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Interferon-free therapy for treating hepatitis C virus in difficult-to-treat HIV-coinfected patients

Mínguez, Carlosa; García-Deltoro, Miguelb; Flores, Juanc; Galindo, Maria-Joséd; Montero, Martae; Reus, Sergiof; Carmena, Jorgeg; Masiá, Marh; Amador, Concepcióni; Ortega, Enriquebon the behalf of the COINFECOVA-2 study group

doi: 10.1097/QAD.0000000000001699
CLINICAL SCIENCE
Free
SDC

Background/aims: Data regarding the use of all-oral direct-acting antivirals in HIV/hepatitis C virus (HCV)-coinfected patients with advanced liver fibrosis are required, because they are generally under-represented in clinical trials. This study sought to evaluate the use of these drugs in a cohort of coinfected patients, mostly with factors that have previously been recognized as predictors of treatment failure.

Methods: COINFECOVA-2 is an observational, multicenter study conducted in Eastern Spain. Data of all HIV/HCV-coinfected patients treated with direct-acting antiviral under real-life conditions were retrospectively collected, and factors associated with treatment success or safety were analysed.

Results: Among 515 included patients, 96% were on antiretroviral therapy and 89.5% had an HIV-RNA less than 50 copies/ml. HCV genotype (G) distribution was 47% G-1a, 20% G-4, 14.4% G-1b, and 12.8% G-3. Patients with cirrhosis were 54.2%, and 46% failed to prior HCV-therapies. Overall, 92.8% patients (95% confidence interval: 90.2–94.9) achieved sustained virologic response (SVR12). Cirrhosis was the only factor associated with treatment failure, and SVR12 rate was significantly lower in patients with liver stiffness at least 21 kPa. Adverse events were reported in 36.7%, but only two patients (0.4%) discontinued treatment because of adverse events. The bivariate analysis showed an association between ribavirin use and an increased risk of adverse events (odds ratio 2.84; 95% confidence interval: 1.95–4.1; P ≤ 0.0001).

Conclusion: This heterogeneous cohort of coinfected patients showed a high rate of SVR12. Among cirrhotic patients, those with a liver stiffness at least 21 kPa had a higher probability of treatment failure. Ribavirin use seems to increase the appearance of adverse events.

aInternal Medicine Department/Infectious Diseases Unit, Hospital General Universitario de Castellón, Castellón de la Plana

bInfectious Diseases Department, Consorcio Hospital General Universitario de Valencia

cInternal Medicine Department, Hospital Arnau de Vilanova

dInternal Medicine Department/Infectious Diseases Unit, Hospital Clinico Universitario

eInternal Medicine Department/Infectious Diseases Unit, Hospital Universitari i Politecnic La Fe, Valencia

fInternal Medicine Department/Infectious Diseases Unit, Hospital General Universitario de Alicante, Alicante

gInternal Medicine Department/Infectious Diseases Unit, Hospital Universitario Dr Peset, Valencia

hInternal Medicine Department/Infectious Diseases Unit, Hospital General Universitario de Elche, Elche

iInternal Medicine Department/Infectious Diseases Unit, Hospital Marina Baixa, La Vila Joiosa, Spain.

Correspondence to Carlos Mínguez, Internal Medicine Department, Hospital La Magdalena, Cuadra Collet, 32. Partida Bovalar, 12004 Castellón de la Plana, Spain. Tel: +34 964356800; fax: +34 964356835; e-mail: cminguez@comcas.es

Received 8 July, 2017

Revised 28 September, 2017

Accepted 2 October, 2017

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

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Introduction

The widespread use of antiretroviral therapy (ART) in developed countries is significantly increasing the survival rates of HIV-infected patients. However, despite the fact that mortality in HIV-infected patients is much lower than before, there is still an overall excess of mortality compared with general population, and hepatitis C virus (HCV) coinfection plays an important role in this issue. Deaths in this population are now usually non-AIDS related, with the most frequent causes of death being liver diseases, non-AIDS cancer, and cardiovascular diseases [1,2].

HIV negatively influences the natural history of liver disease in HCV-coinfected patients. Thus, despite ART, HIV infection accelerates HCV-related liver-fibrosis progression and, thus, hepatic decompensation and mortality is higher in coinfected patients than in HCV-monoinfected patients [3–6]. Fortunately, long-term studies have demonstrated that achieving sustained virologic response (SVR) after HCV therapy dramatically reduces liver-related complications and mortality in coinfected patients [7,8].

Worldwide, 6.2% of HIV-infected people are estimated to be HCV antibody positive, but prevalence of coinfection is much higher among those addicted to parenteral drugs (about 80%) [9]. In Spain, HIV infection (affecting an estimated 0.3% of the population) has been traditionally related to intravenous drug injection. However, in recent years, a change in the main route of HIV transmission has occurred with a decline in HCV coinfection prevalence among HIV-infected patients (from 61% in 2002 to 37% in 2015). Despite this, the rate of coinfection remains high [10].

The recent introduction of direct-acting antiviral (DAA) agents for HCV has substantially changed the recommended therapies for patients with HIV and HCV coinfection. Clinical trials have shown that, compared with previous treatment options, all-oral DAA combinations are highly efficacious, well tolerated, and achieve SVR rates of more than 90% in coinfected individuals after only 12–24 weeks of therapy [11–15]. Nevertheless, eligibility restrictions in the patient subgroups included in these clinical trials could limit the generalization of the results obtained to real-life settings, where the prevalence of difficult-to-treat patients is greater [16].

Therefore, more efficacy and safety data regarding the use of DAAs in large cohorts of coinfected patients (among which there is also a higher prevalence of advanced fibrosis, previous HCV therapy failure, and/or advanced HIV infection stages) are required, because these groups are generally under-represented in clinical trials.

Thus, the aim of this study was to evaluate the efficacy and safety of interferon-free DAA therapies in a real-life multicenter cohort of patients with chronic HCV and HIV coinfection, most of them with factors that have previously been recognized as predictors of treatment failure.

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Patients and methods

Study design and patients

COINFECOVA 2 is an observational, longitudinal multicentre study conducted at hospitals in the Comunidad Valenciana (Eastern Spain), which retrospectively collects data that are routinely generated in the course of usual care of coinfected patients. This autonomous community has more than 5 million of inhabitants with free access to a public health system which is constituted by 24 health departments, each of whom has a referral centre where specialist physicians attending HIV-infected patients are available. These specialists were invited to participate in the study. Once a centre had agreed to participate, patients were included if they were HCV/HIV coinfected, older than 18 years of age, and started routine HCV treatment with interferon-free DAA therapy between January 2015 and September 2015 (24-week regimen) or December 2015 (12-week regimen). During this study period, access to HCV therapy was restrained by public health authorities to people with advanced liver fibrosis, people with serious extrahepatic manifestations of chronic HCV infection, patients with HCV recurrence after liver transplantation, recipients of nonliver solid organ or stem-cell transplant, and to women of childbearing age with desire for pregnancy [17].

The patient demographics, clinical and laboratory data, and adverse events obtained from clinical registries were collected and transferred to an electronic case report form designed for this study. The fibrosis stage was determined before therapy by liver biopsy or by transient elastography (FibroScan; Echosens, Paris, France) on an F0–F4 scale (where F0 is the absence of fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis with occasional septa; F3, many septa without cirrhosis; and F4, cirrhosis), using the following cut-off values: F0/F1: 7.3 kPa or less; F2: 7.4–9.0 kPa, F3: 9.1–13.1 kPa, and F4: at least 13.2 kPa [18]. Stage F4 (cirrhosis) could also be diagnosed if clinical criteria (signs or symptoms of portal hypertension) were present. When elastography was employed to establish the fibrosis stage, a cut-off value of 21 kPa was used to predict significant portal hypertension because values close to this figure have been established in previous studies to be reliable for diagnosing portal hypertension [19].

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Treatment and study endpoints

DAAs available in Spain during the study period were simeprevir (SMV), sofosbuvir (SOF), daclatasvir (DCV), ledipasvir/SOF (LDV/SOF), dasabuvir (DBV), and ombitasvir/paritaprevir/ritonavir (OBV/PTV/r). The treatment regimen used, whether combined with ribavirin (RBV) or not, and its duration were selected at the discretion of each physician based on the individual patient's clinical history. Likewise, adverse events were managed according to best clinical practice and at the discretion of the attending physician.

The primary endpoint of this study was SVR12, which was defined as maintenance of undetectable HCV-RNA levels (<15 UI/ml) for at least 12 weeks after the end of therapy. Secondary endpoints were the occurrence of treatment-related adverse events and premature treatment discontinuation. Anaemia was defined as a drop in haemoglobin (Hb) levels to less than 12 g/dl compared with baseline, and severe anaemia was Hb less than 9 g/dl or a decrease of more than 2 g/dl if anaemia was present at baseline.

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Statistical methods and ethical issues

Descriptive statistical analyses were conducted for the study population. Excel 2007 software (Microsoft, Seattle, Washington, USA) was used to store the information as a database, and SPSS statistical software version 20.0 (IBM Corporation, Armonk, New York, USA) was used for statistical analysis. Continuous variables were expressed as the median (interquartile range), and categorical variables as the absolute number and percentage (95% confidence interval; CI). The rate of SVR12 was calculated based on an intention-to-treat approach, in which missing values were considered failures. The association between continuous variables and the endpoints was analysed using the Mann–Whitney U test, and the association with categorical variables was tested using the chi-squared test or Fisher's test, when applicable. Factors highlighted by the univariate analysis as showing an association and with a P value less than 0.2 were included in a multivariate logistic regression model, and the adjusted odds ratio and the corresponding 95% CI were calculated. A P value less than 0.05 was considered to indicate statistical significance in this model.

This study was sponsored by the Infectious Diseases Society of the Comunidad Valenciana (SEICV) and was conducted according to the ethical precepts set out in Spanish law (order number SAS/3470/2009) and in the Declaration of Helsinki. The study did not require informed consent because the patients were not directly interviewed, and completely anonymous information from existing records was collected ensuring the protection of personal data in accordance with Law 15/1999 of 13 December on Personal Data Protection and Spanish Royal Decree 1720/2007 of 21 December. The study protocol (code: SEICV-2015-1) was approved by the ethics committee at the lead study centre (Dirección General de Salud Pública and Centro Superior de Investigación en Salud Pública; CEIC DGSP-CSISP).

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Results

Baseline characteristics of the study population

Researchers of 13 centres agreed to participate in the study. All together, these centres provide health coverage for about 62% of the population of the Comunidad Valenciana[20]. During the study period, 515 coinfected patients at the participating centres started a combination of DAAs without interferon, and their data were collected and included in the study. The median (Q1–Q3) age was 50 (47–53) years and 76.7% were men. Intravenous drug use was the most common infection route, reported in 431 patients (83.7%), other routes of transmission were sexual contact in 48 (9.4%), blood transfusion in 13 (2.5%), and mother-to-child transmission in two (0.4%). In 21 patients (4.1%), the route of infection was unknown. The main baseline characteristics, grouped according to virus genotype, are shown in Table 1. Overall, 279 treated patients (54.2%) were cirrhotic. The fibrosis stage was determined by elastography in 489 patients (94.9%), liver biopsy in five (0.97%), and cirrhosis was diagnosed based on clinical criteria alone in the remaining 21 patients (4.1%).

Table 1

Table 1

With regard to HIV infection, 213 patients (41.4%) were stage 3 and 169 (32.8%) were stage 2 according to the Centers for Disease Control and Prevention case classifications (revised surveillance case definitions 2008) [21]. Most of the patients (95.9%) were on ART. The ART treatment backbone contained tenofovir disoproxil fumarate in 49.7% and abacavir in 27% of cases, and the core agents used were integrase inhibitors (57.5%), protease inhibitors (32.8%), nonnucleoside reverse transcriptase inhibitors (28.1%), or maraviroc (6.5%). HIV-RNA was less than 50 copies/ml in 89.5% of patients, and the median (Q1–Q3) CD4+ cell count was 585 (379–833) cells/μl. To avoid drug–drug interactions, ART was modified before initiating HCV therapy in 167 patients (33.8%). Changed drugs were boosted protease inhibitors in 58% and nonnucleoside reverse transcriptase inhibitors in 36.5% of cases. The new ART combination was mostly integrase inhibitor based (dolutegravir 46.7% and raltegravir 38.3%). No adverse events after ART switching were reported, and HIV suppression was overall maintained, but 8.9% presented ‘blips’ (plasma HIV RNA >50 copies/ml with a subsequent measure <50 copies/ml) in comparison with 7.7% in patients without antiretroviral change; similar rate of virologic failure (two consecutive plasma HIV RNA measures >200 copies/ml) was observed in both, the group in which the treatment was changed (4.2%) and the group that it was not (4.2%).

The most commonly used DAA combination was LDV/SOF (56.5%) followed by SOF and SMV (20%), SOF and DCV (15.1%), and OBV/PTV/r with or without DBV (7.6%). In 190 patients (36.9%), RBV was added to the DAAs, and only 38 patients (7.4%) underwent a 24-week scheduled therapy.

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Efficacy results

Overall, 478 patients achieved SVR12 (92.8%); the rates of SVR12 according to HCV genotype and treatment regimen are shown in Table 2. Most of the basal characteristics did not influence the therapy response (Fig. 1a). Of note, there were no significant differences in the SVR12 rate between patients who were treatment-naïve to prior HCV therapy, those who had previously been exposed to pegylated interferon (pegIFN) + RBV (P = 0.21), or patients with prior failure to triple-therapy including telaprevir or boceprevir (P = 0.44). Likewise, the response rate in patients with baseline HCV-RNA levels less than 800 000 IU/ml was not statistically different to that of patients with HCV-RNA levels at least 800 000 IU/ml (93.7 vs. 92.4%; P = 0.62). There were also no significant difference between patients with baseline HCV-RNA levels less than or at least 6 × 106 IU/ml (92.7 vs. 93.7%; P = 0.75). However, the response in patients treated with RBV was poorer than those not treated with RBV (Fig. 1b), whereas other factors related to the selected therapeutic regimen, as well as the ART used, did not influence the treatment outcome (Fig. 1b and c).

Table 2

Table 2

Fig. 1

Fig. 1

Although there were no significant differences in the SVR12 rate between patients with fibrosis stages F0–F3, the probability of treatment success was significantly lower in patients at stage F4 (Fig. 2a). Considering only cirrhotic patients diagnosed by elastography (253/279: 90.7%), the treatment response rate in patients with liver stiffness less than 21 kPa was lower, but not statistically different, from that of patients with F0–F3-stage fibrosis; nevertheless, it was significantly better than that of patients with liver stiffness at least 21 kPa (Fig. 2b).

Fig. 2

Fig. 2

Overall, SVR12 was not achieved in 37 (7.2%) patients, 24 of them (4.7%) due to virological failure (refer to Supplemental Digital Content 1, http://links.lww.com/QAD/B191 that shows patients outcome according to direct acting antiviral regimen), and among these, 21 (87.5%) were cirrhotic, they all received a scheduled 12-week treatment scheme, and 13/21 (61.9%) received RBV treatment. The three noncirrhotic patients who had a virological failure were a GT-3 patient with F2-stage liver fibrosis who discontinued a previous pegIFN + RBV therapy and went on to 12-week SOF + DCV + RBV treatment; a GT-1a, F2-stage, treatment-naïve patient, treated with LDV/SOF for 12 weeks; and a GT-4, F3-stage patient, who discontinued a previous pegIFN + RBV therapy and started LDV/SOF treatment.

The intent-to-treat approach multivariate analysis for possible factors that could predict successful SVR12 showed that the presence of cirrhosis was the only factor significantly associated with treatment failure. RBV use shows a significant association with treatment failure in univariate but not in multivariate analysis (refer to Supplemental Digital Content 2, http://links.lww.com/QAD/B191, that shows univariate and multivariate analysis to identify predictors for sustained virologic response).

RBV was added to the therapy combination in 190 patients, 148 (77.9%) of whom were cirrhotic. Analysing only the cirrhotic patients (n = 279), 126 were treated with a DAA regimen with RBV for 12 weeks, and 93.6% achieved SVR12 (with eight virologic failures; 6.3%), while 96.6% of the 119 treated for 12 weeks without RBV achieved a SVR12 (four virologic failures; 3.4%). None of the patients with cirrhosis treated for 24 weeks (22 with and 12 without RBV) had a virologic failure: 94.1% achieved a SVR12 and only 2, both receiving RBV, did not reach therapeutic success because of voluntary drop-out or lost follow-up.

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Safety results

Only two patients (0.4%) discontinued treatment prematurely because of adverse events. Both were GT-1a, F4-stage patients, who stopped therapy before week 8; one of them because of a cirrhosis decompensation while receiving LDV/SOF + RBV treatment, and the other on SOF + DCV + RBV who was newly diagnosed with high-degree lymphoma. Both died within 24 weeks of withdrawal. Overall, 189 patients (36.7%) had 280 adverse events, most of which were mild (Table 3); 15 patients (2.9%) had 16 serious adverse events, all but one in patients with F4 cirrhosis. Severe anaemia occurred in 10 patients (eight of them treated with RBV), cirrhosis decompensation in two, digestive bleeding in two, and thrombocytopenia and the aforementioned lymphoma in one patient.

Table 3

Table 3

Among the 190 patients treated with RBV, 102 (53.7%) reported adverse events, of which 13 (6.8%) were serious, especially in the case of severe anaemia, requiring reduction of the RBV dose in 27 patients (14.2%; Table 3). Our analysis did not identify any significant relationships between the DAA regimens and the appearance of adverse events. However, it shows a nearly three-fold increased risk of adverse events associated with the use of RBV (refer to Supplemental Digital Content 3, http://links.lww.com/QAD/B191, that shows univariate analysis to identify associations between used drugs and reported adverse events).

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Discussion

In Spain, the prevalence of HIV/HCV coinfection remains high. There are no local epidemiological data, but the rates would be similar to those of the whole of Spain, and it is estimated that in the Comunidad Valenciana, about 14 000 people would be infected with HIV, of which approximately 30% would be HCV coinfected, and could benefit from the new DAA.

The results of this study, including a large cohort of HIV-1 coinfected patients treated with interferon-free DAA-based HCV therapy under standard clinical practice conditions, are similar to those found in other clinical trials, reaching global SVR12 rates exceeding 90%, and virologic failure in less than 5% of treated patients [11–15]. Likewise, the real-life results of studies performed in developed countries implementing all-oral DAA-based regimens in cohorts principally including difficult-to-treat patients (HIV coinfected, cirrhotic, and/or with previous therapy failures) confirm these results [22–26].

The therapeutic response does not appear to be influenced by baseline characteristics such as age, sex, previous HCV therapy, HCV viral load, HIV-infection virologic control, or CD4+ lymphocyte count. Similarly, it also appears that the DAA regimen implemented does not influence the therapeutic outcome. However, although without significant differences, the OBV/PTV-based regimens achieved 100% SVR12 rates. It should be noted that in our study, only 7.6% of patients received OBV/PTV-based regimens (probably due to an increased risk of interactions with ART), and almost 75% of them had a genotype 1b or 4; this regimen was likely selected because patients with these two genotypes have been reported to achieve very high rates of virologic response in previous studies in monoinfected patients [27]. The impact of ART and DAA drug–drug interactions on virologic response was a matter of concern, and so the ART had to be changed before administering HCV therapy in about one-third of patients, without evidence of significant new adverse events, nor greater loss of HIV suppression.

Our multivariate analysis indicated that the presence of cirrhosis was the only factor that negatively influenced the results, resulting in an almost four-fold higher risk of not reaching a SVR12. This agrees with previous findings showing that cirrhotic patients usually present a poorer therapeutic response in clinical trials [28]. The role of cirrhosis as a negative predictor of outcome in observational studies is controversial because cirrhotic patients usually receive more intensive treatments and/or for longer periods than noncirrhotic patients. Recently, an observational study carried out in Madrid (Spain) which included a large cohort of HCV-monoinfected and HCV/HIV-coinfected patients showed that F4-stage fibrosis was associated with worse responses [25]. This is in contrast to the French ANRS CO13 HEPAVIH cohort which included 323 coinfected patients treated with all-oral-DAA-based regimens and showed no differences in SVR12 between patients with and without cirrhosis [26]. Perhaps, this difference in these studies can be explained by the different cut-off values used to define F4-stage cirrhosis, the different treatment regimens used, or the variable degrees of liver stiffness present in cirrhotic patients.

In our study, the fibrosis stage was established by elastography in 94.9% of patients. The SVR12 rate among patients with liver cirrhosis diagnosed by this approach was significantly lower in those with liver stiffness at least 21 kPa, reflecting a worse therapeutic response in cirrhotic patients with elastography data compatible with the presence of portal hypertension. Previous studies have established that liver stiffness assessed by transient elastography is correlated with the hepatic-venous pressure gradient. Despite there is a wide variation in the suggested cut-off to identify portal hypertension, we have chosen the 21-kPa cut-off because most of the relevant studies agree that a cut-off value around 21 kPa accurately predicts significant portal vein hypertension and related complications [19,29]. In coinfected patients, the same cut-off value was shown to be useful in identifying patients with oesophageal varices at a risk of bleeding [30]. Values in this range are currently employed in clinical practice, and the Baveno VI Consensus Workshop in portal hypertension suggests that in patients with virus-related advanced liver disease, liver stiffness value of 20–25 kPa by elastography, either alone or combined with platelet count and/or spleen size, is sufficient to confirm the presence of clinically significant portal hypertension [31]. Thus, based on the results obtained in our study, this elastography value (21 kPa) may be useful for selecting subsets of coinfected patients that could benefit from more intensive treatments (e.g., 24-week regimens with RBV). The therapeutic response in cirrhotic patients with liver stiffness less than 21 kPa also tended to be poorer than those with F0–F3-stage liver fibrosis, but the difference was not statistically significant, and a less intense treatment (12 weeks without RBV) could perform just as effectively.

Another subject that has not yet been clearly resolved is the need to add RBV to treatment combinations, given the little benefit and greater toxicity described in previous studies on cirrhotic populations when adding RBV to treatment [23,32]. In our study, univariate analysis of factors that are potentially involved in the therapeutic response shows that RBV use has a negative impact on success, although this effect disappeared in multivariate analysis. Being a nonrandomized study, it is probable that RBV was added to patients with potential higher risk of worse response, and its role may be underestimated, thus not allowing a definite conclusion to be drawn. On the other hand, it seems that the use of RBV significantly increases the risk of adverse events, even though the overall rate of discontinuation due to adverse events was very low (0.4%). Significantly, none of the cirrhotic patients treated for 24 weeks (35% of them without RBV) had virologic failure, and no increases in the incidence of adverse events were observed in this population despite the longer treatment duration.

The present work considered a heterogeneous, unselected cohort of coinfected patients who were treated for their HCV infection under normal clinical practice conditions and contrasts with highly selective randomized clinical trials which do not always equate well to real-life settings. However, this study did have certain limitations. First, because the attending clinicians were fully responsible for selecting the treatment regimen for each patient, we could not rule out indication bias when the most appropriate DAA combination for each patient was assessed. Second, the fact that there were missing data due to the retrospective nature of this study may have also caused bias. Nonetheless, the data we analysed are generally required for pretreatment patient evaluation and so were available in more than 95% of cases. Third, although the sample size is quite large, the low rate of virologic failures may limit the appearance of associations with treatment success because of the resulting lack of statistical power. Finally, all the patients treated during the study period were included to try to avoid selection bias, thereby resulting in a heterogeneous cohort that could make it difficult to allow meaningful conclusions to be drawn. Nevertheless, some subgroups are large enough to achieve statistical significance, and despite the problems introduced by heterogeneity, it is always interesting to analyse real-world data of large cohorts of patients because it can help to answer some questions that are not resolved during clinical trials and also helps to design new studies [33].

In conclusion, in real-life conditions, difficult-to-treat HIV/HCV-coinfected patients treated with all-oral DAA combinations reach high rates of SVR12, similar to those achieved by monoinfected patients in such conditions. Three main conclusions can be drawn from the results obtained in our study. First, cirrhotic patients with a baseline liver stiffness at least 21 kPa have a higher probability of virologic failure; second, RBV use is associated with an increase in the appearance of adverse events; and finally, drug–drug interactions with ART are possibly the main concern that arises when deciding the therapeutic regimen. These results should be confirmed by further carefully designed studies, but fortunately, new DAA regimen will soon be available, and almost all of them will be pangenotypic, RBV-free, and effective in patients who need a retreatment after failing a prior DAA combination. However, drug–drug interactions are expected to remain common, and it will be difficult to avoid ART changes. Future drugs should be focused on reducing the risk of drug–drug interactions, along with an improvement in efficacy in patients with increased liver stiffness.

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Acknowledgements

We would like to express our gratitude to: Carolina V González-Miño and María Ledrán for helping in translation work.

C.M. and E.O. designed the study. C.M. created the database and conducted the literature review. The statistical analysis was performed by Enrique J. Vera-Remartinez (author in acknowledgement). All authors assessed clinical data from the study. C.M. wrote the first draft of the article. M.G.-D., S.R., Joaquín Portilla, and José López-Aldeguer (authors in acknowledgement) provided writing assistance during the preparation of the article. All authors reviewed, and approved the final article.

Data managers: Adsuar A, Cuéllar S, Díez M, Ferrando R, Pampliega M, Portilla I, Fernández-Blest M, and Rubio P.

COINFECOVA-2 Study group: Manuel Arnal (H. de Vinarós). Carlos Mínguez, Jorge Usó (H. General Universitario de Castellón). Vicente Abril, Jose E. Ballester, Magdalena García, Miguel García-Deltoro, Enrique Ortega, Carmen Ricart (Consorcio H. General Universitario de Valencia). Ana Ferrer, María José Galindo, María Rosa Oltra (H. Clínico Universitario de Valencia). Juan Flores (H. Arnau de Vilanova, Valencia). Jorge Carmena, Rogelio Vicente (H. Universitario Doctor Peset). Marino Blanes, José López-Aldeguer, Marta Montero, Miguel Salavert, María Tasias (H. Universitari i Politecnic La Fe, Valencia). Carlos Tornero (H. Francesc de Borja, Gandía). Karenina Antelo, Patricia Martin-Rico (H. de Denia-Marina Salud, Denia). Concepción Amador, Francisco Pasquau (H. de la Vilajoiosa). José María Cuadrado, Francisco Jover (H. Universitario de San Juan, Alicante). Vicente Boix, Esperanza Merino, Joaquín Portilla, Sergio Reus, Diego Torrús (H. General Universitario de Alicante). Félix Gutiérrez, Mar Masiá, Sergio Padilla (H. General Universitario de Elche).

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Conflicts of interest

C.M., M.G.-D., J.F., M.-J.G., M.M., J.C., and M.M. have received financial compensation for speaking, teaching or have attended advisory board meetings from Abbvie, Bristol-Myers Squibb, Gilead, Janssen-Cilag, Merck, and ViiV Healthcare.

E.O., C.A., and S.R. declare no potential conflicts of interest.

The current study was promoted by the Sociedad de Enfermedades Infecciosas de la Comunidad Valenciana (SEICV). None to be declared regarding the present work.

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Keywords:

direct acting antivirals; hepatitis C virus/HIV coinfection; hepatitis C virus; liver cirrhosis; liver stiffness; Spain

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