Low-Dose Adefovir for the Treatment of Chronic Hepatitis B in HIV-Infected People
Hepatitis, or inflammation of the liver, is a frequent problem among HIV-infected people that can have serious health consequences. The disease has many causes, but generally originates from either a viral infection that attacks the liver, or a toxin/medication that damages liver cells. Viral infections commonly associated with hepatitis include the hepatitides (hepatitis A, B, C, D, and E viruses) and the herpes viruses (cytomegalovirus [CMV] and Epstein-Barr Virus [EBV]). Alcohol (ethanol) is the most prevalent toxin that causes hepatitis, and a long list of medications are associated with the disease, including many HIV antiretrovirals (such as ritonavir and nevirapine) and cholesterol lowering drugs (such as atorvastatin [Lipitor]). In the majority of cases, the liver inflammation gets better (i.e. the hepatitis resolves) when the offending medication is stopped, or the viral infection goes away on its own or after specific treatment. However, some infections, most notably hepatitis B virus (HBV) and hepatitis C virus (HCV), can become chronic, and the resulting long-standing liver inflammation can lead to the development of irreversible liver scarring (called cirrhosis). Cirrhosis is linked to many grave medical complications, including a dangerous form of liver cancer known as hepatocellular carcinoma.
Because HCV and HBV are acquired by the same routes of transmission as HIV (i.e. through blood and/or body fluid exchange during sexual contact, needle sharing, transfusion, or childbirth), HIV-infected people are frequently co-infected with one, or sometimes both, of these viruses. While much attention has been focused on the problem of HCV infection, co-infection with HBV has been virtually ignored, despite up to 10% of HIV-positive people in the USA having this potentially life-threatening liver infection.1 Because HBV is much easier to transmit sexually than HCV, the disease is particularly prevalent among people who acquired HIV sexually, and in particular, in the USA, is most frequently seen among men who have sex with men (MSM). Emerging medical evidence indicates that HIV/HBV co-infected people are at a higher risk of developing advanced liver disease (cirrhosis) and are at an increased risk of dying when compared to people infected with HIV alone.2 Moreover, co-infection with HBV can make treating HIV infection challenging, because studies have suggested that chronic hepatitis B makes it more difficult for people to tolerate their HIV medications because they are more susceptible to some of the drugs' liver damaging side-effects.3 These potentially devastating consequences of HBV infection point to the urgent need for more research to better understand the natural history and treatment of HBV in HIV-positive people.
In the vast majority of HIV-negative people (approximately 95%), infection with HBV causes temporary liver disease that goes away on its own without any specific treatment. During the period of liver inflammation, HBV infected people may develop clinical hepatitis, an illness characterized by fever, malaise, fatigue, decreased appetite, nausea, vomiting, abdominal pain, and white stools. A hallmark symptom of hepatitis is jaundice (yellowing of the skin and mucus membranes), a condition that is not necessarily seen in every infected person, but is a result of the inability of the diseased liver to normally process pigments being produced by the natural turnover of red blood cells. In some people, however, including a higher proportion of HIV-infected individuals, the acute hepatitis does not get better, and the virus is not cleared from the liver. These people go on to have chronic hepatitis B, a disease that is characterized by on-going HBV reproduction (replication) that causes chronic liver disease and may lead to early death from cirrhosis or cancer.
Unfortunately, because of the poverty of research conducted on the therapy of HBV in HIV infection, the optimal way to treat chronic hepatitis B in HIV-positive people is not known. Studies of alpha interferon, one of the standard chronic hepatitis B therapies for HIV-negative people, demonstrated that the drug was not effective in the setting of HIV infection.4 The exact reason for the medication's poor activity against HBV in HIV-infected people is unclear, although one potential explanation is that the drug acts as an immunomodulator and therefore may only be effective in people with intact immune function (i.e. it may work better in people who have preserved CD4+ T-cell counts). Because most alpha interferon clinical trials for HIV/HBV co-infected people were conducted prior to the introduction of effective HIV therapy, the drug may still prove to have utility in treating chronic HBV in people who have had their HIV infection successfully controlled with highly active antiretroviral therapy (HAART), although the medication has not been adequately studied in this setting. Nonetheless, even if future studies demonstrate that it is effective, alpha interferon is frequently poorly tolerated and associated with multiple toxic side effects. Lamivudine (3TC [Epivir]), another standard HBV drug, works well against both HIV and HBV, and in the overwhelming majority of cases, was most likely prescribed to the HIV/HBV co-infected person for the treatment of his/her HIV disease.5 However, similar to the HIV lamivudine resistance seen with prolonged therapy, lamivudine-resistant HBV inevitably emerges with long-term use. After using lamivudine for four years, 90% of HIV/HBV co-infected people have HBV that is resistant to the drug, a substantially higher rate of resistance than that seen in HIV-negative people treated with lamivudine for a similar period of time (67%).6 It is currently thought, although not proven, that the lamivudine-resistant strain of HBV can cause liver disease as serious as HBV strains that are lamivudine sensitive (also called wild-type HBV). Because lamivudine and alpha interferon are the only two FDA approved agents available for the treatment of chronic hepatitis B in the USA, people who have developed lamivudine resistant virus and are failing lamivudine therapy with evidence of progressive liver disease have no medical alternatives aside from experimental drugs. Most US clinical trials of investigational hepatitis B medications exclude enrollment of HIV-positive people. Moreover, liver transplant, a viable surgical option for HIV-negative people with advanced HBV liver disease, is not available to most HIV/HBV co-infected people because livers are rarely offered to HIV-positive people at most transplant centers.
Adefovir dipivoxil, an investigational agent, may offer a medical alternative to HIV/HBV co-infected people failing lamivudine therapy. Adefovir dipivoxil is the oral prodrug form of adefovir, a nucleotide reverse transcription inhibitor that works against HIV and HBV (both the wild-type HBV and the lamivudine resistant form). The medicine has a jaded history in the HIV-positive community because of kidney damage seen after its use in some individuals who were receiving high doses as part of clinical trials aimed at developing the drug as an HIV antiretroviral. The manufacturer (Gilead Sciences) halted development of the drug as an HIV medicine, and instead designed trials questioning the potential of the agent at a lower dose (up to 12 times less than people were receiving in the HIV clinical trials) as a therapy for chronic hepatitis B infection. At this substantially lower dose (10 mg daily, a dose that is not active against HIV), preliminary results from a large on-going clinical trial in HIV-negative people with HBV infection indicate that over a 48 week period, the drug was not associated with any form of kidney damage, was generally well-tolerated, and was effective in lowering the amount of HBV in the blood and improving the health of the liver. Importantly, a recent study suggests that these encouraging adefovir results may be extended to the treatment of lamivudine-resistant HBV in HIV-positive people.7
A French research group reported that adefovir is safe and effective in suppressing HBV replication in a small group of HIV/HBV co-infected people with lamivudine resistant HBV.7 Thirty-five HIV-positive people who had HBV in their blood despite taking lamivudine and had well-controlled HIV disease at enrollment in the study (receiving antiretrovirals with an average HIV viral load = 759 copies/mL and an average CD4+ T-cell count = 423 cells/mm3) were treated with low-dose adefovir (10 mg daily by mouth) for a median period of 48 weeks. In the 29 patients completing evaluation at Week 48, HBV blood levels dropped approximately 10,000 times when compared to starting values, a finding that indicates that adefovir potently and durably stopped the HBV from reproducing. The study did not address the impact of this impressive viral load reduction on the health of the liver (as indicated by the pathology seen on liver biopsy before and after therapy), a critically important indicator of the overall utility of adefovir in treating hepatitis B liver disease.
At this low dose, adefovir was well tolerated and, most significantly, did not cause kidney damage. Two individuals had mild abnormalities in their kidney function tests, but these were not thought to be related to adefovir use because they improved with the discontinuation of other medications known to affect the kidneys. As is frequently seen with standard HBV therapy, approximately eight weeks after the initiation of adefovir, fifteen people experienced increases in their liver function tests (a hepatitis flare) that did not make them ill (i.e. they did not have clinical hepatitis). This flare period lasted approximately 12 weeks, after which liver function tests declined and continued to improve until the end of the study. Similar to prior studies on interferon and lamivudine, people on the study who experienced a hepatitis flare had a greater reduction in their HBV blood levels than subjects who did not experience a treatment-induced hepatitis flare, indicating that hepatitis flare might not be a bad side-effect of the drug, but a good indicator of the medication's effectiveness.
These encouraging findings of the efficacy and safety of adefovir for the treatment of lamivudine-resistant hepatitis B in HIV-infected people give hope to HIV/HBV co-infected people with no HBV treatment options. Ongoing clinical trials at the National Institutes of Health (National Institute of Allergy and Infectious Diseases) are enrolling HIV-infected people into adefovir studies for hepatitis B treatment. For more information on participating in an adefovir clinical trial, call 1-800-772-5466 extension 4-9905.
To read GMHC's interview with Dr. Brust, in which he further discusses HBV treatment for HIV-positive people, click here.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.