The purpose of the treatment is to eliminate the virus, and thus the HBs ag in favor of the anti-HBs antibody, but rarely achieved. So we try to stop the viral multiplication to reduce the activity of chronic hepatitis and accelerate the transition to the inactive carrier phase of the virus. Seroconversion HBe (disappearance of HBeAg and appearance of anti-HBe antibody) is an important criterion, but it sometimes occurs late. Several drugs are used.
The action of interferon (IFN) is first antiviral, it inhibits the DNA of the virus and activates the antiviral enzymes. It is also immunomodulatory, it increases the activity of certain cells of the immune system. The antiviral action of the treatment is verified by the decrease of the viral load from the first weeks. The immunomodulatory action itself often results in an increase in transaminases (usually after 2 months). This shows the increase of the immune response and increases the chances of eliminating the virus. At this stage, there may be a temporary rise in hepatic inflammation and necrosis, due to the elimination of infected liver cells. When the treatment works, the transas normalize after a few months and the condition of the liver improves. Efficacy is confirmed by the negativation of HBeAg and the appearance of anti-HBe antibodies. In the longer term, a complete cure, confirmed by the subsequent seroconversion of HBsAg with the appearance of the anti-HBs antibody is sometimes obtained, it can be favored by a prolonged treatment. The treatment is more effective during the period of immune reaction. The IFN then causes a response in about 50% of cases. On the other hand, in the phase of immune tolerance, the treatment is not very effective. Unlike other drugs used, IFN has the advantage of being administered over a short period, not to cause resistance and, when effective, to induce prolonged seroconversion in 80 90% of patients. Its main disadvantage is relative to the tolerance, the side effects are important. In 20% of the cases, it is necessary to reduce the dose, in 5% of the cases, one stops the treatment. In addition, IFN is formally contraindicated in a number of cases (decompensated cirrhosis, psychiatric disorders, etc.).
Previously, only standard IFN was offered against chronic hepatitis B, now pegylated IFN is preferred. Easier to use, it is more effective and increases the chances of HBe seroconversion (37% with IFN peg against 25% with standard IFN).
Lamivudine (Zeffix® or Epivir® for HIV co-infected) is the first antiviral to have been proposed as an alternative to IFN. It is in the form of tablets and has several advantages over IFN. Its antiviral effect is rapid (normalization of transas, decreased activity of hepatitis and fibrosis) and its tolerance is good. However, when treatment is stopped, the reactivation of hepatitis is almost constant in the absence of HBe seroconversion. The chances of HBe seroconversion are low: 20% after one year. If treatment is prolonged in the hope of achieving seroconversion, the risk of developing resistant viral strains associated with relapse is increased. The frequency of appearance of a resistant HBV is 24% after one year of treatment, it climbs to 38% after 2 years, 50% after 3 years, 67% after 4 years.
When the HBe antigen disappears in favor of the anti-HBe antibody, the 3 treatment is continued for at least 6 months in order to reduce the risk of reactivation. In the absence of HBe seroconversion, it is advisable to continue treatment as long as there is no viral resistance. If a resistance appears, it is possible to switch to adefovir, respecting a period of overlap of 3 months.
Adefovir dipivoxil (Hepsera®) is in the form of tablets. HBe seroconversion with adefovir dipivoxil is ineffective, 12 only. It causes, in half of the cases, a normalization of transas and an improvement of the state of the liver and it is very well tolerated. It can therefore be prescribed over long periods because it causes little resistance. After one year of treatment, no resistant mutant was noted. After 2 years, there is a resistance in 6% of cases, after three years: 11%. After five years, the rate is 28%. It is effective on lamivudine-resistant viruses and can therefore be used as a replacement for lamivudine in resistant mutant viruses. The duration of treatment is not clearly established. In case of HBe seroconversion, it is recommended to continue the treatment during 3 at 6 months to reduce the risk of reactivation when stopped. In the absence of HBe seroconversion, or in the case of hepatitis negative for HBeAg, it is recommended to continue the treatment because in case of a discontinuation, there is a relapse.
Already authorized in the United States, entecavir (Baraclude®) has obtained a European Marketing Authorization and should be placed on the French market at the end of 2006. Its dosage is one tablet per day and its tolerance is good (almost no side effects). More effective than lamivudine or adefovir, it negatively affects the viral load in 90% of cases. However, HBe seroconversion only occurs in a minority of cases (and, exceptionally, HBs seroconversion) and treatment must be prolonged. Like adefovir, entecavir is effective against lamivudine-resistant hepatitis B virus but should be used at a higher dose.
At what stage to start treatment
The treatment is more effective during the period of immune reaction (moderate viral load, high transas and marked activity lesions). It has thus been shown that when a treatment is started during a period of reactivation of chronic hepatitis B, the chances of an early response are greater (3,5 times more, on average) than when it is starts during a slow period. An early response is considered an important factor in the long-term success of a treatment.
The ideal time to start a treatment could be defined by a moderate viral load (less than 10 million copies of HBV DNA), an elevation of transas (ALAT) greater than 100 and moderate or severe fibrosis (A2 or A3).
Chronic hepatitis B with mutant virus
With standard IFN, experts recommend treating mutated hepatitis B (HBeAg negative) for longer than one year instead of six months. Pegylated interferon has not been formally evaluated for periods of one year, so this is the official reference period. For other drugs, whether or not the HBe antigen is positive at the beginning of the treatment does not change the gait. With lamivudine, adefovir or entecavir, the results and resistance rates are identical in chronic hepatitis B with positive or negative HBe antigen
Resistance to treatment
It is useless to continue a treatment generating a mutant resistant virus. You have to change your medicine because hepatitis is likely to relapse. The appearance of viral resistance is defined by the increase of an 10 factor (1 log) of the viral load relative to the lowest viral load obtained during the treatment. It is considered that the mutant strain has become dominant and that the proportion of hepatocytes infected with this strain has become important. Resistance may especially occur if the viral load remains detectable. Very rare when the viral load is undetectable, because if the multiplication of the virus is blocked, it can not mutate. By genotyping the virus, it can be seen that the resistance is due to the emergence of a mutant viral strain. This resistance can be detected even before the viral breakthrough takes place. There is a latency period of three to six months during which mutant strains can be detected, while the viral load has not yet increased. This information is useful for controlling the replication of the resistant strain and preventing the risk of aggravating hepatitis. When resistance is demonstrated during treatment with lamivudine and adefovir is used, the two treatments are overlapped for at least three months while adefovir is effective. . But when the disease is severe (with stage F3 or F4 fibrosis), it is advisable to continue dual therapy indefinitely.
Entecavir is also effective for resistance to lamivudine, but it is a little less effective and should be used at higher doses. Its effectiveness, in case of resistance to adefovir, remains to be studied.
New molecules soon available
Among the new drugs being evaluated are:
- emtricitabine (Emtriva®), close to lamivudine, and also effective in the treatment of HIV infections, but whose efficacy does not seem to be much greater than that of lamivudine or adefovir;
- tenofovir (Viréad®), also used against HIV, close to adefovir, it could be more effective than the latter, with even less resistance;
- telbivudine, whose initial studies suggest greater efficacy than lamivudine, whether in terms of transaminase normalization or viral load reduction, current trials will make it possible to better specify its efficacy and the frequency of resistance;
- clévudine, which appears to be effective in decreasing viral load with good tolerance, but studies are less advanced than for telbivudine.
Even if these antivirals used in monotherapy do not have a much higher efficiency than current treatments, their availability will allow the development of multi therapies adapted to each patient, and will prevent the appearance of resistance. Another line of research is not on the fight against viruses, but on how to stop the development of liver fibrosis (see the article on antifibrosants Jds No. 187).
Finally, researchers are studying vaccine therapy. The aim is to induce an immune response in patients with chronic hepatitis B by vaccinating them against this virus, which in theory could either accelerate the natural response (and seroconversion) or improve the response to treatment. Vaccine therapy does not work with current vaccines. "Supervaccins", specially designed for this purpose, seem more promising.
Co-infection with hepatitis C virus
When both viruses are present in the body, most often, the hepatitis C virus takes precedence over hepatitis B. The replication of the first is strong and that of the second is weak. In this case, HBV / HCV coinfection is treated as chronic hepatitis C is treated by combining pegylated interferon with another drug, ribavirin. However, we must be vigilant and monitor the evolution of hepatitis B. Indeed, eliminating the hepatitis C virus, paradoxically risk to disinhibit that of hepatitis B, and thus reactivate hepatitis B. Rarely, the opposite occurs and HBV dominates with strong replication whereas HCV remains unobtrusive with low replication. Co-infection is then treated as hepatitis B, with a preference for pegylated interferon, since it is also effective against hepatitis C virus (which is not the case for lamivudine, adefovir or entecavir).
Co-infection with HIV
About 10% of HIV carriers are infected with HBV. With the advent of multidrug therapy for AIDS, many people have managed to stabilize their HIV infection, while hepatitis has continued to grow. Many coinfected people are more seriously threatened by HBV than by HIV. Treatment for hepatitis B can be undertaken in coinfected patients whose immune status is preserved on antiretroviral therapy. For those whose immune system is very depressed, antiretroviral treatment of HIV must, beforehand, allow a rise in the level of CD4. Interferon treatment is possible, but less effective than in the absence of co-infection. Good results can however be obtained, the main difficulty being to find the balance between tolerance and efficiency.
HIV infection increases both the risk of progression to HBV chronicity, viral replication B and the frequency of viral B reactivation responsible for an outbreak of hepatitis. It accelerates the evolution of fibrosis and increases mortality. The introduction of HIV antiretroviral therapy has led to severe reactivation due to immune restoration. The same is true for stopping or replacing active anti-retroviral drugs against HBV, including lamivudine.
The indication for HBV therapy depends on the presence of HBsAg, HBeAg / HBeAg and HBV viral load expressed by a sensitive quantitative test. When HIV antiretroviral therapy is indicated, it should have an active combination against HBV, lamivudine (Epivir®) or emtricitabine (Emtriva®) + tenofovir (Viréad®). In patients who have already been treated with lamivudine and whose virus has become resistant to this product, it must be replaced by tenofovir. When HIV antiretroviral therapy is not necessary, the indication of HBV therapy depends on the condition of the liver.
Only patients whose fibrosis score is F2 are treated. When the level of CD4 lymphocytes is conserved, this treatment may be interferon, pegylated interferon or adefovir. When the CD4 lymphocyte count is less than 500, anti-HBV therapy should be a combination of lamivudine or emtricitabine + tenofovir. The ANRS is conducting a multicenter pilot study (ANRS HB 01 EMVIPEG) evaluating the efficacy and safety of additive treatment with pegylated IFN alpha-2a, in combination with tenofovir and emtricitabine, in the treatment of chronic hepatitis B HBe antigen in HIV / HBV patients.
Monitoring during treatment
To monitor the effectiveness of treatment, several indicators are useful. First, you must dose the transas every month at the beginning of treatment, then every three months. The measurement of the viral load is more precise, can be done every three months, or more in case of cirrhosis. When it is a chronic hepatitis positive for ag-HBe, it is important to identify a possible seroconversion. That is why it is advisable to look for this antigen, as well as the anti-HBe antibody, when the viral DNA has strongly decreased in a second time, if the HBV DNA and the HBe antigen are Negative, HBs seroconversion should be monitored in the same way.
The monitoring of adverse effects mainly concerns IFN: regular blood tests (NFS, TSH, etc.). Finally, the appearance of a resistance strain will result in a further increase in viral load. After stopping treatment, surveillance of biological and virological markers is continued due to the risk of viral reactivation.
There is no "right answer" to treatment for hepatitis B, but several types of responses, corresponding to successive stages:
- 1er time, the viral load decreases and, hopefully, falls below the threshold of 100 000 copies per ml. This virological response is accompanied or followed by a normalization of transaminases and a decrease in the activity of hepatitis, or even the fibrosis score. At this stage, the risk of reactivation persists;
- 2e time, seroconversion HBe occurs and the risk of reactivation becomes low. This type of response is usually taken into account in trials to evaluate the effectiveness of treatments;
- XnumXe time, the HBs ag can be negativer, which corresponds to the cure of the chronic hepatitis B without risk of reactivation. This type of response is more rare, often late, occurring after stopping treatment. Moreover, as in hepatitis C, a significant decrease in viral load at the very beginning of treatment is predictive of a better subsequent response.