General Approach to Monitoring Patients on Therapy
The following discussion will address the monitoring and management after starting a patient on therapy for chronic hepatitis B virus (HBV) infection. All patients starting on hepatitis B therapy should have monitoring for medication-related side effects and for response to therapy. The exact monitoring and duration of treatment differ based on the patient's baseline HBeAg status and whether the patient is taking an interferon-based regimen or an oral antiviral regimen (nucleoside or nucleotide analogue). The most important measures of response to therapy consist of normalization of serum ALT levels, a decrease in serum HBV DNA level, loss of HBeAg (in patients HBeAg-positive at baseline), and loss of HBsAg (in patients HBeAg-negative at baseline). According to American Association for the Study of Liver Diseases (AASLD) guidelines, all patients on therapy for HBV should have a liver panel measured every 3 months and HBV DNA levels quantified every 3-6 months. Our opinion is that ALT monitoring would be sufficient for the liver panel monitoring if the patient has no evidence of cirrhosis. For patients with cirrhosis, an increase in bilirubin or decrease in albumin would be concerning. Although the development of resistance is uncommon in treatment-naïve patients starting on tenofovir or entecavir, patient adherence should be assessed at every visit. A general approach to monitoring the response to nucleos(t)ide analogue therapy, including an approach to management based on the response, is outlined in Figure 1. In addition, specific monitoring and management of patients on nucleos(t)ide analogue therapy based on their baseline HBeAg status is outlined in Figure 2 and discussed below.
In general, interferon (or peginterferon) treatment for hepatitis B is given for a fixed duration, whereas duration of therapy with nucleos(t)ide analogues varies significantly, depending on the baseline HBeAg status and the treatment response (Figure 3). When using standard interferon, the AASLD recommends treating for 16 weeks in HBeAg-positive patients and 48 weeks in HBeAg-negative patients. When using peginterferon in either HBeAg-positive or HBeAg-negative patients, the AASLD recommends a treatment duration of 48 weeks. For the HBeAg-positive patients, the 16-week course with standard interferon is inferior to the 48-week course of peginterferon and thus we do not recommend using the 16-week standard interferon regimen. Further, because peginterferon has widely replaced the use of standard interferon for the treatment of hepatitis B, the following discussion will not include any further discussion of standard interferon. When oral antiviral therapy is used, it is typically given for at least 1 to 2 years. For HBeAg-positive patients, the AASLD recommends administering oral antiviral therapy until the following three conditions are met: (1) the patient achieves an undetectable HBV DNA level, (2) HBeAg seroconversion occurs (HBeAg loss and anti-HBe detection on two occasions 1 to 3 months apart), and (3) the patient completes at least 6 months of therapy after anti-HBe has appeared. Close monitoring of relapse should occur after treatment is withdrawn. For HBeAg-negative patients, the recommendation is to continue therapy until clearance of HBsAg occurs, which unfortunately happens in an extremely low proportion of patients.
Side Effect Monitoring
Frequent clinical and laboratory monitoring for adverse effects is extremely important for patients taking standard interferon or peginterferon, as these medications can potentially cause a broad array of psychiatric, endocrinologic, and hematologic side effects. Along with regularly inquiry about psychiatric side effects, clinicians should check a complete blood cell count and liver panel every 4 weeks, and thyroid-stimulating hormone every 3 months. Several of the nucleos(t)ide analogue medications can also cause side effects that require monitoring. Telbivudine has been associated with peripheral neuropathy, particularly when given with peginterferon, and myositis. Therefore, patients on telbivudine should be queried for signs and symptoms of neuropathy and have a creatine kinase level drawn every 3 to 6 months. Reports of adefovir-associated nephrotoxicity exist, but they have predominantly involved patients in earlier trials who received a higher daily adefovir dose (30 mg) than the currently used daily dose (10 mg). Tenofovir can also cause nephrotoxicity, but the reports have mainly involved the use of tenofovir to treat HIV infection. Among HIV-infected patients on tenofovir, approximately 1% will develop renal insufficiency, including some with Fanconi's syndrome. Toxicity can manifest as weakness, glycosuria, proteinuria, hypophosphatemia, and elevated creatinine. In a large clinical trial involving patients with chronic HBV monoinfection, none of the 426 patients treated with tenofovir developed renal insufficiency. Nevertheless, since patients receiving adefovir or tenofovir can potentially develop renal insufficiency, monitoring of creatinine every 3 months is warranted for patients on chronic adefovir or tenofovir therapy.
Monitoring Response to Therapy: Terminology
The AASLD guidelines provide the following terms outlining the different response to antiviral therapy and the time points when responses are assessed in persons with chronic hepatitis B virus infection.
Category of Response
Time of Assessment of Response (Figure 4)
Patterns of HBV DNA Responses
The pattern of HBV DNA decline (kinetics) can be characterized while patients are on therapy. The proportion of patients who achieve undetectable HBV DNA levels after 1 year of therapy varies depending on the nucleos(t)ide analogue agent used (Figure 5)[7,8,9,10]. In addition, some nucleos(t)ide analogue agents cause a more rapid reduction of HBV DNA to undetectable levels than others[7,8,9,10]. For example, tenofovir causes a more rapid decline than adefovir, telbivudine more rapid than lamivudine, and entecavir more rapid than adefovir. In addition, with nucleos(t)ide analogue therapy, the reduction of HBV DNA to undetectable levels generally occurs more frequently (Figure 6) and more rapidly (Figure 7) with HBeAg-negative patients than with HBeAg-positive patients, primarily due to lower baseline HBV DNA levels in HBeAg-negative patients[7,8].
Monitoring and Management of HBeAg-Positive Patients
For HBeAg-positive patients receiving a nucleos(t)ide analogue, the most important factor that determines duration of therapy is whether HBeAg seroconversion takes place (HBeAg changes from positive to negative and anti-HBe changes from negative to positive). One-year HBeAg seroconversion rates are similar (12 to 30%) for all nucleos(t)ide analogues and interferon-based therapies (Figure 8)[1,8,11]. With nucleos(t)ide analogues, the HBeAg seroconversion rates tend to increase by 5 to 10% with each subsequent year of therapy. For patients who are HBeAg-positive at baseline, HBeAg and anti-HBe should be assessed at the end of 1 year of therapy, and every 3 to 6 months thereafter. For HBeAg-positive patients, the AASLD guidelines recommend nucleos(t)ide analogue therapy may be discontinued if the following three conditions are met: (1) the patient achieves an undetectable HBV DNA level, (2) HBeAg seroconversion occurs, and (3) the patient completes at least 6 months of therapy after anti-HBe has appeared. If therapy is discontinued, the LFTs and HBV DNA should be checked every 3 months in the first year and then every 6-12 months thereafter. We recommend extending the duration of consolidation therapy after seroconversion to a minimum of 12 months, particularly considering nucleoside analogue therapy is generally safe and well tolerated, and recent data suggest higher sustained response rates with a longer duration of post seroconversion therapy. Patients who have persistently undetectable HBV DNA levels and convert to HBeAg negative should have HBsAg checked every 6 to 12 months. Patients who do not achieve HBeAg seroconversion are quite unlikely to have continued HBV DNA suppression after stopping therapy; thus therapy should continue until this endpoint is reached.
Monitoring and Management of HBeAg-Negative Patients
For patients who are HBeAg-negative at baseline, the HBV DNA level should be followed every 12 to 24 weeks and if it becomes undetectable, a surface antigen (HBsAg) should subsequently be obtained every 6 to 12 months. The duration of therapy with nucleoside analogue therapy for HBeAg-negative patients has not been established, but generally requires more than 1 year and often is continued for at least 3-5 years. A long duration of therapy is required because of the high relapse rates, even in patients who achieve sustained on-therapy undetectable HBV DNA levels[1,13]. If, however, HBsAg clearance occurs, therapy can be discontinued. When therapy is discontinued, the LFTs and HBV DNA should be checked every 3 months in the first year and then every 6 to 12 months thereafter.
Clearance of HBsAg
Clearance of HBsAg is an important goal for all HBV antiviral therapies. For HBeAg-positive patients this occurs infrequently after 1 to 2 years of nucleos(t)ide analogue therapy[1,8,14]. The HBsAg clearance rates after receiving 1 year of therapy are less than 1% for lamivudine[9,15,16], adefovir, and telbivudine, less than 2% for entecavir, and less than 3% for tenofovir. Extending therapy for 2 years increases the clearance rates to 1 to 3% with lamivudine[3,14], 1% with telbivudine , 5% with entecavir, and 6% for tenofovir. The year 2 clearance rates reported with entecavir and tenofovir should be placed in perspective, because most of these events occurred in Caucasians, who likely acquired HBV as adults and thus have a different natural history and higher likelihood of immune-mediated clearance than in Asian counterparts. The HBsAg clearance rates for HBeAg-positive patients receiving peginterferon are 3% after 1 year of treatment, but the rate appears to increase by 2 to 3% each year after therapy has stopped. For HBeAg-negative patients, clearance of HBsAg with nucleos(t)ide analogue therapy is even more unlikely than with HBeAg-positive patients, with reported rates less than 1% with all nucleos(t)ide analogue agents[1,19]. For HBeAg-negative patients treated with peginterferon, the HBsAg clearance rates are about 6% after 1 year of therapy, increasing to about 9% 4 years after stopping therapy.
Durability of Response after Stopping Therapy
Comparing durability for each antiviral agent is difficult because of different sensitivities of the DNA assays used in the studies, the non-standardized length of follow-up, variability in study designs, and limited data on most agents. For HBeAg-positive patients who achieve an undetectable HBV DNA levels, the percentage who maintain undetectable HBV DNA levels 24 to 48 weeks after stopping nucleos(t)ide analogue therapy varies significantly depending on the antiviral agent . For HBeAg-negative patients who achieved an undetectable HBV DNA levels, fewer than 10% maintain undetectable HBV DNA levels after stopping nucleos(t)ide analogue therapy[13,20,22,23]. Based on available data, in HBeAg-negative patients, peginterferon appears to have a more durable response (normalization of ALT, HBV DNA response, and clearance of HBsAg) than nucleos(t)ide analogue therapy (Figure 9), possibly because of the immunomodulatory effects of peginterferon[1,20,21]. When therapy is discontinued, the LFTs and HBV DNA should be checked every 3 months in the first year and then every 6-12 months thereafter. There are no formal guidelines for management of a patient who has a rising HBV DNA level after stopping therapy, but if the HBV DNA level increases more than 2 log after stopping therapy, it is probably prudent to restart antivirals. In the situation where HBV levels increase after stopping therapy, drug resistance would not need to be invoked, since the patient has rising HBV DNA levels in the absence of medication pressure.
Management of Primary Non-Response and Virologic Breakthrough
If a patient has a primary non-response, they should first be questioned regarding their medication adherence. If adherence is problematic, then this issue should be addressed. If the patient apparently has good adherence, they are considered to be a primary non-responder, and, unfortunately, sparse data exist to provide definitive guidance for these non-responders. In this situation, the AASLD guidelines and other expert hepatologists recommend switching to an alternative agent of higher potency and different resistance profile. If such an agent is not available, then addition of a second agent without cross-resistance to the first agent should be made[1,19]. Patients who have developed breakthrough most likely have developed antiviral resistance. In these cases, it is recommended that resistance testing be performed and therapy tailored based on these results. Please see the case Management of Patients with Chronic Hepatitis B and Antiviral Resistance for more details.