Spontaneous clearance and treatment of acute hepatitis C infection in HIV-positive men with 48 weeks of interferon-alpha and Ribavirin

Abstract

Acute hepatitis C infection in the context of HIV is an emerging problem in men who have sex with men (MSM). We conducted a retrospective cohort study of MSM diagnosed with and treated for acute hepatitis C infection over 10 years. Genotype 1 was the commonest type representing 69% of cases; the spontaneous clearance rate was 20%. The overall sustained virological response (SVR) rate on an intention-to-treat basis was 83%; SVR and was 92% for those completing 48 weeks of treatment. The presence of detectable RNA at week 12 had a 100% negative predictive value for SVR. This is the largest single cohort treated with 48 weeks of interferon and ribavirin and the treatment SVR is one of the highest reported. We propose that a 48-week treatment regimen may be superior to shorter (24-week) regimens though we acknowledge the need for a randomized controlled trial.

Keywords

hepatitis C acute HIV men who have sex with men MSM treatment interferon ribavirin

Hepatitis C virus (HCV) is a common infectious agent worldwide, affecting approximately 170 million people.¹ Because of shared routes of transmission, HCV and HIV co-infection is an important issue, with approximately one in 10 individuals infected with HIV also infected with HCV worldwide.² This figure is one in four in developed countries and can be up to 50–95% in certain risk groups such as intravenous drug users.³ In the era of combination antiretroviral therapy (cART), HCV-related liver disease has emerged as a major cause of morbidity and mortality among these patients.^4–6

Since 2000, outbreaks of acute HCV among HIV-positive men who have sex with men (MSM) have been reported in the UK and Europe, the USA and Australia.^7–10 This reflects a significant change in the epidemiology of HCV, with it emerging as a sexually transmitted infection (STI) within this population.^11,12 The mechanism of sexual transmission remains uncertain but there is an emerging association with certain sexual practices (fisting, use of sex toys and group sex)^11,13 and ulcerative STIs (notably syphilis and lymphogranuloma venereum).¹⁴ Cases of sexual transmission of HCV infection in heterosexuals remain uncommon.¹⁵

Several studies have demonstrated that co-infection with HIV adversely impacts on every stage in the natural history of HCV infection. Co-infection with HIV enhances HCV transmission, decreases rates of spontaneous HCV clearance leading to higher rates of chronic infection,¹⁶ and is associated with higher HCV RNA loads.¹⁷ Once chronic infection is established, HIV/HCV co-infected patients have higher necro-inflammatory activity on liver biopsies, faster rates of fibrosis progression and higher rates of and earlier development of end-stage liver disease.^18,19

Recent studies on the natural course of acute HCV infection in HIV-positive individuals have reported rates of spontaneous clearance in between 13% and 16% of patients.²⁰ In patients not clearing the virus, early treatment (within 3–6 months) with a combination of pegylated interferon-alpha and ribavirin is generally recommended and leads to sustained virological response (SVR) rates considerably higher than in the treatment of chronic infection in HIV-positive individuals.^21,22 Treatment studies have reported SVR rates for treatment in the acute phase between 59% and 82%.^10,22–29 The patient demographics are broadly similar between the different published studies but they are heterogeneous in their distribution of HCV genotypes and in the length of combination treatment administered. It was initially believed that different genotypes had no influence on treatment response rates; however, recent data suggest that treatment of acute HCV genotype 2 and 3 infections are associated with a higher SVR rate than for genotype 1, similar to the genotype effects seen in chronic HCV therapy.²⁶ The data on the effect of treatment duration on SVR rates are conflicting. In one cohort, longer treatments were associated with higher SVR rates,²⁶ whereas in the only direct comparison of 24-week and 48-week regimens, there was no significant difference in treatment outcomes.²⁵

Here we present our experience of a 48-week treatment regimen of pegylated interferon-alpha and ribavirin. This is the largest cohort from a single treatment centre treated with 48 weeks of combination therapy.

Subjects and Methods

This is a retrospective cohort study of HIV-positive men who have sex with men (MSM) diagnosed with acute hepatitis C infection undertaken between October 2001 and October 2010. The case definition of a case of acute HCV was taken from the European AIDS Treatment Network (NEAT) consensus guidelines as below. No diagnoses were made on the basis of criterion 3.

(1)

Positive anti-HCV immunoglobin (IgG) in the presence or absence of a positive HCV RNA and a documented negative anti-HCV IgG in the previous 12 months or

(2)

Positive HCV RNA and a documented negative HCV RNA and negative anti-HCV IgG in the previous 12 months or

(3)

Positive HCV RNA regardless of anti-HCV IgG with an acute rise in alanine aminotransferase (ALT >5× upper limit of normal [ULN]or >3.5× previous abnormal ALT) and exclusion of other causes of hepatitis.

We calculated an estimated date of HCV infection for each case using an established formula from large observational studies (to allow for interstudy comparisons), as follows (whichever occurred first):

(1)

Six weeks prior to the midpoint between the first abnormal ALT and the last normal ALT or

(2)

Six weeks before the midpoint between last negative anti-HCV antibody and first positive anti-HCV antibody (or HCV RNA).

Patients were seen every 3–4 months for routine blood tests (including liver function tests) and were tested annually for anti-HCV IgG. HCV RNA testing was performed if there were unexplained abnormal liver function tests or a patient had a sexual exposure to a known HCV-positive individual.

Patients in whom acute HCV was diagnosed were assessed regularly for HCV RNA to assess for spontaneous clearance as determined by a repeated negative HCV polymerase chain reaction three months apart (limit of detection 30 IU/mL). All patients were referred to a dedicated co-infection clinic and those who failed to clear the virus were offered treatment within 24 weeks of diagnosis. Forty-eight weeks of weekly pegylated interferon-α2a (Roche, Welwyn Garden City, UK) and weight-based ribavirin (1200 mg/day for subjects > 75 kg and 1000 mg/day for subjects < 75 kg) were planned in all cases. Patients on treatment were monitored using quantitative HCV RNA at 0,12, 24, 48 and 96 weeks. From 2008, quantitative HCV RNA was also undertaken at week 4. Rapid and end-of-treatment virological responses were defined as having undetectable HCV RNA at week 4 and at cessation of treatment, respectively (RVR and ETR). Early virological responses, cEVR and EVR, were defined as undetectable and ≥2-log drop in HCV viral load by week 12. An SVR was defined as having an undetectable HCV RNA 24 weeks after cessation of treatment.

Analysis

Data were collected on patient demographics as well as reason for HCV testing, CD4 count, HIV history, maximal measured ALT and HCV genotype. Details of sexual health screens in the last 12 months were also taken.

Statistical analysis was performed using SPSS for Windows version 17 (SPSS Inc, Chicago, IL, USA). Dichotomous variables were analysed by the Fisher's Exact test and continuous, non-normally distributed variables (CD4 count and ALT) were analysed by Mann-Witney U test.

Predictors (above variables) of attaining an SVR on treatment were analysed by binary logistic regression.

Results

We identified 74 cases of acute HCV in 71 individuals. All cases were presumed to be sexually acquired as only one patient admitted intravenous drug use but also engaged in high-risk sexual behaviour. Of these, 15 cleared spontaneously (20%) and of the remaining 59, 49 were deemed suitable for treatment and 43 accepted (see Figure 1). In 30% of those cases that did not clear spontaneously, the viral load fluctuated over three months, falling below 1000 IU/mL or becoming negative before rebounding to higher levels.

Figure 1

Spontaneous clearance and treatment of 74 cases of acute hepatitis C

The demographics, how diagnosed and distribution of HCV genotypes are shown in Table 1. The median age of patients was 42 and 51% were taking cART. Genotype 1 was by far the commonest representing 69% of cases. Of those treated, 88% (38) were genotypes 1 or 4 and 12% (5) were genotypes 2 or 3.

Table 1

Demographic of cases of acute HCV

	Variable	Number (n = 74)
Median age (years) (range)	42 (22–62)
Ethnicity
White UK	61 (82%)
White non-UK	11 (15%)
Black/Other	2 (3%)
How diagnosed
ALT rise	45 (61 %)
Surveillance	22 (30%)
Partner HCV five	4 (5%)
At HIV diagnosis	3 (4%)
Median CD4 count (cells/mm³)	482 (126–996)
On cART	38 (51 %)^∗
HCV genotype
1	51 (69%)
2/3	7 (9%)
4	7 (9%)
Unknown	9(12%)

cART= combination antiretroviral therapy; ALT = alanine aminotransferase;

HCV= hepatitis C virus

∗

Thirty-eight patients were on cART of whom 33 had an undetectable viral load

In 58 cases (78%) a sexual health screen had been undertaken in the preceding 12 months. The incidence of STIs was high with 57% of those tested having an STI and 16% having two or more STIs (Table 2).

Table 2

Incidence of recent sexually transmitted infection in cases

	Disease	Percentage (N = 58)
Chlamydia	21
LGV	10
Gonorrhoea	17
Syphilis	10
HSV	9
Any STI	57
≥2 STI	16

LGV = lymphogranuloma venereum; HSV = herpes simplex virus; STI = sexually transmitted infection

None of the variables collected predicted spontaneous clearance. Indeed, a higher ALT or presence of an abnormal ALT at diagnosis was associated with the development of chronicity in this cohort (Table 3).

Table 3

Spontaneous clearance of acute HCV

	Variable	Cleared (n = 15)	Not cleared (n = 59)
Median CD4 count	505	483	0.586
CD4 nadir	259	252	0.725
Time HIV+	7.2 years	6.1 years	0.472
On cART	6	32	0.393
Abnormal ALT	9	55	0.004
Median Max ALT	606 (33–3409)	785 (44–2736)	0.027
Jaundice	2	12	0.721

cART = combination antiretroviral therapy; ALT = alanine aminotransferase

One subject was lost to follow-up and four subjects stopped treatment before 48 weeks (see Figure 1) due to intolerable side-effects or virological failure. The median length of time from the calculated infection date to the initiation of treatment was 31 weeks (range: 16–48 weeks). There was no association between the duration of infection and the likelihood of treatment success.

The rates of RVR (n = 16), cEVR, EVR and SVR are shown in Table 4. The overall SVR rate on an intention-to-treat basis was 83% (35/42) and was 92% (35/38) for those completing 48 weeks of treatment. The presence of detectable RNA at week 12 (lack of cEVR) had a 100% negative predictive value for SVR. All patients but one had at least a 2-log drop in viral load at week 12 (EVR). An RVR had a 100% positive predictive value for SVR. We identified no factors that predicted a successful treatment response.

Table 4

Treatment outcome by early viral kinetics

Outcome	Number	SVR	No SVR	PPV
cEVR	39	35	4	PPV: 90%
No cEVR	3	0	3	NPV: 100%
EVR	41	35	6	PPV: 85%
No EVR	1	0	1	NPV: 100%
RVR^∗	9	9	0	PPV: 100%
No RVR	7	5	2	NPV: 29%
Overall	42	35 (83.3%)	7

NPV = negative predictive value; PPV = positive predictive value; RVR = rapid virological response; EVR = early virological response; cEVR = complete virological response

∗

Week 4 viral load (RVR) was only measured from 2008 and therefore there are only data on 16 cases

Conclusion

This is the largest report from a single centre in which subjects were all treated with 48 weeks of pegylated interferon-α2a and ribavirin. This is also one of the highest reported SVR rates of currently published studies despite 88% of treated subjects being infected with the more difficult to treat genotypes 1 and 4.²⁶ We suggest that this current study lends weight to an argument that a longer treatment duration, 48 versus 24 weeks, may be optimal treatment for acute HCV infection in this setting. However, a large, randomized, controlled clinical trial is required to answer this question. This is a retrospective study with no control arm and there is considerable heterogeneity between published studies in terms of subjects and distributions of genotypes. The first published treatment study of acute HCV infection in HIV-positive MSM by Gilleece et al.²³ (n = 27) treated subjects for 24 weeks and reported a treatment success rate of 59% which is significantly lower. In the largest published European series combining several European cohorts from Boesecke et al.,²⁶ longer treatment durations were associated with improved outcomes. This study examined treatment responses in 211 patients with a median treatment duration of 24 weeks and reported an SVR rate of 65% which again is significantly lower. However, a study from Matthews et al.¹⁰ (n = 20) in Australia reported an SVR rate of 80% for a 24-week treatment regimen. In their study 64% of patients were genotype 1 compared with 89% in Gilleece's study which may explain, in part, differences in treatment success rates.^10,23 The only study directly comparing a 48-week and a 24-week treatment regimen found an odds ratio in favour of the longer course of 2.32, which was not statistically significant and had large 95% confidence intervals (0.39–13.97).²⁵ This concluded that a 24-week regimen was comparable to the 48-week regimen but was arguably underpowered to definitively draw this conclusion. Most studies have had relatively small numbers of subjects and thus the calculated confidence intervals are broad and often overlapping. They are also heterogeneous and difficult to compare directly. There is some evidence that treatment regimen success rates have improved over time and this may be due to an increased use of supportive measures such as granulocyte-macrophage colony stimulating factor and erythropoietin. There is a clear need for a large, prospective study directly comparing different treatment regimens in well-defined populations.

In the management of patients chronically infected with HCV, viral kinetics strongly correlates with treatment response. Patients who demonstrate an RVR will achieve an SVR between 85% and 95% of the time, for genotype 1 and non-genotype 1 infection respectively. Furthermore, lack of an EVR is the single greatest predictor of treatment failure in chronic HCV.³⁰ Treatment durations can therefore be determined on the basis of rapid and early viral kinetics.³¹ Our study provides evidence that this approach could potentially be applied in the management of acute HCV infection in HIV where response rates are significantly lower than in non-HIV patients. We show that an RVR has a 100% positive predictive value for ultimate SVR with a 48-week treatment regimen. Some authors would argue that patients attaining an RVR could be treated effectively with a shorter 24-week course of interferon and ribavirin though there is little direct evidence to support this.²¹ Our study is unable to comment on this. Failure to achieve a cEVR has a 100% negative predictive value for ultimate SVR and therefore these people could stop treatment at week 12, saving both considerable financial expense and significant side-effects of continuing treatment. They might then be candidates for treatment with newer agents.

Our study found no demographic, clinical or laboratory parameters that were associated with either spontaneous clearance or successful treatment. In contrast to other studies,²¹ in our cohort a higher ALT and the presence of an abnormal ALT at diagnosis actually predicted the development of chronicity rather than spontaneous clearance. Although our numbers are relatively small (n = 74), they are larger than several other studies and thus the presence of severe hepatitis at diagnosis can no longer be thought of as reassuring and necessarily predictive of clearance. In non-HIV patients, a high ALT (>500 IU/L) has been associated with attaining an SVR on treatment,³² but our study and others have failed to show this in the context of HIV co-infection.²² However, patients in this study had blood samples at three or four monthly intervals and so the rates of ALT elevation could be an underestimation. There are conflicting data on whether HIV variables predict clearance and treatment response and we found no associations in our cohort.^22,23,33 Gilleece et al. found that a higher baseline CD4 count was associated with treatment success but we were unable to confirm this. However, in our study most patients had high CD4 counts with a median of 482 cells/μL.

In almost one-third of cases in this study that did not spontaneously clear, the HCV viral load fluctuated, dropping below 1000 IU/mL and in some cases becoming negative, before chronic infection was established. This confirms the findings of a recent study by Thomson et al.²⁷ We hypothesize that there is a degree of transient immunological control of the acute infection before immune defences are overwhelmed. This reiterates the need for regular monitoring particularly in patients where HCV viral loads appear to be falling or become negative as these patients are not necessarily clearing the virus.

In most published studies, treatment was initiated within 12 weeks of diagnosis. Our aim was to start interferon and ribavirin treatment within 24 weeks of diagnosis and this was initiated at a median time of 31 weeks (range: 16–48 weeks) from the calculated time of infection. Although the calculated time of infection has problems of accuracy, the method of measurement used was consistent in these studies. In this study, we have initiated treatment significantly later than in other studies and yet have preserved excellent SVR rates. There is always a balance between early treatment of acute HCV and not wanting to treat patients who will spontaneously clear, particularly in light of our data confirming that individuals may have fluctuating viral kinetics before chronic infection can be diagnosed. Our data suggest that there may be less urgency to treat acute HCV than previously thought and this would allow more time for patients who are going to spontaneously clear to do so, minimizing the risk of inappropriate treatment and associated drug toxicity.

In summary, we have shown that a 48-week course of combination therapy of interferon-ct and ribavirin leads to very high SVR rates in the treatment of acute HCV in HIV infection. This is in spite of the majority of cases being the relatively treatment-resistant genotypes 1 and 4.

Footnotes

Conflict of interest: The authors declare that they have no conflicts of interest in association with this manuscript.

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