- Email: [email protected]
Are there any challenges left in hepatitis C virus therapy of HIV-infected patients?
Accepted Manuscript
Are there any challenges in HCV therapy of HIV infected patients left? Jenny Bischoff , Jurgen K Rockstroh ¨ PII: DOI: Reference:
S0924-8579(18)30245-0 https://doi.org/10.1016/j.ijantimicag.2018.08.019 ANTAGE 5527
To appear in:
International Journal of Antimicrobial Agents
Received date: Revised date: Accepted date:
30 May 2018 10 August 2018 18 August 2018
Please cite this article as: Jenny Bischoff , Jurgen K Rockstroh , Are there any challenges in HCV ¨ therapy of HIV infected patients left?, International Journal of Antimicrobial Agents (2018), doi: https://doi.org/10.1016/j.ijantimicag.2018.08.019
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ACCEPTED MANUSCRIPT Highlights: High cure rates of HCV are achieved in HIV/HCV coinfected patients Liver cirrhosis and an impaired immune function seem to decrease the chance of cure Drug-Drug interactions are safely manageable, if considered accordingly Enhanced preventive measures including behavioural interventions are required
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Are there any challenges in HCV therapy of HIV infected patients left? Jenny Bischoff1, Jürgen K Rockstroh1 1
Department of Medicine I, University Hospital Bonn, Bonn
Corresponding author:
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Dr. Jenny Bischoff Department of Medicine I University Hospital Bonn Sigmund-Freud-Str. 25 D-53127 Bonn Phone: +49 228 287 16558
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Fax: +49 228 287 15034
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Email: [email protected]
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Abstract word count: 192/250
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Total word count: 2506/2500
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Tables and Figures: 3 Tables + 1 supplementary table
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Are there any challenges in HCV therapy of HIV infected patients left? Abstract Direct acting antivirals (DAAs) have tremendously improved treatment of Hepatitis C virus (HCV) infections also in Human immunodeficiency virus (HIV) positive individuals. Curing
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HCV is of particular importance in HIV positive individuals as liver disease progression is accelerated in the course of concomitant HIV infection. Former challenges, such as safety and tolerability as well as reduced treatment uptake of a peginterferon (pegIFN) and ribavirin (RBV) based treatment have been overcome with the approval of DAAs. Indeed, rates of
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discontinuation under modern all oral DAA therapy in HIV/HCV coinfection have been
reported to be less than 1%. Rates of sustained virological response (SVR) after treatment have aligned with those seen in HCV monoinfected patients, resulting in an equalization of treatment recommendations for HCV monoinfected and HIV/HCV coinfected patients.
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Nevertheless, coinfection with HIV has been associated with slightly higher relapse-rates in
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some real-world cohorts, arousing a discussion concerning a more individualized treatment once again. Moreover, an ongoing epidemic of acute HCV infections in HIV positive MSM
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with high reinfection rates challenges physicians and researchers. A concise summary of the
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review.
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remaining challenges in HCV treatment of HIV positive individuals is given in the present
Keywords: HIV/HCV coinfection, DAA Treatment, HIV, challenges in HIV
ACCEPTED MANUSCRIPT Introduction The introduction of highly effective antiretroviral therapy (ART) has dramatically reduced HIV-associated morbidity and mortality. Indeed, near to normal life expectancy can be expected in human immunodeficiency virus (HIV) infections if antiviral therapy is started before the onset of AIDS or advanced immunodeficiency. Therefore, concomitant diseases are
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increasingly gaining importance. Coinfections with the Hepatitis C virus (HCV) are of
substantial concern, as HIV is known to accelerate the progression of HCV related liver
disease, which has emerged as a leading cause of death in HIV infected individuals [1]. It is
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estimated, that about 80 million people are chronically infected with HCV globally [2]. An estimated 2.3 million HIV positive individuals are coinfected with HCV, resulting in an overall prevalence of 6.2% worldwide [3]. Prevalence varies widely by route of transmission and region, with a higher burden in people who inject drugs (PWID) and men who have sex
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with men (MSM) as well as in Eastern Europe and central Asia [3].
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In order to reduce the burden of liver disease related morbidity and mortality in HIV/HCV coinfected individuals, treatment of HCV should be prioritized in this subgroup [4-6]. In the
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era of peginterferon (PegIFN) and ribavirin (RBV), treatment of HCV had been particularly
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challenging in HIV positive individuals, due to severe adverse events and drug-drug interactions as well as disappointingly low cure rates, with sustained virological response
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(SVR) rates ranging from 27% - 40% [7-9]. Telaprevir and boceprevir, two NS3/4A Protease Inhibitors (PI), led to improved SVR rates in combination with pegIFN and RBV in HCV genotype (GT) 1 coinfected individuals, but came along with a further increased toxicity [1012]. Since then, new generations of direct acting antivirals, including NS5A inhibitors, nucleotide and non-nucleos(t)ide NS5B inhibitors and second generation PIs, have remarkedly improved treatment outcomes along with shortened treatment durations and a far
ACCEPTED MANUSCRIPT better safety profile. Thus, interferon-based treatment is no longer recommended in HIV/HCV coinfected persons [4,5]. DAA based treatment in HIV Management and Treatment Initiation
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Initially, international guidelines prioritized HCV treatment initiation in HIV/HCV coinfected individuals because of the faster fibrosis progression and increased risk of dying from liver disease in this particular patient group. More recently, guidelines now recommend HCV treatment in all HCV infected patients regardless of HIV coinfection [4-6] (table 1). Most
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importantly, guidelines no longer separate between HCV mono- or HIV/HCV-coinfected subjects with regard to DAA choice or treatment duration as comparable cure rates have been obtained in HCV treatment studies for both patient groups. Treatment duration varies from 8
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to 24 weeks, depending on HCV viral load, genotype, cirrhosis status and past treatment experience. Ribavirin might be added in compensated and decompensated cirrhosis or
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treatment experienced patients according to treatment regimen and HCV genotype. The effectiveness and safety of these drugs were proved in several clinical trials and supported by
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real-life data from numerous studies (supplementary table S1 and table 3).
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[Insert table 1 here]
A shortened treatment duration of 8 weeks for HIV/HCV coinfected patients has been successful in clinical trials as well as real-life cohorts. Rates of sustained virologic response were high for patients treated with 8 weeks of glecaprevir (GLE) and pibrentasvir (PIB) or ledipasvir (LDV) and sofosbuvir (SOF), but disappointing for patients being administered 8 weeks of daclatasvir (DCV) and SOF with an overall rate of 76% in HIV/HCV coinfected
ACCEPTED MANUSCRIPT patients [13-15]. Indeed, 12 weeks of DCV/SOF is the recommended treatment duration for non-cirrhotic HCV patients.
For patients with decompensated cirrhosis the use of protease inhibitors is not recommended as higher drug exposures lead to increased toxicity [4]. Feasible treatment options are SOF
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and velpatasvir (VEL) (all genotypes), SOF/LDV (GT 1, 4, 5, 6) or SOF/DCV (all genotypes) [4,5].
Systematic resistance testing prior to commencing DAA therapy is not recommended, since
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there are highly effective treatment regimens for patients with resistance associated substitutions (RAS) at baseline [4]. For those patients, who failed to achieve SVR despite an all oral interferon free DAA treatment, high SVR rates have been achieved with 12 weeks of
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SOF, VEL and voxilaprevir (VOX) in HCV monoinfected patients (POLARIS 1: Pretreatment containing an NS5A inhibitor, overall SVR 96%, POLARIS 4: Pretreatment
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without an NS5A Inhibitor, overall SVR 98%) [16]. No impact of pre-retreatment RAS at baseline on achievement of SVR12 was detected. The combination of SOF+GLE/PIB+RBV
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seems to be promising, with an overall SVR12 rate of 96% (22/23) and 100% in GT2 and
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GT3 infections [17]. Nevertheless, retreatment in the few patients with DAA failure can be
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challenging and is best managed in a multidisciplinary team.
Drug-Drug Interactions Drug-Drug-Interactions have to be considered carefully in every HIV-coinfected patient prior to starting DAA therapy and can be very challenging for the physician in care. In general, HCV direct acting antivirals and HIV antiretrovirals can affect metabolism or absorption of each other, resulting in either higher, potentially toxic, serum concentrations of the DAA or
ACCEPTED MANUSCRIPT ARV or a reduction of mainly the DAA, risking treatment failure. Induction or inhibition of several cytochrome P450 enzymes, specifically the CYP3A4 family, permeability glycoproteins (p-gp), breast cancer resistance protein (BCRP)-transporters and organic anion transporting polypeptides (OATP) 1B1 and 1B3 bear a high potential of drug-drug interactions.
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Concomitant use of HIV PIs and PI containing DAA regimens is contraindicated, as HIV PI inhibit OATP and are often boosted with cobicistat or ritonavir, both strong inhibitors of CYP3A4. Moreover, PI containing DAA regimens should not be co-administered, if the
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patient is treated with NNRTIs, which induce CYP3A4 and p-gp. For some combinations dose adjustments (e.g. DCV + HIV PIs) or closer monitoring for adverse events (e.g. combinations containing Tenofovir-DF) are necessary. A detailed overview of all relevant
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[Insert table 2 here]
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drug-drug interactions between HIV and HCV drugs is provided in table 2.
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Real world effectiveness of DAA based treatment in HIV/HCV coinfected patients Since the implementation of IFN free DAA based treatment regimens comparable SVR rates
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have been achieved between monoinfected and coinfected patients and treatment recommendations were standardized for HIV/HCV coinfected and HCV monoinfected patients [4,5]. Nevertheless, the applicability of study results from controlled clinical trials to a very heterogenous patient population in real life has been questioned, as a high proportion of patients would not fit the eligibility criteria [18]. Outside of these deliberately chosen conditions several socio-economic and clinical variables may affect treatment initiation and outcome. Indeed, SVR rates varied between monoinfected and coinfected patients in real-life
ACCEPTED MANUSCRIPT cohort studies and some were lower compared to those achieved in large Phase II/III trials (supplementary table S1 and table 3)[19,20].
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[Insert table 3 here]
Recently, data from two Spanish trials, suggested that HIV coinfection may serve as a risk factor for treatment failure. This has raised the question, whether a more individualized
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treatment is necessary in this subgroup [19,29]. In a prospective multi-cohort study from Spain dually infected patients receiving IFN-based or IFN free DAA treatment regimens showed significantly lower SVR 12 rates compared to monoinfected patients (DAA based treatment, intention-to-treat: 86.3% vs 94.9%, p = 0.002, on-treatment: 94.8% vs. 98.6%; p =
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0.032). These findings were consistent after stratifying for sex, IDU, liver disease at baseline, pre-treatment response and genotype. A higher frequency of relapses seemed to be
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responsible for differences in SVR rates. Moreover, HIV infection was an independent
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predictor of non-achievement of SVR12 in the multivariable logistic regression (MLR) analyses. It must be noted, that treatment regimens differed between monoinfected and
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coinfected patients, which might have introduced a bias to the analysis. Approximately one half (42%, 108/256) of the coinfected patient population was administered simeprevir (SMV)
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+ SOF [19]. SMV+SOF have been associated with treatment failure in the Madrid CoRe registry. Furthermore, gender, baseline CDC class C, CD4 cell count < 200/µl, HCV RNA> 800.000/IU, the use of other suboptimal DAA regimens, cirrhosis and decompensated liver disease were associated with treatment failure in this large prospective cohort. Nevertheless, SVR rates of 92% and 94% were achieved in the intent-to-treat (ITT) and modified intent-totreat (m-ITT) analysis respectively, and discontinuations due to adverse events were low. SVR rates in patients with GT3 and LDV/SOF treatment were considerably low and therefore
ACCEPTED MANUSCRIPT the authors suggest that LDV/SOF is a suboptimal treatment regimen in GT3 patients [23]. This is in line with current guidelines, were this regimen is not recommended for this particular patient population [4,5]. Liver cirrhosis was established as a risk factor for non-achievement of SVR in HIV/HCV coinfection in several studies [20,27,30]. In a multicentre cohort from Germany, the GECCO
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Cohort, SVR rates dropped considerably in patients suffering from liver cirrhosis and having a CD4 cell count less than 350/µl [30]. The association between the CD4 cell count and nonachievement of SVR lost significance in the MLR, which is in line with other reports, were
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SVR rates did not differ by CD4 cell count [20,28,30]. In contrast, SVR12 rates assessed in the German hepatitis C-registry (DHC-R) did not differ significantly between coinfected and monoinfected patients with or without cirrhosis. Age, gender and treatment experience were the only variables associated with non-achievement of SVR12 in the MLR. Overall 90.3%
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(5111/5657) of monoinfected and 91.2% (445/488) of coinfected patients achieved SVR12 in
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the ITT analysis. In patients with underlying cirrhosis at baseline 87.8% and 89.3% of monoinfected and coinfected patients achieved SVR12, respectively [24]. Additional support
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comes from the French ARNS CO13 HEPAVIH cohort. In this French cohort 93.5% of patients achieved SVR12 and no difference was detected between patients with and without
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liver cirrhosis [21]. Of note, coinfected patients enrolled in the DHC-R (29.5 vs 17.2%) and
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the GECCO cohort (31% vs 22%) were less likely to be cirrhotic compared to the patient populations from the three Spanish cohorts (51% vs 65% IFN based treatment group; 48% vs 83% IFN free treatment group; Madrid CoRE: compensated cirrhosis 33.9%, decompensated cirrhosis 6.6%, COINFECOVA-2 : F4 Fibrosis 54.2%, F4 fibrosis with > 21kPa 27.2%, recently decompensated Cirrhosis 5.6%) [19,20,23,24,30]. Differences in these study results might be in part explained by differentiating graduations of liver cirrhosis as well as different treatment regimens.
ACCEPTED MANUSCRIPT Compromised treatment responses have occurred in monoinfected as well as coinfected patients with decompensated liver cirrhosis. A proportion of these treatment failures however, are not virological, resulting in higher SVR rates after adjustment. Supporting evidence comes from a Spanish cohort, where HIV coinfection lost significance as a risk factor for treatment failure after adjusting for severe liver disease [27].
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Another important factor associated with treatment response in coinfected patients might be the baseline HIV viral load, reflecting therapy adherence and immune function. Undetectable HIV RNA has been a mandatory inclusion criterion in most clinical studies. Thus, patients in
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real life cohorts may differ from those patients enrolled in clinical trials by HIV suppression, explaining differentiating SVR rates. Supporting evidence comes from a real-life cohort from Baltimore, showing an HIV viral load <20 copies/ml to be predictive of SVR achievement [31]. In contrast, in the French ARNS CO13 HEPAVIH Cohort, levels of HIV RNA < 50
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copies/ml and >50 copies/ml were not associated with SVR-achievement in the logistic
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regression analysis [21].
Furthermore, with an aging HIV-positive population co-morbidities and polypharmacy may
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impact treatment initiation, drug adherence and tolerability and thus influence treatment
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outcomes in the real world apart from an intrinsic antiviral effect.
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Remaining challenges and future perspectives Acute HCV infection Management, treatment initiation,- regimen and – duration in acute HCV infections are still under investigation with slightly varying recommendations in international guidelines [4-6]. The EACS guidelines recommend repeated testing of HCV RNA 4 weeks after intial HCV viral load determination [5]. Only 11.9% of patients enrolled in the PROBE-C cohort (464
ACCEPTED MANUSCRIPT coinfected patients enrolled, 99% MSM) were able to spontaneously clear their acute HCV infection, indicating a high risk of progression to a chronic phase of disease [32]. HCV treatment should be considered in patients with a < 2log10 decrease in the HCV RNA viral load 4 weeks after initial assessment as this was predictive of non spontaneous clearance and a progression to a chronic phase of disease is very likely otherwise [32]. Treatment in acutely
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infected patients has been shown to be beneficial for the patients’ outcome, can prevent transmission and is cost effective. Best treatment duration remains controversial at this point. Studies looking at shorter treatment durations of 6 weeks with SOF/LDV in HIV/HCV coinfected subjects showed several relapses particularly in patients with very high baseline
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HCV viral loads [33]. In HCV monoinfected patients however all patients responded to 6 weeks SOF/LDV. More recently data from 8 weeks SOF/LDV in HIV-positive individuals were presented which again showed HCV cure in all patients so that 8 weeks of therapy
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appear to be the safest approach for now[4,34]. The subgroup of HIV/HCV coinfected patients comprises a high proportion of intravenous drug users and MSM, two populations
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known to be particularly vulnerable to acute HCV infections [3,22]. An ongoing epidemic of sexually transmitted acute HCV infections in predominantly HIV positive men who have sex
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with men (MSM) has occurred in the last two decades and incidence rates of HCV in HIV+
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MSM are still not decreasing in Europe [35,36]. An unrestricted access to DAA treatment resulted in a high treatment uptake and a decline in acute HCV infections as well as high cure
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rates in HIV/HCV coinfected MSM in the Netherlands [37]. The Swiss HCVree trial, a treatment as prevention trial offering early access to treatment and counselling, achieved comparable results, reducing acute HCV infections by almost 50% and chronic infections by >90% in HIV+ MSM [38]. Despite this promising development, other STDs increased in the Dutch population indicating that the reduction of acute HCV in HIV positive MSM was not caused by behavioural changes, which appear to be necessary to reduce the risk of reinfection and achieve the WHO goal of HCV eradication by 2030
[37,39].
Reinfections and
ACCEPTED MANUSCRIPT transmission of resistance mutations particularly in those who failed to achieve SVR with prior treatment remain challenging and call for further innovative prevention measures [40,41]. Barriers
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An evaluation of patients enrolled in the ATHENA HIV cohort not treated for their HCV infection observed a higher proportion of women, carribean/latin American, GT3 infections and PWID [22]. These findings are in line with a retrospective analysis from San Diego, California, observing that a lack of engagement in care, being non-white and ongoing barriers
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to care as drug and alcohol abuse, neuropsychiatric diseases and unstable housing were predictive of non-referral to treatment in coinfected patients [42]. With the latest approval of highly effective DAAs in GT3 infections and evidence of high cure rates and tolerability in PWID a deferral of those two subgroups for treatment can be expected [43,44]. But so far, it
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remains a gap in treatment initiation for women and marginalized patients, which has to be
Conclusion
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overcome.
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HIV/HCV coinfected patients are no longer regarded as a ‘special population’ as depicted by
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current guidelines. Tremendous improvements have been made since the implementation of DAA therapy, resulting in a highly efficacious and well-tolerated treatment for almost all patients. Drug-drug interactions with ARVs have to be considered carefully but appear safely manageable if considered correspondingly. HCV reinfections after successful DAA therapy, particularly in MSM remain challenging, highlighting the need for intensified risk reduction programs.
ACCEPTED MANUSCRIPT Declarations Funding: No funding Competing Interests: Jenny Bischoff has nothing to disclose. Jürgen K. Rockstroh has received honoraria for lectures and/or consultancies from Abbott, AbbVie, Gilead, Hexal, Janssen, Merck, and ViiV
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Ethical Approval: Not required
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ACCEPTED MANUSCRIPT Meeting of the American Association for the Study of Liver diseases, October 20-24, 2017, Washington DC, USA; abstract 196 Hagan H, Jordan AE, Neurer J, Cleland CM. Incidence of sexually transmitted hepatitis C virus infection in HIV-positive men who have sex with men. AIDS. 2015;29(17):2335-2345. van Santen DK, van der Helm JJ, Del Amo J, Meyer L, D'Arminio Monforte A, Price M, et al. Lack of decline in hepatitis C virus incidence among HIV-positive men who have sex with men during 1990-2014. J Hepatol. 2017;67(2):255-262. Boerekamps A, van den Berk GE, Lauw FN, Leyten EM, van Kasteren ME, van Eeden A, et al. Declining Hepatitis C Virus (HCV) Incidence in Dutch Human Immunodeficiency VirusPositive Men Who Have Sex With Men After Unrestricted Access to HCV Therapy. Clin Infect Dis. 2018;66(9):1360-1365. Braun DL, Hampel BH, Nguyen H, Flepp M, Stoeckle M, Béguelin C, et al. for the Swiss HIV Cohort Study. A treatment as prevention trial to eliminate HCV in HIV+ MSM: The Swiss HCVFREE trial. 25th Conference on Retroviruses and Opportunistic Infections; March 04-07, 2018, 2018; Boston. Martin NK, Boerekamps A, Hill AM, Rijnders BJA. Is hepatitis C virus elimination possible among people living with HIV and what will it take to achieve it? J Int AIDS Soc. 2018;21 Suppl 2:e25062. Newsum AM, Ho CK, Lieveld FI, van de Laar TJ, Koekkoek SM, Rebers SP, et al. The hepatitis C virus nonstructural protein 3 Q80K polymorphism is frequently detected and transmitted among HIV-infected MSM in the Netherlands. AIDS. 2017;31(1):105-112. Ingiliz P, Martin TC, Rodger A, Stellbrink HJ, Mauss S, Boesecke C, et al. HCV reinfection incidence and spontaneous clearance rates in HIV-positive men who have sex with men in Western Europe. J Hepatol. 2017;66(2):282-287. Cachay ER, Hill L, Wyles D, Colwell B, Ballard C, Torriani F, et al. The hepatitis C cascade of care among HIV infected patients: a call to address ongoing barriers to care. PLoS One. 2014;9(7):e102883. Christensen S, Buggisch P, Mauss S, Boker KHW, Schott E, Klinker H, et al. Direct-acting antiviral treatment of chronic HCV-infected patients on opioid substitution therapy: Still a concern in clinical practice? Addiction. 2018;113(5):868-882. Jacobson IM, Lawitz E, Gane EJ, Willems BE, Ruane PJ, Nahass RG, et al. Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials. Gastroenterology. 2017;153(1):113-122.
35. 36.
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HCV Genotype
Table 1: DAA Treatment options and duration of treatment (adapted from EACS guidelines)
1
DAA Treatment Regimen
Non-cirrhotic
Compensated cirrhotic (CTP class A)
Decompensated cirrhotic (CTP class B,C)
SOF/LDV
1a: 8a-12 wkb,e 1b: 8a-12 wkd
1a: 12wkc, e 1b: 12wk,c,
12 wk ± RBVc
SOF+DCV SOF+SMV (3) SOF/VEL (1,2) SOF/VEL/VOX OBV/PTV/r + DSV EBR/GZR (1,2) GLE/PIB (1,2)
12 wkb 12 wk 8 wk/12wki 1a: 12 wk + RBV (1) 1b: 8 wk (F0-F2 (2)) 12 wkd 1a: 12 wkf 1b: 8 wk (F0-F2 (2)) 12 wkd 8 wk
12 wk 12 wki 1a: 24 wk + RBV (1) 1b: 12 wk 12 wkf 12 wk
12 wk ± RBVc NR 12 wk + RBV NR NR NR NR
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3
4
SOF+DCV SOF/VEL (1,2) SOF/VEL/VOX GLE/PIB (1,2)
12 wk 12 wkd 12 wki 12 wk
8 wk/12wki 8wk
SOF+DCV SOF/VEL SOF/VEL/VOX (1,2) GLE/PIB (1,2)
12 wkj 12 wk, j
SOF/LDV (1,2) SOF/DCV SOF/SMV SOF/VEL (1,2) SOF/VEL/VOX GLE/PIB (1,2) EBR/GZR (1,2) OBV/PTV/r
8a (1)-12 wke
12 wk + RBV 12 wk + RBV NR NR
24 wk + RBV 12 wk j (1), NR (2) 8 wk (1), 12 wkd,i(1,2) 12 wk/16 wkd
8 wk/12 wkd
12 wkc,e 12 wk 12 wk + RBV 12 wk 12 wki 12 wk 12 wkg,e 12 wk + RBV
8 wk/12wki 8 wk
24 wk + RBV 24 wk + RBV NR NR 12 wk + RBVc 12 wk + RBVc NR 12 wk + RBV NR NR NR NR
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12 wke ± RBV 12 wkc,e 12 wk ± RBVc SOF/LDV 12 wk ± RBV 12 wkc 12 wk ± RBVc SOF/DCV d 12 wk 12 wk + RBV SOF/VEL (1,2) 8 wk/12wki 12 wki,d NR SOF/VEL/VOX 8 wk 12 wk NR GLE/PIB (1,2) Abbreviations: NR: Not recommended; DAA: direct acting antiviral; CTP: child-pugh turcotte; OBV: ombitasvir; PTV: paritaprevir; r: ritonavir; DSV: dasabuvir; SMV: simeprevir; SOF: sofosbuvir; VEL: velpatasvir; VOX: voxilaprevir; GLE: glecaprevir; PIB: pibrentasvir; GZR: grazoprevir; EBR: elbasvir; DCV: daclatasvir; LDV: ledipasvir; 1 EACS guidelines, 2 EASL guidelines, 3 AASLD guidelines
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if HCV RNA <6000000IU/ml, treatment naïve and absence of liver fibrosis or cirrhosis F>3
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additionally RBV in GT1a treatment-experienced patients, if tested, not in the absence of NS5A RASs (1)
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additionally RBV, unless treatment - naïve or – experienced persons with compensated cirrhosis without baseline NS5A RASs (1)
d
in RBV + peg-IFN alfa ± SOF or SOF + RBV experienced patients (2)
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not recommended in RBV + peg-IFN alfa ± SOF or SOF + RBV experienced patients (2)
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16wk + RBV if HCV RNA >800000IU/ml and NS5A RASs
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16 wk + RBV if treatment experienced and HCV RNA >800000IU/ml
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24 wk + RBV in treatment experienced patients with compensated cirrhosis in DAA treatment experienced patients
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ABC FTC 3TC TDF
SOF/VE Lc,e,g/ VOXc,e,g
GLE/ PIB
GZR/E BR
c,e,g
↑ARV ↑ARV5
↑ARV5
↓DAA
↓DAA
↓DA A
↓VEL ↑SOF
↓DAA
↓DAA
↓DA A1
ETVb,f
↓DAA
↓DAA
↓DAA
↓DAA
↓DAA
NVPb
↓DAA ↑ARV ↑ARV
↓DAA ↑ARV ↑ARV
↓DA A ↓DA A
↓DAA
↓DAA
↓DAA
↓DA A ↓DA A
ATVc/ ra,e ATVc/ ca,c
↑DAA
↑DAA2
↑DAA
↑DAA
↑DAA
↑DAA
↑DAA
DRVc/ ra,e
↓ARV ↑DAA
↓ARV2
DRVc/ ca.c LPV/r
↑DAA
↑DAA
↑DAA
↑DAA
↑DA A ↑DA A ↑AR V ↑DA A ↑AR V ↑DA A ↑DA A
a,e
↑DA A1 ↑DA A1
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NS 5B SO F
NS5A/NS5B SOF/LD Ve,g
SOF/VE Lc,e,g
↓LDV ↑TDF
↑ARV
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TAF AZT EFVb,f
RPV
PIs
OBV/PTVa/ra,e +DSV
↑DAA
↑DAA
↑DAA
↑DAA
↑DAA
↑DAA
↓DAA
↓VEL, ↑SOF ↓DAA ↓DAA
↑COBI
↑ DAA
↑DAA
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ARV
NNRTIs
NRTIs
OBV/PTV a a,e /r
NS5 A DCV
↑DA A
↑COBI
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Entry/ Integrase inhibitors
↑ARV ↑ARV MVC DTG RAL ↑DAA ↑DAA ↑DA ↑DAA ↑DA EVG/ A A1 ca ↑ARV4 ↑ARV4 BIC3 Abbreviations: DAA: direct acting antiviral; ARV: antiretroviral; PI: protease inhibitor; NNRTI: non nucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; OBV: ombitasvir; PTV: paritaprevir; r: ritonavir; DSV: dasabuvir; SMV: simeprevir; SOF: sofosbuvir; VEL: velpatasvir; VOX: voxilaprevir; GLE: glecaprevir; PIB: pibrentasvir; GZR: grazoprevir; EBR: elbasvir; DCV: daclatasvir; LDV: ledipasvir; ABC: abacavir; FTC:emtricitabine; 3TC:lamivudine; TDF: tenofovir disoproxil fumarate; TAF: tenofovir alafenamide fumarate; AZT: azidothymidine; EFV: efavirenz; ETV: etravirine; NVP: nevirapine; RPV: rilpivirine; ATV: atazanavir; DRV: darunavir; LPV: lopinavir; MVC: maraviroc; DTG: dolutegravir; RAL; raltegravir; EVG: elvitegravir; BIC: bictegravir; c: cobicistat; CYP3A4: cytochrom P3A4, OATP: organic anionic transporting polypeptides, p-gp: permeability glycoproteins; BCRP: breast cancer resistantance protein;
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1 Dose adjustment of DCV necessary, 2ARV should be administered without additional r, 3FDA approved 2018, 4coadministration not studied, bictegravir increase expected, 5dose reduction TAF necessary, a
inhibitor of CYP3A4, binducer of CYP3A4, cinhibitor of OATP, dinducer of OATP, einhibitor of p-gp, finducer of p-gp, ginhibitor of BCRP, inducer of BCRP
h
No clinically significant interactions expected Potential interactions- additional monitoring or dose adjustments required Co-administration is not recommended
Data from www.hep-druginteractions.org
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Genotype
Participants, no. (%)
SVR12
COINFECOVA-2 [20]
SOF+RBV SOF/LDV±RBV SOF+SMV ± RBV SOF+DCV ± RBV OBV/PTV/r ± DSV ± RBV
GT 1-4
Overall n = 515 Liver Cirrhosis n = 279 (54) TE: n = 200 (39)
Overall: 92.8% (478/515) No liver cirrhosis: 97% (229/236) Liver cirrhosis: 89.2% (249/279; p=0.001) TE (prior DAA): 91.4% (32/35) TE (prior pegIFN): 91.5% (151/165) TN: 94.6% (261/276)
ANRS CO13 HEPAVIH [21]
SOF+RBV SOF/LDV±RBV SOF+SMV ± RBV SOF+DCV ± RBV
GT 1-4
Overall: n = 323 Liver cirrhosis n = 194 (60.2) TE n = 221 (68.4)
Overall: 93.5% No liver cirrhosis: 93.8% Liver cirrhosis: 93.3% TN: 94.1% TE: 93.2%
ATHENA HIV [22]
Every in the Netherlands approved treatment regimen since 2000
GT 1-4
Overall (DAA and IFN- based treatment) n=1471 DAA treatment n = 612
Overall: DAA Treatment 98% (598/612)
Madrid Co-RE [23]
SOF/LDV SOF+DCV SOF+SMV SOF+RBV OBV/PTV/r+DSV OBV/PTV/r
GT 1-4
Overall n = 2369 Compensated cirrhosis n = 803 (33.9) Decompensated cirrhosis n = 156 (6.6%)
Overall: 94.1% (m-ITT; 2180/2318) No liver cirrhosis: 95.9% (m-ITT; 1323/1380) Comp. Cirrhosis: 93.1% (m-ITT; 731/785) Decomp. Cirrhosis: 82.4% (m-ITT; 126/153)
German Hepatitis CRegistry [24]
SOF+RBV SOF+pegIFN+RBV SOF+SMV±RBV SOF+DCV±RBV LDV/SOF±RBV OBV/PTV/r ± DSV ± RBV PegIFN+RBV+boceprevir PegIFN+RBV+telaprevir PegIFN+RBV+SMV PegIFN+RBV+SOF LDV/SOF SOF/SMV SOF/DCV OBV/PTV/r ± DSV
GT 1-4
Overall n = 488 Liver cirrhosis n = 84 (17.2) TE n = 227 (46.5)
Overall: 91.2% (445/488) No liver cirrhosis: 91.6% (370/404) Liver Cirrhosis: 89.3% (75/84)
GT 1-4
Overall = 426 IFN free treatment cohort: Overall n = 256 Liver cirrhosis n = 213 (83.0) TE n =110 (43.0)
Overall 86.3% (221/256ITT, IFN free) 67.3% (179/226; ITT, IFN based) No liver cirrhosis 86 % (37/43) Liver cirrhosis 86% (184/213) TN 84 % (91/108) TE 88 % (97/110)
LDV/SOF±RBV OBV/PTV/r + DSV ± RBV
GT 1
Overall n = 996 Liver cirrhosis n = 225 (22.6) TE n = 160 (16.1)
Overall: 90.9% (823/905) No liver cirrhosis: 92.4% (647/700;p=0.006) Liver cirrhosis: 85.9% (176/205) TN: 91% (687/755) TE: 90.7% (136/150)
Grady Health Systems IDP-Clinic Atlanta, Georgia [26]
LDV/SOF SOF+RBV SOF+DCV SOF+SMV
GT 1-3
Overall n= 172 Liver cirrhosis: n = 28 (16.0) TE n = 36 (21.0)
Overall: 93% (ITT; 160/172) No liver cirrhosis: 93% (135/144) Liver cirrhosis: 89% (25/28; p<0.001) TN: 93% (126/136) TE: 94% (34/36)
HULP-HUGM Study [27]
SOF/LDV ± RBV SOF+DCV ± RBV SOF+SMV ± RBV OBV/PTV/r±DSV OBV/PTV/r OBV/PTV/r+DSV ±RBV
GT 1-4
Overall n = 482 Liver cirrhosis n =233 (48.4) TE n = 283 (58.7)
Overall: 94.2% (454/482) No liver cirrhosis 96.8% (240/248) Liver cirrhosis: 91.4% (213/233)
GT 1/4
Overall n = 210 Liver cirrhosis n = 23 (11.0) TE n = 114 (54.3)
Overall: 96.7% (203/210) No liver cirrhosis: 96.3% (180/187) Liver cirrhosis: 100% (23/23) TN: 97.9% TE: 93.6%
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Prospective multicohort Study, Spain (HEPAVIRDAA Cohort) [19]
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Veterans Affairs Clinical Case Registry [25]
Italian Compassionate Use Program (CUP) [28]
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Table 3: Important real-life cohort studies in HIV/HCV coinfected persons
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Abbreviations: DAA: direct acting antiviral; GT: genotype; TE: treatment experienced TN: treatment naive; OBV: ombitasvir; PTV: paritaprevir; r: ritonavir; DSV: dasabuvir; SMV: simeprevir; SOF: sofosbuvir; VEL: velpatasvir; VOX: voxilaprevir; GLE: glecaprevir; PIB: pibrentasvir; GZR: grazoprevir; EBR: elbasvir; DCV: daclatasvir; LDV: ledipasvir;pegIFN: pegylated interferon;
Are there any challenges in HCV therapy of HIV infected patients left? Jenny Bischoff , Jurgen K Rockstroh ¨ PII: DOI: Reference:
S0924-8579(18)30245-0 https://doi.org/10.1016/j.ijantimicag.2018.08.019 ANTAGE 5527
To appear in:
International Journal of Antimicrobial Agents
Received date: Revised date: Accepted date:
30 May 2018 10 August 2018 18 August 2018
Please cite this article as: Jenny Bischoff , Jurgen K Rockstroh , Are there any challenges in HCV ¨ therapy of HIV infected patients left?, International Journal of Antimicrobial Agents (2018), doi: https://doi.org/10.1016/j.ijantimicag.2018.08.019
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ACCEPTED MANUSCRIPT Highlights: High cure rates of HCV are achieved in HIV/HCV coinfected patients Liver cirrhosis and an impaired immune function seem to decrease the chance of cure Drug-Drug interactions are safely manageable, if considered accordingly Enhanced preventive measures including behavioural interventions are required
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Are there any challenges in HCV therapy of HIV infected patients left? Jenny Bischoff1, Jürgen K Rockstroh1 1
Department of Medicine I, University Hospital Bonn, Bonn
Corresponding author:
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Dr. Jenny Bischoff Department of Medicine I University Hospital Bonn Sigmund-Freud-Str. 25 D-53127 Bonn Phone: +49 228 287 16558
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Fax: +49 228 287 15034
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Are there any challenges in HCV therapy of HIV infected patients left? Abstract Direct acting antivirals (DAAs) have tremendously improved treatment of Hepatitis C virus (HCV) infections also in Human immunodeficiency virus (HIV) positive individuals. Curing
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HCV is of particular importance in HIV positive individuals as liver disease progression is accelerated in the course of concomitant HIV infection. Former challenges, such as safety and tolerability as well as reduced treatment uptake of a peginterferon (pegIFN) and ribavirin (RBV) based treatment have been overcome with the approval of DAAs. Indeed, rates of
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discontinuation under modern all oral DAA therapy in HIV/HCV coinfection have been
reported to be less than 1%. Rates of sustained virological response (SVR) after treatment have aligned with those seen in HCV monoinfected patients, resulting in an equalization of treatment recommendations for HCV monoinfected and HIV/HCV coinfected patients.
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Nevertheless, coinfection with HIV has been associated with slightly higher relapse-rates in
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some real-world cohorts, arousing a discussion concerning a more individualized treatment once again. Moreover, an ongoing epidemic of acute HCV infections in HIV positive MSM
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with high reinfection rates challenges physicians and researchers. A concise summary of the
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remaining challenges in HCV treatment of HIV positive individuals is given in the present
Keywords: HIV/HCV coinfection, DAA Treatment, HIV, challenges in HIV
ACCEPTED MANUSCRIPT Introduction The introduction of highly effective antiretroviral therapy (ART) has dramatically reduced HIV-associated morbidity and mortality. Indeed, near to normal life expectancy can be expected in human immunodeficiency virus (HIV) infections if antiviral therapy is started before the onset of AIDS or advanced immunodeficiency. Therefore, concomitant diseases are
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increasingly gaining importance. Coinfections with the Hepatitis C virus (HCV) are of
substantial concern, as HIV is known to accelerate the progression of HCV related liver
disease, which has emerged as a leading cause of death in HIV infected individuals [1]. It is
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estimated, that about 80 million people are chronically infected with HCV globally [2]. An estimated 2.3 million HIV positive individuals are coinfected with HCV, resulting in an overall prevalence of 6.2% worldwide [3]. Prevalence varies widely by route of transmission and region, with a higher burden in people who inject drugs (PWID) and men who have sex
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with men (MSM) as well as in Eastern Europe and central Asia [3].
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In order to reduce the burden of liver disease related morbidity and mortality in HIV/HCV coinfected individuals, treatment of HCV should be prioritized in this subgroup [4-6]. In the
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era of peginterferon (PegIFN) and ribavirin (RBV), treatment of HCV had been particularly
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challenging in HIV positive individuals, due to severe adverse events and drug-drug interactions as well as disappointingly low cure rates, with sustained virological response
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(SVR) rates ranging from 27% - 40% [7-9]. Telaprevir and boceprevir, two NS3/4A Protease Inhibitors (PI), led to improved SVR rates in combination with pegIFN and RBV in HCV genotype (GT) 1 coinfected individuals, but came along with a further increased toxicity [1012]. Since then, new generations of direct acting antivirals, including NS5A inhibitors, nucleotide and non-nucleos(t)ide NS5B inhibitors and second generation PIs, have remarkedly improved treatment outcomes along with shortened treatment durations and a far
ACCEPTED MANUSCRIPT better safety profile. Thus, interferon-based treatment is no longer recommended in HIV/HCV coinfected persons [4,5]. DAA based treatment in HIV Management and Treatment Initiation
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Initially, international guidelines prioritized HCV treatment initiation in HIV/HCV coinfected individuals because of the faster fibrosis progression and increased risk of dying from liver disease in this particular patient group. More recently, guidelines now recommend HCV treatment in all HCV infected patients regardless of HIV coinfection [4-6] (table 1). Most
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importantly, guidelines no longer separate between HCV mono- or HIV/HCV-coinfected subjects with regard to DAA choice or treatment duration as comparable cure rates have been obtained in HCV treatment studies for both patient groups. Treatment duration varies from 8
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to 24 weeks, depending on HCV viral load, genotype, cirrhosis status and past treatment experience. Ribavirin might be added in compensated and decompensated cirrhosis or
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treatment experienced patients according to treatment regimen and HCV genotype. The effectiveness and safety of these drugs were proved in several clinical trials and supported by
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real-life data from numerous studies (supplementary table S1 and table 3).
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A shortened treatment duration of 8 weeks for HIV/HCV coinfected patients has been successful in clinical trials as well as real-life cohorts. Rates of sustained virologic response were high for patients treated with 8 weeks of glecaprevir (GLE) and pibrentasvir (PIB) or ledipasvir (LDV) and sofosbuvir (SOF), but disappointing for patients being administered 8 weeks of daclatasvir (DCV) and SOF with an overall rate of 76% in HIV/HCV coinfected
ACCEPTED MANUSCRIPT patients [13-15]. Indeed, 12 weeks of DCV/SOF is the recommended treatment duration for non-cirrhotic HCV patients.
For patients with decompensated cirrhosis the use of protease inhibitors is not recommended as higher drug exposures lead to increased toxicity [4]. Feasible treatment options are SOF
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and velpatasvir (VEL) (all genotypes), SOF/LDV (GT 1, 4, 5, 6) or SOF/DCV (all genotypes) [4,5].
Systematic resistance testing prior to commencing DAA therapy is not recommended, since
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there are highly effective treatment regimens for patients with resistance associated substitutions (RAS) at baseline [4]. For those patients, who failed to achieve SVR despite an all oral interferon free DAA treatment, high SVR rates have been achieved with 12 weeks of
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SOF, VEL and voxilaprevir (VOX) in HCV monoinfected patients (POLARIS 1: Pretreatment containing an NS5A inhibitor, overall SVR 96%, POLARIS 4: Pretreatment
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without an NS5A Inhibitor, overall SVR 98%) [16]. No impact of pre-retreatment RAS at baseline on achievement of SVR12 was detected. The combination of SOF+GLE/PIB+RBV
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seems to be promising, with an overall SVR12 rate of 96% (22/23) and 100% in GT2 and
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GT3 infections [17]. Nevertheless, retreatment in the few patients with DAA failure can be
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challenging and is best managed in a multidisciplinary team.
Drug-Drug Interactions Drug-Drug-Interactions have to be considered carefully in every HIV-coinfected patient prior to starting DAA therapy and can be very challenging for the physician in care. In general, HCV direct acting antivirals and HIV antiretrovirals can affect metabolism or absorption of each other, resulting in either higher, potentially toxic, serum concentrations of the DAA or
ACCEPTED MANUSCRIPT ARV or a reduction of mainly the DAA, risking treatment failure. Induction or inhibition of several cytochrome P450 enzymes, specifically the CYP3A4 family, permeability glycoproteins (p-gp), breast cancer resistance protein (BCRP)-transporters and organic anion transporting polypeptides (OATP) 1B1 and 1B3 bear a high potential of drug-drug interactions.
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Concomitant use of HIV PIs and PI containing DAA regimens is contraindicated, as HIV PI inhibit OATP and are often boosted with cobicistat or ritonavir, both strong inhibitors of CYP3A4. Moreover, PI containing DAA regimens should not be co-administered, if the
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patient is treated with NNRTIs, which induce CYP3A4 and p-gp. For some combinations dose adjustments (e.g. DCV + HIV PIs) or closer monitoring for adverse events (e.g. combinations containing Tenofovir-DF) are necessary. A detailed overview of all relevant
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drug-drug interactions between HIV and HCV drugs is provided in table 2.
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Real world effectiveness of DAA based treatment in HIV/HCV coinfected patients Since the implementation of IFN free DAA based treatment regimens comparable SVR rates
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have been achieved between monoinfected and coinfected patients and treatment recommendations were standardized for HIV/HCV coinfected and HCV monoinfected patients [4,5]. Nevertheless, the applicability of study results from controlled clinical trials to a very heterogenous patient population in real life has been questioned, as a high proportion of patients would not fit the eligibility criteria [18]. Outside of these deliberately chosen conditions several socio-economic and clinical variables may affect treatment initiation and outcome. Indeed, SVR rates varied between monoinfected and coinfected patients in real-life
ACCEPTED MANUSCRIPT cohort studies and some were lower compared to those achieved in large Phase II/III trials (supplementary table S1 and table 3)[19,20].
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Recently, data from two Spanish trials, suggested that HIV coinfection may serve as a risk factor for treatment failure. This has raised the question, whether a more individualized
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treatment is necessary in this subgroup [19,29]. In a prospective multi-cohort study from Spain dually infected patients receiving IFN-based or IFN free DAA treatment regimens showed significantly lower SVR 12 rates compared to monoinfected patients (DAA based treatment, intention-to-treat: 86.3% vs 94.9%, p = 0.002, on-treatment: 94.8% vs. 98.6%; p =
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0.032). These findings were consistent after stratifying for sex, IDU, liver disease at baseline, pre-treatment response and genotype. A higher frequency of relapses seemed to be
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responsible for differences in SVR rates. Moreover, HIV infection was an independent
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predictor of non-achievement of SVR12 in the multivariable logistic regression (MLR) analyses. It must be noted, that treatment regimens differed between monoinfected and
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coinfected patients, which might have introduced a bias to the analysis. Approximately one half (42%, 108/256) of the coinfected patient population was administered simeprevir (SMV)
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+ SOF [19]. SMV+SOF have been associated with treatment failure in the Madrid CoRe registry. Furthermore, gender, baseline CDC class C, CD4 cell count < 200/µl, HCV RNA> 800.000/IU, the use of other suboptimal DAA regimens, cirrhosis and decompensated liver disease were associated with treatment failure in this large prospective cohort. Nevertheless, SVR rates of 92% and 94% were achieved in the intent-to-treat (ITT) and modified intent-totreat (m-ITT) analysis respectively, and discontinuations due to adverse events were low. SVR rates in patients with GT3 and LDV/SOF treatment were considerably low and therefore
ACCEPTED MANUSCRIPT the authors suggest that LDV/SOF is a suboptimal treatment regimen in GT3 patients [23]. This is in line with current guidelines, were this regimen is not recommended for this particular patient population [4,5]. Liver cirrhosis was established as a risk factor for non-achievement of SVR in HIV/HCV coinfection in several studies [20,27,30]. In a multicentre cohort from Germany, the GECCO
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Cohort, SVR rates dropped considerably in patients suffering from liver cirrhosis and having a CD4 cell count less than 350/µl [30]. The association between the CD4 cell count and nonachievement of SVR lost significance in the MLR, which is in line with other reports, were
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SVR rates did not differ by CD4 cell count [20,28,30]. In contrast, SVR12 rates assessed in the German hepatitis C-registry (DHC-R) did not differ significantly between coinfected and monoinfected patients with or without cirrhosis. Age, gender and treatment experience were the only variables associated with non-achievement of SVR12 in the MLR. Overall 90.3%
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(5111/5657) of monoinfected and 91.2% (445/488) of coinfected patients achieved SVR12 in
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the ITT analysis. In patients with underlying cirrhosis at baseline 87.8% and 89.3% of monoinfected and coinfected patients achieved SVR12, respectively [24]. Additional support
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comes from the French ARNS CO13 HEPAVIH cohort. In this French cohort 93.5% of patients achieved SVR12 and no difference was detected between patients with and without
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liver cirrhosis [21]. Of note, coinfected patients enrolled in the DHC-R (29.5 vs 17.2%) and
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the GECCO cohort (31% vs 22%) were less likely to be cirrhotic compared to the patient populations from the three Spanish cohorts (51% vs 65% IFN based treatment group; 48% vs 83% IFN free treatment group; Madrid CoRE: compensated cirrhosis 33.9%, decompensated cirrhosis 6.6%, COINFECOVA-2 : F4 Fibrosis 54.2%, F4 fibrosis with > 21kPa 27.2%, recently decompensated Cirrhosis 5.6%) [19,20,23,24,30]. Differences in these study results might be in part explained by differentiating graduations of liver cirrhosis as well as different treatment regimens.
ACCEPTED MANUSCRIPT Compromised treatment responses have occurred in monoinfected as well as coinfected patients with decompensated liver cirrhosis. A proportion of these treatment failures however, are not virological, resulting in higher SVR rates after adjustment. Supporting evidence comes from a Spanish cohort, where HIV coinfection lost significance as a risk factor for treatment failure after adjusting for severe liver disease [27].
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Another important factor associated with treatment response in coinfected patients might be the baseline HIV viral load, reflecting therapy adherence and immune function. Undetectable HIV RNA has been a mandatory inclusion criterion in most clinical studies. Thus, patients in
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real life cohorts may differ from those patients enrolled in clinical trials by HIV suppression, explaining differentiating SVR rates. Supporting evidence comes from a real-life cohort from Baltimore, showing an HIV viral load <20 copies/ml to be predictive of SVR achievement [31]. In contrast, in the French ARNS CO13 HEPAVIH Cohort, levels of HIV RNA < 50
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copies/ml and >50 copies/ml were not associated with SVR-achievement in the logistic
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regression analysis [21].
Furthermore, with an aging HIV-positive population co-morbidities and polypharmacy may
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impact treatment initiation, drug adherence and tolerability and thus influence treatment
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outcomes in the real world apart from an intrinsic antiviral effect.
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Remaining challenges and future perspectives Acute HCV infection Management, treatment initiation,- regimen and – duration in acute HCV infections are still under investigation with slightly varying recommendations in international guidelines [4-6]. The EACS guidelines recommend repeated testing of HCV RNA 4 weeks after intial HCV viral load determination [5]. Only 11.9% of patients enrolled in the PROBE-C cohort (464
ACCEPTED MANUSCRIPT coinfected patients enrolled, 99% MSM) were able to spontaneously clear their acute HCV infection, indicating a high risk of progression to a chronic phase of disease [32]. HCV treatment should be considered in patients with a < 2log10 decrease in the HCV RNA viral load 4 weeks after initial assessment as this was predictive of non spontaneous clearance and a progression to a chronic phase of disease is very likely otherwise [32]. Treatment in acutely
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infected patients has been shown to be beneficial for the patients’ outcome, can prevent transmission and is cost effective. Best treatment duration remains controversial at this point. Studies looking at shorter treatment durations of 6 weeks with SOF/LDV in HIV/HCV coinfected subjects showed several relapses particularly in patients with very high baseline
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HCV viral loads [33]. In HCV monoinfected patients however all patients responded to 6 weeks SOF/LDV. More recently data from 8 weeks SOF/LDV in HIV-positive individuals were presented which again showed HCV cure in all patients so that 8 weeks of therapy
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appear to be the safest approach for now[4,34]. The subgroup of HIV/HCV coinfected patients comprises a high proportion of intravenous drug users and MSM, two populations
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known to be particularly vulnerable to acute HCV infections [3,22]. An ongoing epidemic of sexually transmitted acute HCV infections in predominantly HIV positive men who have sex
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with men (MSM) has occurred in the last two decades and incidence rates of HCV in HIV+
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MSM are still not decreasing in Europe [35,36]. An unrestricted access to DAA treatment resulted in a high treatment uptake and a decline in acute HCV infections as well as high cure
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rates in HIV/HCV coinfected MSM in the Netherlands [37]. The Swiss HCVree trial, a treatment as prevention trial offering early access to treatment and counselling, achieved comparable results, reducing acute HCV infections by almost 50% and chronic infections by >90% in HIV+ MSM [38]. Despite this promising development, other STDs increased in the Dutch population indicating that the reduction of acute HCV in HIV positive MSM was not caused by behavioural changes, which appear to be necessary to reduce the risk of reinfection and achieve the WHO goal of HCV eradication by 2030
[37,39].
Reinfections and
ACCEPTED MANUSCRIPT transmission of resistance mutations particularly in those who failed to achieve SVR with prior treatment remain challenging and call for further innovative prevention measures [40,41]. Barriers
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An evaluation of patients enrolled in the ATHENA HIV cohort not treated for their HCV infection observed a higher proportion of women, carribean/latin American, GT3 infections and PWID [22]. These findings are in line with a retrospective analysis from San Diego, California, observing that a lack of engagement in care, being non-white and ongoing barriers
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to care as drug and alcohol abuse, neuropsychiatric diseases and unstable housing were predictive of non-referral to treatment in coinfected patients [42]. With the latest approval of highly effective DAAs in GT3 infections and evidence of high cure rates and tolerability in PWID a deferral of those two subgroups for treatment can be expected [43,44]. But so far, it
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remains a gap in treatment initiation for women and marginalized patients, which has to be
Conclusion
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overcome.
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HIV/HCV coinfected patients are no longer regarded as a ‘special population’ as depicted by
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current guidelines. Tremendous improvements have been made since the implementation of DAA therapy, resulting in a highly efficacious and well-tolerated treatment for almost all patients. Drug-drug interactions with ARVs have to be considered carefully but appear safely manageable if considered correspondingly. HCV reinfections after successful DAA therapy, particularly in MSM remain challenging, highlighting the need for intensified risk reduction programs.
ACCEPTED MANUSCRIPT Declarations Funding: No funding Competing Interests: Jenny Bischoff has nothing to disclose. Jürgen K. Rockstroh has received honoraria for lectures and/or consultancies from Abbott, AbbVie, Gilead, Hexal, Janssen, Merck, and ViiV
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Ethical Approval: Not required
ACCEPTED MANUSCRIPT References
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Neukam K, Morano-Amado LE, Rivero-Juarez A, Mancebo M, Granados R, Tellez F, et al. HIV-coinfected patients respond worse to direct-acting antiviral-based therapy against chronic hepatitis C in real life than HCV-monoinfected individuals: a prospective cohort study. HIV Clin Trials. 2017;18(3):126-134. Minguez C, Garcia-Deltoro M, Flores J, Galindo MJ, Montero M, Reus S, et al. Interferonfree therapy for treating hepatitis C virus in difficult-to-treat HIV-coinfected patients. AIDS. 2018;32(3):337-346. Piroth L, Wittkop L, Lacombe K, Rosenthal E, Gilbert C, Miailhes P, et al. Efficacy and safety of direct-acting antiviral regimens in HIV/HCV-co-infected patients - French ANRS CO13 HEPAVIH cohort. J Hepatol. 2017;67(1):23-31. Boerekamps A, Newsum AM, Smit C, Arends JE, Richter C, Reiss P, et al. High Treatment Uptake in Human Immunodeficiency Virus/Hepatitis C Virus-Coinfected Patients After Unrestricted Access to Direct-Acting Antivirals in the Netherlands. Clin Infect Dis. 2018;66(9):1352-1359. Berenguer J, Gil-Martin A, Jarrin I, Moreno A, Dominguez L, Montes M, et al. All-oral DAA therapy against HCV in HIV/HCV-coinfected subjects in real-world practice: Madrid-CoRe Findings. Hepatology. 2018;10.1002/hep.29814. Bischoff J, Mauss S, Cordes C, Lutz T, Scholten S, Moll A, et al. Rates of sustained virological response 12 weeks after the scheduled end of direct-acting antiviral (DAA)-based hepatitis C virus (HCV) therapy from the National German HCV registry: does HIV coinfection impair the response to DAA combination therapy? HIV Med. 2018;19(4):299-307. Bhattacharya D, Belperio PS, Shahoumian TA, Loomis TP, Goetz MB, Mole LA, et al. Effectiveness of All-Oral Antiviral Regimens in 996 Human Immunodeficiency Virus/Hepatitis C Virus Genotype 1-Coinfected Patients Treated in Routine Practice. Clin Infect Dis. 2017;64(12):1711-1720. Patel M, Rab S, Kalapila AG, Kyle A, Okosun IS, Miller L. Highly Successful Hepatitis C Virus (HCV) Treatment Outcomes in Human Immunodeficiency Virus/HCV-Coinfected Patients at a Large, Urban, Ryan White Clinic. Open Forum Infect Dis. 2017;4(2):ofx062. Montes ML, Olveira A, Ahumada A, Aldamiz T, Garcia-Samaniego J, Clemente A, et al. Similar effectiveness of direct-acting antiviral against hepatitis C virus in patients with and without HIV infection. AIDS. 2017;31(9):1253-1260. Massimo A, Teti E, Antinori A, Milazzoi L, Sollima S, Rizzardini G, et al. Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir Combination Treatment in Patients with HIV/HCV Co-Infection: Results of an Italian Compassionate Use Program. Clin Infect Dis. 2017;64(5):680-683. Arias A, Aguilera A, Soriano V, Benitez-Gutierrez L, Lledo G, Navarro D, et al. Rate and predictors of treatment failure to all-oral HCV regimens outside clinical trials. Antivir Ther. 2017;22(4):307-312. Boesecke C, Ingiliz P, Berger F, Lutz T, Schewe K, Schulze Zur Wiesch J, et al. Liver Cirrhosis as a Risk Factor for Direct-Acting Antiviral Therapy Failure in Real-Life Hepatitis C Virus/Human Immunodeficiency Virus Coinfection. Open Forum Infect Dis. 2017;4(3):ofx158. Falade-Nwulia O, Sutcliffe C, Moon J, Chander G, Wansom T, Keruly J, et al. High hepatitis C cure rates among black and nonblack human immunodeficiency virus-infected adults in an urban center. Hepatology. 2017;66(5):1402-1412. Boesecke C, Müller Martínez E, Nelson M, Ingiliz P, Lutz T, Scholten S, et al. Fueling the epidemic: Low rates of spontaneous clearance of acute HCV coinfection. 25th Conference on Retroviruses and Opportunistic Infections; 04-07 March, 2018, 2018; Boston. Deterding K, Spinner CD, Schott E, Welzel TM, Gerken G, Klinker H, et al. Ledipasvir plus sofosbuvir fixed-dose combination for 6 weeks in patients with acute hepatitis C virus genotype 1 monoinfection (HepNet Acute HCV IV): an open-label, single-arm, phase 2 study. Lancet Infect Dis. 2017;17(2):215-222. Naggie S et al.: 100% SVR with 8 weeks of ledipasvir/sofosbuvir in HIV-infected Men with Acute HCV Infection: Results from the SWIFT-C Trial (Sofosbuvir-Containing Regimens without Interferon for Treatment of Acute HCV in HIV-1 Infected Individuals). 68th Annual
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19.
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ACCEPTED MANUSCRIPT Meeting of the American Association for the Study of Liver diseases, October 20-24, 2017, Washington DC, USA; abstract 196 Hagan H, Jordan AE, Neurer J, Cleland CM. Incidence of sexually transmitted hepatitis C virus infection in HIV-positive men who have sex with men. AIDS. 2015;29(17):2335-2345. van Santen DK, van der Helm JJ, Del Amo J, Meyer L, D'Arminio Monforte A, Price M, et al. Lack of decline in hepatitis C virus incidence among HIV-positive men who have sex with men during 1990-2014. J Hepatol. 2017;67(2):255-262. Boerekamps A, van den Berk GE, Lauw FN, Leyten EM, van Kasteren ME, van Eeden A, et al. Declining Hepatitis C Virus (HCV) Incidence in Dutch Human Immunodeficiency VirusPositive Men Who Have Sex With Men After Unrestricted Access to HCV Therapy. Clin Infect Dis. 2018;66(9):1360-1365. Braun DL, Hampel BH, Nguyen H, Flepp M, Stoeckle M, Béguelin C, et al. for the Swiss HIV Cohort Study. A treatment as prevention trial to eliminate HCV in HIV+ MSM: The Swiss HCVFREE trial. 25th Conference on Retroviruses and Opportunistic Infections; March 04-07, 2018, 2018; Boston. Martin NK, Boerekamps A, Hill AM, Rijnders BJA. Is hepatitis C virus elimination possible among people living with HIV and what will it take to achieve it? J Int AIDS Soc. 2018;21 Suppl 2:e25062. Newsum AM, Ho CK, Lieveld FI, van de Laar TJ, Koekkoek SM, Rebers SP, et al. The hepatitis C virus nonstructural protein 3 Q80K polymorphism is frequently detected and transmitted among HIV-infected MSM in the Netherlands. AIDS. 2017;31(1):105-112. Ingiliz P, Martin TC, Rodger A, Stellbrink HJ, Mauss S, Boesecke C, et al. HCV reinfection incidence and spontaneous clearance rates in HIV-positive men who have sex with men in Western Europe. J Hepatol. 2017;66(2):282-287. Cachay ER, Hill L, Wyles D, Colwell B, Ballard C, Torriani F, et al. The hepatitis C cascade of care among HIV infected patients: a call to address ongoing barriers to care. PLoS One. 2014;9(7):e102883. Christensen S, Buggisch P, Mauss S, Boker KHW, Schott E, Klinker H, et al. Direct-acting antiviral treatment of chronic HCV-infected patients on opioid substitution therapy: Still a concern in clinical practice? Addiction. 2018;113(5):868-882. Jacobson IM, Lawitz E, Gane EJ, Willems BE, Ruane PJ, Nahass RG, et al. Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials. Gastroenterology. 2017;153(1):113-122.
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Tables
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Are there any challenges in HCV therapy of HIV infected patients left?
HCV Genotype
Table 1: DAA Treatment options and duration of treatment (adapted from EACS guidelines)
1
DAA Treatment Regimen
Non-cirrhotic
Compensated cirrhotic (CTP class A)
Decompensated cirrhotic (CTP class B,C)
SOF/LDV
1a: 8a-12 wkb,e 1b: 8a-12 wkd
1a: 12wkc, e 1b: 12wk,c,
12 wk ± RBVc
SOF+DCV SOF+SMV (3) SOF/VEL (1,2) SOF/VEL/VOX OBV/PTV/r + DSV EBR/GZR (1,2) GLE/PIB (1,2)
12 wkb 12 wk 8 wk/12wki 1a: 12 wk + RBV (1) 1b: 8 wk (F0-F2 (2)) 12 wkd 1a: 12 wkf 1b: 8 wk (F0-F2 (2)) 12 wkd 8 wk
12 wk 12 wki 1a: 24 wk + RBV (1) 1b: 12 wk 12 wkf 12 wk
12 wk ± RBVc NR 12 wk + RBV NR NR NR NR
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3
4
SOF+DCV SOF/VEL (1,2) SOF/VEL/VOX GLE/PIB (1,2)
12 wk 12 wkd 12 wki 12 wk
8 wk/12wki 8wk
SOF+DCV SOF/VEL SOF/VEL/VOX (1,2) GLE/PIB (1,2)
12 wkj 12 wk, j
SOF/LDV (1,2) SOF/DCV SOF/SMV SOF/VEL (1,2) SOF/VEL/VOX GLE/PIB (1,2) EBR/GZR (1,2) OBV/PTV/r
8a (1)-12 wke
12 wk + RBV 12 wk + RBV NR NR
24 wk + RBV 12 wk j (1), NR (2) 8 wk (1), 12 wkd,i(1,2) 12 wk/16 wkd
8 wk/12 wkd
12 wkc,e 12 wk 12 wk + RBV 12 wk 12 wki 12 wk 12 wkg,e 12 wk + RBV
8 wk/12wki 8 wk
24 wk + RBV 24 wk + RBV NR NR 12 wk + RBVc 12 wk + RBVc NR 12 wk + RBV NR NR NR NR
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2
12 wke ± RBV 12 wkc,e 12 wk ± RBVc SOF/LDV 12 wk ± RBV 12 wkc 12 wk ± RBVc SOF/DCV d 12 wk 12 wk + RBV SOF/VEL (1,2) 8 wk/12wki 12 wki,d NR SOF/VEL/VOX 8 wk 12 wk NR GLE/PIB (1,2) Abbreviations: NR: Not recommended; DAA: direct acting antiviral; CTP: child-pugh turcotte; OBV: ombitasvir; PTV: paritaprevir; r: ritonavir; DSV: dasabuvir; SMV: simeprevir; SOF: sofosbuvir; VEL: velpatasvir; VOX: voxilaprevir; GLE: glecaprevir; PIB: pibrentasvir; GZR: grazoprevir; EBR: elbasvir; DCV: daclatasvir; LDV: ledipasvir; 1 EACS guidelines, 2 EASL guidelines, 3 AASLD guidelines
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5 & 6
if HCV RNA <6000000IU/ml, treatment naïve and absence of liver fibrosis or cirrhosis F>3
b
additionally RBV in GT1a treatment-experienced patients, if tested, not in the absence of NS5A RASs (1)
c
additionally RBV, unless treatment - naïve or – experienced persons with compensated cirrhosis without baseline NS5A RASs (1)
d
in RBV + peg-IFN alfa ± SOF or SOF + RBV experienced patients (2)
e
not recommended in RBV + peg-IFN alfa ± SOF or SOF + RBV experienced patients (2)
f
16wk + RBV if HCV RNA >800000IU/ml and NS5A RASs
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a
g
16 wk + RBV if treatment experienced and HCV RNA >800000IU/ml
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24 wk + RBV in treatment experienced patients with compensated cirrhosis in DAA treatment experienced patients
j
additionally RBV in treatment experienced patients with NS5A RASs
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ACCEPTED MANUSCRIPT Table 2: Relevant Drug-drug-interactions between direct acting antivirals and antiretrovirals (adapted from www.hep-druginteractions.org) DAA PI containing SMV a,c,e
ABC FTC 3TC TDF
SOF/VE Lc,e,g/ VOXc,e,g
GLE/ PIB
GZR/E BR
c,e,g
↑ARV ↑ARV5
↑ARV5
↓DAA
↓DAA
↓DA A
↓VEL ↑SOF
↓DAA
↓DAA
↓DA A1
ETVb,f
↓DAA
↓DAA
↓DAA
↓DAA
↓DAA
NVPb
↓DAA ↑ARV ↑ARV
↓DAA ↑ARV ↑ARV
↓DA A ↓DA A
↓DAA
↓DAA
↓DAA
↓DA A ↓DA A
ATVc/ ra,e ATVc/ ca,c
↑DAA
↑DAA2
↑DAA
↑DAA
↑DAA
↑DAA
↑DAA
DRVc/ ra,e
↓ARV ↑DAA
↓ARV2
DRVc/ ca.c LPV/r
↑DAA
↑DAA
↑DAA
↑DAA
↑DA A ↑DA A ↑AR V ↑DA A ↑AR V ↑DA A ↑DA A
a,e
↑DA A1 ↑DA A1
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NS 5B SO F
NS5A/NS5B SOF/LD Ve,g
SOF/VE Lc,e,g
↓LDV ↑TDF
↑ARV
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TAF AZT EFVb,f
RPV
PIs
OBV/PTVa/ra,e +DSV
↑DAA
↑DAA
↑DAA
↑DAA
↑DAA
↑DAA
↓DAA
↓VEL, ↑SOF ↓DAA ↓DAA
↑COBI
↑ DAA
↑DAA
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ARV
NNRTIs
NRTIs
OBV/PTV a a,e /r
NS5 A DCV
↑DA A
↑COBI
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Entry/ Integrase inhibitors
↑ARV ↑ARV MVC DTG RAL ↑DAA ↑DAA ↑DA ↑DAA ↑DA EVG/ A A1 ca ↑ARV4 ↑ARV4 BIC3 Abbreviations: DAA: direct acting antiviral; ARV: antiretroviral; PI: protease inhibitor; NNRTI: non nucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; OBV: ombitasvir; PTV: paritaprevir; r: ritonavir; DSV: dasabuvir; SMV: simeprevir; SOF: sofosbuvir; VEL: velpatasvir; VOX: voxilaprevir; GLE: glecaprevir; PIB: pibrentasvir; GZR: grazoprevir; EBR: elbasvir; DCV: daclatasvir; LDV: ledipasvir; ABC: abacavir; FTC:emtricitabine; 3TC:lamivudine; TDF: tenofovir disoproxil fumarate; TAF: tenofovir alafenamide fumarate; AZT: azidothymidine; EFV: efavirenz; ETV: etravirine; NVP: nevirapine; RPV: rilpivirine; ATV: atazanavir; DRV: darunavir; LPV: lopinavir; MVC: maraviroc; DTG: dolutegravir; RAL; raltegravir; EVG: elvitegravir; BIC: bictegravir; c: cobicistat; CYP3A4: cytochrom P3A4, OATP: organic anionic transporting polypeptides, p-gp: permeability glycoproteins; BCRP: breast cancer resistantance protein;
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1 Dose adjustment of DCV necessary, 2ARV should be administered without additional r, 3FDA approved 2018, 4coadministration not studied, bictegravir increase expected, 5dose reduction TAF necessary, a
inhibitor of CYP3A4, binducer of CYP3A4, cinhibitor of OATP, dinducer of OATP, einhibitor of p-gp, finducer of p-gp, ginhibitor of BCRP, inducer of BCRP
h
No clinically significant interactions expected Potential interactions- additional monitoring or dose adjustments required Co-administration is not recommended
Data from www.hep-druginteractions.org
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Genotype
Participants, no. (%)
SVR12
COINFECOVA-2 [20]
SOF+RBV SOF/LDV±RBV SOF+SMV ± RBV SOF+DCV ± RBV OBV/PTV/r ± DSV ± RBV
GT 1-4
Overall n = 515 Liver Cirrhosis n = 279 (54) TE: n = 200 (39)
Overall: 92.8% (478/515) No liver cirrhosis: 97% (229/236) Liver cirrhosis: 89.2% (249/279; p=0.001) TE (prior DAA): 91.4% (32/35) TE (prior pegIFN): 91.5% (151/165) TN: 94.6% (261/276)
ANRS CO13 HEPAVIH [21]
SOF+RBV SOF/LDV±RBV SOF+SMV ± RBV SOF+DCV ± RBV
GT 1-4
Overall: n = 323 Liver cirrhosis n = 194 (60.2) TE n = 221 (68.4)
Overall: 93.5% No liver cirrhosis: 93.8% Liver cirrhosis: 93.3% TN: 94.1% TE: 93.2%
ATHENA HIV [22]
Every in the Netherlands approved treatment regimen since 2000
GT 1-4
Overall (DAA and IFN- based treatment) n=1471 DAA treatment n = 612
Overall: DAA Treatment 98% (598/612)
Madrid Co-RE [23]
SOF/LDV SOF+DCV SOF+SMV SOF+RBV OBV/PTV/r+DSV OBV/PTV/r
GT 1-4
Overall n = 2369 Compensated cirrhosis n = 803 (33.9) Decompensated cirrhosis n = 156 (6.6%)
Overall: 94.1% (m-ITT; 2180/2318) No liver cirrhosis: 95.9% (m-ITT; 1323/1380) Comp. Cirrhosis: 93.1% (m-ITT; 731/785) Decomp. Cirrhosis: 82.4% (m-ITT; 126/153)
German Hepatitis CRegistry [24]
SOF+RBV SOF+pegIFN+RBV SOF+SMV±RBV SOF+DCV±RBV LDV/SOF±RBV OBV/PTV/r ± DSV ± RBV PegIFN+RBV+boceprevir PegIFN+RBV+telaprevir PegIFN+RBV+SMV PegIFN+RBV+SOF LDV/SOF SOF/SMV SOF/DCV OBV/PTV/r ± DSV
GT 1-4
Overall n = 488 Liver cirrhosis n = 84 (17.2) TE n = 227 (46.5)
Overall: 91.2% (445/488) No liver cirrhosis: 91.6% (370/404) Liver Cirrhosis: 89.3% (75/84)
GT 1-4
Overall = 426 IFN free treatment cohort: Overall n = 256 Liver cirrhosis n = 213 (83.0) TE n =110 (43.0)
Overall 86.3% (221/256ITT, IFN free) 67.3% (179/226; ITT, IFN based) No liver cirrhosis 86 % (37/43) Liver cirrhosis 86% (184/213) TN 84 % (91/108) TE 88 % (97/110)
LDV/SOF±RBV OBV/PTV/r + DSV ± RBV
GT 1
Overall n = 996 Liver cirrhosis n = 225 (22.6) TE n = 160 (16.1)
Overall: 90.9% (823/905) No liver cirrhosis: 92.4% (647/700;p=0.006) Liver cirrhosis: 85.9% (176/205) TN: 91% (687/755) TE: 90.7% (136/150)
Grady Health Systems IDP-Clinic Atlanta, Georgia [26]
LDV/SOF SOF+RBV SOF+DCV SOF+SMV
GT 1-3
Overall n= 172 Liver cirrhosis: n = 28 (16.0) TE n = 36 (21.0)
Overall: 93% (ITT; 160/172) No liver cirrhosis: 93% (135/144) Liver cirrhosis: 89% (25/28; p<0.001) TN: 93% (126/136) TE: 94% (34/36)
HULP-HUGM Study [27]
SOF/LDV ± RBV SOF+DCV ± RBV SOF+SMV ± RBV OBV/PTV/r±DSV OBV/PTV/r OBV/PTV/r+DSV ±RBV
GT 1-4
Overall n = 482 Liver cirrhosis n =233 (48.4) TE n = 283 (58.7)
Overall: 94.2% (454/482) No liver cirrhosis 96.8% (240/248) Liver cirrhosis: 91.4% (213/233)
GT 1/4
Overall n = 210 Liver cirrhosis n = 23 (11.0) TE n = 114 (54.3)
Overall: 96.7% (203/210) No liver cirrhosis: 96.3% (180/187) Liver cirrhosis: 100% (23/23) TN: 97.9% TE: 93.6%
AN US
M
ED
Prospective multicohort Study, Spain (HEPAVIRDAA Cohort) [19]
AC
CE
Veterans Affairs Clinical Case Registry [25]
Italian Compassionate Use Program (CUP) [28]
CR IP T
DAA regimen
PT
Real-world-Setting
Table 3: Important real-life cohort studies in HIV/HCV coinfected persons
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AC
CE
PT
ED
M
AN US
CR IP T
Abbreviations: DAA: direct acting antiviral; GT: genotype; TE: treatment experienced TN: treatment naive; OBV: ombitasvir; PTV: paritaprevir; r: ritonavir; DSV: dasabuvir; SMV: simeprevir; SOF: sofosbuvir; VEL: velpatasvir; VOX: voxilaprevir; GLE: glecaprevir; PIB: pibrentasvir; GZR: grazoprevir; EBR: elbasvir; DCV: daclatasvir; LDV: ledipasvir;pegIFN: pegylated interferon;