Mechanism Of Antiviral Drug Resistance
Nucleoside- and nucleotide-analogues selectively target HBV DNA polymerase, resulting in premature chain termination of viral replication. Drug-resistant strains of HBV have signature mutations in the reverse transcriptase domains of the viral polymerase gene . Resistance mutations alter the interaction between HBV polymerase and drug, which interfere the inhibitory effect of drug on viral polymerase. After emergence of primary resistance mutations, compensatory mutations that restore replication capacity may arise , as well as secondary resistance mutations that increase drug resistance when they accumulate on the same viral genome.
Evolution of drug-resistant hepatitis B virus. Adapted from Bartholomeusz A, et al. Semin Liver Dis 2006 26:162170.64 Fournier C, et al. Clin Liver Dis 2007 11:869892.65
LAM, lamivudine LdT, telbivudine CLV, clevudine ETV, entecavir ADV, adefovir dipivoxil W, wild type HBV strain R, resistant HBV strain.
Patent Expirations Will Help
While it is potentially very inexpensive to manufacture generic ETV, current prices of the drug are unfortunately very high, with a lowest global price of US$427 for a generic version not approved by a stringent regulatory authority such as the U.S. Food and Drug Administration, and US$6,127 for a generic version sold in the United States. This is because use of entecavir is currently very low, due in part to the very high prices of branded ETV and TDF, which have to some degree limited the uptake of these drugs in middle- and high-income countries . However, patents on ETV have recently expired in much of the world, including in the United States, and TDFs main patents will have expired by 2018 in most countries. This will create a dramatically different situation, as it should enable patients throughout the world to receive the most effective treatments while also making it economically feasible to explore the provision of treatment earlier in infection using a simplified public health approach.
Medications For Hepatitis B
Several drugs are currently available for treatment of hepatitis B. Most of these are antiviral drugs that directly stop hepatitis B from reproducing. Hepatitis B treatment may also include pegylated interferon, which stimulates the body’s immune response against the virus.
Most hepatitis B drugs are nucleoside or nucleotide analogues, similar to one class of drugs used to treat HIV. In fact, some commonly used anti-HIV drugs are also active against hepatitis B. This can make treatment of both viruses easier, since it requires fewer drugs, but it must be done carefully to avoid either virus becoming resistant. These are:
- lamivudine .
- emtricitabine .
- tenofovir disoproxil or TDF .
- tenofovir alafenamide or TAF .
Other antiviral drugs are used to treat hepatitis B but not HIV:
- adefovir
- telbivudine .
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How Long Does It Take To Recover
The recovery period depends on how much the virus has affected your liver and how far your body has cooperated with the antiviral drugs. For some, the results of the treatment can be immediate, but for others, it can be long term. The antiviral drugs may also not work across for some sections of people. Consult with your doctor about these implications and the recovery period.
How Is It Transmitted
Hepatitis B is highly infectious, and is spread from one person to another through exposure to infected blood and body fluids . It can be spread through:
- blood transfusions or organ transplantation in countries where blood or blood products have not been properly screened for hepatitis B and other viruses transmitted through blood
- unprotected sex with an infected person
- sharing needles or equipment for injecting drugs
- unsterilized medical/dental equipment and shared/contaminated materials or equipment used for tattooing, body piercing or acupuncture
- sharing toothbrushes or razors
- childbirth
- household contact between family members
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Treatment Guidelines And Resistance Management
Improvement in the availability of better therapies and virological monitoring tools have led to a progressive change in treatment guideline recommendations. Besides lowering HBV DNA and ALT thresholds for treatment indications, international guidelines recommend that therapy be initiated with a potent antiviral with a high barrier to resistance, such as entecavir or tenofovir, to reach undetectable HBV DNA as a primary endpoint thus minimizing the risk of selecting resistant variants .
Treatment guidelines for treatment of chronic hepatitis B with nucleoside analogues
Avoid unnecessary treatment
Avoid sequential monotherapy
Recommendations for the management of patients who develop antiviral resistance are consistent among treatment guidelines . One key principle is that sequential monotherapy should be avoided in mostcases. If initial monotherapy fails, a second drug with a non-overlapping resistance profile should be added or a switch should be made to a more potent combination of drugs . Most patients in treatment failure can be controlled with this rescue strategy.
What Medicines Are Used To Treat Chronic Hepatitis B
There are several antiviral medicines that can be used to treat chronic hepatitis B. They are sorted into two groups:
- Interferons, such as interferon alfa-2b and peginterferon alfa-2a. Interferons are given as a shot 1 to 3 times a week for 4 to 12 months.
- Nucleoside reverse transcriptase inhibitors such as adefovir, entecavir, lamivudine, telbivudine, and tenofovir. NRTIs are taken as a pill once a day for at least a year, and usually for many years.
When you take interferons, you are less likely to relapse after you stop taking the medicine than if you took NRTIs. But fewer people are helped by interferons than by NRTIs.footnote 2
Experts recommend antiviral medicines if you have high levels of both the hepatitis B virus and liver enzymes in your blood for at least 6 months or if you have liver disease.
But antiviral medicines may not be right for everyone. The medicines can be helpful if you have or are likely to get liver damage, such as cirrhosis. But they may not help if you already have severe liver damage. People who have had an organ transplant or who drink too much alcohol or use illegal drugs may not be able to take some of these medicines.
You may not need to take antiviral medicines if you have normal or only slightly higher-than-normal levels of liver enzymes in your blood and if your liver isn’t damaged. Your doctor may remove a tiny piece of your liver to see if it has been affected by the virus.
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Are There Any Side Effects
Yes, these antiviral drugs and medications are of strong dosages, and there can be side effects that can be short term to long term. Consult with your doctor about your medical conditions and take care of the symptoms that can arise as a result of using these medications. There can be some interferon shots given to young people who do not want long-term treatments, and those side effects can include depression and difficulty in breathing.
How Is Hepatitis C Treated
Hepatitis C virus is treated with all-oral medications. These pills, calledantiviral medications, are usually taken once per day. These antiviral medications are extremely good at attacking the virus and preventing it from multiplying.
Antiviral medications were not the original treatment for hepatitis C. Before 2014, the only treatment for hepatitis C was called interferon and ribavirin, taken as weekly injections under the skin, plus pills. Interferon treatment caused many unpleasant side effects and was not usually successful. Then a new generation of medications became available. These antiviral treatments are extremely successful at curing the virus and have very minimal side effects.
Ribavirin is still sometimes prescribed to be taken along with the new antiviral medicines, but it has become more and more uncommon that ribavirin is needed at all. Ribavirin has some mild-moderate side effects. Ribavirin is a pill taken twice per day, as 2 or 3 pills in the morning plus 2 or 3 pills at night, depending on the patient’s body weight. Most patients do not need ribavirin.
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Why Should People Take Antiviral Medications For Hepatitis C
The purpose of taking antiviral medications for hepatitis C is to:
- remove all the hepatitis C virus from your body permanently
- stop or slow down the damage to your liver
- reduce the risk of developing cirrhosis
- reduce the risk of developing liver cancer
- reduce the risk of liver failure and the need for a liver transplant
Chronic Hepatitis B Therapy
The ultimate goals of therapy for chronic hepatitis B are to prevent disease progression and to prolong patient survival . These goals can be achieved as long as HBV replication can be suppressed and sustained. Major clinical studies have demonstrated the role of viral replication in the pathogenesis and progression CHB. A large prospective cohort study from Taiwan has shown that elevated HBV DNA and its persistence significantly increase the risk of cirrhosis, hepatocellular carcinoma and death, regardless of HBeAg status or baseline ALT levels. These data have been supported by several other similarly designed studies. Furthermore, one randomized controlled clinical trial of lamivudine in CHB patients with advanced fibrosis or cirrhosis showed the benefit of antiviral therapy on disease progression . However, the clinical benefit of reducing disease progression was limited in patients who developed lamivudine resistance . Histological improvement has been observed during treatment with lamivudine, adefovir, tenofovir and entecavir, although the development of resistance had a negative impact on the histological improvement observed with lamivudine .
Thus, a maintained long-term response to therapy or a sustained off-treatment response are necessary to prevent liver damage and hepatic decompensation and to delay the onset of the long-term complications of CHB such as hepatocellular carcinoma .
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What Does It Mean To Have A Successful Treatment What Is A Sustained Virologic Response
In an untreated state, the hepatitis C virus infects the cells of the liver and then continuously lives there, making copies of itself that circulate in the bloodstream. Antiviral medications can destroy the ability of the virus to reproduce, so the amount of virus in the bloodstream then decreases. The amount of virus in the blood is measured by aviral load.
Treatment is successful when the viral load drops toundetectablelevels, which means the virus cannot be detected in the bloodstream at all. The viral load becomes undetectable during treatment and remains undetected after treatment has ended. If there is still no detectable virus in the blood 12 weeks after the end of the treatment, the treatment was successful. This is called a Sustained Virologic Response .
A patient who has achieved an SVR is considered to be cured of the hepatitis C virus.
What Are The Side Effects Of Antiviral Medicines
Antiviral medicines can have serious side effects that may cause problems throughout your treatment. Some people are not bothered by the side effects, while others stop taking their medicines because they feel too sick to finish them.
If you take interferons, you’re more likely to have side effects than if you take NRTIs.
Side effects of interferons include:
- Fever.
- Depression, which can be severe.
In rare cases, interferons can cause confusion and might affect your heart, thyroid, or kidneys.
Side effects of NRTIs may include:
- Fever.
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Treatment For People With Hiv And Hepatitis B Co
In the UK, standards for HIV treatment and care are set and monitored by the British HIV Association , the professional association for HIV doctors and other healthcare professionals. The most recent guidelines on HIV and hepatitis co-infection were produced in 2017 .
“The health of your liver should be regularly monitored during HIV and hepatitis B treatment.”
Like everyone else living with HIV, people with HIV and hepatitis B co-infection are advised to start antiretroviral treatment soon after they are diagnosed with HIV. People with co-infection may particularly benefit from early antiretroviral treatment because undetectable HIV viral load and restored immune function are linked to slower liver disease progression.
Guidelines recommend that all people with HIV and hepatitis B co-infection should use combination antiretroviral therapy containing tenofovir plus either lamivudine or emtricitabine. These drugs are active against both HIV and hepatitis B.
The most widely used option is the Truvada pill combining tenofovir and emtricitabine, along with an additional anti-HIV drug from another class. Fixed-dose combination pills for HIV treatment that contain tenofovir and emtricitabine are also active against hepatitis B. Tenofovir alafenamide is easier on the kidneys and bones than tenofovir disoproxil . People who cannot take tenofovir can use entecavir instead, in addition to combination therapy to treat HIV.
Recommendations For Patients With Hbv/hiv Coinfection
- All patients with chronic HBV should be evaluated to assess the severity of HBV infection . Patients with chronic HBV should also be tested for immunity to hepatitis A virus infection and, if nonimmune, receive the HAV vaccination. In addition, patients with chronic HBV should be advised to abstain from alcohol and counseled on prevention methods that protect against both HBV and HIV transmission.15
- Before ART is initiated, all persons who test positive for hepatitis B surface antigen should be tested for HBV DNA by using a quantitative assay to determine the level of HBV replication , and the test should be repeated every 3 to 6 months to ensure effective HBV suppression. The goal of HBV therapy with nucleoside reverse transcriptase inhibitors is to prevent liver disease complications by sustained suppression of HBV replication.
- Since HBV reactivation has been observed in persons with HBV infection during interferon-free HCV treatment,16,17 persons with HCV/HIV coinfection and active HBV infection should receive ART that includes agents with anti-HBV activity prior to initiating HCV therapy . The diagnosis of HBV reactivation should be considered in persons with current HBV infection who experience elevated liver enzymes during or immediately after HCV therapy.
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Who Is Not Eligible For The Treatment
The treatment depends on how severe the condition is and how far the virus has spread in your body. The antiviral medicines suitable for one body type may not be suitable for the other individual. Have a detailed evaluation with your doctor and look for the symptoms. If you are suffering from other chronic medical conditions, you might not be a suitable candidate to take these medications.
What Are The Post
The post treatment guidelines are very much mandatory when undergoing the medications. You need to make lots of changes to your lifestyle and in most cases your eating habits. Technically your care for your liver should double, and you might not want to indulge in any activity that can hamper your liver again. You have to ultimately curb your smoking and drinking activities and refrain from using drugs. Also, the medications have to be taken religiously and should never be skipped.
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What Is My Risk
Your risk depends of several factors: destination, length of stay, what you do when you are travelling and whether you have direct contact with blood or other body fluids. In certain destinations, your risk may be higher, as some areas have higher numbers of people with chronic hepatitis B in the general population.
The risk increases with certain activities, such as unprotected sex, sharing needles, tattooing and acupuncture.
Aid and health care workers and anyone who receives medical or dental care with unsterilized or contaminated equipment in a country where hepatitis B occurs are also at greater risk.
You May Not Need Treatment
Not everyone with hepatitis C will need to receive these expensive treatments. In up to of people with hepatitis C, the virus clears on its own within a few months without any need for medication. Your doctor will monitor you closely to see if your condition persists, and then decide if you need treatment.
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Who Should Not Take Tenofovir
Anyone who is allergic to tenofovir shouldn’t take this drug. Also, it’s important to know your HIV status because taking tenofovir can significantly complicate treating HIV. If you have HIV and HBV, do not start therapy for either infection without consulting a physician experienced in treating both infections.
Tenofovir is generally recognized as safe for use during pregnancy, as there is no evidence to suggest it is harmful to a pregnant mother or her fetus.
Approved Drugs For Adults
There are currently 7 approved drugs in the United States for adults living with chronic hepatitis B infection. These include 5 types of antiviral drugs that are taken as a pill once a day for 1 year or longer. And there are 2 types of immune modulator drugs called interferon that are given as an injection for 6 months to 1 year.
It is important to know that not everyone needs to be treated. A liver specialist should evaluate your health through a physical exam, blood tests, and an imaging study of your liver . Then you can discuss together whether you are a good candidate for treatment since the approved drugs are most effective when there are signs of active liver disease. In addition, talk to your provider about HBV Clinical Trials since there are several new drugs being tested that are available for infected adults.
All adults, however, should be seen regularly by a liver specialist whether they are on treatment or not.
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Key Challenges: Testing Treatment Eligibility And Retention
Despite the low costs and clear benefits of antivirals, drugs will not be a magic bullet in and of themselves. To begin with, the proportion of people who have been tested for HBV is very low in most countries WHO estimates that globally less than 5% of people living with chronic HBV and/or HCV are aware of their status. On a more positive note, even a one-time HBV test for adults could enable the identification of most people who would benefit from treatment, because the vast majority of HBV-associated liver cancer and cirrhosis occurs among people who were infected perinatally or as children. Rapid, point-of-care tests have been developed for HBV and could boost efficiencies. However, the majority of rapid tests have not yet been prequalified by WHO, and multiple tests lack international validation of sensitivity and specificity in the populations in which they might be used.
The proportion of people tested for HBV is very low in most countries, but rapid point-of-care tests could help.