Thomas C.S. Martin, Natasha K. Martin, Matthew Hickman, Peter Vickerman, Emma E. Page, Rhiannon Everett, Brian G. Gazzard, Mark Nelson
AIDS. 2013;27(16):2551-2557.
Abstract and Introduction
Abstract
Objective: Liver disease secondary to hepatitis C virus (HCV) infection in the context of HIV infection is one of the leading non-AIDS causes of death. Sexual transmission of HCV infection among HIV-positive MSM appears to be leading to increased reports of acute HCV infection. Reinfection after successful treatment or spontaneous clearance is reported among HIV-positive MSM but the scale of reinfection is unknown. We calculate and compare HCV reinfection rates among HIV-positive MSM after spontaneous clearance and successful medical treatment of infection.
Design: Retrospective analysis of HIV-positive MSM with sexually acquired HCV who subsequently spontaneously cleared or underwent successful HCV treatment between 2004 and 2012.
Results: Among 191 individuals infected with HCV, 44 were reinfected over 562 person-years (py) of follow-up with an overall reinfection rate of 7.8/100 py [95% confidence interval (CI) 5.8–10.5]. Eight individuals were subsequently reinfected a second time at a rate of 15.5/100 py (95% CI 7.7–31.0). Combining all reinfections, 20% resulted in spontaneous clearance and treatment sustained viral response rates were 73% (16/22) for genotypes one and four and 100% (2/2) for genotypes two and three. Among 145 individuals with a documented primary infection, the reinfection rate was 8.0 per 100 py (95% CI 5.7–11.3) overall, 9.6/100 py (95% CI 6.6–14.1) among those successfully treated and 4.2/100 py (95% CI 1.7–10.0) among those who spontaneously cleared. The secondary reinfection rate was 23.2/100 py (95% CI 11.6–46.4).
Conclusion: Despite efforts at reducing risk behaviour, HIV-positive MSM who clear HCV infection remain at high risk of reinfection. This emphasizes the need for increased sexual education, surveillance and preventive intervention work.
Introduction
Following the introduction of effective antiretroviral therapy (ART), liver disease has become the leading non-AIDS cause of death among HIV-positive individuals in the resource rich world.[1] The majority of liver disease in HIV-positive patients is caused by coinfection with the hepatitis C virus (HCV).[1–3] Coinfection with HIV and HCV is associated with accelerated liver fibrosis and shorter time to progression to cirrhosis and hepatic decompensation when compared with those with HCV monoinfection.[4–8]
Over the past decade, an epidemic of sexually transmitted HCV among HIV-positive MSM in Europe, the USA and Australia has been reported.[9–17] Phylogenetic analyses of circulating HCV strains in European countries suggest sexual transmission occurring since the mid-1990s.[10,18] The incidence of HCV infection among HIV-positive MSM is increasing with recent reports of rates as high as 2–5 per 100 person-years (py).[18–21] Identified risk factors for transmission include ulcerating genital infections, unprotected anal intercourse and high-risk sexual activity such as toy use, group sex, fisting and recreational drug use.[9,17,21–23]
Reinfection with HCV following either treatment or spontaneous clearance has been demonstrated in animal models, people who inject drugs (PWID) and, more recently, HIV-positive MSM.[24–27] Among PWID, weak evidence exists to suggest that individuals who spontaneously clear HCV monoinfection are at lower risk of developing chronic reinfections. This lower risk may in part be explained by the development of partial immunity leading to a higher probability of spontaneous clearance of reinfection. However, study results are highly heterogeneous and conflicting results may in part be explained by variable testing intervals during follow-up.[24,28] One retrospective study in the Netherlands revealed an alarmingly high HCV reinfection rate of 15.2 per 100 py among HIV-positive MSM who had previously been treated for acute HCV infection.[29] No studies to date have investigated the rate of reinfection among HIV-positive MSM in the United Kingdom, and whether there are differing reinfection rates among those who spontaneously clear their infections and those who are successfully treated.
We, therefore, calculated and compared the HCV reinfection rate among individuals who had either been treated for acute or chronic HCV infection, or who had spontaneously cleared their HCV infection within a cohort of over 8000 HIV-infected individuals attending clinic at Chelsea and Westminster Hospital in London, United Kingdom.
Methods
Study Population
All HIV-positive MSM who had a positive HCV antibody result between January 2004 and April 2012 who attended the dedicated HIV clinic at Chelsea and Westminster Hospital were identified. Individuals were excluded if their primary documented mode of transmission was via contaminated blood products or injecting drug use. The following subgroups were extracted for inclusion within the study.
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Successfully treated HCV infection with results indicating a sustained viral response (SVR) defined as undetectable viral replication 24 weeks following end of treatment and at least one subsequent HCV PCR measurement.
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Spontaneously cleared HCV infection with evidence for undetectable HCV PCR for at least 24 weeks following infection and at least one subsequent HCV PCR measurement.
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Spontaneously cleared or treated HCV infection who were subsequently reinfected with a different HCV genotype from their previous infection but within the 24-week period required to formally reach SVR.
Data Collection
All HCV PCR results subsequent to the first identified HCV infection were recorded. Basic HIV infection and patient characteristics were collected from medical files including age, HIV viral load, CD4+ lymphocyte subset count, ART details, HCV genotype and peak alanine transaminase (ALT) levels. Behavioural data was not routinely collected at the centre and was, therefore, unavailable for our study.
Case Definitions
HCV reinfections were defined as any newly detectable HCV PCR following SVR for treated infections or 24 weeks after spontaneous clearance. In addition, cases were defined as reinfection if patients had detectable HCV viraemia within 24 weeks of end of treatment or spontaneous clearance if there was an HCV genotype switch.
Patients were subdivided depending on whether it was possible to determine that the initial infection was their primary infection (shown by a negative HCV antibody within a year prior to positive HCV antibody detection), or that the nature of the initial infection was uncertain (no previous antibody result available or previously HCV antibody positive).
Data Analysis
For those individuals who underwent HCV antiviral treatment, the commencement of follow-up was taken from the end-of-treatment date. For those who spontaneously cleared their HCV infection, start of follow-up was the midpoint between the last positive and first negative HCV PCR. The date of reinfection for all patients was taken as the midpoint between the last undetectable HCV PCR and the first positive HCV PCR.
Reinfection rates were calculated by dividing the number of reinfections by the total number of patient-years of follow-up. Kaplan–Meier survival curves were created to assess the proportion reinfected over time. Comparisons of median testing intervals, age and peak ALT levels were performed using Kruskal–Wallis rank test. Analysis of proportion of patients on ART was performed using Fisher's exact test. Equality of variances was assessed using Bartlett's test. All statistical calculations were performed using Stata 10.0 (Stata Corp, College Station, Texas, USA).
Results
Eight hundred and fifty-eight individuals were identified with a positive HIV and HCV antibody result. Of these, 191 HIV-positive MSM with HCV who fulfilled our inclusion criteria were identified, representing 562 patient-years of follow-up. Among these patients, 145 had a documented primary infection and 46 had uncertain initial infection details. The stratification of patients is summarized in Fig. 1.
Figure 1. Flow schematic of patients included in the study. HCV, hepatitis C virus; SVR, sustained viral response.
Flow schematic of patients included in the study. HCV, hepatitis C virus; SVR, sustained viral response.
Among the 145 who had either spontaneously cleared or had been successfully treated for a primary HCV infection, there were 400 py of follow-up with a median follow-up time of 2.1 years. The median testing intervals during follow-up were 105 and 173 days among those successfully treated and those who spontaneously cleared their primary infection, respectively. The difference in testing interval was statistically significant (P < 0.0001). The median age of patients included was 41 years. Group characteristics and follow-up details are summarized in .
Table 1. Group characteristics divided by hepatitis C virus infection status during initial primary infection and during follow-up post primary infection.
| | Treated HCV infection | Spontaneously cleared HCV infection | |||
|---|---|---|---|---|---|
| All patients | Nonreinfected | Reinfected | Nonreinfected | Reinfected | |
| Incident infection | |||||
| Total | 145 | 87 | 27 | 26 | 5 |
| Median age (IQR) | 41 (38–47) | 41 (37–43) | 39 (34–43) | 36 (35–42) | |
| Incident genotype (%) | |||||
| 1 | 97 | 67 (77) | 22 (82) | 7 (27) | 1 (20) |
| 2 | 1 | 1 (1) | 0 (0) | 0 (0) | 0 (0) |
| 3 | 6 | 5 (6) | 0 (0) | 1 (4) | 0 (0) |
| 4 | 18 | 13 (15) | 4 (15) | 0 (0) | 1 (20) |
| Unknown | 23 | 1 (1) | 1 (1) | 18 (69) | 3 (60) |
| Median peak ALT of incident infection (IQR) | 476 (251–1014) | 414 (216–832) | 359 (145–755) | 95 (54–327) | |
| Follow-up | |||||
| Median testing interval, days (IQR) | 112 (62–224) | 106 (62–210) | 99 (55–161) | 189 (89–343) | 99 (63–247) |
| cART use during follow-up (%) | 129 (89) | 82 (94) | 22 (81) | 21 (81) | 4 (80) |
| Median peak ALT during follow up (IQR) | 38 (26–55) | 254 (140–892) | 58 (35–125) | 226 (168–499) | |
| Median CD4รพ at last negative HCV RNA PCR/first positive HCV RNA (IQR) | 547 (444–681) | 429 (379–624) | 531 (392–687) | 397 (280–710) | |
| Reinfection genotype (%) | |||||
| 1 | 22 (69) | 19 (70) | 3 (60) | ||
| 2 | 0 (0) | 0 (0) | 0 | ||
| 3 | 1 (3) | 1 (4) | 0 | ||
| 4 | 2 (6) | 1 (4) | 1 (20) | ||
| Unknown | 7 (22) | 6 (22) | 1 (20) | ||
Figure 2. Kaplan–Meier curves of survival free from reinfection for patients who were either spontaneously cleared or achieved sustained viral response for their primary infection. CI, confidence interval; SVR, sustained viral response.
There was no evidence of a difference in CD4+ cell count, age, use of ART or peak ALT during primary infection between patients who underwent reinfection and those who did not or between those who were treated and those who spontaneously cleared their primary HCV infection. Use of ART during follow-up was high (89%) and did not differ between groups (P = 0.11). Peak ALT levels did not significantly differ between primary infection and primary reinfection. However, peak ALT among patients who were reinfected was significantly higher than peak ALT during follow-up of patients who had no reinfection (median 253 vs. 41 U/l, P < 0.0001).
When including those with uncertain incident infection details, the overall reinfection rate was similar at 7.8/100 py (95% CI 5.8–10.5). Among the 191 patients there were 44 reinfections of whom seven (16%) spontaneously cleared their infection. Seventeen were successfully treated and the remainder failed therapy (n = 6) opted out of treatment (n = 1) or are pending final SVR results (n = 13).
Twenty-four patients had available HCV PCR results following successful treatment or spontaneous clearance of their first reinfection. Among these patients there were eight second reinfections yielding a second-reinfection rate of 15.5/100 py (95% CI 7.7–31.0). From these eight, four (50%) spontaneously cleared their infection, one opted out of treatment developing chronic infection and three were treated with results pending. From the four patients who spontaneously cleared their second reinfection, two patients underwent a third reinfection: one was successfully treated and the other is pending SVR. A summary of the eight patients who were reinfected more than once is shown in Fig. 3.
Figure 3. Flow chart of eight individuals with more than one reinfection.
Combining first, second and third reinfections, there were 54 reinfections in total. Thirty-two (59%), one (2%), two (4%), seven (13%) and twelve (22%) were genotype 1, 2, 3, 4 and unknown genotype, respectively. From the 54 reinfections, 11 patients (20%) spontaneously cleared HCV. Among patients who spontaneously cleared their reinfections, the median time to achieve undetectable viraemia was 43 days [interquartile range (IQR) 28–76.5] and the median number of positive HCV PCRs per infection was one (IQR 1–3). A total of 76% (41 of 54) of those with reinfection underwent treatment. Following reinfection, the median period until treatment was initiated was 57 days (IQR 38–112). The SVR rate among reinfections was 73% (16 of 22) for genotypes one and four and 100% (2 of 2) for genotypes two and three. Ten patients are pending SVR results.
Discussion
Our results demonstrate a high risk of HCV reinfection among HIV-positive MSM who are either treated for or who spontaneously clear their initial HCV infection. As many as 25% of individuals treated for HCV will become reinfected within 2 years. These results emphasize the need for effective sexual education for HIV-positive MSM presenting with primary HCV infection and the implementation of preventive interventions to reduce the risk of reinfection. Given their high risk, we recommend enhanced surveillance of previously infected individuals to enable the early detection and treatment of any reinfections. New UK guidelines have been updated to reflect this by recommending HCV PCR testing every 3–6 months among individuals who remain at risk following incident infection clearance.[30]
Our rate of reinfection among spontaneous clearers was lower than treated individuals (4.2/100 py vs. 9.6/100 py); however, the evidence for a difference lacked power (P = 0.15) and may have been influenced by different median testing intervals in the two groups (173 vs. 105 days, P < 0.0001), therefore providing only weak evidence for protective immunity.[24,28] The rate of reinfection among spontaneous clearers was high overall and this group should, therefore, be followed up with regular HCV PCR testing as for individuals who have been previously treated for their HCV infection.
SVR rates for individuals treated for their HCV reinfection were generally high (73% for genotype 1 and 4 and 100% for genotype 2 and 3). The majority of reinfections were treated in the acute phase of the infection (median time to treatment following first positive HCV PCR was 57 days) and SVR rates were consistent with studies treating acute HCV infections in HIV-positive MSMs.[31]
Our spontaneous clearance rate of reinfection (11 of 54 reinfections, 20%) is consistent with spontaneous clearance rates of primary HCV infection in HIV-positive MSM (5–40%).[32–36] The true spontaneous clearance rate of reinfection is likely to be higher, although, as spontaneously cleared infections may have been missed due to variable testing intervals (median 112 days, IQR 62–224). This study provides the first large cohort estimates of spontaneous clearance of HCV reinfection among HIV-infected individuals and supports monitoring for spontaneous clearance of reinfection before initiating treatment as for primary infection with HCV.
Our reinfection rate following treatment for HCV infection (9.6/100 py 95% CI 6.6–14.1) is comparable to that found by Lambers et al. (15.2/100 py 95% CI 8.0–26.5).[29] Strengths of our study in comparison to Lambers et al. are the considerably larger sample size (191 patients and 562 py follow-up vs. 56 patients and 72 py follow-up), the inclusion of spontaneous clearers in the analysis and the analysis of individuals who subsequently had multiple reinfections. The higher incidence of reinfection found by Lambers et al. may be explained by their inclusion of patients who underwent reinfection with the same genotype but different phylogeny within the 24 weeks required for definitive SVR and also shorter testing intervals during follow-up (median 91 days, IQR 58–130 vs. 112 days, IQR 62–224).[28]
Limitations of our study include its retrospective nature, the absence of behavioural data and the lack of phylogenetic analysis to prove reinfection in cases where reinfection was with the same genotype. The true reinfection rate in our cohort is likely to be higher for the following reasons: the testing interval postprimary infection was variable and long in comparison to the duration of possibly missed spontaneous clearances; and we excluded patients who developed recurrent viraemia within the 24 weeks required for SVR, whereas previous phylogenetic studies have shown a proportion of these 'relapses' to, in fact, be true reinfections.
Unfortunately, it remains difficult, as in previous studies, to definitively say that the reappearance of viraemia following treatment is not the emergence of a nondominant quasispecies or superinfection after treatment of a dominant HCV strain.[32,37] However, we believe the reemergence of viraemia is most likely to represent reinfection in our study, supported by the long duration to reinfection in most cases with multiple negative HCV PCR results between infections and the excellent response of reinfection to treatment. Finally, the patients included in our study were all from a single HIV clinic and as such our results may not be representative of other areas in London, the United Kingdom or Europe.
In conclusion, our results show high HCV reinfection rates for HIV-positive MSM who have previously cleared the infection either spontaneously or through treatment. We recommend enhanced surveillance of patients who have cleared HCV infection to allow the early detection and treatment of any reinfection. In addition, we recommend directed education and prevention interventions to HIV-positive MSMs with HCV infection. Future work will include evaluation of interventions and prospective studies to evaluate further protective immunity in this population.
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Acknowledgements
T.C.S.M. designed the study, collected and analysed the data and wrote the article. N.K.M. contributed to the study design, statistical analysis and article editing. MH and PV contributed to study design, analysis and paper editing. E.E.P. contributed to data analysis and article editing. R.E. assisted with data collection. B.G.G. and M.N. contributed to study design, data analysis and article editing.
T.C.S.M acknowledges funding to attend conferences from St Stephens AIDS Trust. N.K.M.: This work is produced by N.K.M. under the terms of the postdoctoral research training fellowship issued by the NIHR. The views expressed in this publication are those of the authors and not necessarily those of the NHS, The National Institute for Health Research or the Department of Health. P.V.: Medical Research Council New Investigator Award G0801627. M.H.: NIHR School of Public Health, Nationally Integrated Quantitative Understanding of Addiction Harm (NIQUAD) MRC addiction research cluster, and support of The Centre for the Development and Evaluation of Complex Interventions for Public Health Improvement (DECIPHer), a UKCRC Public Health Research: Centre of Excellence. Funding from the British Heart Foundation, Cancer Research UK, Economic and Social Research Council (RES-590-28-0005), Medical Research Council, the Welsh Assembly Government and the Wellcome Trust (WT087640MA), under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. E.E.P., R.E., B.G.G. and M.N. received no direct funding for the study.
AIDS. 2013;27(16):2551-2557. © 2013 Lippincott Williams & Wilkins
Lippincott Williams & Wilkins
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