Important note: Information in this article was accurate in March 2002. The state of the art may have changed since the publication date.
HIV/hepatitis C (HCV) co-infection was a particularly hot topic at the 9th CROI. Cohort studies continued to produce data regarding the long-term complications of HCV infection as well as the interaction of HAART and HCV, and treatment trials with both pegylated and non-pegylated interferon alpha with ribavirin were presented.
Zhang and colleagues used molecular epidemiologic techniques to track HIV and HCV outbreaks in China in the past year [Abstract 16]. Two distinct outbreaks of HIV and HCV occurring in different regions of China were reported: one due to contaminated blood products and blood donation techniques and the other due to injection drug use (IDU). Using molecular epidemiologic tools, they discovered that illegal blood donors and recipients of these blood products had HIV subtype B and HCV genotypes 1 and 2, whereas IDUs had HIV subtype C and HCV genotypes 1, 2, and 3. Zhang concluded that while government officials have made attempts to stop illegal blood donation, transmission is clearly still occurring, and more governmental interventions will be needed to prevent further transmission.
Carten and colleagues reported data from a study investigating the comparative sensitivity of HCV antibody against qualitative RNA screening for HCV in HIV-infected patients [Abstract 642]. They screened 221 patients in their urban cohort and found 16% positivity by antibody test. Seventy-seven percent of those with positive antibody had positive viremia, but there were no false negatives by antibody. Therefore, they concluded that HCV antibody was a reasonable screening test for the presence of HCV in HIV-infected individuals.
Several studies were presented that showed worsening morbidity in the HIV/HCV co-infected population, but data on mortality were conflicting. With 10 years of follow-up data from the Atlanta HIV VA cohort, Rimland and colleagues reported a decrease in survival time from the diagnosis of AIDS [Abstract 658]. Controlling for CD4 count at the time of HCV diagnosis, use of antiretroviral therapy, and history of opportunistic infections, the time from AIDS diagnosis to death was significantly shorter in HCV/HIV co-infected patients (Hazard Ratio 1.48, 95% CI 1.096, 1.985) as was time from HIV diagnosis to death (HR 1.39, 95% CI 1.02, 1.89).
Tedaldi presented approximately 5 years of follow-up data from the three HIV Outpatient Study (HOPS) sites [Abstract 659]. While deaths per 100 person years of follow-up were higher among HIV/HCV co-infected individuals (3.4 vs 1.7 per 100 PY, p =.008), after adjustment for baseline CD4 count and number of weeks on HAART, there was no statistically significant difference in survival time between those who were co-infected and those with HIV alone.
This author reported that while hospitalizations decreased between 1995-97 and remained flat between 1998-2000 in HIV-infected but HCV negative patients, there was a significant increase in hospitalizations for HCV/HIV co-infected patients between 1998-2000 [Abstract 660]. The bulk of the increase was due to problems related to liver disease (GI hemorrhage, hepatic encephalopathy, hepatorenal syndrome, hepatocellular carcinoma, hepatitis, chronic liver disease, or necrosis of the liver). IDU related complications remained stable between 1995-2000, while the incidence of opportunistic infections decreased between 1995-97 for both HCV negative and HCV infected patients.
Multiple studies were presented on the treatment of HCV/HIV co-infected patients. Sulkowski reported data from a multicenter randomized study of interferon (IFN) alpha 2b plus ribavirin in co-infected patients (HRN-002) [Abstract 651]. This study involved patients who had detectable serum HCV RNA, compensated liver disease, and were on stable HAART regimens. One hundred eighty patients were randomized: 90 to IFN alpha 2b 3 MU qd plus ribavirin 800 mg qd and 90 patients to IFN alpha 2b 3mU three times weekly (tiw) with the same dose of ribavirin. By intent to treat analysis at 12 weeks, daily IFN plus ribavirin was significantly more effective than standard tiw IFN and ribavirin (25.2% vs 9.8%, p =.01). However, there were significant side effects, most commonly psychiatric complications and asthenia that led to discontinuation of treatment in 20 patients (10 in each group) prior to 12 weeks. Perez-Olmeda and colleagues reported data from the Spanish HIV Interferon Ribavirin Trial (SHIRT) that demonstrated similar findings [Abstract 653]. One hundred eleven patients were randomized to receive standard dosing of IFN 3mU tiw for 6 months with ribavirin 800 mg PO bid or induction therapy with IFN 6mU daily for 6 weeks followed by IFN 3mU tiw for 6 months with the same dose of ribavirin. The study population was predominately male (82%); 47% had HCV genotype 1, 38% had genotype 3, and 15% had genotype 4. The combination of IFN and ribavirin was well tolerated, with 12% of patients discontinuing treatment due to side-effects. Sustained viral response was achieved by 22%, with no difference between treatment arms. Of note, 70% of responders had HCV genotype 3. The researchers hypothesized that the relatively low rate of sustained viral response in this trial may be explained by the relatively short duration of therapy (6 months) for patients with genotype 1.
Perez-Olmeda also presented safety and efficacy data from another Spanish study on pegylated IFN plus ribavirin [Abstract 652]. Sixty-five patients, all of whom were naïve to IFN were treated with Peg-IFN (Schering-Plough) 150 mg sc once weekly plus ribavirin 400 mg PO bid in an open-label fashion for 6-12 months. Sustained viral response was seen in 33%, but only 10% had genotypes 1 or 4. In addition, adverse events led to discontinuation of drug in 14% of patients. Adverse events included weight loss greater than 10% of pre-study weight in 70% of patients and a significant CD4 drop in 3% of study patients, though no increases in plasma HIV RNA were seen.
Sherman and colleagues reported data from ACTG 5071/5091 on IFN-2a with ribavirin vs pegylated IFN plus ribavirin [Abstract 122]. There were five patients in each arm; one patient had cirrhosis on liver biopsy, and 9/10 of patients had HCV genotype 1. The authors reported that while Peg IFN had a slightly delayed onset of action compared to IFN (9 hrs vs 7.7 hrs), the efficacy was greater (90% vs 65%), and it appeared to increase phase 1 HCV viral clearance (194 days vs 2398 days, p<.05). They concluded that by increasing the phase 1 viral clearance, viral clearance predicted by phase II kinetics may also be more rapid.
Chung also presented data from ACTG A5071, in which 133 patients were randomized to receive IFN alpha 2a 6MU tiw for 12 weeks followed by 3MU for 26 weeks versus Peg-IFN alpha 2a 180 mcg per week for 48 weeks [Abstract B15]. Patients in each arm also received ribavirin beginning at 600 mg per day and escalating to a maximum of 1 g per day. By intent-to-treat analysis, Peg-IFN had superior week-24 viral response compared with IFN alpha 2a (44% vs 15% p =.0003). The Peg group experienced more grade 4 toxicity events (17 vs 5, p =.004), but premature discontinuation of the drug was the same in both groups (15% vs 12%). Data on sustained viral response were not presented, but will be especially interesting in this group of patients, as relapse is common.
The question of the interaction of HAART and HCV RNA was further discussed at this meeting. Dietrich and colleagues conducted a retrospective analysis of 1,325 HCV/HIV co-infected patients treated with protease inhibitors for at least 3 months [Abstract 663]. Mean time on PI-containing HAART was 37.8 months. Thirty-nine percent received nelfinavir, 32% indinavir, 17% saquinavir, 13% ritonavir, and 1% amprenavir. Overall, patients had a mean increase in CD4 count of 160 cells/mm3 and a decrease in viral load of 1.12 log10 c/mL. Six percent had grade 3 or 4 elevations in AST, whereas only 3% of those on nelfinavir had this toxicity. The mean increase in CD4 count was higher than with any of the other PIs. In conclusion, nelfinavir was found to be a safe and efficacious treatment for HIV in co-infected patients.
Law reported data from a cohort of Thai HIV-infected patients enrolled in 8 HIV NAT trials [Abstract 661]. All 692 patients had received at least two nucleosides, while 215 received an NNRTI, and 135 received a PI. The prevalence of HCV was 7.7%. Despite longer time to viral suppression, median HIV RNA reductions were approximately 1.5 log10 c/mL regardless of HCV status. In addition, HIV disease progression was similar. They concluded that although it takes longer to achieve viral suppression in co-infected patients than in those without HCV, there are no significant sequelae of this delay.
Hare also presented data on the effect of viral hepatitis in HIV-infected patients treated with HAART [Abstract 662]. A higher incidence of chronically elevated ALT was found in patients co-infected with viral hepatitis, and nevirapine was the only antiretroviral agent associated with increased liver toxicity among co-infected patients in their population. In addition, those with HCV were significantly less likely to receive antiretroviral therapy than those without (AOR 0.35, 95% CI 0.13, 0.92).
Two studies regarding transplant in patients with HCV/HIV co-infection were presented. Ragni presented mortality data on 26 liver transplants performed at 5 sites [Abstract 125]. Of the 26 patients, 17 had end-stage liver disease due to HCV, 6 from HBV, and 3 had fulminant liver failure. The primary HIV risk factor was hemophilia in 27%. Seven deaths were reported from HCV: one from post-operative pancreatitis and one from acute liver rejection. Post-operatively, most patients tolerated HAART well, with the mean VL being <50 c/mL, and an increase in mean CD4 count from 250 to 295 cells/mm3 (p<.01).
Roland presented data on liver and kidney transplantation in HIV-infected patients [Abstract 655]. Eligibility criteria included no history of OI, with a CD4 count >200 cells/mm3 for kidney transplants and >100 cells/mm3 for liver transplants. Other criteria included undetectable viral load or, for liver patients, detectable HIV RNA off HAART with prediction of viral control post-transplant. Eight centers identified 23 eligible subjects (10 liver recipients and 13 kidney recipients). Two deaths occurred: one due to recurrent HCV at 14.5 months, and another due to ischemic bowel 6 months post kidney transplant. All but one graft remained viable. No opportunistic illnesses have been reported in this cohort, though in six comparison patients who did not meet inclusion criteria but were transplanted, two died from PML, and one developed MAC and aspergillosis. These two preliminary studies indicate that in patients with viable HAART options, liver transplant may be feasible for those with end stage liver disease, though further studies regarding transplant in this population will need to be completed.
While pharmacologic treatments dominated most of the hepatitis management discussion, Teshale and colleagues from Atlanta revealed that some of the most effective preventive treatments, such as vaccination for hepatitis A and abstention from alcohol, are underutilized in this population [Abstract 665]. They conducted a study of 1933 HIV/HCV co-infected patients identified as part of the Adult/Adolescent Spectrum of HIV Disease cohort. Only 6% of the co-infected patients had been vaccinated against hepatitis A, and 20% of co-infected patients were still using alcohol after diagnosis of HCV. These findings suggested that increased efforts should be made by providers to vaccinate against hepatitis A and to instruct patients on the potential interaction of alcohol and HCV.
While optimistic data regarding treatment of both HIV and HCV in co-infected patients were presented at the 9th CROI, long term effects of co-infection, including increased mortality and morbidity, suggest that these patients should be followed carefully. In addition, preventive treatment including abstention from alcohol and hepatitis A vaccination should be incorporated into routine care.
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