The Proof Is in the Patient: Hepatitis C Virus Microelimination in the Swiss Human Immunodeficiency Virus Cohort Study
Year: 2018
Type: article
Abstract: (See the Major Article by Braun et al on pages 561-8 and Major article by Braun et al on pages 569-76.) With the advent of highly effective direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV), the World Health Organization (WHO) and other local, regional and national entities have outlined ambitious goals for HCV elimination by 2030 [1]. Goals set by the WHO for reducing the burden of HCV include a 90% reduction in incident cases and a 65% reduction in HCV-related mortality. The WHO also established clinical service coverage targets that, if met, are expected to lead to the achievement of these goals, including the diagnosis of 90% of infections and treatment of 80% of those eligible. In 2017, Hill and colleagues [2] found that few countries were on target to achieve the WHO benchmarks for eliminations. This observation is not unexpected, given that, to achieve HCV elimination globally or even locally, each step of the HCV care continuum must be improved dramatically, including (1) identification of persons with active HCV infection; (2) linkage of persons with active HCV infection to care; (3) delivery of curative HCV therapy; and (4) prevention of HCV reinfection after cure. In the absence of vaccination to prevent HCV infection and reinfection, an essential element of HCV elimination strategies is the treatment of persons at high risk for transmitting HCV to others, including persons who inject drugs and human immunodeficiency virus (HIV)–infected men who have sex with men (MSM) [3, 4]. On a global scale, the challenges to HCV elimination are formidable, leading to the implementation of smaller-scale, microelimination programs focused on the elimination of HCV infection in defined target populations or clinical settings [5]. Persons living with HIV infection (PLWH) have been identified as a population in which HCV microelimination seems feasible, because persons with HIV/HCV coinfection are more likely to have been identified, more engaged in medical care. and have greater access to HCV DAAs than other populations [6, 7]. However, the last step in the care continuum, the prevention of incident HCV infection reinfection after cure, may represent a unique challenge to HCV elimination in PLWH, for whom rates of reinfection, particularly among MSM, have been higher than observed in other populations [8]. Accordingly, HCV microelimination strategies in PLWH must include harm reduction interventions; the rapid dissemination of curative HCV therapy to may also prevent reinfection in populations of PLWH. To evaluate the strategy of HCV microelimination and treatment as prevention in PLWH, researchers involved in the Swiss HIV Cohort Study (SHCS) conducted an investigator-initiated study to eliminate HCV infection in MSM, among whom incident HCV infection has increased over the last decade [9]. Since 1988, the SHCS has prospectively followed >75% of all PLWH in Switzerland and is highly representative of the Swiss HIV epidemic. The Swiss HCVree Trial was designed as 3 phases or periods (clinicaltrials.gov identifier NCT02785666). Period A included HCV screening with HCV RNA testing for all MSM during cohort study visits over a 9-month period. The researchers tested the novel strategy of HCV RNA screening added to annual HCV antibody testing and HCV RNA testing for detection of elevated alanine aminotransferase (ALT) levels. Period B was HCV treatment with grazoprevir-elbasvir for all MSM with HCV genotype 1 or 4 infections; MSM who reported unprotected sex with occasional partners were offered a risk reduction–oriented behavioral intervention. Period C is a monitoring phase in which all MSM will undergo repeated HCV RNA testing to assess the impact of the Swiss HCVree Trial on HCV prevalence and incidence in the SHCS. Merck Sharp & Dohme provided grazoprevir-elbasvir and funding for HCV RNA testing. In this issue of Clinical Infectious Diseases, Braun and coworkers [10, 11] report the findings from the first and second phases of the Swiss HCVree Trial. During the HCV RNA screening phase (period A), researchers classified HCV RNA–positive MSM as having (1) known HCV infection, (2) new HCV infection, or (3) HCV reinfection after treatment. In this phase, the research question to be answered was how many HIV-infected MSM with active HCV infection are detected by adding HCV RNA screening to the standard approach of annual HCV antibody screening and reflex HCV RNA testing for elevated ALT levels assessed quarterly? The answer requires careful dissection of the study findings. First, HCV RNA testing was successfully implemented. Most (87%) of the 4257 MSM were tested during the 9-month period, of whom 177 (4.8%) had active HCV infection and 5 (0.1%) had false-positive HCV RNA results. Of the 177 active HCV infections, 147 (83%) were known, 24 (14%) were new, and 6 (3%) were reinfections. Because most persons remain HCV seropositive after cure, HCV RNA testing is the standard approach for identifying reinfection. Second, of the 24 MSM with new HCV infections, 16 were also HCV antibody positive, and 8 were HCV antibody negative, of whom most (n = 6) had an elevated ALT level at the time of screening (>50 U/L), leaving just 2 that were identified solely by means of the added RNA testing. The findings from the HCV RNA screening phase of the SwissHCVree suggest that most persons with active HCV infection (all but 2) were identified by the standard screening approach of HCV antibody testing for seronegative persons and HCV RNA testing for those with elevated ALT levels and those previously cured. Based on these findings, what is the role of HCV RNA testing in identifying active HCV infection in PLWH? For the growing population of cured persons, HCV RNA testing is the standard approach to identifying reinfection; further research is needed to define which PLWH should be routinely screened for reinfection and the appropriate testing interval (6 or 12 months). The role of routine HCV RNA screening in identifying undiagnosed HCV infection in PLWH is less clear. In light of false-positive results and the relatively large number of persons needed to find undiagnosed hepatitis C in PLWH is less clear. Given the higher cost of HCV RNA testing and the relatively large number of persons needed to be screened to identify an individual missed by HCV antibody testing, formal cost-effectiveness analysis should be performed before the widespread adoption of HCV RNA screening. During the HCV treatment phase of the Swiss HCVree Trial, Braun and colleagues [11] provided HCV treatment with grazoprevir-elbasvir to eligible MSM, incorporating the use of HCV NS5A resistance testing for those with genotype 1a infection. Of the 177 persons with active HCV identified in period A, 1 died, 3 (1.7%) had spontaneous clearance, 122 (69%) were treated in period B, and 38 (21%) were treated outside the study (mainly owing to ineligibility for treatment with grazoprevir-elbasvir). Of the 160 MSM treated for HCV infection in the Swiss HCVree Trials and in Swiss clinical practice, cure was achieved in 99%; only 1 individual had HCV nonresponse. These data confirm the effectiveness of HCV DAAs in PLWH and, for persons with HCV genotype 1a infection, the study validated the approach of pretreatment testing for HCV NS5A resistance-associated substitutions (RASs) to guide therapy with grazoprevir-elbasvir. Persons with no HCV NS5A RASs at amino acid positions 28, 30, 31, and 93 received 12 weeks of therapy with grazoprevir-elbasvir alone, whereas those with RASs (<10% of the population) receive 16 weeks of therapy with the addition of ribavirin. After period B, the number of persons with active HCV infection declined from 177 to only 13. Notably, with the successful prosecution of parts A and B of the SwissHCVree Trial, the investigators have exceeded the 2 major clinical service targets projected by the WHO to be sufficient to eliminate HCV. Will the achievement of these diagnosis and treatment targets actually lead to the goal of HCV microelimination in MSM followed in the SHCS? The answer to this question will depend, in part, on the incidence of new HCV infections and reinfections among the cohort participants. During period C of the SwissHCVree Trial, HCV RNA testing will be repeated to answer this question for the 9-month period after the treatment phase. Importantly, Braun and colleagues [11] incorporated measures to reduce the risk of reinfection in the treatment phase. All persons were counseled on HCV reinfection; MSM who reported risky sex practices were offered behavioral counseling interventions aimed at reducing the risk of HCV infection. The inclusion of counseling is a significant strength of the study; however, the effectiveness of this intervention is not yet known. Another critical question is the role of other patient populations—those not targeted for microelimination—on the risk of HCV reinfection; for example, PLWH who inject drugs in the SHCS. In the SwissHCVree study, 29% of the MSM with active HCV infection (identified in period A) also reported injection drug use, an exposure that had a strong association with active HCV infection (adjusted odds ratio, 7.13). This observation serves as a reminder that PLWH may engage in >1 behavior placing them at risk for HCV infection. In some locales, strategies for HCV elimination PLWH may need to target all individuals with active HCV infection to reduce the risk of reintroducing HCV into the population. Nonetheless, the 3-phase approach deployed in the Swiss HCVree Trial—intensive case finding, curative treatment for all, and prevention/detection of reinfection—provides an excellent blueprint for HCV elimination in other patient populations, including persons who inject drugs. Potential conflicts of interest. The author received personal fees and grants (to his institution) outside the submitted work, from Gilead, Merck, AbbVie, and Janssen, as well as nonfinancial support from Trek. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Source: Clinical Infectious Diseases
DOI: 10.1093/cid/ciy551
Author: Mark S Sulkowski
Institution: Johns Hopkins University
Language: English
Topic: Hepatitis C virus research
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2886037579