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