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Toxicities in HIV/HCV Coinfected Treated with Peg-Intron + RBV
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RANDOMIZED TRIAL OF INTRON A AND RIBAVIRIN VERSUS PEG-INTRON AND RIBAVIRIN IN HIV HCV COINFECTED PATIENTS. INTERIM REPORT ON SAFETY DATA
(abstract 985. AASLD, Dallas, Nov 2001)
Alberto Juarez, Juan I Esteban, Hosp Univ Vall d' Hebron, Barcelona Spain; Silvia Sauleda, CTBT, Barcelona Spain; Esteban Ribera, Inmaculada Ocana, Isabel Ruiz, Vicens Falco, Rafael Esteban, Jaume Guardia, Hosp Univ Vall d' Hebron, Barcelona Spain
Study reports early results at 12 weeks. They report concern about seeing perhaps more significant or faster declines in platelets and neutrophils in coinfected patients receiving Peg-Intron than in patients receiving standard IFN. 1 patient receiving DDI+d4T experienced symptomatic lactic acidosis requiring hospitalization within 20 weeks. 3 additional patients experienced elevated lactate within 11-19 weeks on: AZT/3TC, d4T/3TC, or ddI/d4T. Authors recommend more frequent monitoring in coinfected patients, certainly with regards to WBCs and serum lactate levels.
Background: With the increased life expectancy associated with the use of highly active antiretroviral therapy (HAART), adequate treatment of chronic hepatitis C has become a priority in HIV HCV coinfected patients. Although limited data suggest that interferon (IFN) and Ribavirin (RBV) combination therapy in these patients may be as effective as in HIV-negative individuals, concerns still remain regarding its safety in patients receiving multiple antiretroviral drugs.
In January 2001 we started a randomized trial to compare the safety and efficacy of IFN a2b + RBV with that of Pegilated IFN a2b + RBV in HIV HCV coinfected patients receiving HAART. We here report preliminary safety data on this ongoing trial.
Patients and Methods: Coinfected patients under HAART with stable HIV infection (CD4 ≥200; HIV RNA ≥10,000), stratified according to sex and HCV genotype (1/4 or 2/3), are randomized to receive Intron A 3 MU/tiw + RBV 800 mg/d (group I) or Peg-Intron 1.5 mg/Kg/w + RBV 800 mg/d (group II) for 6-12 months according to genotype. Patients are monitored weekly during the first month and monthly thereafter for side effects, hematological parameters, LF tests, HCV RNA, HIV RNA and CD4 cell count.
Results: As of June 2001, 36 patients (24 males, 12 females; mean age: 37±5 years; all but 3 receiving one-5 patients-or two-28 patients-nucleoside reverse transcriptase inhibitors-NRTI-as part of their HAART) have been enrolled (18 per group) and treated for 13±7 weeks (range:2-21 wks). Changes in blood cell counts in each group are shown in table 1. Similar changes in Hb level and absolute CD4 occurred in both groups. Only one of the 9 patients receiving zidovudine has required a reduction in RBV dose because of Hb£10gr/dl. A significant decrease in platelets was not seen in group I until week 12, but was evident in group II (Peg-Intron) patients 1 week after treatment onset (185±64 vs 150±52; p=0.03). Similarly, neutrophils decreased faster and more markedly in group II patients (mean decrease from baseline at week 4: 27±22% in gI vs 54±15% in gII; p£0.001) and although values tended to stabilize by week 4, further decrease beyond 8 weeks occurred in 4 patients. Overall, 6 group II patients, but none in group I, reached counts £ 1.0x109/L and 3 required a reduction in Peg-Intron dose because of serious neutropenia (£0.75x109/L). One group I patient (47 y-old female on stavudine, didanosine and efavirenz) required hospitalization because of symptomatic lactic acidosis developing at week 20. Despite initial improvement she developed bacterial pneumonia and died with multiorgan failure 1 week later. Three additional patients (1 on stavudine + didanosine + efavirenz; 1 on stavudine + lamivudine + ritonavir; 1 on lamivudine + zidovudine + efavirenz) have subsequently been found with asymptomatic hyperlactacidemia (serum lactate 2.8-3.6 ng/ml) 11-19 weeks after treatment onset and had RBV discontinued.
Conclusions: 1. Peg-Intron at 1.5 mg/Kg/wk dose is associated with significantly greater neutropenia than Intron A in HIV+ patients and requires more frequent monitoring of WBCs. 2. Even low dose RBV may precipitate life-threatening lactic acidosis in patients taking NRTI-containing HAART. Until more data is available, frequent monitoring of serum lactate levels (and perhaps modification of HAART regimen) in these patients is mandatory.
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