Therapy of Chronic Delta Hepatitis With Peginterferon Alfa
Therapy of Chronic Delta Hepatitis With Peginterferon Alfa
Between October 2002 and June 2006, 13 patients were recruited with characteristics summarised in Table 1 . All patients had bridging fibrosis and only one patient had HBV DNA values above 10,000 IU/mL. One patient had an untypeable genotype and HDV RNA levels, and was thus excluded from the HBsAg and HDV RNA quantitative analyses. One patient dropped out after 7 weeks of therapy due to social reasons. Two patients died while enrolled in the study. One was diagnosed with hepatocellular carcinoma (HCC) at week 81 of treatment (at which time treatment was withdrawn) and later died from HCC complications. The patient was reported to have bridging fibrosis on his baseline biopsy but had thrombocytopaenia and markedly abnormal HVPG suggesting actual cirrhosis. The other patient had confirmed cirrhosis and Crohn's disease and was off peginterferon therapy for 6 months due to a bacterial foot infection, when he developed herpes colitis which precipitated hepatic decompensation and death.
Patients were treated for a median of 140 weeks (6–260) with an average weekly peginterferon dose of 180 μg/week (excluding treatment interruptions). The overall flow of patients is described in Figure 1. Dose reductions below 180 μg/week were required in three patients because of bone marrow suppression. Three patients were treated with a maximal dose of 225 μg/week and another three with doses up to 270 μg/week, and were able to tolerate the high dose for prolonged durations (up to 2 years). No patient was escalated to the highest permitted dose of 360 μg/week.
(Enlarge Image)
Figure 1.
Patient flow throughout the study. Of the 19 patients screened, 13 were enrolled into the study. This figure shows the follow-up and responses of the patients enrolled in the study at years 1, 3 and 5.
Biochemical Response. Six of 12 patients treated for >6 months achieved normalisation of ALT (<31 U/L), on at least one occasion while on therapy. In these six patients, the median time to ALT normalisation was 18 weeks (range 4–188, Figure 2). However, only three patients maintained a long-term biochemical response.
(Enlarge Image)
Figure 2.
This figure shows the fraction of patients becoming HDV RNA negative (red), HBsAg negative (black) or have ALT <31 U/L (blue) during course of treatment out to 240 weeks.
After 1 year of therapy, histological inflammation decreased significantly from baseline [median HAI: 10 (7–14) to 7 (5–10), P = 0.01]. The HAI score declined in 10 patients, and was unchanged or worsened in two (Figure 3a). After 3 years of therapy, liver biopsies were obtained in five patients and continued to be lower than baseline [median HAI: 7 (5–13)]. At the end 5 years of therapy, liver biopsies were obtained in four patients and HAI scores continued to be lower than baseline [median HAI: 7.5 (4–8)]. After 1, 3 and 5 years of therapy, histological fibrosis did not change significantly (Figure 3b).
(Enlarge Image)
Figure 3.
This figure shows the effect of 1 year of peginterferon treatment on histological activity (a), fibrosis (b) and HVPG (c). At 1 year, histological inflammation significantly improved (P = 0.01) but fibrosis did not, and HVPG trended towards significance (P = 0.085).
Overall histological response was achieved by six (50%) of 12 patients at 1 year. All patients who developed histological response at year 1 continued to meet the criterion for response at years 3 and 5.
Paired HVPG measurements were obtained in 11 patients at baseline and after the first year of therapy. After 1 year, the median HVPG decreased from 11.1 ± 6.4 mmHg to 8.1 ± 3.5 (P = 0.085). Of these 11 patients, seven (64%) had improved HVPG by 1–13 mmHg, three (27%) worsened by 1 mmHg and one patient had no change (Figure 3c).
After 3 years of therapy, five patients had paired HVPG measurements, with a mean of 6.2 ± 3.5 mmHg. When compared with their own HVPG at year 1, the five patients experienced a change of −1 ± 2 mmHg. At year 5 of therapy, four patients had HVPG obtained and no additional improvement was seen.
Three patients required treatment interruption due to a serious adverse event, two of which were possibly related to peginterferon. One patient (mentioned previously) had a soft tissue infection of his foot requiring hospitalisation and surgical debridement. Following treatment interruption, his infection and resultant ulcers healed. This patient later succumbed to herpes colitis as previously described. Another patient developed an autoinflammatory syndrome after 192 weeks of treatment, characterised by fevers, headaches and intermittent confusion. A thorough workup was unable to identify the specific cause of the patient's autoinflammatory syndrome. Treatment was stopped and his symptoms subsequently resolved. He was restarted on peginterferon at week 200 and did not have recurrence of symptoms and eventually achieved and maintained a VR. A third patient developed subarachnoid haemorrhage from an arteriovenous malformation at week 4 of treatment. Following successful therapy, peginterferon was resumed and she eventually achieved a CVR. Two patients required dose reduction due to cytopaenias (one anaemia and one anaemia/thrombocytopaenia).
Several distinct patterns of virological response are demonstrated in Figure 4.
(Enlarge Image)
Figure 4.
Examples of response patterns of individual patients. (a–c) complete responders, (d–e) response and breakthrough, (f–g) nonresponders.
Complete Virological Responders. Of the 12 patients treated for at least 6 months, three patients achieved a CVR after 24, 37 and 202 weeks of treatment (Figure 4a–c) by demonstrating a continuous decline in HDV RNA until it was undetectable and HBsAg seroconversion. HBsAg loss and appearance of anti-HBs occurred simultaneously and only in patients with a VR. Two of these three patients also had a biochemical response. Therapy was discontinued 12–36 weeks after loss of HBsAg, and in all three patients, HBsAg and HDV RNA remained undetectable for the duration of follow-up (58–246 weeks after stopping therapy). For two subjects (Figure 4a,b), this occurred rapidly (decline slopes of 0.29 and 0.52 log10/week in the first 4 weeks), while a third subject (Figure 4c) had an initial comparable rapid decline of 0.24 log10/week during the first 4 weeks that slowed to an average overall slope of decline of 0.03 log10/week. HBsAg levels declined in all three patients, lagging behind the HDV RNA decline, and were <100 IU/mL at the time of HDV RNA negativity and <1 IU/mL subsequently. ALT decline did not correlate well with virological decline, and in one subject ALT levels did not improve despite HDV RNA and HBsAg loss (Figure 4b).
Virological Response and Relapse. Two patients (Figure 4d,e) became HDV RNA negative but subsequently had virological breakthrough while on treatment. One of the two (Figure 4d) had a relatively fast virological response (decline slope of 0.29 log10/week in the first 4 weeks) and became HDV RNA negative by week 20 of treatment. However, HDV RNA levels subsequently rose and reached baseline levels despite continued peginterferon treatment. HBsAg levels also fell and were transiently undetectable, but later rose towards baseline. The other subject (Figure 4e) had a rapid decline in HDV RNA levels (0.21 log10/week in the first 4 weeks), which reached the lower limit of detection (100 GE/mL) by week 45. However, HDV RNA levels then rose despite continued treatment only to decline again to undetectable levels by week 129 of treatment, accompanied by marked decline in HBsAg titre. Shortly thereafter, the patient developed an autoimmune inflammatory syndrome that required a discontinuation of treatment on week 177. This treatment withdrawal resulted in a rise, initially in HBsAg, followed by HDV RNA and finally by ALT (35 weeks after stopping treatment); there was a rapid and synchronous response of all three markers to reinstitution of peginterferon on week 202, followed by achievement and maintenance of a virological response (Figure S2). Thus, this patient exhibited a flare of disease (rise in ALT to >5 times baseline) concurrent with the virological breakthrough early on treatment which was followed by loss of HDV RNA (possibly a 'clearance flare') and another flare when therapy was temporarily suspended ('withdrawal flare').
(Enlarge Image)
Figure S2.
Response pattern of patient described in Figure 4e during the period of peginterferon withdrawal which describes a withdrawal flare with a rise in HBsAg preceding the rise in HDV RNA titres.
Nonresponse. Other subjects (Figure 4f-g) never became HDV RNA negative despite an initial response (4 week slope of 0.21 and 0.27 log10/week, respectively), and demonstrate plateau or rebounding of HDV levels while on prolonged therapy. Although ALT levels improved compared to baseline, they did not fall into the normal range and neither liver histology scores nor HVPG measurements improved at subsequent evaluation.
After the initial declines in HDV RNA levels during the first 24 weeks of treatment, decreases or increases in the dose of peginterferon were not clearly associated with changes in HDV RNA levels.
Baseline and on-treatment features were evaluated for their ability to predict virological response to treatment in the 11 subjects who had HDV RNA measurements for at least 8 weeks ( Table 2 ). The three complete responders demonstrated a trend towards lower alkaline phosphatase, bilirubin and histological fibrosis scores at baseline and numerically lower HVPG and platelet count, consistent with milder disease, though statistical significance could not be reached due to the small number. Age, ALT, HBV and HDV viral levels, HBsAg titre and histological activity did not predict complete response. When comparing patients who had any virological response on treatment to those who did not ( Table 2 ), responders had lower bilirubin levels and HBsAg levels and a trend towards lower ALT. The IL28B-associated rs12989760 genotype frequency was similar for responders and nonresponders.
When assessing early kinetics of response as predictors of overall virological outcomes ( Table 3 ), the slopes of decline of HDV RNA and HBsAg during the first 4 weeks were similar for responders and nonresponders. In fact, all patients had an initial virological response with a 4-week decline in HDV RNA >0.5 log10 (mean 0.97 ± 0.35 log10), irrespective of their final outcome. By week 12 of treatment, the magnitude of decline of HBsAg was greater for patients who responded to treatment and became HDV RNA negative. However, there was still an overlap between responders and nonresponders and even more so, between complete responders and subject with virological breakthrough (Figure 5). Detailed modelling of the kinetics of response is reported separately.
(Enlarge Image)
Figure 5.
Logarithmic decline in HBsAg level from baseline to week 12 according to virological response to treatment. Squares represent complete responders, while X represents patients who became HDV RNA negative but broke through while on treatment. Compared to nonresponders, patients with response had a significantly different decline in HBsAg (P = 0.05).
Results
Patient Population
Between October 2002 and June 2006, 13 patients were recruited with characteristics summarised in Table 1 . All patients had bridging fibrosis and only one patient had HBV DNA values above 10,000 IU/mL. One patient had an untypeable genotype and HDV RNA levels, and was thus excluded from the HBsAg and HDV RNA quantitative analyses. One patient dropped out after 7 weeks of therapy due to social reasons. Two patients died while enrolled in the study. One was diagnosed with hepatocellular carcinoma (HCC) at week 81 of treatment (at which time treatment was withdrawn) and later died from HCC complications. The patient was reported to have bridging fibrosis on his baseline biopsy but had thrombocytopaenia and markedly abnormal HVPG suggesting actual cirrhosis. The other patient had confirmed cirrhosis and Crohn's disease and was off peginterferon therapy for 6 months due to a bacterial foot infection, when he developed herpes colitis which precipitated hepatic decompensation and death.
Patients were treated for a median of 140 weeks (6–260) with an average weekly peginterferon dose of 180 μg/week (excluding treatment interruptions). The overall flow of patients is described in Figure 1. Dose reductions below 180 μg/week were required in three patients because of bone marrow suppression. Three patients were treated with a maximal dose of 225 μg/week and another three with doses up to 270 μg/week, and were able to tolerate the high dose for prolonged durations (up to 2 years). No patient was escalated to the highest permitted dose of 360 μg/week.
(Enlarge Image)
Figure 1.
Patient flow throughout the study. Of the 19 patients screened, 13 were enrolled into the study. This figure shows the follow-up and responses of the patients enrolled in the study at years 1, 3 and 5.
Treatment Responses
Biochemical Response. Six of 12 patients treated for >6 months achieved normalisation of ALT (<31 U/L), on at least one occasion while on therapy. In these six patients, the median time to ALT normalisation was 18 weeks (range 4–188, Figure 2). However, only three patients maintained a long-term biochemical response.
(Enlarge Image)
Figure 2.
This figure shows the fraction of patients becoming HDV RNA negative (red), HBsAg negative (black) or have ALT <31 U/L (blue) during course of treatment out to 240 weeks.
Histological Outcomes
After 1 year of therapy, histological inflammation decreased significantly from baseline [median HAI: 10 (7–14) to 7 (5–10), P = 0.01]. The HAI score declined in 10 patients, and was unchanged or worsened in two (Figure 3a). After 3 years of therapy, liver biopsies were obtained in five patients and continued to be lower than baseline [median HAI: 7 (5–13)]. At the end 5 years of therapy, liver biopsies were obtained in four patients and HAI scores continued to be lower than baseline [median HAI: 7.5 (4–8)]. After 1, 3 and 5 years of therapy, histological fibrosis did not change significantly (Figure 3b).
(Enlarge Image)
Figure 3.
This figure shows the effect of 1 year of peginterferon treatment on histological activity (a), fibrosis (b) and HVPG (c). At 1 year, histological inflammation significantly improved (P = 0.01) but fibrosis did not, and HVPG trended towards significance (P = 0.085).
Overall histological response was achieved by six (50%) of 12 patients at 1 year. All patients who developed histological response at year 1 continued to meet the criterion for response at years 3 and 5.
HVPG Measurements
Paired HVPG measurements were obtained in 11 patients at baseline and after the first year of therapy. After 1 year, the median HVPG decreased from 11.1 ± 6.4 mmHg to 8.1 ± 3.5 (P = 0.085). Of these 11 patients, seven (64%) had improved HVPG by 1–13 mmHg, three (27%) worsened by 1 mmHg and one patient had no change (Figure 3c).
After 3 years of therapy, five patients had paired HVPG measurements, with a mean of 6.2 ± 3.5 mmHg. When compared with their own HVPG at year 1, the five patients experienced a change of −1 ± 2 mmHg. At year 5 of therapy, four patients had HVPG obtained and no additional improvement was seen.
Treatment Safety
Three patients required treatment interruption due to a serious adverse event, two of which were possibly related to peginterferon. One patient (mentioned previously) had a soft tissue infection of his foot requiring hospitalisation and surgical debridement. Following treatment interruption, his infection and resultant ulcers healed. This patient later succumbed to herpes colitis as previously described. Another patient developed an autoinflammatory syndrome after 192 weeks of treatment, characterised by fevers, headaches and intermittent confusion. A thorough workup was unable to identify the specific cause of the patient's autoinflammatory syndrome. Treatment was stopped and his symptoms subsequently resolved. He was restarted on peginterferon at week 200 and did not have recurrence of symptoms and eventually achieved and maintained a VR. A third patient developed subarachnoid haemorrhage from an arteriovenous malformation at week 4 of treatment. Following successful therapy, peginterferon was resumed and she eventually achieved a CVR. Two patients required dose reduction due to cytopaenias (one anaemia and one anaemia/thrombocytopaenia).
Kinetics of Response
Several distinct patterns of virological response are demonstrated in Figure 4.
(Enlarge Image)
Figure 4.
Examples of response patterns of individual patients. (a–c) complete responders, (d–e) response and breakthrough, (f–g) nonresponders.
Complete Virological Responders. Of the 12 patients treated for at least 6 months, three patients achieved a CVR after 24, 37 and 202 weeks of treatment (Figure 4a–c) by demonstrating a continuous decline in HDV RNA until it was undetectable and HBsAg seroconversion. HBsAg loss and appearance of anti-HBs occurred simultaneously and only in patients with a VR. Two of these three patients also had a biochemical response. Therapy was discontinued 12–36 weeks after loss of HBsAg, and in all three patients, HBsAg and HDV RNA remained undetectable for the duration of follow-up (58–246 weeks after stopping therapy). For two subjects (Figure 4a,b), this occurred rapidly (decline slopes of 0.29 and 0.52 log10/week in the first 4 weeks), while a third subject (Figure 4c) had an initial comparable rapid decline of 0.24 log10/week during the first 4 weeks that slowed to an average overall slope of decline of 0.03 log10/week. HBsAg levels declined in all three patients, lagging behind the HDV RNA decline, and were <100 IU/mL at the time of HDV RNA negativity and <1 IU/mL subsequently. ALT decline did not correlate well with virological decline, and in one subject ALT levels did not improve despite HDV RNA and HBsAg loss (Figure 4b).
Virological Response and Relapse. Two patients (Figure 4d,e) became HDV RNA negative but subsequently had virological breakthrough while on treatment. One of the two (Figure 4d) had a relatively fast virological response (decline slope of 0.29 log10/week in the first 4 weeks) and became HDV RNA negative by week 20 of treatment. However, HDV RNA levels subsequently rose and reached baseline levels despite continued peginterferon treatment. HBsAg levels also fell and were transiently undetectable, but later rose towards baseline. The other subject (Figure 4e) had a rapid decline in HDV RNA levels (0.21 log10/week in the first 4 weeks), which reached the lower limit of detection (100 GE/mL) by week 45. However, HDV RNA levels then rose despite continued treatment only to decline again to undetectable levels by week 129 of treatment, accompanied by marked decline in HBsAg titre. Shortly thereafter, the patient developed an autoimmune inflammatory syndrome that required a discontinuation of treatment on week 177. This treatment withdrawal resulted in a rise, initially in HBsAg, followed by HDV RNA and finally by ALT (35 weeks after stopping treatment); there was a rapid and synchronous response of all three markers to reinstitution of peginterferon on week 202, followed by achievement and maintenance of a virological response (Figure S2). Thus, this patient exhibited a flare of disease (rise in ALT to >5 times baseline) concurrent with the virological breakthrough early on treatment which was followed by loss of HDV RNA (possibly a 'clearance flare') and another flare when therapy was temporarily suspended ('withdrawal flare').
(Enlarge Image)
Figure S2.
Response pattern of patient described in Figure 4e during the period of peginterferon withdrawal which describes a withdrawal flare with a rise in HBsAg preceding the rise in HDV RNA titres.
Nonresponse. Other subjects (Figure 4f-g) never became HDV RNA negative despite an initial response (4 week slope of 0.21 and 0.27 log10/week, respectively), and demonstrate plateau or rebounding of HDV levels while on prolonged therapy. Although ALT levels improved compared to baseline, they did not fall into the normal range and neither liver histology scores nor HVPG measurements improved at subsequent evaluation.
After the initial declines in HDV RNA levels during the first 24 weeks of treatment, decreases or increases in the dose of peginterferon were not clearly associated with changes in HDV RNA levels.
Predictors of Response
Baseline and on-treatment features were evaluated for their ability to predict virological response to treatment in the 11 subjects who had HDV RNA measurements for at least 8 weeks ( Table 2 ). The three complete responders demonstrated a trend towards lower alkaline phosphatase, bilirubin and histological fibrosis scores at baseline and numerically lower HVPG and platelet count, consistent with milder disease, though statistical significance could not be reached due to the small number. Age, ALT, HBV and HDV viral levels, HBsAg titre and histological activity did not predict complete response. When comparing patients who had any virological response on treatment to those who did not ( Table 2 ), responders had lower bilirubin levels and HBsAg levels and a trend towards lower ALT. The IL28B-associated rs12989760 genotype frequency was similar for responders and nonresponders.
When assessing early kinetics of response as predictors of overall virological outcomes ( Table 3 ), the slopes of decline of HDV RNA and HBsAg during the first 4 weeks were similar for responders and nonresponders. In fact, all patients had an initial virological response with a 4-week decline in HDV RNA >0.5 log10 (mean 0.97 ± 0.35 log10), irrespective of their final outcome. By week 12 of treatment, the magnitude of decline of HBsAg was greater for patients who responded to treatment and became HDV RNA negative. However, there was still an overlap between responders and nonresponders and even more so, between complete responders and subject with virological breakthrough (Figure 5). Detailed modelling of the kinetics of response is reported separately.
(Enlarge Image)
Figure 5.
Logarithmic decline in HBsAg level from baseline to week 12 according to virological response to treatment. Squares represent complete responders, while X represents patients who became HDV RNA negative but broke through while on treatment. Compared to nonresponders, patients with response had a significantly different decline in HBsAg (P = 0.05).
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