 |
|
|
| |
PegIntron Plus Ribaivin in HCV/HIV Coinfection: French RIBAVIC Study
|
| |
| |
Reported by Jules Levin
At the Retrovirus Conference the final 72-week results were reported in 3 studies using pegylated interferon plus ribavirin for coinfected patients. These studies started several years ago and although we have been eagerly awaiting the results, it was known that coinfected patients in these studies would have significantly lower response rates than monoinfected patients. This difference is not news. Of interest, however, is the differences seen between the studies in the response rates they see for the patients in these 3 studies. It is difficult to compare between these 3 studies because the patient populations are different, they have different baseline characteristics. It is of note that the sustained viral response rate (SVR) was 40% for patients receiving Pegasys/RBV vs 12% for patients receiving standard IFN/RBV in the APRICOT study; and the SVR was 27% for PegIntron/RBV and 19% for patients taking standard IFN/RBV in this ANRS French study. Not comparing between studies but just within the studies, the magnitude of the difference between the IFN and pegylated arms are different. So in the ANRS study 27% for PegIntron/RBV vs 19% for IFN/RBV, the magnitude of the difference is 8% points and the p value was 0.03. In the APRICOT study the magnitude of the difference between Pegasys/RBV and IFN/RBV was 40% vs 12% and the p value was 0.0001). I would like to hear an explanation for this. For patients with genotypes 2/3 the SVR was 62% for Pegasys/RBV in APRICOT vs 36% for patients receiving IFN/RBV, the magnitude of difference was double. For non-1 genotypes in the ANRS study the SVR was 43% for patients receiving PegIntron/RBv and 40% for patients receiving IFN/RBV, no difference. For genotype 1 in APRICOT SVR was 29% for Pegasys/RBV vs 7% for IFN/RBV, 4 times magnitude of difference. For genotype 1 in ANRS, SVR was 11% or 15% vs 5% (see below for these figures).
My report on ACTG 5071 is forthcoming but it is difficult to compare to APRICOT. Although ACTG 5071 also compares Pegasys/RBV to IFN/RBV they dose escalated RBV from 600 mg daily to 1000 mg daily over a period of time from the beginning of the study. We learned from the HALT-C study that a lower RBV dose at the start of therapy can reduce response rates. In addition, there were 33% African-Americans and 14% Hispanics in ACTG 5071 and this high percentage may have had the effect of reducing the overall study SVR, because we know that African-Americans and perhaps Hispanics as well do not usually respond as well to IFN/RBV.
To read my report detailing the results from APRICOT (Pegasys/RBV vs Pegasys monotherapy vs IFN/RBV) go to this link on my website, where a provide a further comparative analysis of the 3 coinfection studies, and again I remind you that it isdifficult to compare between studies:
http://www.natap.org/2004/CROI/croi_5.htm
This is link to section where NATAP Retrovirus Conference reports are posted, so far youÕll find about 10 reports but more are coming from me and researchers/doctors covering the conference for NATAP:
http://www.natap.org/2004/CROI/croi.htm
THE STUDY ANRS PegIntron/RBV vs IFN/RBV
Christian Perrone and colleagues presented for the French ANRS trials group the final 72-week (48 weeks treatment plus 24 week follow-up) at the 11th Retrovirus Conference in San Francisco on Feb 12, 2004. The ANRS HC02 (RIBAVIC) study is a 400-person randomized controlled trial of PegIntron (pegylated interferon a-2b) plus ribavirin vs standard interferon (alfa-2b) plus ribavirin for the initial treatment of hepatitis C in HIV & HCV coinfected patients.
This is a multicenter, randomized, parallel-group, open-label trial comparing:
--PEG-IFN a-ab 1.5 ug/kg/week plus 800 mg ribavirin daily
--IFN a-2b 3 Million Units (MU) x 3/week plus RBV 800 mg daily
for 48 weeks.
INCLUSION CRITERIA:
Naive to HCV treatment
HCV-RNA positive
Liver biopsy within 18 months before entry
Stable HIV-RNA
Stable HAART or no HAART
CD4 count >200
PRIMARY END-POINT:
Long-term virologic response (loss of detectable HCV RNA at week 72
SECONDARY ENDPOINTS:
Safety & tolerability
Quantitative HCV RNA
Alanine aminotransferase serum values
CD4 cell count, HIV RNA
Liver histology (second biopsy sample taken at week 72)
OUTCOMES:
418 patients were randomized
4 were excluded : 3 HCV RNA negative, 1 previous IFN treatment
205 assigned PEG-IFN and RBV: 11 (5%) never treated; 77 (38%) stopped treatment;
117 (57%) achieved treatment
207 assigned IFN & RBV: 18 (9%) never treated; 72 (35%) stopped treatment; 117
(57%) achieved treatment
BASELINE CHARACTERISTICS:
Age 39 yrs
Male sex- 71-77%
Body weight- 66-67 kg
HIV
Time from seroconversion- 10.8-12.1 yrs
CD4 count- 501-527
Plasma HIV RNA: 63-69% <400 copies/ml; log10 level in >400 c/ml- 3.6
On HAART- 82-83%
HCV
Duration of HCV infection- 16-16.7 yrs
Source of infection: 78-80% IDU; 6-9% transfusion
Histology (Metavir)
--inflammation. 1.7-1.8
--fibrosis- 2.3
--F3 bridging fibrosis 22-25%
--F4 cirrhosis- 14-18%
genotype 1- 58-59%
HCV RNA 5.9 log10 copies/ml
ALT 2.2 x ULN (upper limit of normal)
Sustained ALT < ULN- 17-18%
VIROLOGIC RESPONSE
SVR (sustained viral response), ITT analysis:
--PegIntron+RBV: 55/205 (27%) SVR
--IFN/RBV SVR: 39/207 (19%)
p=0.03
Genotype 1 or 4: 15% in slides and 11% in program for patients taking PegIntron/RBV, (they combined responses for genotypes 1 & 4. For patients taking IFN/RBV, 5% had SVR (reported in slide). Difference between PEG & IFN: p=0.01).
Other Genotypes: 43% SVR for patients taking PegIntron/RBV vs 40% for patients taking IFN/RBV (p=0.68).
Authors also reported viral response (VR), in patients, who did not discontinue treatment (PEG=117, IFN=117 pts), which is like an as-treated population in HIV studies:
Week 4: 20% PEG/RBV, IFN/RBV 12%
Week 12: 41% PEG/RBV, 34% IFN/RBV
Week 24: 54% PEG/RBV, 41% IFN/RBV
Week 48: 52% PEG/RBV, 35% IFN/RBV (ETR-end of treatment response)
Week 72: 36% PEG/RBV, 28% IFN/RBV (SVR)
POSITIVE & NEGATIVE PREDICTIVE VALUES OF VIRAL RESPONSE
At different time-points with regard to SVR in patients who did not discontinue (n=234).
At week 4, 92% (PPV), 79% NPV
At week 12, 74% (PPV), 93% (NPV)
If a study patient did not have a viral response by week 12 the percent 93% that they did not achieve an SVR. Week 4 was a poor predictor for SVR, 79%. Presumably the basis for early response was a 2 log or greater HCV RNA reduction or undetectavle viral load. If a patient achieved an early viral response by week 4 92% achieved an SVR; if an early response was achieved by week 74% achieved an SVR. If a patient did not have early response by week 12 79% did not achieve SVR. So, this data plus data from ACTG 5071 supports the idea that if a coinfected patient has not achieved an early response by week 12 they are unlikely to achieve SVRÑonly 7% of study patients did not achieve early week 12 response but had SVR. I think we need more data to confirm that week 12 is a reliable cutoff for early response predicting SVR in coinfected patients. WeÕve had other data suggesting that coinfected patients may not respond as quickly to IFN/RBV therapy compared to monoinfection. Nonetheless, these results are helpful in predicting outcomes (SVR).
PREDICTORS OF RESPONSE IN THIS STUDY
--GENOTYPE. Patients with genotype 1 or 4 had better response (SVR) to PEG/RBV vs IFN/RBV (15% vs 5%), p=0.01)
--for other genotypes, there was no statistical difference (p=0.68), whether they used IFN/RBV or PEG/IFN
--FIBROSIS. They did not find fibrosis predicted outcome (p=0.28); 25% of patients with F0-F1 had SVR with PEG/IFN vs 32% with F3-F4 taking PEG/IFN. Patients taking IFN/RBV had same response rates, about 20%, regardless if they had PEG/IFN or IFN/RBV.
--ALAT. Patients with higher ALT at baseline had better viral response; when ALAT was ² 2xULN for patients taking PEG/IFN they had about 25% SVR, while 40% of patients taking PEG/IFN with ³3xULN had SVR (p=0.002). This appeared to also apply to patients taking IFN/RBV (15% vs 34%).
--CD4 count was not significant. For patients taking PEG/IFN with <500 CD4s they had 22% SVR and when CD4s were ³500 SVR was 34% (p=0.20). For patients taking IFN/RBV, SVR was about 20% regardless if CD4s were <500 or >500.
--HIV protease inhibitors. They reported that patients using protease inhibitors who were taking PEG/IFN did worse but this does not appear to be a reliable barometer because we do not know other predictive factors for patients taking or not taking PI. Patients taking PEG/IFN and a PI had 16% SVR vs 35% SVR for patients taking PEG/IFN & PI therapy (p=0.013).
--HCV RNA was not a significant predictor of outcome. In studies of HCV monoinfection, baseline HCV RNA is a significant predictor of outcome. We will await results from APRICOT where I think they looked at this and other predictors of outcome. About 28% of patients taking PEG/IFN with low viral load had SVR compared to 26% taking PEG/RBV with high viral load (p=0.36), and similarly for patients taking IFN/RBV (23% vs 17%).
HISTOLOGIC RESPONSE
Preliminary results
In the conference program book the study authors reported that in responders there was a significant decrease in Metavir scores F (-0.4 ± 0.7) and A (-1.0 ± 0.7) was observed.
Histologic responses have not yet been resported from APRICOT but will be. But histology responses were reported from ACTG 5071. ANRS researchers appeared to evaluate histologic response differently than in ACTG 5071. In ACTG 5071 52% of patients receiving Pegasys/RBV (12/23) and 62% (8/13) of patients taking IFN/RBV had HAI improvement, defined by decrease by 2 or more points; HAI was unchanged in 46% of patients taking Pegasys/RBV and in 38% of patients taking IFN/RBV.
ANRS researchers evaluated histology by median Metavir and Ishak scores at baseline and week 72 and did not see improvements for responders or non-responders.
ADVERSE EVENTS
*Where there was a difference between PEG & IFN groups (p<0.05)
percentages are approximated based on visual observation of graphs in slides.
GENERAL
Fatigue: similar in both groups, about 70% in PEG/RBV group
*Headache: 58% vs 52% (PEG vs IFN)
*Pyrexia (fever): 50% vs 40%
Myalgia: 60% vs 50%
Weight loss: 24% vs 20%
Arthralgia: 7% vs 8%
PSYCHIATRIC
*Insomnia: 30% vs 20%
Depression: 28% vs 32%
Irritability: 18% vs 21%
Anxiety: 12% vs 14%
GASTROINTESTINAL
Anorexia: 21% vs 19%
Diarrhea: 21% vs 28%
Nausea: 21% for both
DERMATOLOGICAL
Dermatitis: 22% vs 20%
Pruritis (itching): 18% vs 11%
*Injection site reaction: 18% vs 3%
Alopecia (hair loss): 12% for both
HIV-RELATEDbr clear="all" />
Increased lipodystrophy: 20% for both
Oral candidiasis: 20% vs 17%
HEMOGLOBIN, PLATELETS, NEUTROPHILS, LYMPHOCYTES
A decrease was observed at week 12 of treatment, IFN and PEG groups respectively, significant for hemoglobin (-1.4 g/dL vs -1.8 g/dL, p=0.002), and platelets (-19,000 vs -33,000, p=0.04), but not for neutrophils (-692 vs -1071), lymphocytes (-543 vs -662), or CD4 cells (-116 vs -124).
MITOCHONDRIAL TOXICITY
Researchers reported there were "mitochondrial toxicity events" mostly for patients on d4T/ddI but did not go into detail. They reported 6 cases of symptomatic hyperlactemia and 5 cases of acute pancreatitis. They reported taking ddI was associated (multivariate analysis) (OR for ddI: 44 (95%, CI: 7.1-infinity) with toxicity.
SERIOUS ADVERSE EVENTS
There were 127 serious adverse events (31%) in both groups (63 PEG, 64 IFN).
The authors summarized: PegIntron plus RBV was more effective than IFN a-2b plus RBV, and less effective than in HIV negative patients. They said there was a high proportion of severe liver disease in this study, (40%) of bridging fibrosis or cirrhosis. They said there was difficulty in maintaining patients on treatment, thus the 38% discontinuation rate.
|
|
| |
| |
|
| |
|
|
|
|
|
