Hepatitis C virus (HCV) causes chronic infection in 50%-84% of HIV-negative individuals,1,2 resulting in cirrhosis, hepatocellular carcinoma, and end-stage liver failure, and affects nearly 300 million people worldwide. HIV infection is increasingly complicated by coinfection with HCV.3 The prevalence of HIV/HCV coinfection in Europe is reported as 30%, with higher rates observed in countries with larger numbers of intravenous drug users.4 Evidence shows increasing sexual transmission of HCV among HIV-positive men who have sex with men (MSM), particularly among those treated at central London clinics.5,6 HCV is more problematic in HIV-positive patients because of higher HCV RNA titers, more rapid progression to fibrosis and cirrhosis, and ultimately increased mortality.7-11 HCV infection is also associated with an increased risk of progression to AIDS or death despite the use of highly active antiretroviral therapy (HAART),12-14 although this remains controversial.15 The appropriate treatment of this group of patients is important.
A sustained virologic response (SVR) rate of 90%-98% has been demonstrated in HIV-negative individuals with acute HCV treated with interferon α-2b alone.16-18 Results from large randomized clinical trials in HIV-negative individuals have shown that combination treatment of pegylated interferon α and ribavirin in chronic HCV infection is virologically superior to interferon α-2b with and without ribavirin.19-21 The efficacy of pegylated interferon α and ribavirin in treating acute HCV has not yet been determined in a large trial.
The aims of this study were to study the factors in the transmission of HCV among HIV-positive MSM, to assess the outcome of treatment of acute HCV infection with pegylated interferon α and ribavirin, and to identify the determinants associated with therapeutic success.
All HIV-positive individuals attending the Kobler Clinic at the Chelsea and Westminster Hospital have an HCV antibody test at their initial visit and annually thereafter, and liver function tests (LFTs) are performed every 3 months. HCV testing is also performed if there are unexplained changes in LFT results or known sexual exposure to an HCV-positive contact. Eligible individuals for this study were HIV-positive patients who were previously HCV antibody negative, in whom acute HCV infection was diagnosed by a new positive HCV antibody test (BioRad, Monolisa AntiHCV Plus, version 2, Marnes-la-Coquette, France). Positive HCV antibody tests were confirmed by a 2nd HCV antibody assay (IMX-MelA, Abbott HCV 3.0 IMX, 3rd generation; Abbott Laboratories, Abbott Park, IL). Quantitative HCV RNA titers were measured using HCV branched DNA (Bayer Healthcare LLC, Tarrytown, NY, <3200 copies/mL) and qualitative HCV RNA was detected by transcription-mediated amplification (TMA, Bayer Diagnostics, <50 copies/mL).
Patients in whom acute HCV infection had been diagnosed were referred to the specialist hepatitis coinfection clinic. Individuals had sequential quantitative HCV RNA titers at 4-weekly intervals for 12 weeks. If at 12 weeks the HCV RNA remained positive, they were offered treatment with Viraferon, Shering-Plough, Kenilworth, NJ, pegylated interferon α-2b 1.5 μg/kg/wk and weight-based ribavirin 800-1200 mg/d for 24 weeks. Patients with rising HCV RNA titers in the first 12 weeks of monitoring were offered treatment earlier. Patients on treatment were followed up at 0, 4, 12, 24, 32, and 48 weeks and their treatment response was monitored using qualitative HCV RNA. An end-of-treatment response was defined as HCV RNA negative at cessation of treatment, and an SVR or treatment success as HCV RNA negative 24 weeks after cessation of treatment.
Data were collected on the demographics, reasons for testing for HCV, and HCV genotype. Individuals were questioned about risk factors for HCV acquisition at their 1st hepatitis clinic visit, specifically about any injecting or nasal drug use, tattoos, blood transfusion prior to 1991, and unprotected receptive anal sex or fisting. Variables analyzed included age, serum alanine aminotransferase levels (ALT, upper limit of normal 37 IU/L), serum hemoglobin (g/dL), neutrophil count (×109/L), antiretroviral history, HIV viral load (<50 copies/mL, branched DNA Quantiplex HIV RNA assay version 3.0, Chiron Diagnostics, Ltd., Essex, UK), and CD4+ lymphocyte count and percentage (standard flow cytometry). Patients were questioned about side effects at each visit and their responses documented. HIV antiretroviral regimens were adjusted to avoid interaction with HCV treatment.22,23
Univariate analysis was performed using SAS (SAS Institute, Inc., Cary, NC, 1988). All P values are 2 tailed. Values found to be significant in univariate model (P < 0.15) were used to build the multivariate model. Logistic regression analysis technique was used to control for other factors.
Fifty individuals were identified with acute HCV infection with a mean age of 37 years (range, 25-58 years). Forty-five were white, 2 were black Afro Caribbean, 1 Asian, 1 Indian, and 1 South American. All were MSM and the most common risk factor for acquisition of HCV was recent unprotected anal sex (44/50, 88%). One individual (2%) admitted to recent intravenous drug use, and in 5 individuals (10%) no risk factor was identified. Of note, in 10 individuals primary or secondary syphilis had been diagnosed within the year preceding HCV seroconversion, in 5 of whom syphilis had been concurrently diagnosed with acute HCV infection.
Forty-four patients (88%) were diagnosed as a result of abnormal LFT results, including 3 with frank jaundice and 1 who had also had sexual contact with a known HCV antibody-positive individual. Four further individuals (8%) were tested because of recent unprotected sex with a known HCV antibody-positive individual. Two individuals (4%) were identified by routine HCV testing at HIV seroconversion but had a documented HCV antibody-negative test result within the previous 6 months. Results of HCV genotyping were available for 36 individuals (24 treated, 12 untreated); 31 (86%) were genotype 1 and 5 (14%) were genotype non-1.
Overall, 12 individuals became HCV RNA negative spontaneously (median time, 11 weeks; range, 3-14 weeks), and all remained HCV RNA negative with a median follow-up of 14.5 months (range, 1-61 months). The remaining 38 patients were offered treatment: 27 patients accepted but 11 declined and remained HCV RNA positive.
The spontaneous HCV RNA-negative group was compared with all patients who remained HCV RNA positive at 12 weeks (Table 1, left column). Factors associated with spontaneous seroconversion were a higher baseline median CD4+ lymphocyte count (566 cells/mm3 vs. 349 cells/mm3, P = 0.029), particularly at >500 cells/mm3 (8/12, 67% vs. 9/38, 24%, P = 0.017) and lower baseline median HCV RNA titer (4.1 log10 vs. 6.4 log10, P = 0.017). There were, however, no significant differences in median baseline HIV RNA viral load, proportion receiving HAART, median peak ALT at diagnosis, or prevalence of HCV genotype 1.
The spontaneous HCV RNA-negative group was then compared with individuals who declined treatment (Table 1, right column). Spontaneous clearance was significantly associated with a higher median baseline CD4+ lymphocyte count (566 cells/mm3 vs. 429 cells/mm3, P = 0.023), particularly a baseline CD4+ lymphocyte count of >500 cells/mm3 (8/12, 67% vs. 2/11, 18%, P = 0.019).
Twenty-seven individuals received standard combination treatment of Viraferon pegylated interferon α-2b I.5 μg/kg/wk and weight-based ribavirin 800-1200 mg/d. Eighteen individuals became HCV RNA negative by week 12, 16 of whom remained negative at 24 and 48 weeks. A further 2 individuals became HCV RNA negative after week 12 but before week 24; however, they both had relapses within 6 months of stopping treatment. Therefore the end-of-treatment response rate was 18/27 (67%) and the SVR rate was 16/27 (59%). The median time to HCV RNA negativity was 4 weeks (range, 1-12 weeks). The only factors associated with an SVR (Table 2) were a higher mean peak ALT (469 IU/L vs. 269 IU/L, P < 0.001) and a higher baseline CD4% (28% vs. 24%, P = 0.041). Univariate and multivariate logistic regression analysis found an ALT change of >176 IU/L to be the only factor significantly associated with treatment success. Treatment success appeared more likely in genotype non-1 than genotype 1 (4/4, 100% vs. 11/20, 55%); however, this result did not reach significance (P = 0.258).
We examined the effect of the dose of ribavirin used, which ranged from 800 mg to 1200 mg/d. Twenty-five individuals commenced ribavirin ≥1000 mg daily and 2 patients received 800 mg per day due to low body weight. Three individuals receiving 1000 mg/d developed anemia while on ribavirin, 1 of whom continued on a reduced dose of ribavirin (600 mg/d) and an SVR was still achieved (genotype 1). Two further individuals required a blood transfusion and discontinuation of ribavirin at week 4 of treatment and treatment ultimately failed (both genotype 1). One further individual discontinued ribavirin (1000 mg/d) at week 4 due to lethargy but still achieved an SVR (genotype 1). Statistical analysis revealed no association between ribavirin dose and treatment outcome (Table 2).
The median HCV RNA titers of those who spontaneously seroconverted and those who responded to treatment were seen to fall below 3.51 log10 copies/mL, the lower limit of detection of our assay, by week 12 (Fig. 1). The median HCV RNA titers of those who did not respond to treatment were seen to fall at week 24 due to the 2 patients described here who became HCV RNA negative after week 12 but before week 24 but who did not have an SVR.
The average CD4+ lymphocyte count drop on treatment was 5 cells/mm3 per week; however, the CD4% was unchanged at +0.13% per week. The median CD4+ lymphocyte count fell significantly from baseline to week 24 in both the treatment success (−55 cells/mm3, P < 0.001) and treatment failure (−59 cells/mm3, P = 0.014) groups. The CD4% remained unchanged. No loss of HIV virologic control was demonstrated during treatment, but additionally anti-HIV response was poor. Of individuals being treated for acute HCV infection but not receiving HAART, 6/11 (55%) had a maximum ≥0.5-log drop in their HIV RNA viral load. One individual who became HCV RNA negative was not receiving HAART and had an HIV RNA viral load drop from 3.8 log to <1.7 log (ie, undetectable).
Adverse Events and Discontinuation of Treatment
Toxicities and treatment discontinuations are summarized in Table 3. Side effects were frequent in both the treatment success and treatment failure groups; however, only 1 individual discontinued treatment because of toxicity (flulike symptoms and myalgia) at week 6 and treatment failed. The most common side effect reported in both groups was depression (10/16, 63% vs. 6/11, 55%) and the commonest laboratory abnormality was neutropenia (9/16, 56% vs. 4/11, 36%). Patients were supported with antidepressant medication and granulocyte colony-stimulating factors as required. Anemia has been discussed in the previous section. Four individuals stopped all treatment due to rising HCV RNA titers on treatment (median, 14 weeks; range, 6-20 weeks), 1 of whom also defaulted HIV treatment.
Previously, rates of sexual transmission of HCV were thought to be low; however, a rise in the sexual transmission of HCV has been reported by HIV centers in London5,6 and Paris.24 Increases in HCV seroconversion among HIV-positive MSM have been associated with high-risk sexual behavior such as unprotected anal sex, fisting, and rimming and suggest an interaction between HIV infection and sexual practice.25 In addition, plasma HCV RNA titers are higher in coinfected patients and correlate with levels in saliva and semen, which may also explain increased sexual transmission of HCV.26 Studies by Browne et al5 and Chaix et al24 revealed recent unprotected anal intercourse as the only reported risk factor for transmission of HCV in 88% and 100% of MSM diagnosed with acute HCV infection, respectively. This suggests a worrying lack of adherence to safe sex guidelines that should be addressed with all HIV clinic attendees and when regular sexual health screening is offered.
We observed a spontaneous clearance in patients with less immune suppression and lower baseline HCV titers, a finding that supports data suggesting that response to anti-HCV therapy is dependent on the CD4+ lymphocyte count and the hypothesis that immune tolerance is thought to play a part in the chronic evolution of HCV.27,28 The spontaneous clearance rate of 24% is lower than the 45% reported in the Irish and German cohorts of pregnant women infected while receiving immunoglobulins to rhesus D29,30; in these studies, the remarkably high recovery rates may have reflected the small size of the inoculum, the young age at the time of infection, and a more favorable outcome of HCV infection in women. The median time to spontaneous recovery in this study was 11 weeks and is consistent with data from studies of acute HCV infection in HIV-negative subjects. These data support a policy of delaying treatment of acute HCV infection for 12 weeks in HIV-positive subjects.18,31
The SVR rate of 59% is not significantly different from SVR rates observed in chronic HCV treatment in coinfected patients but is inferior to response rates reported in HIV-negative subjects treated acutely for HCV infection.16-18 Our findings suggest that unlike data on HIV-negative individuals, the acute treatment of HCV is not more effective than chronic HCV treatment in coinfected individuals. SVR was only significantly associated with a higher peak ALT and CD4%, with no significant difference between genotypes32-34 and no association with CD4+ lymphocyte count or HCV RNA titers.20,27,28
Few studies have examined the treatment of acute HCV in HIV-coinfected individuals. One study evaluated the outcome of acute HCV in 12 HIV-positive individuals treated with pegylated interferon monotherapy for just 12 weeks.35 The findings were comparable to ours in that 75% of individuals were genotype 1 and the rate of SVR of 67% was similar. Chaix et al examined the treatment of 10 HIV-positive patients who received early treatment of acute HCV infection with standard interferon or pegylated interferon alone or in combination with ribavirin, none of whom responded to treatment.24 In contrast, in a retrospective study of 11 patients Vogel et al36 reported an SVR rate of 91% in coinfected patients treated for a median of 25 weeks with interferon (n = 2), pegylated interferon (n = 4), or pegylated interferon plus ribavirin (n = 5). The majority of the patients in the study by Vogel et al were symptomatic, a feature known to be associated with a higher spontaneous clearance in HIV-negative individuals, although data in HIV-positive patients are lacking, making it difficult to ascertain whether this was entirely a treatment effect. The mean peak ALT was significantly higher than in our group (668 IU/L vs. 385 IU/L), a factor we found to be significantly associated with treatment response. There was also less immune depletion in the German group, 50% of whom had a CD4+ lymphocyte count >500 cells/mm3, and so the higher SVR in their group would be consistent with our data.
For the 12 nonresponders to treatment, it may be that higher doses of pegylated interferon α-2b and ribavirin might improve response, but data are lacking. Previous guidelines supported the treatment of individuals with HCV genotype non-1 for 24 weeks but suggested that patients with genotype 1 have 48 weeks of treatment.19-21 Published data on the treatment of acute HCV thus far have been on patients treated for 24 weeks.16-18 However, recent guidelines for the treatment of coinfected patients advise considering extending treatment to 48 weeks for non-1 genotypes37 as there have been several reports of increased relapse in coinfected patients treated for only 24 weeks.38 Our patients, most of whom were genotype 1, received only 24 weeks of treatment as opposed to 48 weeks of treatment, which the majority of studies on treatment outcome in chronic HCV have used. Thus the response to treatment in the acute setting may be improved by extending the duration of treatment of genotype 1 to 48 weeks.
Five individuals who responded to treatment had persistent elevation of ALT despite having an SVR, perhaps due to antiretroviral therapy (2/5) or even HIV itself.19,36 Treatment with pegylated interferon α-2b was associated with a significant fall in CD4+ lymphocyte count that reversed on cessation of treatment, but there was a modest anti-HIV effect only.39 Toxicity was frequent and patients required significant psychologic and medical support, although treatment discontinuation was uncommon, perhaps due to the short duration of treatment.
In conclusion, our study found that in HIV-positive patients in whom acute HCV infection was diagnosed and treated early, the SVR rate did not differ dramatically from SVR rates demonstrated in patients with chronic HCV infection but was associated significantly with a high peak ALT. We also found that the rate of spontaneous recovery was associated with better immune function and lower HCV RNA titers. Therefore, although this study shows that there is certainly benefit for some individuals, treatment of acute HCV infection in HIV-positive individuals is not as effective as is reported in HIV-negative individuals, and we advocate that it be considered only if HCV RNA viral load remains positive after 12 weeks. Whether treatment of acute HCV infection has an impact in reducing the transmission of HCV remains to be seen.
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