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Safety of Pegasys Plus Ribavirin in HIV/HCV Co-infection (APRICOT STUDY)
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"SAFETY of PEGASYS 180 ug/week plus RIBAVIRIN (COPEGUS) 800 mg/day in HIV/HCV CO-INFECTION COMPARED to HCV MONO-INFECTION"
Reported by Jules Levin
Authors: N Brau (Bronx VA, NYC), M Rodriguez-Torres (Santruce, PR), APRICOT Study Group, Roche, and others.
In HCV monoinfected patients the combination of a pegylated interferon plus ribavirin (RBV) is the treatment of choice. Overall sustained virologic response (SVR) rates ranged from 56% to 63% after 48 weeks of treatment with Pegasys plusRBV in pivotal phase III trials by Fried et al and Hadziyannis et al. In HCV/HIV co-infected patient, Pegasys plus RBV (Copegus) therapy led to an overall SVR rate of 40% in the APRICOT Study. This was significantly (p<0.0001) higher than with Pegasys monotherapy (20%) or interferon plus RBV combination therapy (12%).
As safety concerns have been raised about the use ofcombination therapy in HIV/HCV co-infection, Roche compared the safety profile of Pegasys plus RBV in patientswith HIV/HCV co-infection in the Apricot study with that of patients enrolled in Hadziyannes et al with HCV mono-infection. They also examined events specific to HCV/HIV co-infection by comparing patientstreated with Pegasys plus RBV and Pegasys monotherapy in APRICOT.
AUTHOR CONCLUSIONS
In general, the combination of Pegasys 180 ug/wk plusRBV 800mg/day has asimilar AE profile in patients with co-infection and HCV mono-infection. Both groups had similar rates of premature withdrawal for safety reasons.
The need for Pegasys dose reductions was similar in the two populations, but RBV dose reductionsfor anemiawere more frequent in HIV/HCV co-infection. This may be dueto a higher rate of cytopeniain co-infected patients owing to AZT therapy or HIV itself.
A lowincidence of hepaticcompensation was observed in cirrhotic patients enrolled in APRICOT, but there was no difference between the groups treated wth Pegasys plus RBV and Pegasys plus placebo. Thus, it is important to determinethe Child-Pugh score at baseline and monitor hepatic function during treatment of patients with cirrhosis. Hepatic decompensation was not reported during phase III studies of Pegasys plus RBV in HCV mono-infection.
There was no increase in the incidence of metabolic events (eg, symptomatic hyperlactatemia, pancreatitis) in patientstreated with RBV vs placebo in Apricot. This suggests that the background rate of events is related to ART and is not increased by the co-administration of RBV. (note from Jules Levin: studies show RBV can increase ddI exposure).
In patientstaking AZT in addition to Pegasys plusRBV or Pegasys plusplacebo in APRICOT, there seemed to be more profound anemia and neutropenia than in patients who were not taking AZT.
Considering theoverall SVR rate of 40% with Pegasys plus RBV in APRICOT, and the similar safety profile comparedwith HCV mono-infected, thecombination appears to have afavorable benefit to risk ratio with HIV/HCV co-infection.
PATIENTS
Patients eligible for Apricot were HCV-treatment naïve, HCV+, and had detectable HCV RNA, elevated ALT and were supposed to have compensated liver disease. Patients were required to have detecable HIV antibody or HIV RNA and to have stable HIV disease with a CD4 >100. The use of a stable HAART was allowed.
Patients eligible for the study by Hadziyannis et al were required to be HIV-negative. Otherwise the inclusion criteria were similar to those applied in APRICOT. Interferon and RBV naïve adult patients with a positive HCV-antibody test, detectable HCV RNA levels, elevated ALT, and compensated liver disease were included.
STUDY DESIGN
Safety data from HCV/HIV co-infected patients randomized to treatment with Pegasys plus RBV 800 mg/day (n=288) were compared with HCV mono-infected patients (n=361, Hadziyannes et al) treated with Pegasys plus RBV 800 mg/day.
Both studies were conducted by Roche using similar guidelines for patient management, data collection and analysis. The only difference in patient management was that growth factors were allowed for the management of anemia and neutropenia in APRICOT, but not in Hadziyannes. For this reason, and the possible presence of other confounding variables, comparisons between two separate studies must be interpreted with caution since unequal distribution of risk factors associated with safety outcomes may influence the results.
They also compared specific safety data between patients randomized to Pegasys plusRBV with Pegasys plus placebo in Apricot.
RESULTS
COMPARATIVE SAFETY IN CO-INFECTED and MONO-INFECTED PATIENTS
In Apricot, 289 HIV/HCV co-infected patients were randomized to Pegasys180 ug/week plus RBV 800 mg/day andreceived at least one dose of study medication. One patient did not have a post-baseline safety assessment, resulting in a safety population of 288. In the Hadziyannes study, 361 HCV mono-infected patients were randomized to Pegasys 180 ug/week plus RBV and received at least one dose of study medication.
In APRICOT a lower proportion of patients were female & patients were on average younger and of lower weight compared with patients in the Hadziyannes study. HCV/HIV co-infected patients had higher HCV RNA levels than HCV mono-infected patients.
BASELINE CHARACTERISTICS
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APRICOT
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HADZIYANNES
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Mean age
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39
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42
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% females
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20%
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37%
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mean body wt
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72 kg
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77 kg
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Wh/bl/Asian/other
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80/11/1/8%
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87/3/9/1%
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Mean ALT in IU/L
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85
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81
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Mean HCV RNA
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12 mill c/ml
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7 mill c/ml
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HCV genotype 1
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61%
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69%
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Bidging fibrosis or cirrhosis
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15%
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25%
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Cirrhosis
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8%
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7%
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Mean HIV log c/ml
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2.3
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na
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<50 c/ml HIV-RNA
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60%
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na
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Mean CD4
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520
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na
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<200 CD4
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6%
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na
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on HAART
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85%
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na
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In HCV/HIV co-infected patients the incidence of serious adverse events was higher than in HCV mono-infected patients (Table 2), but treatment related serious AE and premature withdrawal for safety reasons were similar in the two groups. Of patients treated with Pegasys/RBV 800mg/day there was 1 death (0,3%) in Hadziyannes and 4 deaths (1.4%) in APRICOT. Two of the 4 deaths in APRICOT occurred after completion of the 24-week untreated follow-up period. One death in each study (0.3%) was judged to be treatment-related.
Table 2. OVERVIEW OF THE SAFETY PROFILE OF PEGASYS/RBV
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Co-infection
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Mono-infection
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N=288
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n=361
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Serious AE
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17%
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9%
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Treat-related AE
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9%
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4%
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Deaths
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1.4%
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0.3%
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Deaths, treat-related
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0.3%
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0.3%
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Premature withdrawal for safety reasons
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15%
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16%
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The overall incidence of lab abnormalities was low in both groups, but HCV/HIV coinfected patients had a higher incidence of anemia (hemoglobin <8.5 g/dL, 3.8% vs 0.3%) and neutropenia (neutrophils <0.5 x 109/L, 10.8% vs 4.7%) and thrombocytopenia (platelets <50 x 109/L, 7.6% vs 4.2%) than HCV mono-infected patients.
In HIV/HCV co-infected patients the incidence of RBV dose reductions due to AE or anemia was higher than in HCV mono-infected patients. By contrast, dose reductions of Pegasys for AE or to manage neutropenia or thrombocytopenia were similar in the two groups (Table 3).
DOSE REDUCTIONS FOR AE OR LAB ABNORMALITIES
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Co-infection
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Mono-infection
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IFN
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RBV
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IFN
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RBV
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AE or lab abnorm
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38%
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37%
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33%
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28%
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AE
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10%
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24%
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11%
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19%
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LAB ABNORM:
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33%
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18%
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25%
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10%
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--ALT
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0.7%
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0
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0.3%
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0
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--anemia
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1.4%
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16%
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0.3%
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9%
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--neutropenia
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27%
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1%
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22%
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0.6%
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--thrombocytopenia
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6%
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1.4%
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3.9%
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0.6%
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--other
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2.4%
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0.7%
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1.7%
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0.6%
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In general the adverse event profile was similar in HIV/HCV co-infected patients and HCV mono-infected patients. However, HCV/HIV co-infected patients experienced diarrhea (28% vs 18%), asthenia (28% vs 15%), and weight loss (20% vs 6%) more frequently, while mono-infected patients more frequently had headache 51% vs 38%), insomnia (40% vs 26%), alopecia (29% vs 12%), arthralgia (29% vs 19%), irritability (26% vs 16%, and pruritus (22% vs7%).
COMPARATIVE SAFETY IN PATIENTS TREATED with PEGASYS PLUS RBV or PEGASYS MONOTHERAPY in APRICOT
Patients receiving Pegasys plus RBV had greater mean decreases from baseline in hemoglobin levels compared with recipients of Pegasys plus placebo in APRICOT. In both groups, hemoglobin levels decreased to a greater extent in patients receiving AZT at baseline. A similar pattern was seen in proportion of patients with hemoglobin levels <10 g/dL during treatment & followup.
EFFECT OF AZT and/or RBV ON HEMOGLOBIN
ALL PATIENTS
Pegasys/placebo: -2.7 g/dL n=286
Pegasys/RBV: -3.4 g/dL n=288
PATIENTS RECEIVING AZT AT BASELINE
Pegasys/placebo: -3.3 g/dL n=103
Pegasys/RBV: -3.9 g/dL n=96
PATIENTS NOT RECEIVING AZT AT BASELINE
Pegasys/placebo: -2.2 g/dL n=183
Pegasys/rbv: -3.1 g/dL n=192
PERCENT OF PATIENTS IN APRICOT STUDY RECEIVING AZT AND/OR RBV WITH HEMOGLOBIN LEVELS <10 g/dL DURING TREATMENT
ALL PATIENTS
Pegasys/placebo: 8%
Pegasys/RBV: 14%
PATIENTS RECEIVING AZT AT BASELINE
Pegasys/placebo: 17%
Pegasys/RBV: 26%
PATIENTS NOT RECEIVING AZT AT BASELINE
Pegasys/placebo: 3%
Pegasys/RBV: 8%
PERCENT OF PATIENTS IN APRICOT RECEIVING AZT AND/OR RBV WITH NEUTROPHIL COUNTSDECREASED TO <750 CELLS/uL
ALL PATIENTS
Pegasys/placebo: 36%
Pegasys/RBV: 40%
PATIENTS RECEIVING AZT AT BASELINE
Pegasys/placebo: 59%
Pegasys/RBV: 45%
PATIENTS NOT RECEIVING AZT AT BASELINE
Pegasys/placebo: 23%
Pegasys/RBV: 38%
The proportion of patients with neutrophil counts <750 cells/uL was higher among those who were receiving AZT at baseline in both treatment groups, although the difference was much less pronounced for the patients treated with Pegasys plus RBV.
Among patients treated with Pegasys plusRBVandPegasys plusplacebo in APRICOT, the incidence of symptomatic hyperlactatemia and pancreatitis was low and similar (table 5).
Hepatic decompensation occurred in 5 patients (1.7%) treated with Pegasys/RBV and 5 patients (1.8%) treated with Pegasys plus placebo. Among those treated with Pegasys/RBV, the condition resolved in 2 patients, was unresolved at end of followup in a third patient and 2 individualsdied. In those treated with Pegasys plus placebo, the condition was unresolved at end of followup in 2 patients patients & 3 individuals died.
Table 5. METABOLIC ADVERSE EVENTS IN APRICOT
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Lactic Acidosis/symptomatic hyperlactatemia
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Study wk
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Dose of Peg
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NRTI use
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At onset
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RBV at onset
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at onset
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Pegasys/RBV
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Pt 1
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4
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180 800
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AZT/3TC
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2
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14
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90 800
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ddI/d4T
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3
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20
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135 800
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ddI/d4T
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4
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31
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135 800
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ddI/d4T
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5
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58
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none-a
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d4T/3TC
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Pegasys/placebo
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Pt 1
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12
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180
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ddI/d4T
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2
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16
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180
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d4T/3TC
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3
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31
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180
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AZT/3TC
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4
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31
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180
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d4T/3TC
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a-discontinued prematurely for AE
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Pancreatitis
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Pegasys/RBV
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Pt 1
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14
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90 800
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ddI/d4T
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2
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50
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none-a
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none
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Pegasys/placebo
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Pt 1
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12
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none-a
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ddI/d4T
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2
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12
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180
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d4T/3TC
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3
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42
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180
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d4T/3TC
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4
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76
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none
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ABC/3TC
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