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Guide to Hepatitis B for People Living With HIV

June 2009

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Section 6: HBV Treatment for HIV-Positive People

Because HBV disease progresses faster in HIV-positive people, treating HIV/HBV coinfection is different than treating HBV in people without HIV. For a more detailed discussion on treating HBV monoinfection, please see the appendix.

Treating HBV and HIV can be complicated; people may not need to treat both at the same time. For example, if you were infected with HIV and HBV at the same time, or if you were already immunosuppressed when you were coinfected with HBV, both viral infections will need to be treated at the same time. On the other hand, if you already have chronic HBV (e.g., if you were infected at birth) and then were infected with HIV, your chronic HBV might need to be treated first before HIV treatment is needed.

HBV treatment guidelines for people without HIV are based on HBV viral load and ALT levels; these guidelines are not very useful in HIV coinfection. HIV/HBV-coinfected people usually have higher HBV viral loads; they can also develop liver damage with less liver inflammation, making ALT levels a less reliable indicator of the need for HBV treatment. For these reasons, researchers recommend that HIV/HBV treatment should start earlier in HIV/HBV-coinfected people. Some HIV treatment guidelines have begun to recommend starting treatment at higher CD4 cell counts (>350 cells/mm3).

Since coinfection with HIV speeds up HBV disease progression, starting HIV treatment earlier may delay or prevent liver damage from HBV. HIV-positive people, even those with higher CD4 cell counts, also have persistent low levels of inflammation; this may contribute to ongoing liver damage in people coinfected with HBV. There may be additional benefits to starting HIV treatment earlier; however, other factors -- such as adherence and long-term drug toxicity -- need to be considered.

Goals of HBV Treatment for HIV-Positive People

The primary goal of HBV treatment is to bring viral load down and to keep it suppressed, which can prevent, delay, stop, and in some cases reverse liver damage. Another goal is to stimulate the immune system to control the infection, although this approach has not been very successful to date. Following are some measurable goals based on test results.

Undetectable HBV Viral Load: When the amount of virus in your blood drops to a level that cannot be detected, it means the virus is under control, even though a small amount of HBV may still be present. While any drop in viral load is good, having a detectable viral load after one year of treatment increases the risk of developing HBV drug resistance. This is particularly important because HBV drug resistance can develop faster in HIV-positive people.

Normalization of ALT: After the viral load becomes undetectable, the immune system will stop killing infected liver cells, and ALT levels fall back within the normal range; this means that HBV infection has stabilized. However, HIV-positive people often experience ALT elevations caused by some HIV drugs even when their HBV infection is under control, so this measure might be less useful in HIV-positive people.

HBeAg Seroconversion: In people who are HBeAg-positive, HBV treatment can stimulate the immune system to eliminate HBeAg in the blood and produce HBeAg antibodies (anti-HBe); this is called HBeAg seroconversion. HIV-positive people on treatment can achieve HBeAg seroconversion at about the same rate as people without HIV, but the long-term benefit of this has not been studied in HIV coinfection.

HBsAg Seroconversion: After HBeAg seroconversion, some people can go on to achieve HBsAg seroconversion. HIV-positive people are less likely to develop antibodies to HBV surface antigen (anti-HBs) and become HBsAgnegative on treatment. HBsAg seroconversion provides the strongest control of the virus and is the closest thing to a cure at present, but the risk of HBV reactivation is higher in HIV-positive people. Due to this increased risk, HIVpositive people should not switch their HIV/HBV treatment even if they have achieved HBsAg seroconversion.

Current HBV treatment cannot get rid of the virus completely. This is because HBV inserts small pieces of its DNA (cccDNA) inside liver cells, where drugs cannot reach. People with chronic HBV need lifelong monitoring with HBV viral-load and ALT tests.

HBV treatment works better when the baseline (meaning pretreatment) viral load is lower and when there is less liver damage. Doctors recommend starting HBV treatment before the development of serious liver damage.

There are two types of HBV treatment:

1. Pegylated Interferon (Peg-IFN)

Interferon is a protein made by the human body; it sends virus-fighting messages to the immune system. HBV treatment involves a large dose of man-made interferon, much more than the human body produces on its own. This treatment is not recommended for people with decompensated cirrhosis.

Peg-IFN is rarely used to treat HBV in HIV-positive people. It is recommended only for coinfected people with a CD4 cell count above 350 cells/mm3 who do not need to start HIV treatment. It has not been studied in people coinfected with HIV, but about one in ten people who are HIV/HBV-coinfected can achieve HBeAg seroconversion using the older form of interferon, according to one study. Peg-IFN is more effective for people who are HBeAg-positive and have an elevated ALT level at the start of treatment.

A major drawback of Peg-IFN is its severe side effects. For a more detailed discussion of Peg-IFN, please see the appendix.

2. Antiviral Drugs

Antivirals help control the virus by interfering with the HBV life cycle so the virus cannot make more copies of itself; these drugs are taken once a day by mouth.

There are currently six HBV antivirals:

  • Lamivudine (Epivir HBV), approved in 1989;
  • Adefovir (Hepsera), approved in 2002;
  • Entecavir (Baraclude), approved in 2005;
  • Telbivudine (Tyzeka), approved in 2006;
  • Tenofovir (Viread), approved in 2008; and
  • Tenofovir/emtricitabine (Truvada) (not yet approved as a treatment for HIV/HBV coinfection; it is currently being tested as a combination therapy drug).

Three of these drugs are also effective against HIV: tenofovir, lamivudine, and emtricitabine. People coinfected with HIV and HBV should choose a drug combination of tenofovir plus either emtricitabine or lamivudine, with a third HIV drug from a different class.

The HBV drug entecavir should not be used as an HBV monotherapy in HIV-positive people since it has a very weak effect on HIV and has been linked to the development of lamivudine resistance to HIV.

Telbivudine and adefovir may also have a weak effect against HIV; further studies are needed to determine this.

Large-scale clinical trials comparing the effectiveness of these drugs in people with HIV vs. people without HIV are still ongoing. Small studies have shown similar response rates regardless of HIV coinfection. Tenofovir is the preferred drug; about 90% of people are able to bring their HBV viral load down to undetectable levels after one year of treatment. Response rates to lamivudine are only about 40%, and it is not recommended except in combination with tenofovir. Emtricitabine has very similar response rates to lamivudine, and it is being tested as a combination pill with tenofovir.

Antivirals are better at controlling the virus in HBeAg-negative people than in people who are HBeAg-positive; treatment outcome does not vary by HBV genotype.

Drug Resistance

One major limitation of HBV and HIV treatment with antiviral drugs is the development of drug resistance. Drug resistance can happen because HIV and HBV replicate rapidly and can make many mistakes in the process of replication; these mistakes are called mutations.

Unfortunately, some mutations can prevent drugs from blocking HIV and HBV replication. When people start on treatment, the drugs will be able to stop most of the normal HBV and HIV (called wild-type virus) from reproducing. Over time, the drugs can control wild-type viruses, but some mutated viral strains can still replicate during treatment, and these mutated viruses will eventually take over, causing the viral load to increase. This is called drug resistance.

Most people taking oral drugs will likely develop drug resistance eventually, but some drugs are harder to develop resistance to than others (called having a higher resistance barrier). Studies have shown that, after four years on lamivudine, 94% of HIV/HBV-coinfected people will develop HBV mutations that are resistant to it. Tenofovir has a much higher resistance barrier than lamivudine. To date, no tenofovir-resistant mutations have been shown to cause the drug to lose effectiveness in clinical trials, but it has only been studied for two years. Coinfected people develop HBV drug resistance faster than those with HBV alone, so using two drugs that are active against HBV in your HIV regimen will help to prevent or delay development of HBV drug resistance.

Drug resistance can also develop when there is not enough drug in the body to control the virus. This happens when people don't take the pills every day or skip doses; as a result, drug levels become too low to block viral replication. It is very important to take HIV/HBV drugs as they are prescribed to avoid drug resistance.

Managing Drug Resistance

When people develop drug resistance, they will need to either switch to a newer, more potent drug or add a second drug. Unfortunately, given that there are only three drugs that work against both HIV and HBV, alternative treatment options are sorely needed. Studies have shown that using two drugs instead of one can prevent or delay the development of resistant mutations, but combination therapy does not make the treatment more effective in bringing down viral load.

Long-Term Outcomes of Antiviral Treatment

Given the slow progression of chronic HBV disease, the long-term benefits of antiviral therapy are hard to measure. Since all of these drugs were approved within the last decade, longterm follow-up is limited. Some small studies of older drugs are reporting that long-term use can prevent, and in some cases reverse, liver damage from HBV; however, the ability of antiviral drugs to prevent the development of liver cancer is still unclear (this is especially true of the newer and more potent antivirals). More long-term and large-scale studies are needed to provide this vital information.

Immune Reconstitution Inflammatory Syndrome (IRIS)

Coinfected people with fewer than 200 CD4 cells/mm3 need to be monitored for potentially fatal flares of hepatitis B more frequently (every week) when they start HIV (and HBV) treatment. Flares can happen when a weakened immune system recovers enough to respond to hepatitis B. Once HIV treatment starts, the immune system will start to restore itself and become stronger; this is called immune reconstitution, or IRIS (Immune Reconstitution Inflammatory Syndrome). A stronger immune system can start to respond to HBV by attacking infected liver cells. This response can be very intense and may lead to rapid liver failure, a life-threatening condition.

HIV/HBV-coinfected people with fewer than 200 CD4 cells/mm3 who are starting antiretroviral therapy should be on the lookout for these symptoms: nausea; vomiting; appetite loss; fever; fatigue; abdominal and joint pain; liver swelling; and jaundice (yellow skin and eyes). If these symptoms develop, contact your doctor immediately; you probably need to stop taking your drugs immediately. Immune reconstitution flares can be prevented by including HBV-active agents in your HIV treatment regimen.

Stopping or Switching HBV Treatment

There is a risk of severe HBV flares when people stop taking oral antivirals. If you have to stop taking your HIV drugs or change them for any reason, be very careful and talk to your doctor beforehand. Since these drugs are controlling HIV and HBV, stopping or changing them can cause HBV reactivation, which can quickly lead to severe liver damage and life-threatening liver failure.

For HIV/HBV-coinfected people who cannot use tenofovir because of kidney damage, adding entecavir, adefovir, or telbivudine in addition to a three-drug HIV combination might be a potential strategy to treat HBV at the same time. This approach, however, has not been studied.

Antiviral Treatment Side Effects

Side effects from HBV antiviral drugs are usually mild; many people don't have any. Common side effects include: dizziness, nausea, vomiting, headache, fatigue, stomach pain, itchiness, weakness, diarrhea, and indigestion.

In rare cases, there may be some serious side effects, especially if a person has serious liver damage or has kidney disease, since HBV antivirals are broken down by the kidneys. Most of these drugs are very new, so potential long-term side effects are not known yet.

Some of these rare side effects can be halted and sometimes reversed when you stop taking the drug, but going off the drug can itself be a serious problem because of the risk of HBV reactivation and the lack of alternative treatment options. If you experience these symptoms, do not stop taking the drug without consulting with your doctor.

These rare but serious side effects may include:

  • Peripheral neuropathy: damage to the nerves in the hands and feet. Symptoms are burning, tingling, or numbing sensations in the hands and feet; these can be very painful. This condition can be debilitating and may become irreversible, so it is very important to change your treatment regimen as soon as you start to experience symptoms.
  • Lactic acidosis: an abnormal buildup of lactic acid in the bloodstream. People with liver damage.especially cirrhosis.are most susceptible. Symptoms include weakness and fatigue; muscle weakness or tenderness; trouble breathing; stomach and/or liver pain; nausea and vomiting; feeling cold (especially in your arms and legs); dizziness or lightheadedness; and fast or irregular heartbeat. If you are experiencing any of these symptoms, contact your doctor immediately; you may need to stop taking medication right away. A blood test can confirm whether you have lactic acidosis.
  • Kidney damage: All approved HBV drugs are eliminated from the body by the kidney. Tenofovir and adefovir in particular can cause severe kidney damage (nephrotoxicity), especially in people who already have kidney problems. Kidney damage can be reversed quickly when the drug that's causing it is stopped or the dose is reduced. Kidney function should be checked before starting treatment with any HBV drug and monitored regularly during treatment by assessing creatinine clearance rate. Creatinine is a natural waste product produced by the body and processed by the kidney. A low creatinine clearance rate can mean the kidney is not functioning properly.
  • Bone loss: There is a concern about potential loss of bone density from longterm use of tenofovir and adefovir. In clinical trials, HIV-positive people taking tenofovir have been observed to experience bone loss, but it is still unclear if the loss is due to the drug itself. There are ongoing studies examining this issue in HIV-negative people with chronic HBV.
  • Myopathy: Telbivudine can cause myopathy (muscle weakness) in some people during the first few months on therapy. Myopathy is reversible when you stop taking telbivudine. If you experience muscle tenderness or weakness, telbivudine might have to be discontinued.

HIV Drugs and Liver Toxicity

Many HIV drugs are broken down by the liver; these can sometimes cause damage to it (referred to as liver toxicity). Liver toxicity is more likely for coinfected people with serious liver damage, because a damaged liver is not fully functional, and these drugs add an extra burden to it. Having liver-enzyme levels checked regularly is very important for coinfected people who are on treatment because they are vulnerable to liver problems caused by HIV drugs and/or other factors.

Nevirapine is known to cause liver toxicity in some coinfected people due to a hypersensitivity reaction to the drug, though some have used it without having any problem. Stavudine and didanosine can cause damage to the part of liver cells that produces energy; these are called mitochondria. Because of these toxicities, nevirapine, didanosine, and stavudine should be avoided by people who are coinfected.

Protease inhibitors such as lopinavir, ritonavir, tipranavir, and darunavir also cause liver toxicity. Careful monitoring of liver-enzyme levels is recommended for people using these drugs.

Because a damaged liver works less efficiently, the amount of drug in the blood could increase to dangerous levels and should (ideally) be checked using therapeutic drug monitoring (TDM) so that the dose can be modified if necessary.

TDM is a blood test that checks whether you are getting adequate levels of a protease inhibitor, an NNRTI, and possibly the entry inhibitor enfurvitide. Doses for HIV drugs are worked out for an average person as a one-size-fits-all solution; however, individual differences in absorption can vary considerably in real life.especially in people with reduced liver function related to HBV coinfection. TDM is currently available only in research settings and certain clinics in the U.S., but it may be an important option if you're coinfected and having problems with your HIV regimen.

Interferon and CD4 Cell Count

Interferon can dramatically lower a person's white blood cell count, including CD4 cells, even when they are on HIV treatment; however, because the total number of white blood cell count lowers, the percentage of CD4 cells stays stable or may increase. Researchers believe this means your level of immune protection is not affected, and clinical trials have not reported more opportunistic infections in people who had a decrease in CD4 cells from taking interferon. Seeing your CD4 cell count plummet can be frightening, but it is temporary.the CD4 cell count goes back up after stopping interferon.

 

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This article was provided by Treatment Action Group.
 
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