Direct-Acting Antivirals Improve Access to Care and Cure for Patients With HIV and Chronic HCV Infection

Direct-Acting Antivirals Improve Access to Care and Cure for Patients With HIV and Chronic HCV... Open Forum Infectious Diseases MAJOR ARTICLE Direct-Acting Antivirals Improve Access to Care and Cure for Patients With HIV and Chronic HCV Infection 1 2 3 3,4 4,5 4,5 2,4 Lauren F. Collins, Austin Chan, Jiayin Zheng, Shein-Chung Chow, Julius M. Wilder, Andrew J. Muir, and Susanna Naggie 1 2 3 4 Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Division of Infectious Diseases, Department of Biostatistics and Bioinformatics, Duke Clinical Research Institute, and Division of Gastroenterology, Duke University, Durham, North Carolina Background. Direct-acting antivirals (DAA) as curative therapy for hepatitis C virus (HCV) infection oer >95% s ff ustained virologic response (SVR), including in patients with human immunodeficiency virus (HIV) infection. Despite improved safety and efficacy of HCV treatment, challenges remain, including drug-drug interactions between DAA and antiretroviral therapy (ART) and restrictions on access by payers. Methods. We performed a retrospective cohort study of all HIV/HCV co-infected and HCV mono-infected patients captured in care at our institution from 2011–2015, reflecting the DAA era, to determine treatment uptake and SVR, and to elucidate barriers to accessing DAA for co-infected patients. Results. We identified 9290 patients with HCV mono-infection and 507 with HIV/HCV co-infection. Compared to mono-in- fected patients, co-infected patients were younger and more likely to be male and African-American. For both groups, treatment uptake improved from the DAA/pegylated interferon (PEGIFN)-ribavirin to IFN-free DAA era. One-third of co-infected patients in the IFN-free DAA era required ART switch and nearly all remained virologically suppressed aer 6  ft months. We observed SVR >95% for most patient subgroups including those with co-infection, prior treatment-experience, and cirrhosis. Predictors of access to DAA for co-infected patients included Caucasian race, CD4 count ≥200 cells/mm , HIV virologic suppression and cirrhosis. Time to approval of DAA was longest for patients insured by Medicaid, followed by private insurance and Medicare. Conclusions. DAA therapy has significantly improved access to HCV treatment and high SVR is independent of HIV status. However, in order to realize cure for all, barriers and disparities in access need to be urgently addressed. Keywords. access to care; antiretroviral therapy; direct-acting antivirals; hepatitis C virus; human immunodeficiency virus. In the United States, approximately 30% of persons living e ra Th pid development and implementation of curative with human immunodeficiency virus (HIV) are co-infected HCV therapy with direct-acting antivirals (DAA) is dramatic- with hepatitis C virus (HCV), accounting for roughly 1 mil- ally changing the landscape for treating HIV/HCV co-infected lion individuals [1]. Liver disease is the third leading cause of patients. Prior to the approval of DAA, uptake of HCV treat- death in patients with HIV [2], and it is well-established that ment was low, particularly for co-infected patients; for example, patients with HIV/HCV co-infection, compared with those in 1 urban HIV clinic, only 10.5% of patients with HIV/HCV HCV mono-infected, experience an accelerated natural his- co-infection referred for anti-HCV therapy actually received tory of liver disease with increased morbidity and mortality [3]. treatment [11]. Overall sustained virologic response (SVR) Specifically, co-infected patients are less likely to naturally clear rates were lower for co-infected patients, especially in the case HCV infection [4, 5] and have higher rates of progression to of infection with HCV genotype 1 [12–14]. DAA therapy oer ff s b fi rosis [6–8], hepatic decompensation [9], and hepatocellular >95% SVR for the vast majority of HCV-infected patients, carcinoma [10]. It is therefore imperative to prioritize HCV regardless of HIV-1 infection [15]. Importantly, this equal cure in persons living with HIV to avoid devastating clinical opportunity for HCV cure among mono-infected and HIV/ consequences, especially in the era of highly efficacious and tol- HCV co-infected patients is independent of prior treatment erable antiretroviral therapy (ART). experience and presence of cirrhosis [16, 17]. While the safety and efficacy of HCV therapy has markedly improved, challenges have emerged for HIV/HCV co-infected Received 25 October 2017; editorial decision 24 November 2017; accepted 8 December 2017. patients to successfully achieve cure, including treatment uptake Correspondence: S. Naggie, MD, MHS, Infectious Diseases Section, Duke Clinical Research limited by drug-drug interactions (DDIs) between antiretrovi- Institute, 2400 Pratt Street, Durham, NC 27705 (susanna.naggie@duke.edu). rals (ARVs) and HCV therapeutics [18, 19], active substance Open Forum Infectious Diseases © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases abuse [20], and high rates of insurance denials [21]. The Society of America. This is an Open Access article distributed under the terms of the Creative American Association for the Study of Liver Diseases (AASLD)/ Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any Infectious Diseases Society of America (IDSA) HCV treatment medium, provided the original work is not altered or transformed in any way, and that the work and management guidance panel prioritizes HIV/HCV co-in- is properly cited. For commercial re-use, please contact journals.permissions@oup.com fected patients for HCV treatment access and recommends DOI: 10.1093/ofid/ofx264 Access to DAAs in HIV/HCV Coinfection • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018 treatment for all HCV-infected patients, independent of fibro- ethnicity. HIV- and HCV-specific elements for treated patients sis score [22]. Yet many insurance companies continue to apply were determined by manual chart review including CD4 lym- restrictions to access based on stage of liver disease, including in phocyte count (cells/mm ), HIV RNA (copies/mL), ARV regi- patients with HIV/HCV co-infection. men, and need for ART switch as documented at the latest visit Our aim was to better understand how the availability of prior to initiation of DAA; also, HCV genotype, prior HCV DAA has changed the landscape of treating patients with HCV, treatment experience, presence of cirrhosis and/or hepatitis B and specifically those co-infected with HIV. Our objectives virus (HBV) infection. ARV regimens were classified as non-nu- included measuring DAA treatment uptake and SVR at our cleoside reverse transcriptase inhibitor (NNRTI), protease institution from 2011 to 2015, determining predictors of access, inhibitor (PI), integrase strand transfer inhibitor (INSTI), sal- and investigating the role of ARV-DAA interactions and insur- vage (if more than 3 antiretroviral agents prescribed), or other. ance status as barriers to curative HCV treatment. Elucidating SVR was ascertained by manual chart review and recorded as the challenges and successes in treating HIV/HCV co-infected “yes” or “no”; if no, the reason was documented as virologic patients in the DAA era is urgently needed in order to strategize breakthrough, relapse, or patient lost to follow-up. A diagnosis and advocate for optimized care delivery and outcomes for this of cirrhosis was determined by querying DEDUCE for ICD-9/- special population. 10 codes for cirrhosis and sequelae of decompensated cirrho- sis (Supplementary Table 1). HBV infection was defined as the METHODS presence of HBV surface antigen. Mortality was determined by the date of death, if listed, in the EHR. Study Population We performed a retrospective cohort study of HCV- and HIV/ Study Definitions HCV-infected adult patients captured in care at our center from Treatment uptake was defined as the proportion of patients who 2011 to 2015, reflecting the DAA era. Subjects age 18 years and were prescribed DAA each year per total number of patients older with at least 1 clinical encounter in the Duke University with a clinical encounter for HCV that year. Patients who Health System between January 1, 2011, and December 31, 2015, achieved SVR or died during the study period were excluded with HCV and/or HIV/HCV were ascertained using the Duke from the uptake analysis in all subsequent years following SVR Enterprise Data Unified Content Explore (DEDUCE) research or death, respectively. Treatment era was defined as “DAA/ tool. DEDUCE is a structured query language interface used to PEGIFN-RBV” or “IFN-free DAA.” The prior era included extract data from the electronic health record (EHR) [23]. patients treated with PEGIFN-RBV along with a single DAA including telaprevir, simeprevir, boceprevir, or sofosbuvir. Data Procurement The “IFN-free DAA” era included patients treated with 1 of Subjects were ascertained using DEDUCE by (1) searching the following oral combination DAA regimens: daclatasvir + for International Classification of Diseases, Ninth and Tenth sofosbuvir, ledipasvir/sofosbuvir, simeprevir + sofosbuvir, or Revision (ICD-9/-10) codes for HCV and HIV (Supplementary paritaprevir/ritonavir/ombitasvir ± dasabuvir (± ribavirin). Table 1), then (2) confirming the identified subjects had a clin- Treatment experience was defined as documentation of any ical encounter at our institution during the study period. For HCV therapy prior to the regimen prescribed during the study subjects ascertained to be HIV/HCV co-infected, patients were period. SVR was defined as an undetectable (<lower limit of included only if both infections could be confirmed by viro- quantification target not detected) HCV RNA at ≥10 weeks fol- logic evidence (HIV-1 enzyme-linked immunosorbent assay: lowing completion of HCV treatment. HIV viral suppression immunoblot or RNA; HCV antibody: RNA or genotype) or in was defined as HIV RNA <200 copies/mL. “ART switch” was clinical documentation by a provider. For subjects ascertained defined as a change in the ARV regimen prior to the initiation to be HCV mono-infected, HCV diagnosis was attributed to of DAA due to a potential DDI, as documented by the provider. ICD-9/-10 code without additional confirmation. Prescriptions for DAA were queried to determine treatment numbers for Time to DAA Approval each year, including boceprevir, daclatasvir, ledipasvir/sofosbu- Records of insurance approval of DAA were available for a sub- vir, paritaprevir/ritonavir/ombitasvir ± dasasbuvir, simeprevir, set of patients who had their initial DAA prescription sent to sofosbuvir, and telaprevir. Additionally, concomitant prescrip- the Duke specialty pharmacy. For these patients, median time tions for ribavirin (RBV) and pegylated interferon (PEGIFN)– to DAA approval was calculated by the number of days between RBV were queried to determine supplemental therapy to DAA first receipt of the DAA prescription from provider to phar- and treatment era, respectively. macy and the date of final approval. For patients missing a final Persons with a diagnosis of HCV or HIV/HCV had demo- approval date, a date was applied using the median number of graphic and clinical data extracted by DEDUCE and supple- days between the approval and initial DAA fill date based on mented by manual chart review. Data elements of interest for the remainder of the cohort. Insurance status was classified as the entire cohort included age, self-identified gender, race, and North Carolina Medicaid, Medicare, or Private. 2 • OFID • Collins et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Statistical Analysis and Caucasian patients with HCV mono-infection (11.8% vs Descriptive statistics were calculated for demographic and clin- 12.7%; P = .296); however, it was significantly lower in African ical characteristics. Comparisons were performed using chi- Americans compared with Caucasians with HIV/HCV square tests or Fisher exact tests for categorical variables and t co-infection (16.1% vs 33.3%; P  =  .003). Of the 9290 HCV tests or Wilcoxon tests for continuous variables, as appropriate. mono-infected patients with at least 1 HCV care encounter dur- Univariate logistic regression was performed independently for ing the study period, 1125 (12.1%) received DAA-based therapy. each candidate covariate (age, gender, race, CD4 count, HIV For the 506 HIV/HCV co-infected patients with at least 1 HCV viral suppression, PI-based ART, presence of cirrhosis and/ care encounter during the study period, 97/506 (19.2%) received or HBV infection); each was identified a priori as a potential DAA-based therapy. Figure  1 displays DAA-based treatment predictor based on prior studies [24–26]. All covariates with uptake from 2011 to 2015 for all patients with HCV and HIV/ P values  <.05 were selected into a multivariate logistic regres- HCV who had an HCV encounter in the health system for each sion model for further analysis using backward selection. The respective year and highlights the more rapid rate of uptake for point estimation and 2-sided 95% confidence intervals of odds co-infected patients over time, reaching nearly 40% by 2015. ratios were calculated. All statistical analysis was performed HIV/HCV Co-infected Patients and ART Switching using Statistical Analysis System, version 9.4. HIV/HCV co-infected patients treated with DAA compared Human Subjects with those co-infected and not treated with DAA were more This retrospective cohort study was conducted under an likely to be male (78.4% vs 68.0%; P  =  .049), to be Caucasian approved human subjects protocol by the Duke University (33.0% vs 15.7%; P = .001), to be HIV virologically suppressed Medical Center Institutional Review Board. (95.9% vs 69.2%; P  <  .0001), and to have cirrhosis (36.1% vs 14.9%; P  <  .0001) (Table  1). Nearly a quarter of HIV/HCV RESULTS co-infected patients not treated with DAA were deceased by Treatment Uptake the end of the study period compared with co-infected patients We identified 9290 patients with HCV mono-infection and treated with DAA (P < .0001). 506 with HIV/HCV co-infection seen for an HCV care–related Thirty-one of the 97 co-infected patients (32%) treated encounter within the Duke University Health System between with DAA required a switch in their ARV regimen due to pre- 2011 and 2015 (Supplementary Table  2). Patients with HIV/ dicted DDI with DAA therapy. Figure  2 shows the proportion HCV co-infection, compared with those with HCV mono- of patients who switched their ART stratified by baseline ARV infection, were younger (median age, 58 vs 60 years; P < .0001) regimen. The majority of ART switches occurred on PI-based and more likely to be male (67.0% vs 60.1%; P  <  .0001) and regimens (60.7% switched), followed by salvage- (33.3%), African American (75.9% vs 35.9%; P  <  .0001). Treatment NNRTI- (27.3%), and INSTI-based (5.6%) regimens. The most uptake did not significantly differ between African American common reasons cited by providers for switching ARVs were (1) 900 45 HCV only treated patients HIV-HCV treated patients HCV only percent treated HIV-HCV percent treated 600 30 500 25 400 20 100 5 37 3 0 0 2011 2012 2013 2014 2015 Figure 1. Treatment uptake with direct-acting antiviral therapy for all patients with hepatitis C virus (HCV) and HIV/HCV presenting to care by study year. Access to DAAs in HIV/HCV Coinfection • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Total # of patients treated annually % of patients treated annually Table  1. Demographic and Clinical Characteristics of Patients With co-infection. Comparatively, 940/9174 (10.2%) of mono-in- HIV/HCV Co-infection Stratified by Treatment Uptake With Direct-Acting fected and 90/500 (18.0%) of co-infected patients were treated Antiviral Therapy with IFN-free DAA regimens. The SVR in this era was 90.9% (854/940) for HCV mono-infected patients and 96.7% (87/90) HIV/HCV for HIV/HCV co-infected patients (Table  2). In the IFN-free Not Treated With Treated With DAA era, 383/436 (87.8%) patients with HCV mono-infection DAA DAA (n = 409) (n = 97) P Value and cirrhosis achieved SVR. For HIV/HCV co-infected patients Age, median (IQR), y 58 (53–62) 55 (51–62) .46 with cirrhosis, 30/32 (93.8%) achieved SVR. The reason for % male 68.0% 78.4% .049 treatment failure in all patients was relapse, with the exception Race, No. (%) of 1 HCV mono-infected patient in the IFN-free DAA era who African American 322 (78.7) 62 (63.9) .004 was lost to follow-up. Caucasian 64 (15.7) 32 (33.0) .001 Other 18 (4.4) 1 (1.0) N/A Predictors of Access to DAA in HIV/HCV Co-infected Patients Unknown/declined 5 (1.2) 2 (2.1) N/A We constructed a multivariable logistic regression model com- Ethnicity prised of demographic and clinical characteristics to deter- Hispanic, No. (%) 15 (3.7) 1 (1.0) N/A mine predictors of access to DAA for patients with HIV/HCV Non-Hispanic, No. (%) 384 (93.9) 94 (96.9) .33 co-infection. As shown in Table  3, Caucasian race, CD4 count Unknown/declined, 10 (2.4) 2 (2.1) N/A No. (%) ≥200 cells/mm , HIV viral suppression, and the presence of CD4 count, median (IQR) 411.5 (230–718) 561.5 (403–910) <.0001 cirrhosis were identified as predictors of access to DAA for HIV viral suppression, No. (%) co-infected patients. Age, gender, PI-based ART, and HBV <200 copies/mL 283 (69.2) 93 (95.9) <.0001 infection did not play a significant role in influencing access to ≥200 copies/mL 114 (27.9) 3 (3.1) <.0001 DAA. Supplementary Table 3 lists barriers to initiation of DAA Unknown 12 (2.9) 1 (1.0) N/A ARV regimen, No. (%) for treatment of HCV as documented by the provider for all PI 115 (28.1) 28 (28.9) .90 409 co-infected patients not yet prescribed DAA. Thirty-seven NNRTI 81 (19.8) 33 (34.0) .004 percent of co-infected patients were undergoing evaluation for INSTI 106 (25.9) 19 (19.6) .23 DAA at the close of the study period, 31% were not yet eval- Salvage 75 (18.3) 12 (12.4) .18 uated, and nearly 25% not treated with DAA died over the Other 4 (1.0) 0 (0) N/A course of the study period. As documented by providers, spe- No ARV regimen, No. (%) Elite controller 4 (1.0) 5 (5.1) .02 cific barriers limiting access to DAA for HIV/HCV co-infected Poor adherence 24 (5.9) 0 (0) .007 patients included active mental health and/or substance abuse ARV switched --- 31 (32.0) N/A issues, newly diagnosed or uncontrolled HIV, other medical % Cirrhosis 14.9 36.1 <.0001 comorbidities. For those who had been referred to an infectious % HBV infection 2.7 6.2 .11 diseases or hepatology subspecialist for DAA initiation, the % Mortality at study end 23.2 0 <.0001 majority of patients at the end of the study period were await- Abbreviations: ARV, antiretroviral therapy; CD4, cluster of differentiation 4; DAA, direct-act- ing antiviral therapy; HBV,  hepatitis B virus; HCV,  hepatitis C virus; HIV,  human immu- ing their appointment, results of HCV genotype or liver fibrosis nodeficiency virus; INSTI,  integrase strand transfer inhibitor; IQR,  interquartile range; assessment, and/or HIV viral suppression after ART switch. NNRTI, non-nucleoside analogue reverse transcriptase inhibitor; PI, protease inhibitor. Original antiretroviral regimen prior to any switching to accommodate DAA. Time to DAA Approval by Insurance Status For patients who had a DAA prescription sent to the Duke pharmacologic boosting agent, (2) increased tenofovir expos- Specialty Pharmacy, insurance status and time to approval of ure, and (3) DDI between efavirenz and DAA. Of note, 20/31 DAA were available for analysis. Figure 3 shows median time to co-infected patients (64.5%) switched to an INSTI-based ARV approval of DAA in days stratified by infection and insurance regimen. Of the 31 patients requiring ART switch, 29 were HIV status for 508 patients with HCV mono-infection and 40 with virologically suppressed at 6 months postswitch. One patient’s HIV/HCV co-infection. Median times to approval for patients HIV RNA was 202 copies/mL at 6  months (though undetect- with HCV compared with HIV/HCV were 23 vs 29 days for pri- able at 1 year postswitch), and the other patient did not have a vate insurance (P = .321), 12 vs 21 days for Medicare (P = .412), repeat viral load during the remainder of the study period. and 52 vs 40.5 days for NC Medicaid (P = .769). Time to approval SVR by Treatment Era differed by insurance status for HCV mono-infected patients During the study period, 185/9290 (2.0%) of patients with HCV (NC Medicaid vs private, P = .0002; NC Medicaid vs Medicare, mono-infection and 7/506 (1.4%) of HIV/HCV co-infected P < .0001; Medicare vs private, P = .001), however, not signifi- patients were prescribed a DAA/PEGIFN-RBV regimen. The cantly for HIV/HCV co-infected patients (NC Medicaid vs pri- SVR in this era was 62.7% (116/185) for patients with HCV vate, P = .300; NC Medicaid vs Medicare, P = .378; Medicare vs mono-infection and 85.7% (6/7) for those with HIV/HCV private, P = .544). 4 • OFID • Collins et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018 120 % Not switched % Switched PI NNRTI INSTI Salvage Initial ARV regimen Figure 2. Antiretroviral switching prior to initiation of direct-acting antiviral therapy for hepatitis C virus (HCV) treatment in patients with HIV/HCV. DISCUSSION In our cohort, HIV/HCV co-infected patients were younger and more likely to be male and African American than HCV DAAs are safer, better tolerated, and more efficacious than inter- mono-infected patients, although these demographics were feron-based therapies. Our single-center findings highlight the not different between patients treated with DAA and those not impact of DAAs on access to HCV therapy and cure for patients treated. This suggests an alternate etiology for the higher treat- with HCV mono- and HIV/HCV co-infection, with HIV/HCV ment uptake in co-infected vs mono-infected patients in the co-infected patients realizing a substantial increase in access to IFN-free DAA era. One possibility is that co-infected patients cure. We found that treatment uptake has markedly improved are already engaged in care for a chronic infection and more from the DAA/PEGIFN-RBV to IFN-free DAA era, and loss to readily identified for HCV treatment. In addition, the increased follow-up was very low. However, access to cure remains much liver-related morbidity and mortality in HIV/HCV co-infection lower than desired for both mono- and co-infected populations, may have been a strong motivator for DAA initiation by both especially given SVR rates of >95% for nearly all patient groups. patient and provider. We identified a multitude of barriers limiting DAA access for Overall, treatment uptake for HIV/HCV co-infected co-infected patients, which reflect bias and disparities that need patients at our institution is low (<20% of the total study confronting so that an HCV cure can be realized for all. cohort), which is especially problematic given the accelerated natural history of liver disease [2, 3]. Per AASLD/IDSA HCV Table 2. Treatment Success in Patients With HCV and HIV/HCV Treated treatment guidance, a well-recognized challenge when treat- in the Era of Interferon-Free Direct-Acting Antivirals ing HCV in patients co-infected with HIV is the potential for DDIs between DAA and ART [22]; however, this did not pose IFN-Free DAA Era a significant barrier to achieving SVR in our cohort. Thirty- HCV HIV/HCV two percent of our HIV/HCV co-infected patients required (n = 940), No. (%) (n = 90), No. (%) P Value ART switch, which is a lower proportion than that reported for SVR, all genotypes 854 (90.9) 87 (96.7) .074 other real-world cohorts [19, 27]. Importantly, 30/31 (96.8%) SVR, by genotype co-infected patients requiring ART switch achieved SVR, 1 95/98 (96.9) 12/12 (100) 1.00 which was similar to those not switched (96.9%) in our cohort. 1a 449/463 (97.0) 47/49 (95.9) .659 1b 197/203 (97.0) 19/20 (95.0) .487 This is in contrast to the Johns Hopkins HIV/HCV cohort, 2 53/54 (98.2) 2/2 (100) N/A which demonstrated a lower SVR rate in co-infected patients 3 47/47 (100) 1/1 (100) N/A requiring ART switch compared with those who remained on 4 12/13 (92.3) 1/1 (100) N/A their baseline ARV regimen [28]. Our findings suggest that the 6 1/1 (100) N/A N/A need for ART switch to safely tolerate DAA should not serve Unknown 0/61 (0) 5/5 (100) N/A as a barrier to initiation of curative HCV therapy in patients SVR, by condition Cirrhosis 383/436 (87.8) 30/32 (93.8) .566 co-infected with HIV/HCV. Tx-experienced 196/211 (92.9) 3/3 (100) N/A In the IFN-free DAA era, HIV/HCV co-infected patients in Cirrhosis/Tx-experienced 121/133 (91.0) 1/1 (100) N/A our cohort achieved a high rate of SVR. This study adds to the Abbreviations: DAA, direct-acting antivirals; HCV, hepatitis C virus; HIV, human immunode- growing body of literature reporting that co-infected patients in ficiency virus; SVR, sustained virologic response at ≥10 weeks after therapy completion; a real-world setting with treatment experience, cirrhosis, and/ Tx, treatment. Access to DAAs in HIV/HCV Coinfection • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018 % of HIV/HCV patients Table 3. Stepwise Multivariable Logistic Regression Model Assessing presence of unfavorable interferon lambda 4 polymorphism in Predictors of HCV Treatment With Direct-Acting Antiviral Therapy in blacks [20]. However, this racial disparity has persisted into the Patients With HIV/HCV DAA era [29], suggesting that nonmedical barriers may hinder black patients in accessing curative HCV therapy. Such struc- Likelihood HIV/HCV Patient Treated With DAA tural obstacles are likely multifactorial and interrelated [30, 31]. Univariate Analysis Multivariate Analysis As seen with racial disparity challenging cancer care access and OR 95% CI OR 95% CI outcomes [32], it is possible that more African Americans in Age <55 y 0.56 0.35–0.89 --- --- our cohort were insured by Medicaid, which has the strictest Male 1.75 1.02–3.00 --- --- approval criteria for HCV treatment with DAA compared with Caucasian race 2.87 1.71–4.82 2.68 1.54–4.68 Medicare or private insurance [21, 33, 34], thus further limiting CD4 count ≥200 cells/mm 4.74 2.00–11.21 3.65 1.41–9.43 treatment uptake for black patients. HIV viral load <200 copies/mL 11.76 3.64–37.98 6.64 1.99–22.16 This study has several limitations, including the single clin- PI-based ART 1.03 0.62–1.72 --- --- ical site and retrospective nature. The study population was Cirrhosis 3.08 1.84–5.16 3.12 1.77–5.51 HBV infection 1.89 0.64–5.56 --- --- identified by an internal research tool (DEDUCE), which pri- marily queries the EHR by ICD-9/-10 codes. Given the smaller Abbreviations: ART, antiretroviral therapy; CD4, cluster of differentiation 4; CI, confidence interval; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency sample size of HIV/HCV co-infected patients (and that this virus; OR, odds ratio; PI, protease inhibitor. population was our study focus), we confirmed both infections by direct virologic evidence or confirmation in clinical docu- or requiring ART switch can realize a cure rate on par with that mentation by a provider; however, this was not done for the reported in clinical trials, and similar to that achieved by HCV 9290 patients identified by DEDUCE as HCV mono-infected. mono-infected patients [15–17]. e Th high mortality observed Treatment uptake for both mono- and co-infected patients is in the untreated group (25%) highlights the gravity of HIV/ likely underestimated given that we included patients with any HCV co-infection, especially in patients with poorly controlled clinical encounter at our institution from 2011 through 2015. HIV, and identifies a subgroup of HIV-infected patients who Duke is a tertiary referral center for a large catchment area; could benefit from a more personalized approach to HIV thus our cohort included patients who were seen at Duke only management. once for subspecialty consultation as an inpatient or outpatient Likelihood of DAA access for co-infected patients in our encounter. Overall treatment numbers were particularly low in cohort increased with Caucasian race, CD4 count ≥200 cells/ the DAA/PEGIFN-RBV era, which may reflect patient and pro- mm , HIV viral suppression, and the presence of cirrhosis. vider anticipation of all oral combination therapy, but also the Racial disparity in accessing HCV treatment existed in the IFN use of clinical prescriptions to identify patients receiving HCV era, which could be explained by providers less frequently oer ff - therapy did not include patients at the institution who were ing therapy due to poorer clinical outcomes with IFN therapy enrolled in clinical trials of DAA therapies, which represents in African American compared with Caucasian patients, at least a significant number of patients with both HCV mono-infec- in part attributed to a higher prevalence of genotype 1 and the tion and HIV/HCV co-infection. Another limitation is that we P = .300 P = .001 P = .545 P = .378 40.5 P < .0001 P = .001 HCV HCV HCV HIV/HCV HIV/HCV HIV/HCV (Private) (Medicare) (NC Medicaid) (Private) (Medicare) (NC Medicaid) Figure 3. Time to approval of direct-acting antiviral therapy for patients with hepatitis C virus (HCV) and HIV/HCV stratified by insurance status. 6 • OFID • Collins et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Median time to approval of DAA, d 10. Kramer JR, Kowalkowski MA, Duan Z, Chiao EY. The effect of HIV viral control only had access to the insurance status of patients with DAA on the incidence of hepatocellular carcinoma in veterans with hepatitis C and prescriptions through the Duke specialty pharmacy, which HIV coinfection. J Acquir Immune Defic Syndr 2015; 68:456–62. was less commonly used for HIV/HCV co-infected patients. 11. Mehta SH, Lucas GM, Mirel LB, et al. Limited effectiveness of antiviral treatment for hepatitis C in an urban HIV clinic. AIDS 2006; 20:2361–9. Furthermore, this did not consistently include information on 12. Chung RT, Andersen J, Volberding P, et  al; AIDS Clinical Trials Group A5071 insurance denials, so time to approval of DAA was used as a Study Team. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004; surrogate. 351:451–9. 13. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et  al; APRICOT Study Group. CONCLUSIONS Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV- infected patients. N Engl J Med 2004; 351:438–50. The introduction of DAA therapy has significantly improved 14. McHutchison JG, Gordon SC, Schiff ER, et  al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis access to HCV treatment, and SVR is high in HIV/HCV co-in- Interventional Therapy Group. N Engl J Med 1998; 339:1485–92. fected patients. Meanwhile <20% of all HCV-infected patients 15. Naggie S, Cooper C, Saag M, et al; ION-4 Investigators. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015; 373:705–13. at Duke have received curative therapy. We identify several bar- 16. Osinusi A, Townsend K, Kohli A, et  al. Virologic response following combined riers to access, including racial disparity, possible bias against ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and treating patients with substance abuse, and strict Medicaid HIV co-infection. JAMA 2015; 313:1232–9. 17. Sulkowski MS, Eron JJ, Wyles D, et  al. Ombitasvir, paritaprevir co-dosed with criteria for funding DAA, all of which need to be urgently ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with addressed so that HCV cure can be realized for all. HIV-1: a randomized trial. JAMA 2015; 313:1223–31. 18. El-Sherif O, Back D. Drug interactions of hepatitis C direct-acting antivirals in the HIV-infected person. Curr HIV/AIDS Rep 2015; 12:336–43. Supplementary Data 19. Cope R, Pickering A, Glowa T, et al. Majority of HIV/HCV patients need to switch Supplementary materials are available at Open Forum Infectious Diseases antiretroviral therapy to accommodate direct acting antivirals. AIDS Patient Care STDS 2015; 29:379–83. online. Consisting of data provided by the authors to benefit the reader, 20. Wansom T, Falade-Nwulia O, Sutcliffe CG, et  al. Barriers to hepatitis C virus the posted materials are not copyedited and are the sole responsibility of (HCV) treatment initiation in patients with human immunodeficiency virus/ the authors, so questions or comments should be addressed to the corre- HCV coinfection: lessons from the interferon Era. Open Forum Infect Dis 2017; sponding author. 4:ofx024. 21. Lo Re V, Gowda C, Urick PN, et  al. Disparities in absolute denial of modern Acknowledgments hepatitis C therapy by type of insurance. Clin Gastroenterol Hepatol. 2016; 14:1035–43. Financial support. This research was funded by a Faculty-Resident 22. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. research grant from the Duke University Department of Medicine (to http://www.hcvguidelines.org. Accessed 19 September 2017. L.F.C.) and by the Duke Center for AIDS Research through biostatistical 23. Horvath MM, Rusincovitch SA, Brinson S, et  al. Modular design, application support. architecture, and usage of a self-service model for enterprise data delivery: the Potential conifl cts of interest. All authors: No reported conflicts of Duke Enterprise Data Unified Content Explorer (DEDUCE). J Biomed Inform interest. All authors have submitted the ICMJE Form for Disclosure of 2014; 52:231–42. Potential Conflicts of Interest. Conflicts that the editors consider relevant to 24. Lin M, Kramer J, White D, et  al. Barriers to hepatitis C treatment in the era of the content of the manuscript have been disclosed. direct-acting anti-viral agents. Aliment Pharmacol Ther 2017; 46:992–1000. 25. Janjua NZ, Islam N, Wong J, et  al. Shift in disparities in hepatitis C treatment from interferon to DAA era: a population-based cohort study. J Viral Hepat 2017; References 24:624–30. 1. Staples CT Jr, Rimland D, Dudas D. Hepatitis C in the HIV (human immuno- 26. Martinello M, Dore GJ, Skurowski J, et al. Antiretroviral use in the CEASE cohort deficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study study and implications for direct-acting antiviral therapy in human immuno- (HAVACS): the effect of coinfection on survival. Clin Infect Dis 1999; 29:150–4. deficiency virus/hepatitis C virus coinfection. Open Forum Infect Dis 2016; 2. Smith CJ, Ryom L, Weber R, et  al; D:A:D Study Group. Trends in underlying 3:ofw105. causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort 27. Höner Zu Siederdissen C, Maasoumy B, Marra F, et  al. Drug-drug interactions collaboration. Lancet 2014; 384:241–8. with novel all oral interferon-free antiviral agents in a large real-world cohort. 3. Bica I, McGovern B, Dhar R, et  al. Increasing mortality due to end-stage liver Clin Infect Dis 2015; 62:561–7. disease in patients with human immunodeficiency virus infection. Clin Infect Dis 28.Falade-Nwulia O, Sutcliffe C, Moon J, et al. High hepatitis C cure rates among 2001; 32:492–7. black and non-black HIV-infected adults in an urban center. Hepatol Baltim Md 4. Danta M, Semmo N, Fabris P, et  al. Impact of HIV on host-virus interactions 2017; 66:1402–12. during early hepatitis C virus infection. J Infect Dis 2008; 197:1558–66. 29. Kanwal F, Kramer JR, El-Serag HB, et al. Race and gender differences in the use of 5. Thomson EC, Fleming VM, Main J, et  al. Predicting spontaneous clearance direct acting antiviral agents for hepatitis C virus. Clin Infect Dis 2016; 63:291–9. of acute hepatitis C virus in a large cohort of HIV-1-infected men. Gut 2011; 30. Zinski A, Westfall AO, Gardner LI, et al. The contribution of missed clinic visits 60:837–45. to disparities in HIV viral load outcomes. Am J Public Health 2015; 105:2068–75. 6. Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in human 31. Dale SK, Bogart LM, Wagner GJ, et al. Medical mistrust is related to lower lon- immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc gitudinal medication adherence among African-American males with HIV. J Group. Hepatology 1999; 30:1054–8. Health Psychol 2016; 21:1311–21. 7. Kirk GD, Mehta SH, Astemborski J, et al. HIV, age, and the severity of hepatitis C 32. Murphy CC, Harlan LC, Warren JL, Geiger AM. Race and insurance differences virus-related liver disease: a cohort study. Ann Intern Med 2013; 158:658–66. in the receipt of adjuvant chemotherapy among patients with stage III colon can- 8. Fierer DS, Dieterich DT, Fiel MI, et al. Rapid progression to decompensated cir- cer. J Clin Oncol 2015; 33:2530–6. rhosis, liver transplant, and death in HIV-infected men after primary hepatitis C 33. Saab S, Jimenez M, Fong T, et al. Accessibility to oral antiviral therapy for patients virus infection. Clin Infect Dis 2013; 56:1038–43. with chronic hepatitis C in the United States. J Clin Transl Hepatol 2016; 4:76–82. 9. Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus 34. Chidi AP, Bryce CL, Donohue JM, et al. Economic and public health impacts of infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect policies restricting access to hepatitis C treatment for medicaid patients. Value Dis 2001; 33:562–9. Health 2016; 19:326–34. Access to DAAs in HIV/HCV Coinfection • OFID • 7 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Direct-Acting Antivirals Improve Access to Care and Cure for Patients With HIV and Chronic HCV Infection

Free
7 pages

Loading next page...
 
/lp/ou_press/direct-acting-antivirals-improve-access-to-care-and-cure-for-patients-kzrUO9ieVl
Publisher
Infectious Diseases Society of America
Copyright
© The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
eISSN
2328-8957
D.O.I.
10.1093/ofid/ofx264
Publisher site
See Article on Publisher Site

Abstract

Open Forum Infectious Diseases MAJOR ARTICLE Direct-Acting Antivirals Improve Access to Care and Cure for Patients With HIV and Chronic HCV Infection 1 2 3 3,4 4,5 4,5 2,4 Lauren F. Collins, Austin Chan, Jiayin Zheng, Shein-Chung Chow, Julius M. Wilder, Andrew J. Muir, and Susanna Naggie 1 2 3 4 Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Division of Infectious Diseases, Department of Biostatistics and Bioinformatics, Duke Clinical Research Institute, and Division of Gastroenterology, Duke University, Durham, North Carolina Background. Direct-acting antivirals (DAA) as curative therapy for hepatitis C virus (HCV) infection oer >95% s ff ustained virologic response (SVR), including in patients with human immunodeficiency virus (HIV) infection. Despite improved safety and efficacy of HCV treatment, challenges remain, including drug-drug interactions between DAA and antiretroviral therapy (ART) and restrictions on access by payers. Methods. We performed a retrospective cohort study of all HIV/HCV co-infected and HCV mono-infected patients captured in care at our institution from 2011–2015, reflecting the DAA era, to determine treatment uptake and SVR, and to elucidate barriers to accessing DAA for co-infected patients. Results. We identified 9290 patients with HCV mono-infection and 507 with HIV/HCV co-infection. Compared to mono-in- fected patients, co-infected patients were younger and more likely to be male and African-American. For both groups, treatment uptake improved from the DAA/pegylated interferon (PEGIFN)-ribavirin to IFN-free DAA era. One-third of co-infected patients in the IFN-free DAA era required ART switch and nearly all remained virologically suppressed aer 6  ft months. We observed SVR >95% for most patient subgroups including those with co-infection, prior treatment-experience, and cirrhosis. Predictors of access to DAA for co-infected patients included Caucasian race, CD4 count ≥200 cells/mm , HIV virologic suppression and cirrhosis. Time to approval of DAA was longest for patients insured by Medicaid, followed by private insurance and Medicare. Conclusions. DAA therapy has significantly improved access to HCV treatment and high SVR is independent of HIV status. However, in order to realize cure for all, barriers and disparities in access need to be urgently addressed. Keywords. access to care; antiretroviral therapy; direct-acting antivirals; hepatitis C virus; human immunodeficiency virus. In the United States, approximately 30% of persons living e ra Th pid development and implementation of curative with human immunodeficiency virus (HIV) are co-infected HCV therapy with direct-acting antivirals (DAA) is dramatic- with hepatitis C virus (HCV), accounting for roughly 1 mil- ally changing the landscape for treating HIV/HCV co-infected lion individuals [1]. Liver disease is the third leading cause of patients. Prior to the approval of DAA, uptake of HCV treat- death in patients with HIV [2], and it is well-established that ment was low, particularly for co-infected patients; for example, patients with HIV/HCV co-infection, compared with those in 1 urban HIV clinic, only 10.5% of patients with HIV/HCV HCV mono-infected, experience an accelerated natural his- co-infection referred for anti-HCV therapy actually received tory of liver disease with increased morbidity and mortality [3]. treatment [11]. Overall sustained virologic response (SVR) Specifically, co-infected patients are less likely to naturally clear rates were lower for co-infected patients, especially in the case HCV infection [4, 5] and have higher rates of progression to of infection with HCV genotype 1 [12–14]. DAA therapy oer ff s b fi rosis [6–8], hepatic decompensation [9], and hepatocellular >95% SVR for the vast majority of HCV-infected patients, carcinoma [10]. It is therefore imperative to prioritize HCV regardless of HIV-1 infection [15]. Importantly, this equal cure in persons living with HIV to avoid devastating clinical opportunity for HCV cure among mono-infected and HIV/ consequences, especially in the era of highly efficacious and tol- HCV co-infected patients is independent of prior treatment erable antiretroviral therapy (ART). experience and presence of cirrhosis [16, 17]. While the safety and efficacy of HCV therapy has markedly improved, challenges have emerged for HIV/HCV co-infected Received 25 October 2017; editorial decision 24 November 2017; accepted 8 December 2017. patients to successfully achieve cure, including treatment uptake Correspondence: S. Naggie, MD, MHS, Infectious Diseases Section, Duke Clinical Research limited by drug-drug interactions (DDIs) between antiretrovi- Institute, 2400 Pratt Street, Durham, NC 27705 (susanna.naggie@duke.edu). rals (ARVs) and HCV therapeutics [18, 19], active substance Open Forum Infectious Diseases © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases abuse [20], and high rates of insurance denials [21]. The Society of America. This is an Open Access article distributed under the terms of the Creative American Association for the Study of Liver Diseases (AASLD)/ Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any Infectious Diseases Society of America (IDSA) HCV treatment medium, provided the original work is not altered or transformed in any way, and that the work and management guidance panel prioritizes HIV/HCV co-in- is properly cited. For commercial re-use, please contact journals.permissions@oup.com fected patients for HCV treatment access and recommends DOI: 10.1093/ofid/ofx264 Access to DAAs in HIV/HCV Coinfection • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018 treatment for all HCV-infected patients, independent of fibro- ethnicity. HIV- and HCV-specific elements for treated patients sis score [22]. Yet many insurance companies continue to apply were determined by manual chart review including CD4 lym- restrictions to access based on stage of liver disease, including in phocyte count (cells/mm ), HIV RNA (copies/mL), ARV regi- patients with HIV/HCV co-infection. men, and need for ART switch as documented at the latest visit Our aim was to better understand how the availability of prior to initiation of DAA; also, HCV genotype, prior HCV DAA has changed the landscape of treating patients with HCV, treatment experience, presence of cirrhosis and/or hepatitis B and specifically those co-infected with HIV. Our objectives virus (HBV) infection. ARV regimens were classified as non-nu- included measuring DAA treatment uptake and SVR at our cleoside reverse transcriptase inhibitor (NNRTI), protease institution from 2011 to 2015, determining predictors of access, inhibitor (PI), integrase strand transfer inhibitor (INSTI), sal- and investigating the role of ARV-DAA interactions and insur- vage (if more than 3 antiretroviral agents prescribed), or other. ance status as barriers to curative HCV treatment. Elucidating SVR was ascertained by manual chart review and recorded as the challenges and successes in treating HIV/HCV co-infected “yes” or “no”; if no, the reason was documented as virologic patients in the DAA era is urgently needed in order to strategize breakthrough, relapse, or patient lost to follow-up. A diagnosis and advocate for optimized care delivery and outcomes for this of cirrhosis was determined by querying DEDUCE for ICD-9/- special population. 10 codes for cirrhosis and sequelae of decompensated cirrho- sis (Supplementary Table 1). HBV infection was defined as the METHODS presence of HBV surface antigen. Mortality was determined by the date of death, if listed, in the EHR. Study Population We performed a retrospective cohort study of HCV- and HIV/ Study Definitions HCV-infected adult patients captured in care at our center from Treatment uptake was defined as the proportion of patients who 2011 to 2015, reflecting the DAA era. Subjects age 18 years and were prescribed DAA each year per total number of patients older with at least 1 clinical encounter in the Duke University with a clinical encounter for HCV that year. Patients who Health System between January 1, 2011, and December 31, 2015, achieved SVR or died during the study period were excluded with HCV and/or HIV/HCV were ascertained using the Duke from the uptake analysis in all subsequent years following SVR Enterprise Data Unified Content Explore (DEDUCE) research or death, respectively. Treatment era was defined as “DAA/ tool. DEDUCE is a structured query language interface used to PEGIFN-RBV” or “IFN-free DAA.” The prior era included extract data from the electronic health record (EHR) [23]. patients treated with PEGIFN-RBV along with a single DAA including telaprevir, simeprevir, boceprevir, or sofosbuvir. Data Procurement The “IFN-free DAA” era included patients treated with 1 of Subjects were ascertained using DEDUCE by (1) searching the following oral combination DAA regimens: daclatasvir + for International Classification of Diseases, Ninth and Tenth sofosbuvir, ledipasvir/sofosbuvir, simeprevir + sofosbuvir, or Revision (ICD-9/-10) codes for HCV and HIV (Supplementary paritaprevir/ritonavir/ombitasvir ± dasabuvir (± ribavirin). Table 1), then (2) confirming the identified subjects had a clin- Treatment experience was defined as documentation of any ical encounter at our institution during the study period. For HCV therapy prior to the regimen prescribed during the study subjects ascertained to be HIV/HCV co-infected, patients were period. SVR was defined as an undetectable (<lower limit of included only if both infections could be confirmed by viro- quantification target not detected) HCV RNA at ≥10 weeks fol- logic evidence (HIV-1 enzyme-linked immunosorbent assay: lowing completion of HCV treatment. HIV viral suppression immunoblot or RNA; HCV antibody: RNA or genotype) or in was defined as HIV RNA <200 copies/mL. “ART switch” was clinical documentation by a provider. For subjects ascertained defined as a change in the ARV regimen prior to the initiation to be HCV mono-infected, HCV diagnosis was attributed to of DAA due to a potential DDI, as documented by the provider. ICD-9/-10 code without additional confirmation. Prescriptions for DAA were queried to determine treatment numbers for Time to DAA Approval each year, including boceprevir, daclatasvir, ledipasvir/sofosbu- Records of insurance approval of DAA were available for a sub- vir, paritaprevir/ritonavir/ombitasvir ± dasasbuvir, simeprevir, set of patients who had their initial DAA prescription sent to sofosbuvir, and telaprevir. Additionally, concomitant prescrip- the Duke specialty pharmacy. For these patients, median time tions for ribavirin (RBV) and pegylated interferon (PEGIFN)– to DAA approval was calculated by the number of days between RBV were queried to determine supplemental therapy to DAA first receipt of the DAA prescription from provider to phar- and treatment era, respectively. macy and the date of final approval. For patients missing a final Persons with a diagnosis of HCV or HIV/HCV had demo- approval date, a date was applied using the median number of graphic and clinical data extracted by DEDUCE and supple- days between the approval and initial DAA fill date based on mented by manual chart review. Data elements of interest for the remainder of the cohort. Insurance status was classified as the entire cohort included age, self-identified gender, race, and North Carolina Medicaid, Medicare, or Private. 2 • OFID • Collins et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Statistical Analysis and Caucasian patients with HCV mono-infection (11.8% vs Descriptive statistics were calculated for demographic and clin- 12.7%; P = .296); however, it was significantly lower in African ical characteristics. Comparisons were performed using chi- Americans compared with Caucasians with HIV/HCV square tests or Fisher exact tests for categorical variables and t co-infection (16.1% vs 33.3%; P  =  .003). Of the 9290 HCV tests or Wilcoxon tests for continuous variables, as appropriate. mono-infected patients with at least 1 HCV care encounter dur- Univariate logistic regression was performed independently for ing the study period, 1125 (12.1%) received DAA-based therapy. each candidate covariate (age, gender, race, CD4 count, HIV For the 506 HIV/HCV co-infected patients with at least 1 HCV viral suppression, PI-based ART, presence of cirrhosis and/ care encounter during the study period, 97/506 (19.2%) received or HBV infection); each was identified a priori as a potential DAA-based therapy. Figure  1 displays DAA-based treatment predictor based on prior studies [24–26]. All covariates with uptake from 2011 to 2015 for all patients with HCV and HIV/ P values  <.05 were selected into a multivariate logistic regres- HCV who had an HCV encounter in the health system for each sion model for further analysis using backward selection. The respective year and highlights the more rapid rate of uptake for point estimation and 2-sided 95% confidence intervals of odds co-infected patients over time, reaching nearly 40% by 2015. ratios were calculated. All statistical analysis was performed HIV/HCV Co-infected Patients and ART Switching using Statistical Analysis System, version 9.4. HIV/HCV co-infected patients treated with DAA compared Human Subjects with those co-infected and not treated with DAA were more This retrospective cohort study was conducted under an likely to be male (78.4% vs 68.0%; P  =  .049), to be Caucasian approved human subjects protocol by the Duke University (33.0% vs 15.7%; P = .001), to be HIV virologically suppressed Medical Center Institutional Review Board. (95.9% vs 69.2%; P  <  .0001), and to have cirrhosis (36.1% vs 14.9%; P  <  .0001) (Table  1). Nearly a quarter of HIV/HCV RESULTS co-infected patients not treated with DAA were deceased by Treatment Uptake the end of the study period compared with co-infected patients We identified 9290 patients with HCV mono-infection and treated with DAA (P < .0001). 506 with HIV/HCV co-infection seen for an HCV care–related Thirty-one of the 97 co-infected patients (32%) treated encounter within the Duke University Health System between with DAA required a switch in their ARV regimen due to pre- 2011 and 2015 (Supplementary Table  2). Patients with HIV/ dicted DDI with DAA therapy. Figure  2 shows the proportion HCV co-infection, compared with those with HCV mono- of patients who switched their ART stratified by baseline ARV infection, were younger (median age, 58 vs 60 years; P < .0001) regimen. The majority of ART switches occurred on PI-based and more likely to be male (67.0% vs 60.1%; P  <  .0001) and regimens (60.7% switched), followed by salvage- (33.3%), African American (75.9% vs 35.9%; P  <  .0001). Treatment NNRTI- (27.3%), and INSTI-based (5.6%) regimens. The most uptake did not significantly differ between African American common reasons cited by providers for switching ARVs were (1) 900 45 HCV only treated patients HIV-HCV treated patients HCV only percent treated HIV-HCV percent treated 600 30 500 25 400 20 100 5 37 3 0 0 2011 2012 2013 2014 2015 Figure 1. Treatment uptake with direct-acting antiviral therapy for all patients with hepatitis C virus (HCV) and HIV/HCV presenting to care by study year. Access to DAAs in HIV/HCV Coinfection • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Total # of patients treated annually % of patients treated annually Table  1. Demographic and Clinical Characteristics of Patients With co-infection. Comparatively, 940/9174 (10.2%) of mono-in- HIV/HCV Co-infection Stratified by Treatment Uptake With Direct-Acting fected and 90/500 (18.0%) of co-infected patients were treated Antiviral Therapy with IFN-free DAA regimens. The SVR in this era was 90.9% (854/940) for HCV mono-infected patients and 96.7% (87/90) HIV/HCV for HIV/HCV co-infected patients (Table  2). In the IFN-free Not Treated With Treated With DAA era, 383/436 (87.8%) patients with HCV mono-infection DAA DAA (n = 409) (n = 97) P Value and cirrhosis achieved SVR. For HIV/HCV co-infected patients Age, median (IQR), y 58 (53–62) 55 (51–62) .46 with cirrhosis, 30/32 (93.8%) achieved SVR. The reason for % male 68.0% 78.4% .049 treatment failure in all patients was relapse, with the exception Race, No. (%) of 1 HCV mono-infected patient in the IFN-free DAA era who African American 322 (78.7) 62 (63.9) .004 was lost to follow-up. Caucasian 64 (15.7) 32 (33.0) .001 Other 18 (4.4) 1 (1.0) N/A Predictors of Access to DAA in HIV/HCV Co-infected Patients Unknown/declined 5 (1.2) 2 (2.1) N/A We constructed a multivariable logistic regression model com- Ethnicity prised of demographic and clinical characteristics to deter- Hispanic, No. (%) 15 (3.7) 1 (1.0) N/A mine predictors of access to DAA for patients with HIV/HCV Non-Hispanic, No. (%) 384 (93.9) 94 (96.9) .33 co-infection. As shown in Table  3, Caucasian race, CD4 count Unknown/declined, 10 (2.4) 2 (2.1) N/A No. (%) ≥200 cells/mm , HIV viral suppression, and the presence of CD4 count, median (IQR) 411.5 (230–718) 561.5 (403–910) <.0001 cirrhosis were identified as predictors of access to DAA for HIV viral suppression, No. (%) co-infected patients. Age, gender, PI-based ART, and HBV <200 copies/mL 283 (69.2) 93 (95.9) <.0001 infection did not play a significant role in influencing access to ≥200 copies/mL 114 (27.9) 3 (3.1) <.0001 DAA. Supplementary Table 3 lists barriers to initiation of DAA Unknown 12 (2.9) 1 (1.0) N/A ARV regimen, No. (%) for treatment of HCV as documented by the provider for all PI 115 (28.1) 28 (28.9) .90 409 co-infected patients not yet prescribed DAA. Thirty-seven NNRTI 81 (19.8) 33 (34.0) .004 percent of co-infected patients were undergoing evaluation for INSTI 106 (25.9) 19 (19.6) .23 DAA at the close of the study period, 31% were not yet eval- Salvage 75 (18.3) 12 (12.4) .18 uated, and nearly 25% not treated with DAA died over the Other 4 (1.0) 0 (0) N/A course of the study period. As documented by providers, spe- No ARV regimen, No. (%) Elite controller 4 (1.0) 5 (5.1) .02 cific barriers limiting access to DAA for HIV/HCV co-infected Poor adherence 24 (5.9) 0 (0) .007 patients included active mental health and/or substance abuse ARV switched --- 31 (32.0) N/A issues, newly diagnosed or uncontrolled HIV, other medical % Cirrhosis 14.9 36.1 <.0001 comorbidities. For those who had been referred to an infectious % HBV infection 2.7 6.2 .11 diseases or hepatology subspecialist for DAA initiation, the % Mortality at study end 23.2 0 <.0001 majority of patients at the end of the study period were await- Abbreviations: ARV, antiretroviral therapy; CD4, cluster of differentiation 4; DAA, direct-act- ing antiviral therapy; HBV,  hepatitis B virus; HCV,  hepatitis C virus; HIV,  human immu- ing their appointment, results of HCV genotype or liver fibrosis nodeficiency virus; INSTI,  integrase strand transfer inhibitor; IQR,  interquartile range; assessment, and/or HIV viral suppression after ART switch. NNRTI, non-nucleoside analogue reverse transcriptase inhibitor; PI, protease inhibitor. Original antiretroviral regimen prior to any switching to accommodate DAA. Time to DAA Approval by Insurance Status For patients who had a DAA prescription sent to the Duke pharmacologic boosting agent, (2) increased tenofovir expos- Specialty Pharmacy, insurance status and time to approval of ure, and (3) DDI between efavirenz and DAA. Of note, 20/31 DAA were available for analysis. Figure 3 shows median time to co-infected patients (64.5%) switched to an INSTI-based ARV approval of DAA in days stratified by infection and insurance regimen. Of the 31 patients requiring ART switch, 29 were HIV status for 508 patients with HCV mono-infection and 40 with virologically suppressed at 6 months postswitch. One patient’s HIV/HCV co-infection. Median times to approval for patients HIV RNA was 202 copies/mL at 6  months (though undetect- with HCV compared with HIV/HCV were 23 vs 29 days for pri- able at 1 year postswitch), and the other patient did not have a vate insurance (P = .321), 12 vs 21 days for Medicare (P = .412), repeat viral load during the remainder of the study period. and 52 vs 40.5 days for NC Medicaid (P = .769). Time to approval SVR by Treatment Era differed by insurance status for HCV mono-infected patients During the study period, 185/9290 (2.0%) of patients with HCV (NC Medicaid vs private, P = .0002; NC Medicaid vs Medicare, mono-infection and 7/506 (1.4%) of HIV/HCV co-infected P < .0001; Medicare vs private, P = .001), however, not signifi- patients were prescribed a DAA/PEGIFN-RBV regimen. The cantly for HIV/HCV co-infected patients (NC Medicaid vs pri- SVR in this era was 62.7% (116/185) for patients with HCV vate, P = .300; NC Medicaid vs Medicare, P = .378; Medicare vs mono-infection and 85.7% (6/7) for those with HIV/HCV private, P = .544). 4 • OFID • Collins et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018 120 % Not switched % Switched PI NNRTI INSTI Salvage Initial ARV regimen Figure 2. Antiretroviral switching prior to initiation of direct-acting antiviral therapy for hepatitis C virus (HCV) treatment in patients with HIV/HCV. DISCUSSION In our cohort, HIV/HCV co-infected patients were younger and more likely to be male and African American than HCV DAAs are safer, better tolerated, and more efficacious than inter- mono-infected patients, although these demographics were feron-based therapies. Our single-center findings highlight the not different between patients treated with DAA and those not impact of DAAs on access to HCV therapy and cure for patients treated. This suggests an alternate etiology for the higher treat- with HCV mono- and HIV/HCV co-infection, with HIV/HCV ment uptake in co-infected vs mono-infected patients in the co-infected patients realizing a substantial increase in access to IFN-free DAA era. One possibility is that co-infected patients cure. We found that treatment uptake has markedly improved are already engaged in care for a chronic infection and more from the DAA/PEGIFN-RBV to IFN-free DAA era, and loss to readily identified for HCV treatment. In addition, the increased follow-up was very low. However, access to cure remains much liver-related morbidity and mortality in HIV/HCV co-infection lower than desired for both mono- and co-infected populations, may have been a strong motivator for DAA initiation by both especially given SVR rates of >95% for nearly all patient groups. patient and provider. We identified a multitude of barriers limiting DAA access for Overall, treatment uptake for HIV/HCV co-infected co-infected patients, which reflect bias and disparities that need patients at our institution is low (<20% of the total study confronting so that an HCV cure can be realized for all. cohort), which is especially problematic given the accelerated natural history of liver disease [2, 3]. Per AASLD/IDSA HCV Table 2. Treatment Success in Patients With HCV and HIV/HCV Treated treatment guidance, a well-recognized challenge when treat- in the Era of Interferon-Free Direct-Acting Antivirals ing HCV in patients co-infected with HIV is the potential for DDIs between DAA and ART [22]; however, this did not pose IFN-Free DAA Era a significant barrier to achieving SVR in our cohort. Thirty- HCV HIV/HCV two percent of our HIV/HCV co-infected patients required (n = 940), No. (%) (n = 90), No. (%) P Value ART switch, which is a lower proportion than that reported for SVR, all genotypes 854 (90.9) 87 (96.7) .074 other real-world cohorts [19, 27]. Importantly, 30/31 (96.8%) SVR, by genotype co-infected patients requiring ART switch achieved SVR, 1 95/98 (96.9) 12/12 (100) 1.00 which was similar to those not switched (96.9%) in our cohort. 1a 449/463 (97.0) 47/49 (95.9) .659 1b 197/203 (97.0) 19/20 (95.0) .487 This is in contrast to the Johns Hopkins HIV/HCV cohort, 2 53/54 (98.2) 2/2 (100) N/A which demonstrated a lower SVR rate in co-infected patients 3 47/47 (100) 1/1 (100) N/A requiring ART switch compared with those who remained on 4 12/13 (92.3) 1/1 (100) N/A their baseline ARV regimen [28]. Our findings suggest that the 6 1/1 (100) N/A N/A need for ART switch to safely tolerate DAA should not serve Unknown 0/61 (0) 5/5 (100) N/A as a barrier to initiation of curative HCV therapy in patients SVR, by condition Cirrhosis 383/436 (87.8) 30/32 (93.8) .566 co-infected with HIV/HCV. Tx-experienced 196/211 (92.9) 3/3 (100) N/A In the IFN-free DAA era, HIV/HCV co-infected patients in Cirrhosis/Tx-experienced 121/133 (91.0) 1/1 (100) N/A our cohort achieved a high rate of SVR. This study adds to the Abbreviations: DAA, direct-acting antivirals; HCV, hepatitis C virus; HIV, human immunode- growing body of literature reporting that co-infected patients in ficiency virus; SVR, sustained virologic response at ≥10 weeks after therapy completion; a real-world setting with treatment experience, cirrhosis, and/ Tx, treatment. Access to DAAs in HIV/HCV Coinfection • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018 % of HIV/HCV patients Table 3. Stepwise Multivariable Logistic Regression Model Assessing presence of unfavorable interferon lambda 4 polymorphism in Predictors of HCV Treatment With Direct-Acting Antiviral Therapy in blacks [20]. However, this racial disparity has persisted into the Patients With HIV/HCV DAA era [29], suggesting that nonmedical barriers may hinder black patients in accessing curative HCV therapy. Such struc- Likelihood HIV/HCV Patient Treated With DAA tural obstacles are likely multifactorial and interrelated [30, 31]. Univariate Analysis Multivariate Analysis As seen with racial disparity challenging cancer care access and OR 95% CI OR 95% CI outcomes [32], it is possible that more African Americans in Age <55 y 0.56 0.35–0.89 --- --- our cohort were insured by Medicaid, which has the strictest Male 1.75 1.02–3.00 --- --- approval criteria for HCV treatment with DAA compared with Caucasian race 2.87 1.71–4.82 2.68 1.54–4.68 Medicare or private insurance [21, 33, 34], thus further limiting CD4 count ≥200 cells/mm 4.74 2.00–11.21 3.65 1.41–9.43 treatment uptake for black patients. HIV viral load <200 copies/mL 11.76 3.64–37.98 6.64 1.99–22.16 This study has several limitations, including the single clin- PI-based ART 1.03 0.62–1.72 --- --- ical site and retrospective nature. The study population was Cirrhosis 3.08 1.84–5.16 3.12 1.77–5.51 HBV infection 1.89 0.64–5.56 --- --- identified by an internal research tool (DEDUCE), which pri- marily queries the EHR by ICD-9/-10 codes. Given the smaller Abbreviations: ART, antiretroviral therapy; CD4, cluster of differentiation 4; CI, confidence interval; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency sample size of HIV/HCV co-infected patients (and that this virus; OR, odds ratio; PI, protease inhibitor. population was our study focus), we confirmed both infections by direct virologic evidence or confirmation in clinical docu- or requiring ART switch can realize a cure rate on par with that mentation by a provider; however, this was not done for the reported in clinical trials, and similar to that achieved by HCV 9290 patients identified by DEDUCE as HCV mono-infected. mono-infected patients [15–17]. e Th high mortality observed Treatment uptake for both mono- and co-infected patients is in the untreated group (25%) highlights the gravity of HIV/ likely underestimated given that we included patients with any HCV co-infection, especially in patients with poorly controlled clinical encounter at our institution from 2011 through 2015. HIV, and identifies a subgroup of HIV-infected patients who Duke is a tertiary referral center for a large catchment area; could benefit from a more personalized approach to HIV thus our cohort included patients who were seen at Duke only management. once for subspecialty consultation as an inpatient or outpatient Likelihood of DAA access for co-infected patients in our encounter. Overall treatment numbers were particularly low in cohort increased with Caucasian race, CD4 count ≥200 cells/ the DAA/PEGIFN-RBV era, which may reflect patient and pro- mm , HIV viral suppression, and the presence of cirrhosis. vider anticipation of all oral combination therapy, but also the Racial disparity in accessing HCV treatment existed in the IFN use of clinical prescriptions to identify patients receiving HCV era, which could be explained by providers less frequently oer ff - therapy did not include patients at the institution who were ing therapy due to poorer clinical outcomes with IFN therapy enrolled in clinical trials of DAA therapies, which represents in African American compared with Caucasian patients, at least a significant number of patients with both HCV mono-infec- in part attributed to a higher prevalence of genotype 1 and the tion and HIV/HCV co-infection. Another limitation is that we P = .300 P = .001 P = .545 P = .378 40.5 P < .0001 P = .001 HCV HCV HCV HIV/HCV HIV/HCV HIV/HCV (Private) (Medicare) (NC Medicaid) (Private) (Medicare) (NC Medicaid) Figure 3. Time to approval of direct-acting antiviral therapy for patients with hepatitis C virus (HCV) and HIV/HCV stratified by insurance status. 6 • OFID • Collins et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Median time to approval of DAA, d 10. Kramer JR, Kowalkowski MA, Duan Z, Chiao EY. The effect of HIV viral control only had access to the insurance status of patients with DAA on the incidence of hepatocellular carcinoma in veterans with hepatitis C and prescriptions through the Duke specialty pharmacy, which HIV coinfection. J Acquir Immune Defic Syndr 2015; 68:456–62. was less commonly used for HIV/HCV co-infected patients. 11. Mehta SH, Lucas GM, Mirel LB, et al. Limited effectiveness of antiviral treatment for hepatitis C in an urban HIV clinic. AIDS 2006; 20:2361–9. Furthermore, this did not consistently include information on 12. Chung RT, Andersen J, Volberding P, et  al; AIDS Clinical Trials Group A5071 insurance denials, so time to approval of DAA was used as a Study Team. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004; surrogate. 351:451–9. 13. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et  al; APRICOT Study Group. CONCLUSIONS Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV- infected patients. N Engl J Med 2004; 351:438–50. The introduction of DAA therapy has significantly improved 14. McHutchison JG, Gordon SC, Schiff ER, et  al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis access to HCV treatment, and SVR is high in HIV/HCV co-in- Interventional Therapy Group. N Engl J Med 1998; 339:1485–92. fected patients. Meanwhile <20% of all HCV-infected patients 15. Naggie S, Cooper C, Saag M, et al; ION-4 Investigators. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015; 373:705–13. at Duke have received curative therapy. We identify several bar- 16. Osinusi A, Townsend K, Kohli A, et  al. Virologic response following combined riers to access, including racial disparity, possible bias against ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and treating patients with substance abuse, and strict Medicaid HIV co-infection. JAMA 2015; 313:1232–9. 17. Sulkowski MS, Eron JJ, Wyles D, et  al. Ombitasvir, paritaprevir co-dosed with criteria for funding DAA, all of which need to be urgently ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with addressed so that HCV cure can be realized for all. HIV-1: a randomized trial. JAMA 2015; 313:1223–31. 18. El-Sherif O, Back D. Drug interactions of hepatitis C direct-acting antivirals in the HIV-infected person. Curr HIV/AIDS Rep 2015; 12:336–43. Supplementary Data 19. Cope R, Pickering A, Glowa T, et al. Majority of HIV/HCV patients need to switch Supplementary materials are available at Open Forum Infectious Diseases antiretroviral therapy to accommodate direct acting antivirals. AIDS Patient Care STDS 2015; 29:379–83. online. Consisting of data provided by the authors to benefit the reader, 20. Wansom T, Falade-Nwulia O, Sutcliffe CG, et  al. Barriers to hepatitis C virus the posted materials are not copyedited and are the sole responsibility of (HCV) treatment initiation in patients with human immunodeficiency virus/ the authors, so questions or comments should be addressed to the corre- HCV coinfection: lessons from the interferon Era. Open Forum Infect Dis 2017; sponding author. 4:ofx024. 21. Lo Re V, Gowda C, Urick PN, et  al. Disparities in absolute denial of modern Acknowledgments hepatitis C therapy by type of insurance. Clin Gastroenterol Hepatol. 2016; 14:1035–43. Financial support. This research was funded by a Faculty-Resident 22. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. research grant from the Duke University Department of Medicine (to http://www.hcvguidelines.org. Accessed 19 September 2017. L.F.C.) and by the Duke Center for AIDS Research through biostatistical 23. Horvath MM, Rusincovitch SA, Brinson S, et  al. Modular design, application support. architecture, and usage of a self-service model for enterprise data delivery: the Potential conifl cts of interest. All authors: No reported conflicts of Duke Enterprise Data Unified Content Explorer (DEDUCE). J Biomed Inform interest. All authors have submitted the ICMJE Form for Disclosure of 2014; 52:231–42. Potential Conflicts of Interest. Conflicts that the editors consider relevant to 24. Lin M, Kramer J, White D, et  al. Barriers to hepatitis C treatment in the era of the content of the manuscript have been disclosed. direct-acting anti-viral agents. Aliment Pharmacol Ther 2017; 46:992–1000. 25. Janjua NZ, Islam N, Wong J, et  al. Shift in disparities in hepatitis C treatment from interferon to DAA era: a population-based cohort study. J Viral Hepat 2017; References 24:624–30. 1. Staples CT Jr, Rimland D, Dudas D. Hepatitis C in the HIV (human immuno- 26. Martinello M, Dore GJ, Skurowski J, et al. Antiretroviral use in the CEASE cohort deficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study study and implications for direct-acting antiviral therapy in human immuno- (HAVACS): the effect of coinfection on survival. Clin Infect Dis 1999; 29:150–4. deficiency virus/hepatitis C virus coinfection. Open Forum Infect Dis 2016; 2. Smith CJ, Ryom L, Weber R, et  al; D:A:D Study Group. Trends in underlying 3:ofw105. causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort 27. Höner Zu Siederdissen C, Maasoumy B, Marra F, et  al. Drug-drug interactions collaboration. Lancet 2014; 384:241–8. with novel all oral interferon-free antiviral agents in a large real-world cohort. 3. Bica I, McGovern B, Dhar R, et  al. Increasing mortality due to end-stage liver Clin Infect Dis 2015; 62:561–7. disease in patients with human immunodeficiency virus infection. Clin Infect Dis 28.Falade-Nwulia O, Sutcliffe C, Moon J, et al. High hepatitis C cure rates among 2001; 32:492–7. black and non-black HIV-infected adults in an urban center. Hepatol Baltim Md 4. Danta M, Semmo N, Fabris P, et  al. Impact of HIV on host-virus interactions 2017; 66:1402–12. during early hepatitis C virus infection. J Infect Dis 2008; 197:1558–66. 29. Kanwal F, Kramer JR, El-Serag HB, et al. Race and gender differences in the use of 5. Thomson EC, Fleming VM, Main J, et  al. Predicting spontaneous clearance direct acting antiviral agents for hepatitis C virus. Clin Infect Dis 2016; 63:291–9. of acute hepatitis C virus in a large cohort of HIV-1-infected men. Gut 2011; 30. Zinski A, Westfall AO, Gardner LI, et al. The contribution of missed clinic visits 60:837–45. to disparities in HIV viral load outcomes. Am J Public Health 2015; 105:2068–75. 6. Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in human 31. Dale SK, Bogart LM, Wagner GJ, et al. Medical mistrust is related to lower lon- immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc gitudinal medication adherence among African-American males with HIV. J Group. Hepatology 1999; 30:1054–8. Health Psychol 2016; 21:1311–21. 7. Kirk GD, Mehta SH, Astemborski J, et al. HIV, age, and the severity of hepatitis C 32. Murphy CC, Harlan LC, Warren JL, Geiger AM. Race and insurance differences virus-related liver disease: a cohort study. Ann Intern Med 2013; 158:658–66. in the receipt of adjuvant chemotherapy among patients with stage III colon can- 8. Fierer DS, Dieterich DT, Fiel MI, et al. Rapid progression to decompensated cir- cer. J Clin Oncol 2015; 33:2530–6. rhosis, liver transplant, and death in HIV-infected men after primary hepatitis C 33. Saab S, Jimenez M, Fong T, et al. Accessibility to oral antiviral therapy for patients virus infection. Clin Infect Dis 2013; 56:1038–43. with chronic hepatitis C in the United States. J Clin Transl Hepatol 2016; 4:76–82. 9. Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus 34. Chidi AP, Bryce CL, Donohue JM, et al. Economic and public health impacts of infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect policies restricting access to hepatitis C treatment for medicaid patients. Value Dis 2001; 33:562–9. Health 2016; 19:326–34. Access to DAAs in HIV/HCV Coinfection • OFID • 7 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx264/4718144 by Ed 'DeepDyve' Gillespie user on 16 March 2018

Journal

Open Forum Infectious DiseasesOxford University Press

Published: Jan 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off