I. Definition of rescue therapy
The development of drug resistance during the treatment of chronic hepatitis B with nucleoside (acid) analogues is an important cause of antiviral efficacy. All four nucleoside (acid) analogues currently marketed in China for the treatment of hepatitis B have been found to have drug resistance, although the frequency and pattern of its occurrence varies. The development of drug resistance can cause a rebound in HBV DNA and an increase in ALT levels in patients, leading to even more serious consequences. For example, once drug resistance develops in patients with compensated cirrhosis, liver failure until death may occur.
Drawing on the experience in the treatment and management of HIV-resistant patients, scholars at home and abroad have referred to the management of HBV resistance as Rescue Treatment (Rescure Treatment; Salvage Therapy). There is a lack of standardized definition of rescue therapy, and the connotation of the definition is constantly evolving, usually referring to the management of drug-resistant patients by seeking a new treatment method to save the serious clinical consequences that may result from drug resistance.
II. Principles of drug selection for rescue therapy
Since the resistance pathways of different nucleoside (acid) analogues are different and cross-resistance problems exist among some drugs, it is necessary to choose the drugs for rescue therapy reasonably. The principle of drug selection is to try not to select drugs with cross- or partial cross-resistance. According to the available studies, lamivudine, telbivudine and entecavir are all nucleoside analogues, and there is a certain degree of cross-resistance among them; while adefovir is a nucleoside analog, and it is generally believed that there is no cross-resistance between them and the three aforementioned drugs. The current comprehensive foreign guidelines on the treatment of chronic hepatitis B recommend the following drug choices for drug-resistant rescue therapy.
Rescue treatment strategy after HBV resistance
Different guidelines
Lamivudine resistance
Adefovir resistance
Entecavir resistance
Tebivudine resistance
2007 American College of Hepatology Guidelines
l Add adefovir or tenofovir
l Switch to emtricitabine + tenofovir
l Switch to entecavir (but be aware of subsequent problems with entecavir resistance and multi-drug resistance)
l Add lamivudine
l Switch to emtricitabine + tenofovir
addition or switch to entecavir (if no past lamivudine resistance)
Add or switch to adefovir or tenofovir
l Addition of adefovir or tenofovir
l Switch to emtricitabine + tenofovir
l Switch to entecavir (but be aware of subsequent problems with entecavir resistance and multi-drug resistance)
2008 Asia Pacific Hepatology Society guidelines
l Add adefovir (preferred)
l Switch to entecavir 1 mg/day
Add or switch to entecavir, telbivudine or lamivudine
l Add adefovir (preferred)
l Switch to alpha interferon
European Society of Hepatology Guidelines 2009
l Addition of tenofovir
l If tenofovir is not available, consider adding adefovir
l If N236T variant, switch to tenofovir and add entecavir or lamivudine or telbivudine, or switch to tenofovir + emtricitabine
l In case of A181T/V variant, switch to tenofovir and add entecavir or switch to tenofovir + emtricitabine
l Add tenofovir
l Add tenofovir
l If tenofovir is not available, add adefovir can be considered
III. Comparison of different rescue therapy regimens
Rescue therapy for lamivudine resistance 1: Adefovir vs. lamivudine combined with adefovir
Studies around 2004 found no significant difference in the antiviral effect of switching to adefovir alone after lamivudine resistance versus combined lamivudine and adefovir for one year, but more studies after 2005 found a significantly higher incidence of adefovir resistance during treatment with adefovir alone, significantly higher than the incidence of adefovir resistance in nucleoside primed patients. A randomized controlled study confirmed that combination therapy reduced the incidence of adefovir resistance. 42 HBeAg-negative patients with chronic hepatitis B presenting with YMDD mutations along with clinical and virological breakthroughs were randomized to 2 groups, one treated with adefovir alone and the other with a combination of lamivudine and adefovir.
Twelve months after treatment initiation, there were no significant differences between the two groups in terms of HBVDNA and ALT indices. However, 21% of the adefovir-treated group developed adefovir genotype resistance, while no adefovir resistance was found in the combination treatment group. Recently Lampertico P et al. studied 145 lamivudine-resistant HBeAg-negative patients, all of whom were treated with adefovir in combination with lamivudine, and all of them did not show virological and clinical breakthroughs, and the cumulative incidence of adefovir resistance was 1%, 2%, 4%, and 4% at 1, 2, 3, and 4 years of treatment, respectively[8] . Therefore, current international and national treatment guidelines recommend a combination therapy approach to manage lamivudine-resistant patients.
However, long-term larger series of study cases are mainly HBeAg-negative patients with low relative viral levels, mainly originating from Mediterranean regions with high prevalence of genotype D. To date, no treatment studies have been designed for larger samples of HBeAg-positive patients.
Rescue therapy for lamivudine resistance 2: entecavir
Entecavir is significantly less effective against lamivudine-resistant strains (compared to HBV wild strains) and the presence of the YMDD variant reduces the genetic barrier to resistance to entecavir. Clinical studies have shown that despite treatment of lamivudine resistance with entecavir at a dose of 1 mg/day, only 19% of patients had HBV DNA levels below detection line at 48 weeks of treatment, compared to 67% of patients on nucleoside priming. Moreover, the proportion of entecavir-resistant patients who developed entecavir resistance at 5 years of treatment reached 50%, compared with 1% of nucleoside primed patients. Therefore, entecavir monotherapy is not currently the preferred option for treating lamivudine-resistant patients.
Rescue therapy for lamivudine resistance 3: Tenofovir
Clinical studies have demonstrated the effectiveness of tenofovir in treating lamivudine resistance, with tenofovir being significantly more effective than adefovir 10 mg/day at a 300 mg/day treatment dose. A study from Germany compared the efficacy of adefovir and tenofovir in lamivudine-resistant patients.9 Of the 53 patients with lamivudine genotype resistance and HBV DNA >106 copies/mL, 35 received tenofovir for 72 to 130 weeks and the other 18 received adefovir for 60 to 80 weeks, and at 48 weeks of treatment, 44% of patients in the adefovir group had At 48 weeks of treatment, 44% of patients in the adefovir group had HBV DNA <105 copies/mL, compared with 100% in the tenofovir group (P = .001). No serious side effects occurred in either group, and no tenofovir genotype resistance was detected (until 130 weeks of treatment).
Based on the available data and the antiviral drugs currently available in China, the best regimen for treating lamivudine resistance is lamivudine + adefovir, and entecavir alone is not advocated for treating lamivudine resistance. Studies on entecavir in combination with adefovir for the treatment of lamivudine resistance are ongoing.
Rescue therapy for lamivudine resistance 4: Long-acting interferon
We compared the efficacy and safety of piroxin and adefovir in Chinese HBeAg-positive lamivudine-resistant patients in a randomized controlled clinical study and found that piroxin reduced HBsAg levels more significantly than adefovir in HBeAg-positive lamivudine-resistant chronic hepatitis B patients. The study included 235 HBeAg-positive chronic hepatitis B patients who were screened for the presence of YMDD variants and randomly assigned to two groups in a 2:1 ratio: patients in the Peroxin group (135) received Peroxin 180 µg/week for 48 weeks and continued to be followed for 24 weeks after discontinuation; patients in the Adefovir group (80) received Adefovir 10 mg/day for 72 weeks, and all patients received Adefovir 10 mg/day for the first 12 weeks of the study. received concomitant treatment with lamivudine 100 mg/day for the first 12 weeks of study initiation.
The results of the 48-week interim analysis showed a higher proportion of patients in the Pyroxine treatment group with HBeAg disappearance (14.2% vs. 5%) and serological conversion (9% vs. 2.5%, P=0.033). The decline in HBsAg was greater in the Pyroxin-treated group, with 4% of patients in the Pyroxin-treated group achieving HBsAg conversion at 48 weeks, while no HBsAg conversion occurred in the adefovir group. More importantly, 43% of patients who achieved HBeAg serologic conversion with Pyroxine achieved HBsAg conversion at 48 weeks (see the presentation at this meeting for details). The study database has been locked, and final analysis of the study results is ongoing.
There are more studies on rescue therapy after lamivudine resistance, but there is less information on clinical studies on adefovir, telbivudine and entecavir, tenofovir resistance, especially the lack of comparison between different treatment regimens.
IV. Timing of rescue therapy
To compare the impact of administering rescue therapy at different time points on disease control, Lampertico et al. conducted a comparative study in which group A included 46 HBeAg-negative chronic hepatitis B patients who were given adefovir combined with lamivudine antiviral therapy only after the development of clinical resistance (HBV DNA >106 copies/ml and elevated ALT levels), whereas 28 patients in group B HBeAg-negative chronic hepatitis B patients were given adefovir combined with lamivudine antiviral therapy at the onset of genotypic resistance (HBV DNA between 103 copies/ml and 106 copies/ml and normal ALT). It was found that at 24 months of treatment, all patients in group B had HBV DNA below the detection line, while only 78% of patients in group A had HBV DNA below the detection line. all patients in group B had normal ALT after switching to treatment, while only 93% of patients in group A had normal ALT at 24 months of treatment, respectively[10] . Therefore, regular clinical control of HBV DNA levels during lamivudine treatment and early detection of genotypic resistance are important. Once an increase in HBV DNA level is detected, genotypic resistance testing should be performed immediately and the treatment regimen should be changed in a timely manner so as to achieve ideal control of the disease.
V. Limitations of the current rescue therapy
1, the therapeutic effect of rescue therapy: rescue therapy is only an after-the-fact remedy, that is, after the emergence of drug resistance to choose a treatment plan to control the development of the disease. Generally speaking, the effect of rescue therapy is lower than the efficacy of the drug in primary care patients, a typical example being entecavir, which is significantly more effective in primary care patients than entecavir in lamivudine-resistant patients.
2. Resistance to rescue therapy: Rescue therapy does not solve the pre-existing resistance problem and may not completely eliminate the emerged resistant strains, even if the resistant strains change from dominant to weak strains, the resistant strains will quickly change back to dominant strains after re-dosing. And with the extension of rescue treatment time, will gradually produce resistance to rescue treatment drugs, which may lead to the possibility of multiple drug resistance.
3, the timing of the combination of drugs: most of the current rescue treatment program recommended combination of drugs, whether it is necessary to long-term combination of drugs or the combination of a period of time can be discontinued after one of the study reports. The safety of long-term drug combinations requires a long period of time and a large sample of clinical studies to be fully elucidated. In addition, the cost of long-term combination drugs will be greatly increased.
4, rescue treatment discontinuation problem: the current rescue treatment research rarely involves the rescue treatment discontinuation problem, whether such patients need to receive long-term rescue treatment or can consider discontinuation after reaching certain treatment standards, there are still few clinical studies to explore this issue.
The role of immunomodulators in rescue therapy has not received much attention: Since there are few international clinical reports on the use of immunomodulators in rescue therapy, none of the three major international hepatology societies’ guidelines recommend the use of immunomodulators as rescue therapy for drug resistance. In fact, our clinical studies have shown that immunomodulators, especially interferon, should have a place as rescue therapy after drug resistance. In particular, the course of interferon is relatively fixed and does not require long-term medication, especially since some patients can achieve a clear resistant strain, HBeAg serological conversion or even the disappearance of HBsAg, which is a treatment endpoint more difficult to achieve with nucleoside analogues.
6, the level of evidence-based medicine is not high: in general, most of the information currently studying rescue therapy is not from strictly designed double-blind controlled clinical studies, and some drugs lack in vivo large sample studies (tipifudin, entecavir, tenofovir, adefovir). Rescue therapy for lamivudine resistance is also mostly from HBeAg-negative chronic hepatitis B patients, and more evidence-based medical evidence is needed on the long-term efficacy of these rescue therapy regimens for HBeAg-positive patients.
VI. Future design of rescue therapy programs
In the future, more prospective multicenter clinical studies should be designed to compare the efficacy and safety of different rescue regimens in drug-resistant patients, such as the multicenter randomized controlled clinical study led by Prof. Hou Jinlin of Southern Hospital, which was conducted in China and Hong Kong to compare the efficacy and safety of long-acting interferon and adefovir in HBeAg lamivudine-resistant patients. The results of the interim study.
Efficacy and safety of three regimens, tenofovir, lamivudine + tenofovir and entecavir + tenofovir, in lamivudine-resistant patients centers are being conducted in Europe and the United States. Multicenter clinical studies are also being planned that will compare the efficacy and safety of adefovir + entecavir, adefovir + lamivudine, and entecavir regimens in lamivudine-resistant patients.
As the duration of adefovir, entecavir, tipifovir and tenofovir administration increases, resistance issues will become apparent and, similar to the experience with lamivudine resistance studies, additional clinical studies of rescue therapy for resistance to these drugs will be needed in the future.