but fragments of HBV DNA can be detected using PCR technology) occurs frequently in people with chronic hepatitis C.

Ghandi found that HIV-positive people may test negative for both HBV surface antigens and surface antibodies, but be positive for HBV core antigens, particularly if they are coinfected with HCV. In a study of 651 HIV-positive patients, 59% tested negative for both HBV surface antigens and antibodies, and of these 42% tested positive for HBV core antigen. 78.3% of these patients were co-infected with HCV and 77.6% had a history of injecting drug use.

Shire found that 2% of 240 geographically and demographically representative HIV-positive individuals participating in two US clinical trials in 1996 and 1997 had occult HIV. A total of 64.6% of individuals had a marker of past or current infection with hepatitis B and 7.5% tested positive for HBV DNA. More than 80% of patients with HBV DNA had either HBsAg or antibodies, but 10% of patients without core antibodies (2% of the entire study population) still had detectable HBV DNA, suggesting occult infection.

Teladi found that in the US HIV Outpatient Study (HOPS), 198 (32.4%) of 612 eligible participants had received at least one dose of HBV vaccine, and only 104 (16.9%) had received all three doses. Hepatitis A vaccination rates were even lower. The researchers recommended that routine HBV and HAV vaccination should be included in the care of people with HIV.

Research into highly active antiretroviral therapy and hepatitis B

Law studied a cohort of 692 HIV-positive individuals in Thailand, of whom 8.7% were co-infected with HBV, 7.2% with HCV, and 0.4% with HBV/HCV. After starting HAART, median HIV viral load reductions were similar in the HIV mono-infected and co-infected groups. CD4 cell increases were significantly lower in the HIV/HBV and HIV/HCV groups at week 4 (62, 29, and 33 cells/mm³, respectively), but were similar by week 48 (115, 113 and 97 cells/mm³). The co-infected patients were equally likely to achieve undetectable viral loads and sustained CD4 increases. The researchers concluded that co-infected individuals could benefit from antiretroviral therapy, even in resource limited settings.

Chihrin (2004) conducted a retrospective chart review of 202 co-infected individuals starting HAART (54% HIV/HCV; 40% HIV/HBV; 6% HIVHCV/HBV). 66 (33%) started on a protease inhibitor-containing regimen and 26 (13%) started on a NNRTI-containing regimen. 42 individuals (21%) had a severe (grade 3 or 4) ALT elevation at least once during follow-up. In a multivariate analysis, only older age and use of lopinavir/ritonavir predicted severe ALT elevations.

Meravaglia (2004) studied 782 HIV-positive patients to assess the association between lopinavir/ritonavir and liver enzyme elevations. During follow-up (median 349 days), 9% overall developed elevated liver enzymes while taking lopinavir. By co-infection status, however, 16% of HBV or HCV co-infected individuals experience liver enzyme increases compared with 3% of patients with HIV alone.

Research into liver transplants in hepatitis B virus infected people

Roland reported on 9 liver transplants, 14 kidney transplants, and 1 liver/kidney transplant in HIV-positive people between March 2000 and September 2003. The median pre-transplant CD4 count was 407 cells/mm³. After a median follow-up of 480 days, 2 patients died (1 liver recipient with recurrent HCV and 1 kidney recipient with pneumonia). 10 (71%) kidney recipients, 1 liver recipient, and 1 liver/kidney recipient experienced organ rejection.

Ragni prospectively followed 24 HIV-positive individuals who underwent a liver transplant for end stage liver disease after the introduction of HAART, between 1997 and 2001. Fifteen individual had HCV infection as the cause of end stage liver disease, seven patients had HBV as the cause, and three patients had fulminant liver failure in association with nevirapine-induced liver necrosis, acute hepatitis A virus infection or acute HBV infection. Anti-HIV therapy had been used by all but two patients prior to transplant, median preoperative CD4 cell count was 188 cells/mm³ and median viral load was below 400 copies/ml. At 12 months, 87.1% of individuals were still alive; this was comparable to the 86% survival seen in age-matched HIV-negative liver transplant recipients (p = 0.365). At 24 and 36 months a little under 73% of the HIV-positive patients were still alive compared to survival probabilities of 81% and 78% for HIV-negative liver transplant recipients. Patients who were unable to tolerate anti-HIV therapy post-transplant were significantly less likely to survive (p = 0.044). Survival was also poorer amongst patients whose last available post-operative CD4 cell count was below 200 cells/mm³ (p = 0.005), or who had a viral load above 400 copies/ml (p = 0.016). CD4 cell count below 200 cells/mm³ (p = 0.602) and viral load viral load above 400 copies/ml (p = 0.494) prior to transplant did not predict poorer survival. Survival was significantly poorer amongst patients coinfected with HCV (50 vs. 100%; p = 0.023).

Neff (2001) reported on 6 HIV-infected patients with viral hepatitis (4 with HBV, 1 with HCV, 1 coinfected) who were added to the liver transplant registry in Florida. 5 had achieved undetectable viral load and a CD4 cell count rise of 100 cells/mm³, while the sixth person died prior to transplantation. Ongoing survival at 5, 6, 7, 12 and 24 months was reported amongst those who received a liver transplant.

Frassetto reported that cyclosporin used to treat transplant recipients interacts with the protease inhibitors, warranting dose reductions of cyclosporine over time. Levels of indinavir, nelfinavir, and saquinavir drop by about 20% during the initial weeks of co-administering with cyclosporin.

Neff (2004) reported that tenofovir salvage therapy was an effective therapy for patients who develop 3TC-resistant HBV after a liver transplant (which occurs about 30% of the time). Tenofovir was given to 8 transplant recipients 1-66 months after they developed 3TC-resistance. After 14-26 months (median 19.3), all experienced HBV suppression; 7 maintained undetectable HBV viral loads.

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