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Microelimination or not? The changing epidemiology of HIV-HCV coinfection in France 2012-2018...MSM
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"it is expected that at some point, HCV-negative MSM will fuel the HIV-HCV epidemiology in MSM
• Overall, the HCV prevalence increased in MSM (6.3% vs 7.6%; p<0.001).
• Among new HIV cases, the HCV prevalence....increased in MSM from 1.9% in 2012 to 3.5% in 2018, although this difference did not reach statistical significance (p=0.093).
• the effect of PrEP...acute HCV also emerged as a significant problem in HIV pre-exposure prophylaxis (PrEP), HIV-negative MSM [16,17,26]. The fact that HIV-infected patients under antiretroviral treatment are considered non-infectious any longer and the protective effect of PrEP regarding HIV transmission probably concurred to an increase of unprotected sex within these two populations.
• Overall, 8.3% were using drugs at last follow-up, including 9.1% of IVDU and 12.3% of MSM
• In MSM, the incidence rate of recently acquired HCV infection increased from 0.36/100PY in 2012 to 1.25/100PY in 2018 (p<0.001).
• The increase was significant for first infections (0.32 to 0.84/100PY; p<0.001) but not for reinfections (2.57 to 5.79/100PY; p=0.57).
• IVDU represented 55.6% of viremic patients in 2012 and 37.0% in 2018 (p<0.001), while MSM represented 14.6% of viremic patients in 2012 and 37.9% in 2018 (p<0.001)...... Among MSM, recently acquired hepatitis represented 11.7% of viremic patients in 2012 and 59.2% in 2018 (p<0.001).
MSM became the first group of viremic patients during the period, preceding IVDU in 2018. Additionally, the number of DAA treatments initiated in MSM exceeded that in IVDU the same year. Both phenomenon are the direct consequence of a persistently active HCV transmission in MSM, illustrated by both the increasing HCV prevalence and incidence in this population, and by the high proportion of recently acquired hepatitis among viremic MSM, almost reaching 60% of cases at the end of the period.......the emerging incidence of recently acquired HCV infections in MSM has also been reported [11]. However, the epidemiological turnabout resulting in MSM currently representing the major epidemiological driver of the HCV epidemic in PLWH was never previously described. ........ Several factors may have contributed to these changes............more than 40% of MSM were currently using drugs (12.3%) or reported a previous use (33.3%)......recently acquired HCV infection in MSM clearly emerged as the major driver of HIV-HCV epidemiology in France, resulting in both an increased prevalence and incidence in this population. Such an increase in HCV incidence in HIV-infected MSM has been reported worldwide during the recent years [11]. More recently, acute HCV also emerged as a significant problem in HIV pre-exposure prophylaxis (PrEP), HIV-negative MSM [16,17,26]. The fact that HIV-infected patients under antiretroviral treatment are considered non-infectious any longer and the protective effect of PrEP regarding HIV transmission probably concurred to an increase of unprotected sex within these two populations. Several reports also highlighted the role of chemsex and mucosal traumatic practices in PrEP users [16,27,28]. HCV transmission from HIV-infected to HIV-negative MSM through sharing of HCV risk practices is probable, as illustrated by phylogenetic studies [16,17]. Considering the evolution of the HIV-HCV epidemiology, it is expected that at some point, HCV-negative MSM will fuel the HIV-HCV epidemiology in MSM as a backlash effect. Additionally, several studies have demonstrated the international diffusion of HCV strains in MSM, suggesting that prevention interventions should also include the role of travel regarding HCV transmission."
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CID Jan 5 2021 Laurent Cotte1, Laurent Hocqueloux2, Maeva Lefebvre3, Pierre Pradat4, Firouze Bani-Sadr5, Thomas Huleux6, Isabelle Poizot-Martin7, Pascal Pugliese8, David Rey9, Andre Cabie10, the Dat'AIDS study group*
1 Department of Infectious Diseases, Croix-Rousse Hospital, Hospices Civils de Lyon, Lyon; INSERM U1052, Lyon, France
2 Department of Infectious Diseases, CHR d'Orleans - La Source, Orleans, France
3 Department of Infectious Diseases, CHU Hotel-Dieu, Nantes; CIC 1413, INSERM, Nantes, France
4 Center for Clinical Research, Croix-Rousse Hospital, Hospices Civils de Lyon, Lyon, France
5 Department of Internal Medicine, Clinical Immunology and Infectious Diseases, Robert Debre Hospital, University Hospital, Reims, France
6 Department of Infectious Diseases and Travel Diseases, Centre Hospitalier Gustave-Dron, Tourcoing, France
7 Immuno-Hematology Clinic, Assistance Publique - Hopitaux de Marseille, Hopital Sainte-Marguerite, Marseille; Aix-Marseille University - Inserm - IRD, Sciences Economiques &
Sociales de la Sante & Traitement de l'Information Medicale, Marseille, France
8 Department of Infectious Diseases, Centre Hospitalier Universitaire de Nice, Hopital l'Archet, Nice, France
9 HIV Infection Care Centre, Hopitaux Universitaires, Strasbourg
Abstract
Background
The arrival of highly effective, well tolerated direct-acting antiviral agents (DAA) led to a dramatic decrease in HCV prevalence. HIV-HCV coinfected patients are deemed a priority population for HCV elimination, while a rise of recently acquired HCV infections in MSM has been described. We describe the variations in HIV-HCV epidemiology in the French Dat'AIDS cohort.
Methods
Retrospective analysis of a prospective HIV-infected cohort from 2012 to 2018. Determination of HCV prevalence, incidence, proportion of viremic patients, treatment uptake and mortality rate in the full cohort and by HIV risk factors.
Results
From 2012 to 2018, 50861 HIV-infected patients with a known HCV status were followed-up. During the period, HCV prevalence decreased from 15.4% to 13.5%. HCV prevalence among new HIV cases increased from 1.9% to 3.5% in MSM but remained stable in other groups. Recently acquired HCV incidence increased from 0.36/100PY to 1.25/100PY in MSM. The proportion of viremic patients decreased from 67.0% to 8.9%. MSM became the first group of viremic patients in 2018 (37.9%). Recently acquired hepatitis represented 59.2% of viremic MSM in 2018. DAA treatment uptake increased from 11.4% to 61.5%. More treatments were initiated in MSM in 2018 (41.2%) than in IVDU (35.6%). In MSM, treatment at acute phase represented 30.0% of treatments in 2018.
Conclusions
A major shift in HCV epidemiology was observed in HIV-infected patients in France from 2012 to 2018, leading to a unique situation in which the major group of HCV transmission in 2018 was MSM.
Discussion
This study demonstrates both the major impact of DAA on the HIV-HCV population and the switch in HIV-HCV epidemiology during the recent years in France. The HIV-HCV coinfection shifted indeed from a chronic infection with limited ongoing transmission in former IVDU, to acute or recent infections with an increasing transmission in MSM. Indeed, while the proportion of viremic patients decreased to 8.9% in early 2019, MSM became the first group of viremic patients during the period, preceding IVDU in 2018. Additionally, the number of DAA treatments initiated in MSM exceeded that in IVDU the same year. Both phenomenon are the direct consequence of a persistently active HCV transmission in MSM, illustrated by both the increasing HCV prevalence and incidence in this population, and by the high proportion of recently acquired hepatitis among viremic MSM, almost reaching 60% of cases at the end of the period. Even if the incidence calculation may be slightly overestimated because some patients lost-to-follow-up or with missing serological result during follow-up were censored at last HCV result, the increasing number of recently acquired hepatitis cases (with a similar cohort size) reflects an increasing incidence over the period.
The impact of a high treatment uptake on the proportion of viremic patients has been previously reported in smaller cohorts of HIV-HCV coinfected patients [21-24]. Similarly, the emerging incidence of recently acquired HCV infections in MSM has also been reported [11]. However, the epidemiological turnabout resulting in MSM currently representing the major epidemiological driver of the HCV epidemic in PLWH was never previously described.
Several factors may have contributed to these changes. First, the analysis of treatment uptake demonstrates an increase throughout the period, while the number of treatments initiated during that time peaked in 2015, then decreased. This point probably illustrates the priority treatment of the most severe cases and the treatment of the easiest to reach and easiest to treat patients. Thus, even in a semi-closed, highly motivated population, patients with erratic follow-up or reluctant to treatment can delay HCV elimination. Secondly, major modifications in HCV risk factors occurred during the period. While less than 10% of patients presumed to have been infected with HIV through IVDU were still using drugs, more than 40% of MSM were currently using drugs (12.3%) or reported a previous use (33.3%). No data was available regarding the kind of drug used and notably the use of drugs in sexual context (chemsex), as well as sexual practices associated with HCV risk such as fisting or sharing sex toys. However, this point clearly demonstrates that HIV and HCV risk factors can evolve independently in a given population, as suggested by phylogenetic analysis [25]. Thus, distinct HCV prevention strategies should be applied in these different populations. Finally, recently acquired HCV infection in MSM clearly emerged as the major driver of HIV-HCV epidemiology in France, resulting in both an increased prevalence and incidence in this population. Such an increase in HCV incidence in HIV-infected MSM has been reported worldwide during the recent years [11]. More recently, acute HCV also emerged as a significant problem in HIV pre-exposure prophylaxis (PrEP), HIV-negative MSM [16,17,26]. The fact that HIV-infected patients under antiretroviral treatment are considered non-infectious any longer and the protective effect of PrEP regarding HIV transmission probably concurred to an increase of unprotected sex within these two populations. Several reports also highlighted the role of chemsex and mucosal traumatic practices in PrEP users [16,27,28]. HCV transmission from HIV-infected to HIV-negative MSM through sharing of HCV risk practices is probable, as illustrated by phylogenetic studies [16,17]. Considering the evolution of the HIV-HCV epidemiology, it is expected that at some point, HCV-negative MSM will fuel the HIV-HCV epidemiology in MSM as a backlash effect. Additionally, several studies have demonstrated the international diffusion of HCV strains in MSM, suggesting that prevention interventions should also include the role of travel regarding HCV transmission.
The overall mortality rate in our population remained stable, as well as the mortality rate in HIV-HCV-coinfected patients, while HCV-related mortality rate sharply declined during the study. Successful DAA treatment has been associated with a significant decrease in liver-related mortality [29,30]. The relative stability of the mortality rate in HIV-HCV coinfected patients probably relates to an increased risk of non-liver-related deaths in HIV-HCV coinfected patients, notably IVDU, as compared with HIV monoinfected patients as previously reported [31].
Regarding our results, HCV elimination in the HIV-HCV coinfected population in France seems at hand. However, the emergence of acute HCV infection in MSM could jeopardize this objective and additional efforts are needed. DAA treatment resulted in few years in a drastic decrease in the number of viremic patients, while the sustained transmission of the virus still maintains a pool of viremic patients. Reducing the delay from diagnosis to treatment of recently acquired hepatitis is probably an important point to reduce transmission. Indeed, the reproduction number (R0) of acute HCV in MSM has been estimated to 2.35 [32], with an infectivity period of less than 6 months, which strongly argues for the rapid treatment of recently acquired HCV infection. In our study, the median time to treatment largely evolved over time, peaking to 1.5 year in 2013, to less than 2 months in 2018. This progression relies on the absence of all oral DAA options in the 2013-2014 years, during which only combinations of pegylated interferon, ribavirin and first-generation protease inhibitors were available. Treatment of recently acquired HCV became easier in 2015, when all oral combinations became available, whereas none of these combinations is currently approved for the treatment of acute HCV infection worldwide. However, the French regulation allows prescription outside the formal approval of a treatment in the absence of any alternative, an option that was clearly used in this cohort to reduce the delay to treatment over time.
Time to treatment can be also greatly impacted by the time to diagnosis, which can be delayed by 3-6 months when based on HCV serology in HIV-infected patients. A recent study within the HIV Swiss cohort demonstrated that an aggressive strategy of HCV-RNA testing in every HIV-infected patient, followed by immediate DAA treatment could significantly reduce the viremic population in a short time and could probably decrease HCV transmission within this population [22]. However, this strategy is limited by the potential reintroduction of HCV in this population, either from HIV-negative patients or from international contacts [14]. Thus, additional efforts regarding the reduction of HCV transmission, through either harm reduction interventions in patients using drugs or through reducing the risk of condomless sex and mucosal traumatic practices are warranted, as well as continuous screening for HCV. The fact that the incidence of a first recently acquired HCV infection decreased in our study, while the incidence of reinfection remained high, probably results from a reduced transmission in naive patients, while patients who had been cleared from a previous infection pursued HCV risk practices despite prevention efforts.
Our study bears some limits. First, this is a retrospective analysis of a cohort initially designed for HIV follow-up in HIV-specialized centers. Most HIV centers in France are currently also treating viral hepatitis, but one cannot exclude that some HCV treatments were initiated in Hepatology units without being registered in the database. Second, the study is based on regular follow-up within the cohort, based on current recommendations. However, specific considerations can hamper general recommendations. For example, systematic STI screening, including HCV, would be of limited interest in older patients who report no sexual activity. Thus, the denominator of epidemiological parameters can evolve from year to year, with less exhaustiveness over time. We chose to use only actual data to assess crude prevalence and incidence rates instead of trying to estimate these rates in patients with lacking information. Considering the relatively short period of time, only crude mortality rates were determined, without standardization.
On the other hand, our study has major strengths, including the prospective collection of data, the large number of patients and the representativeness of the cohort within the French HIV-HCV population.
In conclusion, our study demonstrates that three objectives targeted by WHO for HCV elimination were reached in the HIV-HCV coinfected population in the Dat'AIDS cohort already at the end of 2018. However, these targets did not consider a rapidly evolving epidemiology such as observed during the period. Thus, continuous efforts are needed to maintain these targets and to further reduce HCV transmission within this population. This includes identifying the most at risk patients and practices, educate these patients regarding harm reduction, an early diagnosis of acute HCV infection, reducing time-to-treatment, reaching the HIV-negative MSM population and coordinating international efforts.
Introduction
The arrival in 2012-2013 of new, highly-effective, well-tolerated, direct-acting antiviral agents (DAA), combined with progresses in injection and blood safety resulted in a worldwide drastic decrease in Hepatitis C virus (HCV) prevalence [1,2], leading the WHO to target "HCV elimination" by 2030. WHO objectives included the diagnosis of 90% of patients with viral hepatitis infections, a 90% reduction in new chronic HCV infection, 80% of chronic HCV infections treated and a 65% reduction in mortality [3]. HCV infection is frequent among persons living with HIV (PLWH) and is usually associated with pejorative outcomes [4,5]. DAA treatment efficacy appears similar in HIV-HCV coinfected and in HCV monoinfected patients [6], and regular follow-up for antiretroviral treatment may favor DAA treatment uptake in coinfected patients [7]. As a result, the HIV-HCV population was deemed a priority population for HCV elimination. In France, harm reduction interventions and a facilitated access to opioid substitution treatment (OST) have resulted over the past decades in a dramatic decline in HIV transmission in intravenous drug users (IVDU) [8,9], which accounted for only 2% of new HIV infections in 2018 [9]. On the other hand, new ways of HCV transmission recently arose in populations previously moderately affected, such as men having sex with men (MSM), leading to an increased incidence and prevalence in this population [10-12]. Additionally, international transmission networks of HCV in MSM [13-15] and transmission in both HIV-negative and HIV-infected MSM have been described [16,17] which could fuel an otherwise relatively closed population.
Results
During the 2012-2018 period, 57,339 PLWH were followed-up in the Dat'AIDS cohort of whom 50,861 had at least one HCV follow-up during the study period. Among them, 42,840 (84.2%) remained HCV negative whereas 8021 were HCV positive giving an overall HCV prevalence of 15.8% (Figure 1). Demographics and biological characteristics at last follow-up of patients with a known HCV status in the cohort are described in Table 1.
Drug use and alcohol intake
Overall, 8.3% were using drugs at last follow-up, including 9.1% of IVDU and 12.3% of MSM. Additionally, 33.3% of patients were considered as former drug users or received opioid treatment substitution, a proportion reaching 90.9% in IVDU and 26.8% in MSM. An excessive alcohol intake of more than 20g alcohol/day was reported in 11.7% of patients, a proportion reaching 26.9% in IVDU.
HCV prevalence
Overall, the HCV prevalence decreased in PLWH from 15.4% in 2012 to 13.5% in 2018 (p<0.001) (Table 2). Based on HIV risk factors, HCV prevalence remained stable over the period in IVDU (89.2% vs 89.6%; p=0.856) and in patients with other/unknown risk (17.2% vs 16.3%; p=0.336), decreased in heterosexuals (7.4% vs 6.5%; p<0.001) and increased in MSM (6.3% vs 7.6%; p<0.001).
Among new HIV cases, the HCV prevalence remained stable over time (3.6% vs 3.8%; p=0.773). The prevalence among new HIV cases remained stable in IVDU (44.4% vs 42.9%; p=0.954), in heterosexuals (3.0% vs 2.8%; p=0.849) and in patients with other/unknown HIV risk factors (7.0% vs 7.3%; p=0.940). It increased in MSM from 1.9% in 2012 to 3.5% in 2018, although this difference did not reach statistical significance (p=0.093).
Recently acquired hepatitis
The number of recently acquired HCV cases ranged from 74 in 2012 to 100 cases in 2018 with a peak of 126 in 2013. The trend over time differed according to the type of hepatitis with a regular decrease of first HCV infections from 105 cases in 2013 to 62 cases in 2018 paralleled with an increase of reinfection cases from 15 in 2012 to 38 in 2018. Overall, the incidence rate of recently acquired HCV infection increased from 0.20/100PY in 2012 to 0.73/100PY in 2018 (p<0.001), both for first infections (0.17 to 0.52/100PY; p<0.001) and for reinfections (0.91 to 1.97/100PY; p=0.011). In MSM, the incidence rate of recently acquired HCV infection increased from 0.36/100PY in 2012 to 1.25/100PY in 2018 (p<0.001). The increase was significant for first infections (0.32 to 0.84/100PY; p<0.001) but not for reinfections (2.57 to 5.79/100PY; p=0.57).
HCV viremic patients
The proportion of HCV-RNA positive patients decreased from 67.0% in 2012 to 21.4% in 2018 (p<0.001). Based on the number of DAA treatment initiated in 2018 and considering a 95% cure rate following DAA, the proportion of viremic patients was estimated to 8.9% in early 2019. IVDU represented 55.6% of viremic patients in 2012 and 37.0% in 2018 (p<0.001), while MSM represented 14.6% of viremic patients in 2012 and 37.9% in 2018 (p<0.001). HIV risk factors per calendar year among HCV-RNA positive patients are presented in Figure 2. Recently acquired hepatitis cases represented 2.2% of viremic patients in 2012. This proportion reached 26.7% in 2018 (p<0.001). Among MSM, recently acquired hepatitis represented 11.7% of viremic patients in 2012 and 59.2% in 2018 (p<0.001).
HCV treatment uptake
The number of HCV treatments initiated each year decreased from 379 in 2012 to 265 in 2013, then increased to 604 in 2015 and decreased regularly onwards to reach 325 treatments in 2018. Overall, the HCV treatment uptake among HCV-RNA positive patients increased from 11.4% in 2012 to 61.5% in 2018 (p<0.001). Treatments in MSM represented 22.2% of all treatments initiated in 2012 and 41.2% in 2018 whereas in IVDU, this proportion decreased from 48.6% in 2012 to 35.6% in 2018 (Figure 3). Treatment at acute phase represented 4.7% of all treatments in 2012 and 13.6% in 2018. In MSM, treatment at acute phase represented 19.0% of all treatments in 2012 and 30.0% in 2018 (p=0.123).
The median time to treatment of recently acquired HCV infections was 168 days [IQR 81-1096] in 2012. This delay increased to 610 days [88-848] in 2013 and regularly decreased thereafter to 59 days [34-128] in 2018 (Figure 4).
Mortality
The overall mortality rate remained stable from 1.2/100PY in 2012 to 1.1/100PY in 2018. This rate was constantly higher in IVDU (1.6/100PY in 2012 to 1.2/100PY in 2018) than in non-IVDU (0.8 to 1.0/100PY, respectively).
The HCV-related mortality rate decreased from 0.3/100PY in 2012 to 0.0/100PY in 2018. This decrease was equally observed in IVDU (0.4 to 0.0/100PY) and in non-IVDU (0.2 to 0.0/100PY).
WHO HCV elimination targets
Overall, 3 WHO targets were fulfilled within the cohort, with indeed diagnosis of 94.9% of chronic HCV infection, treatment of 88.9% of chronic infections and 100% reduction in HCV mortality. The decline in new chronic HCV infection was less impressive (35.7%), mainly related to recently acquired HCV infections (Table 3)
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