HCV Snapshots: Macro to Micro
HCV Prevalence in Europe Tracked
The enormously productive EuroSIDA study has reported on the prevalence of HCV in the cohort and on the effect that hepatitis C infection has on response to HAART. At the 9th European AIDS Conference in Warsaw, Poland, Jurgen Rockstroh, from Bonn, presented an evaluation of 4,957 members (50.6%) of the large cohort who have had an HCV antibody test. About a third (1,685) were HCV positive. In general, coinfected persons were slightly more likely to be female and to be Caucasian. Not surprisingly, 75% of those with HCV had used IV drugs compared to less than 4 percent of those without HCV. Ominously, the median age of coinfected persons (34.2 years) was about 3 years younger than people with HIV alone, which suggests ongoing and recent infections. In the U.S. the median age of HIV-positive people with HCV would likely be several years older. An explanation might be the nearly 50 percent prevalence found in individuals from Eastern Europe, on the borders of states of the former Soviet Union where injection drug use, and HIV incidence is exploding. In central and northern Europe the prevalence was less than 25 percent.
Fewer coinfected individuals were receiving HAART, and fewer had an AIDS diagnosis, although median viral load and CD4 counts were not dramatically different between the groups. About 11.5 percent of HCV-infected individuals also had hepatitis B antigen, meaning that they were triply infected. The prevalence of chronic HBV in the non-HCV group was 5.8 percent.
In a multivariate analysis, and after controlling for other factors, there was no correlation between HCV status and progressing to an AIDS diagnosis or dying of any cause. However, those with HCV had a significantly higher relative risk (HR=3.8) for dying of a liver-related illness. The rate of liver-related death (n=53) was 0.5 per 100 patient years in the HCV-positive group and 0.1/100 per 100 patient years in HCV-negative persons.
In this cohort, no impact of HCV on HIV progression for individuals on HIV therapy was apparent. Within 12 months of starting HAART, the time to virological failure (<400 copies/mL) was about the same for both groups (p=0.77). Similarly, within 12 months of starting HAART, the time to achieve a 50 percent increase in CD4 counts was not significantly different between the groups (p= 0.3).
While there are other issues to consider (see the effect of hepatic impairment on Kaletra blood levels reported below), these findings may give some guidance to clinicians deciding whether to treat HCV before HIV in coinfected persons. If the liver disease is not serious, and if there are immunological gains to be made by starting HAART, then there seems to be little reason to expect that response to HIV therapy should be unsatisfactory.
Sexually Transmitted HCV in London
Also at the European meeting, Brian Gazzard of Chelsea and Westminister Hospital in London, reported on an epidemic of acute HCV infection in HIV-positive gay men presenting in their clinic over the past two years. Men with elevated ALT or reported contact with other HCV-positive men are now routinely screened for hepatitis C.
Of the 49 men who seroconverted, 24 were given treatment, and of the 15 who have completed therapy, 10 have become HCV antigen negative, a relatively good showing compared to treatment results in HIV-positive people with chronic HCV. Also encouraging was that 12 individuals who were not treated have had spontaneous clearance of HCV antigen. These tended to be people with higher CD4 counts and higher ALT levels. In the future the clinic will recommend waiting 12 weeks after seroconversion before initiating treatment to allow time for spontaneous clearance to occur. Five treatment failures were reported, including one discontinuation due to toxicity.
Anecdotely, Gazzard commented, he thought nearly all the men had been passive anal sex partners and that many had participated in fisting. About half the men had a recent diagnosis of syphilis. Future reseach plans include genetic fingerprinting of the HCV strains, which will allow drawing a map of the social path this epidemic has followed.
Kaletra PK With Hepatic Impairment
At long last a few studies are starting to investigate the impact that having hepatitis may have on blood levels of some of the most commonly used antiretroviral drugs. Jose Arribas, from Hospital La Paz in Madrid, Spain, presented a report in Warsaw about the effect of mild or moderate hepatic impairment in people with HCV and HIV on the pharmacokinetics of Kaletra (lopinavir/ritonavir). He took six patients with mild hepatic impairment (Child Pugh score 56), six with moderate impairment (scores of 7-9) and matched them with 12 HIV-positive, but HCV-negative controls. Everyone received lopinavir/ritonavir (400/100mg) twice-daily for 14 days, when they underwent intensive 24-hour pharmacokinetic testing.
They found that lopinavir levels were increased to a similar degree in people with both mild and moderate hepatic insufficiency. At 12 hours after a dose, the total exposure (AUC) to lopinavir was about 30 percent higher in the HCV patients than in the controls. However, ritonavir levels were increased to a greater extent in those with moderate hepatic insufficiency than in those with mild impairment. The authors recommend caution when administering Kaletra to persons with either mild or moderate hepatic impairment. With the ever-increasing number of drugs and combinations, the potential for unexpected pharmacokinetic interactions increases, especially in persons with coinfections or taking concomitant medications. Hopefully, more of these small but important studies will continue to fill in the blanks about how to use these drugs in the variety of patients who are out there.
Abnormalities in Liver Mitochondria
An interesting study presented at the European Conference by Leonardo Calza and colleagues from Bologna, Italy looked carefully and closely at the differences in liver cell mitochondria between people with HIV/HCV coinfection and people with HCV alone. Past studies have described ultrastructural mitochondrial abnormalities in HCV-positive persons both with and without HIV, although some studies found a stronger association in those receiving antiretroviral therapy.
Calza obtained liver biopsies from 68 patients and prepared two samples, one for examination by electron microscopy and the other for conventional histologic examination. Persons in Group A (n=40) were coinfected with HIV/HCV. Those in Group B (n=28) had HCV alone. The only significant differences between the groups were increased triglycerides and higher HCV RNA in Group A. Most of those in Group A were on HAART, with half receiving a PI-based regimen.
The histological examination reported more severe disease in Group A (33% vs 12%). Microvesicular liver steatosis was also more common in Group A (97% vs. 63%) as were moderate to severe ultrastructural abnormalities (55% vs. 30%). Intramitochondrial inclusions or crystals were twice as common in Group A (35.9% vs. 17.9%) but universal in persons with HCV genotype 1b (100%). Differences were apparent between these groups, yet it can’t be said if these were due to the impact of HIV on HCV disease or due to the mitochondrial toxicity of the HIV drugs that most of the coinfected patients were taking.
Rockstroh J, Mocroft A, Soriano V, et al. Influence of hepatitis C coinfection on the HIV disease progression within the EUROSIDA cohort. Program and abstracts of the 9th European AIDS Conference; October 25-29, 2003; Warsaw, Poland. Abstract F12/4.
Nelson M, et al. Increasing incidence of acute hepatitis C in HIV-positive men secondary to sexual transmission: epidemiology and treatment. Program and abstracts of the 9th European AIDS Conference; October 25-29, 2003; Warsaw, Poland. Abstract F12-3.
Arribas J, Pulido F, Peng JZ, et al. Evaluation of multiple-dose pharmacokinetics of lopinavir/ritonavir (LPV/R) in HIV and HCV coinfected subjects with mild or moderate hepatic insufficiency. Program and abstracts of the 9th European AIDS Conference; October 25-29, 2003; Warsaw, Poland. Abstract F2-6.
Calza L, Verucchi G, Biagetti C, et al. Liver mitochondrial abnormalities associated with HCV-monoinfection, HIV-HCV-coinfection, and antiretroviral therapy in a cohort of 68 adult patients. Program and abstracts of the 9th European AIDS Conference; October 25-29, 2003; Warsaw, Poland. Abstract F16/3.
Back to the GMHC Treatment Issues October 2003 contents page.