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Pegylated IFN-[alpha]2b plus ribavirin as therapy for chronic hepatitis C in HIV-infected patients
 
 
  AIDS 2003; 17(7):1023-1028. Mayte Perez-Olmeda a; Marina Nunez a; Miriam Romero b; Juan Gonzalez c; Angeles Castro d; Jose Ramon Arribas c; Jose Pedreira d; Pablo Barreiro a; Javier Garcia-Samaniego b; Luz Martín-Carbonero a; Inmaculada Jimenez-Nacher a; Vincent Soriano a
 
Edit note from Jules Levin: this study has limitations. Patients with genotype 2/3 received only 6 months therapy. Until proven otherwise everything we know today suggests that HIV/HCv coinfected patients should receive 12 months therapy regardless of viral load, genotype etc. The doses used in this study of ribavirin and particularly interferon may be too low. PegIFN a-2b was initiated at 150 MU weekly and reduced to 100 MU weekly after 12 weeks. This in particular may have had a significant effect on the ability to achieve a sustained viral response. There were some interesting outcomes from this study, however. There were some concerning side effects and toxicities related to pancreatitis and severe weight loss that are described in more detail below. The relapse rate of 30% was higher than expected. The discontinuation rate due to adverse events was not bad. In the end, I'm not sure how much we learned from this study regarding the rates of sustained viral response achievable in co-infected patients. Several larger and more informing studies are ongoing and we await the final results: the large Roche Apricot study and the ACTG 5071 study also using Pegasys plus ribavirin. The large French study using PegIntron plus ribavirin in co-infected patients yielded discouraging results as sustained viral response rates were lower than in HCV mono-infected patients, and the discontinuation rates were higher than in HCV mono-infected patients. I am disappointed that the study results from this Spanish study did not report a more informed breakdown on side effects and toxicities.
 
"....This trial shows that combination therapy with peg-IFN plus ribavirin is relatively safe in HIV-co-infected individuals with CHC. Overall, treatment was discontinued because of adverse events in 15% of patients, a rate similar to that seen in HIV-negative individuals. However, some unexpected side-effects were recorded.... a significant weight loss (4.5 kg on average within 6 months) was noticed.... The sustained response rate of 35% recorded in this study (28% in the intent-to-treat analysis) is much lower than that seen in HIV-negative individuals with CHC treated with peg-IFN plus ribavirin, which approaches 60%..a fixed dose of 800 mg of ribavirin was used in this study rather than dosing ribavirin by weight..patients with >75 kg weight could have been exposed to low ribavirin doses."
 
A different consideration could apply to the short length of treatment in our trial for patients carrying HCV genotype 3. The prescription to those patients of anti-HCV therapy for only 6 months followed what is currently recommended in HIV-negative individuals. However, this rule has not been validated so far in HIV-co-infected patients. The sustained response in subjects with HCV genotype 3 was 52%, which is clearly below the 80% level reported in HIV-negative patients. Given the 30% relapse rate in those patients, extension of treatment to 12 months in subjects with high HCV loads experiencing early virological response might have improved the response rate. (edit note: after 12 months Pegasys+ribavirin the end-of-treatment response was 69% in the fried study, this 69% figure includes all genotypes).
 
Treatment of hepatitis C virus (HCV) has become a major challenge in HIV-infected individuals. Subcutaneous peg-IFN (150 [mu]g weekly during the first 12 weeks and 100 [mu]g weekly thereafter) plus ribavirin (400 mg twice a day) was given to 68 HIV-infected patients with chronic hepatitis C, having CD4 cell counts greater than 300 cells/[mu]l, plasma HIV-RNA less than 5000 copies/ml, and elevated aminotransferase levels. All were naive for IFN, and 73% were receiving antiretroviral drugs. Plasma HCV-RNA levels greater than 800 000 IU/ml were seen in 50%, and 35% carried HCV genotype 3. Adverse events leading to treatment discontinuation occurred in 10 patients (15%). One patient taking didanosine developed pancreatitis. Severe weight loss occurred in 70% of patients. Clearance of HCV-RNA at the end of therapy (6 months for HCV-3 and 12 months for HCV-1/4) occurred in 50% of patients (81% with HCV-3 versus 30% with HCV-1/4). As 30% relapsed, the overall sustained response rate was 35% (28% in the intent-to-treat analysis). The main predictors of response were infection with HCV-3 and low HCV load. The authors concluded that treatment with peg-IFN and ribavirin is relatively well-tolerated in HIV/HCV-co-infected patients, although new side-effects, including pancreatitis and severe weight loss, may result from the interaction of ribavirin with antiretroviral drugs. Overall, therapy provides cure to one third of patients, a rate significantly lower than that seen in HCV-monoinfected individuals. Given that relapses are common, extended periods of therapy should be investigated.
 
Treatment of chronic hepatitis C (CHC) was only of limited success until the use of dual combination therapy with IFN plus ribavirin. Even then, a complete eradication of hepatitis C virus (HCV) was achieved in no more than half of the patients, although those infected with HCV genotypes 2 or 3 had more than twice the chance of cure than those carrying HCV genotypes 1 or 4. More recently, the availability of a new extended release form of IFN has offered the opportunity to provide the drug once a week. Besides, the antiviral potency of pegylated IFN (peg-IFN) seems to be higher than that of the former standard IFN. Accordingly, dual combination therapy with peg-IFN and ribavirin is currently the recommended treatment for CHC. However, information on the tolerability and efficacy of peg-IFN plus ribavirin in HIV-co-infected individuals with CHC is rather scarce and limited to preliminary information derived from ongoing trials. Herein, we present the final results of a trial conducted in Spain in which HIV-infected individuals with CHC were treated with peg-IFN plus ribavirin.
 
The study began in September 2000, as an open, prospective and multicentre trial. Inclusion criteria required the age to be between 18 and 55 years, elevated transaminase levels, reactive HCV antibodies, and detectable serum HCV-RNA levels. Although a liver biopsy was recommended before beginning therapy, it was not mandatory for recruitment into the trial. All patients were naive for IFN.
 
Among the exclusion criteria were positivity for hepatitis B s antigen, a history of decompensated cirrhosis, platelets below 75 000 cells/[mu]l, haemoglobin below 11 g/dl, neutrophils below 1500 cells/[mu]l, a previous history of severe psychiatric illness, autoimmune diseases, a high alcohol intake (more than 60 g daily), or engagement in drug addiction practices. Moreover, only patients having HIV infection under control were recruited, as were those with CD4 cell counts above 300 cells/[mu]l and plasma HIV-RNA levels below 5000 copies/ml, with or without antiretroviral therapy.
 
Peg-IFN-[alpha]2b (PegIntron A; Schering-Plough, Kenilworth, NJ, USA) and ribavirin (Rebetol; Schering-Plough) were the study drugs. Peg-IFN was administered at doses of 150 [mu]g once a week subcutaneously during the first 12 weeks (induction period), and at doses of 100 [mu]g weekly thereafter. Ribavirin was administered at a fixed dose of 400 mg orally twice a day. All medications were provided for 6 months to patients carrying HCV genotypes 2 or 3, whereas they was extended to 12 months in those infected with HCV genotypes 1 or 4. The reason to prescribe higher doses of peg-IFN during an initial induction phase was taken by the scientific committee, considering the information available at that time on the initial dose-dependent effect of IFN and lower response rates in HIV-HCV-co-infected individuals. The decision to prescribe low doses of ribavirin (< 10.6 mg/kg) in patients weighing more than 75 kg was taken because of concern of a greater risk of toxicity as result of the interaction between ribavirin and some antiretroviral drugs (i.e. anaemia with zidovudine and pancreatitis with didanosine), and knowing from previous studies that most treatment candidates in Spain with HCV/HIV co-infection weigh less than 75 kg.
 
The presence of serum HCV-RNA in patients undergoing therapy and thereafter was examined using a qualitative assay (Cobas Amplicor HCV; Roche), which has a detection limit of 60 IU/ml.
 
RESULTS
 
A total of 68 subjects (76% men; mean age 39 years) were recruited at four clinics participating in the trial. A total of 73% patients were under antiretroviral therapy. The majority had been intravenous drug users. HCV genotype distribution was 1 (57%), 3 (35%) and 4 (7%). Half of the patients harboured more than 800 000 IU/ml. Data on liver histology were available for only 12 subjects; fibrosis grade F1-F3 was recognized in 10 subjects, and two had active cirrhosis (F4). 76% were men. Average age was 39; weight 69 kg (151 lbs). Estimated duration of HCV was 14 yrs and 49% longer than 5 yrs. 94% acquired HCv by IVDU. 73% were on ART: 47% on PI and 56% on NNRTI regimens. 50% had HCV RNA >800,000 IU/ml. 52% had <50 copies/ml HIV RNA and average HIV viral load was 467 copies/ml. Average CD4 count was 491. 60% had >500 Cd4s.
 
A total of 14 subjects did not complete the study. Four (6%) were lost to follow-up, whereas treatment discontinuation was as a result of adverse effects in 10 patients (15%). A woman developed clinical pancreatitis 3 months after starting therapy and required hospitalization. Anti-HCV therapy and antiretroviral drugs were discontinued, and she recovered gradually. She carried HCV genotype 3 and had been on the same antiretroviral regimen including didanosine for one year. Fortunately, she cleared HCV-RNA permanently. Four subjects showed grade 2-3 increases in serum amylase levels without clinical symptoms or just mild abdominal discomfort, which normalized after discontinuing anti-HCV therapy at the end of treatment. All four were taking didanosine concomitantly. Another two subjects showed an increase in lactate levels without clinical symptoms of lactic acidosis. Both were taking didanosine plus stavudine.
 
No patients discontinued therapy due to anaemia, although three (5.5%) needed a reduction in the ribavirin dose because haemoglobin declined more than 2 g/dl. No increases in plasma HIV-RNA levels occurred whereas anti-HCV treatment was administered; conversely, two subjects with low HIV loads who were not taking antiretroviral therapy dropped to undetectable plasma HIV-RNA levels. Two subjects (3.1%) showed a decline in the absolute CD4 cell count greater than 33% after beginning anti-HCV therapy, but the CD4 cell percentage remained unchanged. Finally, body weight declined on average 4.6 kg from baseline in subjects who completed therapy. Two patients lost 8 kg in 6 months, and the physician in charge decided to discontinue anti-HCV therapy for this reason. Both were taking stavudine concomitantly.
 
Early HCV-RNA clearance occurred in 36.1% (22/62) and 53.1% (33/61) of treated patients at 4 and 12 weeks, respectively. HCV-RNA clearance at month 6 for HCV-3 or at month 12 for HCV-1 or HCV-4 (end-of-treatment response) was seen in 27 out of 54 patients (50%) who completed therapy. Relapses occurred in eight of them (30%) within the following 6 months: two of those (20%) with HCV-1 and six of those (30%) with HCV-3 (all of whom had high HCV loads). The sustained response rate was 35.2% (19/54) overall. In the intent-to-treat analyses these figures were 39.7% for the end of therapy and 27.9% for the sustained response. All patients who permanently cleared HCV-RNA normalized their alanine aminotransferase levels.
 
In the univariate analysis, the main predictors of response were infection with HCV genotype 3 and low HCV load. Of note is the fact that 58% of sustained responders carried HCV-3. Likewise, 68.4% of responders harboured HCV loads below 800 000 IU/ml. No differences were seen comparing patients who received low ribavirin doses (< 10.6 mg/kg) in respect to those treated with adjusted doses. These characteristics were not statistically significant in being predictive of response; sex, age, weight, estimated duration of HCV, Cd4 count, HIV viral load. But the numbers of patients were small. There were non-significant trends showing the following may have influenced outcome of sustained response; HCV RNA (54% vs 20% >800,000 IU/ml had sustained viral response (SVR); 46% females vs 30% males had SVR; age was 33% vs 37%, very close; weight 35% vs 33% was very close; estimated age at time of infection 40% <25 yrs vs 26% >25 yrs had SVR; 38% with CD4 over 500 had SVR vs 30% <500 CD4 had SVR; 66% with HIV RNA >50 copies/ml had SVR vs 33% with <50 who did not have SVR—not meaningful. In the multivariate analysis, infection with HCV genotype 3 was the strongest predictor of response at the end of therapy, whereas a low baseline HCV-RNA titre was the best predictor of sustained response: HCV RNA <800,000 IU/ml (OR 5.5, p=0.009); HCV genotype 3 (OR 3,5; p=0.052).
 
Discussion
 
This trial shows that combination therapy with peg-IFN plus ribavirin is relatively safe in HIV-co-infected individuals with CHC. Overall, treatment was discontinued because of adverse events in 15% of patients, a rate similar to that seen in HIV-negative individuals. However, some unexpected side-effects were recorded. First, one subject developed pancreatitis and four additional individuals developed asymptomatic hyperamylasemia, which disappeared after discontinuing therapy. All of them were taking didanosine concomitantly. Second, lactate levels increased slightly in two individuals, both of whom were taking stavudine. Concern exists about the potential fatal development of lactic acidosis or pancreatitis in HIV/HCV-co-infected patients receiving ribavirin concomitantly with either stavudine or didanosine. Although liver histology was not available in many of our patients, variable degrees of fibrosis were recognized in all from whom histology was available, and advanced fibrosis was a common finding in HIV/HCV-co-infected patients. Our data support the cautious use of stavudine or didanosine when treatment with ribavirin is prescribed.
 
A significant weight loss (4.5 kg on average within 6 months) was noticed. It exceeded what is generally seen in HIV-negative individuals undergoing anti-HCV therapy. Long-term exposure to nucleoside analogues, and particularly to stavudine, has been associated with lipoatrophy in HIV-infected patients, most likely through a mechanism of mitochondrial damage. Hypothetically, a potentiation of this side-effect of nucleoside analogues by ribavirin could account for our findings. In fact, nearly half of the patients recruited into our trial were taking stavudine, which seems to be the drug causing more fat wasting [25]. Therefore, a significant weight loss might be another characteristic side-effect resulting from the interaction of ribavirin and HIV nucleoside analogues.
 
The sustained response rate of 35% recorded in this study (28% in the intent-to-treat analysis) is much lower than that seen in HIV-negative individuals with CHC treated with peg-IFN plus ribavirin, which approaches 60%. In HIV-negative individuals, the use of ribavirin doses below 10.6 mg/kg has been proved to reduce the chances of cure. Given that they used a fixed dose of 800 mg ribavirin per day, patients weighing less than 75 kg could have been exposed to low ribavirin doses. However, only a quarter of the study population in our trial received less than 10.6 mg/kg ribavirin, and no significant differences in the response rate were noted when comparing patients with or without ribavirin exposure above 10.6 mg/kg.
 
A different consideration could apply to the short length of treatment in our trial for patients carrying HCV genotype 3. The prescription to those patients of anti-HCV therapy for only 6 months followed what is currently recommended in HIV-negative individuals. However, this rule has not been validated so far in HIV-co-infected patients. The sustained response in subjects with HCV genotype 3 was 52%, which is clearly below the 80% level reported in HIV-negative patients. Given the 30% relapse rate in those patients, extension of treatment to 12 months in subjects with high HCV loads experiencing early virological response might have improved the response rate.
 
The recognition of early predictors of a lack of sustained response in HIV-infected patients receiving peg-IFN plus ribavirin may allow the earlier discontinuation of a medication that will not provide benefit while frequently being associated with side-effects, is expensive, reduces the patient's quality of life, and as stated earlier, may be harmful because of interactions between ribavirin and HIV nucleoside analogues. No data are available so far on the best time for discontinuing therapy in HIV/HCV-co-infected patients receiving peg-IFN plus ribavirin. In our trial, we specifically examined whether the recognition of negative serum HCV-RNA levels at different timepoints could be used for early therapy-off decision-making. The time to the first negative serum HCV-RNA levels among subjects who later achieved sustained responses was one month in 72% of cases, and 3 months in 88%. However, three of the 27 subjects (11.1%) who finally reached sustained response cleared HCV-RNA after the third month of therapy. Of note is the fact that responders carrying HCV genotype 3 did not have an apparently faster HCV-RNA clearance than those with HCV genotypes 1 or 4. Therefore, our results suggest that monitoring the response to peg-IFN plus ribavirin in HIV/HCV-co-infected patients with a sensitive HCV-RNA qualitative test does not permit the discontinuation of treatment earlier than at month 6, presuming that sustained response will not occur. Further studies are needed to determine whether monitoring the response to anti-HCV treatment with an HCV-RNA quantitative assay, following what is standard practice in HIV infection, may allow the recognition much earlier (just 1-3 months after beginning peg-IFN plus ribavirin) of a minimal drop (i.e. above 2 logs), below which no sustained response should be expected, and therefore treatment discontinuation might be warranted. This has recently been demonstrated in HIV-negative patients with CHC. As we enter an era in which HCV treatment is going to be aggressively pursued in HIV/HCV-co-infected individuals, the ability to recognize at early timepoints who will not benefit from an expensive and poorly tolerated therapy must catch more attention.
 
In summary, our results show that treatment with peg-IFN plus ribavirin is relatively well tolerated in HIV/HCV-co-infected patients. The rate of treatment discontinuation found in this study (15%) is similar to that seen in HIV-negative individuals. However, the sustained response rate was 35% (28% in the intent-to-treat analysis), which is clearly lower than that seen in HIV-negative counterparts. The short duration of therapy (6 months instead of 12) in patients with HCV genotype 3 could have contributed to explaining this limited benefit. Moreover, the intrinsic characteristics of HIV infection itself might reduce the activity of peg-IFN plus ribavirin, part of which is immune-mediated and may require a well-preserved immune system to work appropriately.
 
 
 
 
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