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APRICOT- Peginterferon Alfa-2a plus Ribavirin for Chronic Hepatitis C Virus Infection in HIV-Infected Patients
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New England Journal of Medicine July 29, 2004, Vol 351 Number 5
A total of 868 persons who were infected with both HIV and HCV and who had not previously been treated with interferon or ribavirin were randomly assigned to receive one of three regimens: peginterferon alfa-2a (180 µg per week) plus ribavirin (800 mg per day), peginterferon alfa-2a plus placebo, or interferon alfa-2a (3 million IU three times a week) plus ribavirin.
Patients were treated for 48 weeks and followed for an additional 24 weeks. The primary end point was a sustained virologic response (defined as a serum HCV RNA level below 50 IU per milliliter at the end of follow-up, at week 72).
Among patients infected with HCV genotype 1, the rates of sustainedvirologic response were 29 percent with peginterferon alfa-2a plus ribavirin, 14 percent with peginterferon alfa-2a plus placebo, and 7 percent with interferon alfa-2a plus ribavirin.
The corresponding rates among patients infected with HCV genotype 2 or 3 were 62 percent, 36 percent, and 20 percent. Neutropenia andthrombocytopenia were more common among patients treated with regimens that contained peginterferon alfa-2a, and anemia was more common among patients treated with regimens containing ribavirin.
Conclusions
Among patients infected with both HIV and HCV, the combination of peginterferon alfa-2a plus ribavirin was significantly more effective than either interferon alfa-2a plus ribavirin or peginterferon alfa-2a monotherapy.
Potent antiretroviral therapy has reduced the morbidity and mortality associated with untreated human immunodeficiency virus (HIV) infection. At thesame time, the pattern of morbidity and mortality among HIV-infected persons has shifted, and clinicians responsible for the care of HIV-infected personshave been confronted with new challenges. Complications associated with concurrent hepatitis C virus (HCV) infection have emerged as one of the mostfrequent and complex issues in the care of patients with HIV infection and the acquired immunodeficiency syndrome (AIDS).
The current standard of care for chronic infection with HCV in persons without other infections is pegylated interferon (peginterferon) plus ribavirin. This combination eradicates HCV infection and produces sustained virologic responses in 54 to 63 percent of patients. The efficacy of this combination of drugs in persons with both HIV and HCV infection has not been established. In the AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT), we studied the efficacy and safety of combination therapy with peginterferon alfa-2a plus ribavirin in people coinfected with HCV and HIV in an international, randomized, placebo-controlled trial.
72 WEEK DATA RESULTS
Demographic Characteristics of the Patients
Of 1158 subjects screened, 868 were randomly assigned to a treatment group, and 860 received study medication. The characteristics of the treatment groups were similar at baseline. The patients were predominantly white and male and had well-controlled HIV infection. Sixteen percent had cirrhosis or bridging fibrosis.
Mean HCV RNA: 5.2 to 6.4 million IU/m
%patients >800,000 IU/ml: 72%
Genotype 1: 61%
Genotype 2: 4%
Genotype 3: 28%
Genotype 4: 6%
Total cirrhosis or
bridging fibrosis: 16%
Stage 4 fibrosis: 3% IFN/rbv, <1% Peg, 2% Peg/RBV
Stage 5 fibrosis: 5-7%
Stage 6: 6%
Total histology
activity index score: 8.0
Taking ART: 85%
Mean HIV RNA: 2.3 log
% of patients <50 c/ml; 60%
Mean cd4 count: 540
Patients(%) <200 cd4s: 17-20%
Virologic Response
SVR:
Pegasys/RBV: 40% overall; genotype 1: 29%; genotype 2/3: 62%
Pegasys alone: 20% overall; Genotype 1: 14%; genotype 2/3: 36%
IFN/RBV: 12% overall; genotype 1: 7%; genotype 2/3: 20%
END-OF-TREATMENT RESPONSE
ALL PATIENTS
--IFN/RBV: 14%
--Pegasys: 31%
--Pegasys/RBV: 47%
GENOTYPE 1
--IFN/RBV: 8%
--Pegasys: 21%
--Pegasys/RBV: 38%
GENOTYPE 2/3
--IFN/RBV: 27%
--Pegasys: 57%
--Pegasys/RBV: 64%
SVR BY BASELINE VIRAL LOAD
<800,000 IU/ml
--IFN/RBV: 22%
--Pegasys: 34%
--Pegasys/RBV: 61%
>800,000 IU/ml
--IFN/RBV: 7%
--Pegasys: 15%
--Pegasys/RBV: 33%
GENOTYPE 1
<800,000 IU/ml
--IFN/RBV: 19%
--Pegasys: 38%
--Pegasys/RBV: 61%
>800,000 IU/ml
--IFN/RBV: 3%
--Pegasys: 5%
--Pegasys/RBV: 18%
GENOTYPE 2/3
<800,000 IU/ml
--IFN/RBV: 27%
--Pegasys: 38%
--Pegasys/RBV: 61%
>800,000 IU/ml
--IFN/RBV: 17%
--Pegasys: 35%
Pegasys/RBV: 63%
EARLY VIRAL RESPONSE
At week 12, 204 of 289 patients(71%) had EVR. 114 patients (56%) at week 72 had SVR, this 56% positive predictive value (PPV). Of the 85 patients at week 12 who did not have EVR, 2% had SVR, this 98% negative predictive value.
PREDICTORS OF RESPONSE
Two factors that are associated with independently and significantly increased odds of a sustained virologic response: an HCV genotype other than 1 (odds ratio, 3.37; 95 percent confidence interval, 1.96 to 5.80; P<0.001) and a baseline HCV RNA level of 800,000 IU or less per milliliter (odds ratio, 3.56; 95 percent confidence interval, 2.00 to 6.36; P<0.001). HIV-related factors including the CD4+ cell count and the use or nonuse of antiretroviral therapy, which are variables of particular interest in this population, did not meet the criteria for inclusion in the final model.
WITHDREW FROM TREATMENT
| IFN/RBV: 111 (39%) | Pegasys: 90 (31%) | Pegasys+RBV: 72 (25%) |
| 44-safety reasons | 47-safety reasons | 43-safety reasons |
| 34-insuff response | 14-insuff response | 6-insuff response |
Withdrawn
for AE or intercurrent illness: 14% IFN/RBV, 12% Peg, 12% Peg/RBV
for insufficient response: 12% IFN/RBV, 5% Peg, 2% Peg/RBV
for lab abnormality: 1%, 5%, 3%, respectively
SAFETY
The frequency of dose reductions in response to clinical adverse events was generally similar among the three groups; however, the rate of dose reductions in response to laboratory abnormalities varied according to the treatment.
Grade 4 neutropenia (<500 cells per cubic millimeter) occurred in
--1 recipient of interferon alfa-2a plus ribavirin (<1 percent)
--37 recipients of peginterferon alfa-2a plus placebo (13 percent)
--31 recipients of peginterferon alfa-2a plus ribavirin (11 percent).
Grade 4 thrombocytopenia (<20,000 cells per cubic millimeter) occurred in
--one recipient of peginterferon alfa-2a plus placebo
--one recipient of peginterferon alfa-2a plus ribavirin.
Grade 4 anemia (hemoglobin level, <6.5 g per deciliter) occurred in
--five recipients of peginterferon alfa-2a plus placebo (2 percent)
--two recipients of peginterferon alfa-2a plus ribavirin (1 percent).
Two patients withdrew from treatment with interferon alfa-2a plus ribavirin, three from treatment with peginterferon alfa-2a plus placebo, and two from treatment with peginterferon alfa-2a plus ribavirin because of anemia; one, seven, and four, respectively, withdrew because of thrombocytopenia, and none, two, and three because of neutropenia.
REDUCTION OR OMISSION OF ONE OR MORE DOSES
Due to AE:
--IFN/RBV: IFN- 12%, RBV- 22%
--Pegasys: 7% Peg, 23% RBV
--Peg/RBV: 10% Peg, 25% RBV
Due to lab abnormality:
--IFN/RBV: IFN 6%, RBV 12%
--Pegasys: 33% IFN, 12% RBV
--Peg/RBV 34% Peg, 18% RBV
Anemia:
--IFN/RBV: 1% IFN, 11% RBV
--Pegasys: 2% IFN, 6% RBV
--Peg/RBV: 1% peg, 16% RBV
Neutropenia:
--IFN/RBV: 3% IFN, 0% RBV
--Pegasys: 27% IFN, 0% RBV
--Peg/rbv: 27% IFN, 1% RBV
Thrombocytopenia:
--IFN/RBV: 1% IFN, 1% RBV
--Pegasys: 7% IFN, 2% RBV
--Peg/RBV: 6% IFN, 1% RBV
AT LEAST ONE TREATMENT WITH HEMATOPOIETIC GROWTH FACTOR
EPO: 12, 4% IFN/RBV; 14, 5% Pegasys; 30, 10% Peg/RBV
GCSF: 4, 1% IFN/RBV; 35, 12% Pegasys; 34, 12% Peg/RBV
AT LEAST 1 AE: 95%
SAE: 15-21%
Treat-related SAE: 5-10%
DEATHS
Treatment-related: 1 IFN/RBV, 1 Peg/RBV
| IFN/RBV | Pegasys | Pegasys/RBV |
| DEPRESSION: | 22% | 20% | 26% |
| HEPATIC DECOMPENSATION: | 1% | 2% | 2% |
| PANCREATITIS: | <1% | 1% | 1% |
| Symptomatic hyperlactatemia: | 1% | 0 | 1% |
| Lacticacidosis: | <1% | 1% | 1% |
The incidence of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis was low. Hepatic decompensation occurred in 14 of the 860 patients who received at least one dose of study medication and was evenly distributed among the treatment groups. All 14 patients had cirrhosis and Child--Pugh scores of 5 or higher at baseline; 6 of the 14 died.12 Ten deaths occurred during the study, and two after the end of treatment and follow-up. The death of one patient who received interferon alfa-2a plus ribavirin, attributed to respiratory failure, and of one who received peginterferon alfa-2a plus ribavirin, attributed to suicide, were judged to be possibly related to treatment.
| HIV DISEASE STATUS |
| CD4s decreased by | 131 | 135 | 157 |
| Percentage: | +1.3 | +1.4 | +3.0 |
| AIDS defining events: | 1% | 1% | 1% |
Change in HIV RNA- patients with detectable HIV RNA at baseline:
IFN/RBV: +0.016 log copies/ml
Pegasys: -0.789 log copies/ml
Pegasys/RBV: -0.696 log copies/ml
Among the 10 events there were 6 cases of esophageal candidiasis, 2 cases of herpes zoster, (one each in recipients of IFN/RBV and peg/RBV), and 2 presumptive casesof progressive multifocal leukoencephalopathy (1 each in recipients of IFN/RBV & peg/RBV).
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