INTRODUCTION

Hepatitis C virus (HCV) infection is one of the most common comorbidities in patients infected with the human immunodeficiency virus (HIV) ¹. Among the 185 million chronically infected individuals with HCV worldwide, approximately five million are also infected with HIV ². However, the seroprevalence of HCV in HIV infected patients has gradually decreased in Spain. Recent data from Spanish cohorts show seroprevalence rates of 37.7% for anti-HCV antibodies and active disease rates of 22.1% (with detectable HCV RNA) among coinfected individuals ³. Factors that have contributed to this decrease include a dramatic reduction in parenteral substance consumption, which is the main route for HIV transmission, which started in 1997 and the implementation of damage reduction programs in Spain.

It is well known that concomitant infection with HIV modifies the natural history of HCV infection, resulting in an accelerated development of fibrosis and a higher risk of end-stage liver disease ⁴. Observational cohort studies have shown that HCV clearing is associated with lower morbidity and mortality rates from both liver and non-liver disease in these patients ⁵. Reaching a sustained viral response (SVR) results in a significant reduction in fibrosis progression, hepatocarcinoma development and death from hepatopathy, not only in patients with advanced fibrosis but also in patients with moderate fibrosis ⁶. Historically, the standard management of HCV infection was based on dual therapies including pegylated interferon and ribavirin, which were beneficial for most mono-infected patients. SVR rates were substantially lower in coinfected subjects ⁷, who also experienced a high rate of side effects ⁸. Subsequently, the advent of first-generation protease inhibitors (telaprevir, boceprevir) in 2011, which were used in combination with pegylated interferon and ribavirin, resulted in similar response rates for both groups. However, their high cost, unfavorable toxicity profile and numerous interactions with antiretroviral drugs (ARDs) precluded their large-scale use.

The development of direct-acting antivirals (DAAs) has led to a huge improvement in the prognosis of patients with chronic HCV infection ⁹. These oral, interferon-free approaches have proven superior to all prior schemes since their introduction in 2014 ¹⁰. The efficacy of DAAs has been studied in clinical trials with both monoinfected and coinfected subjects ^{11) (12) (13) (14}. However, evidence of the effectiveness of these therapies in Spain is insufficient in prospective, multicenter cohorts.

The goal of this study was to analyze the real-life effectiveness and toxicity of DAA therapy in patients coinfected with HIV and HCV and to identify variables associated with unfavorable outcome.

PATIENTS AND METHODS

RESULTS

A total of 229 patients with a median age of 49.6 years (IQR 46.7-52.8) were included in the study; 83% (190) were male. Table 1 shows the clinical, laboratory and epidemiological characteristics of the patients. Most patients had genotype 1, and genotypes 3 and 4 were less common. The cohort represented a population with advanced liver disease, 50% had cirrhosis (20% Child B or C) and 25% had enolism. In addition, 65% of cases had more than 800,000 copies/ml of HCV VL and the IL28b gene polymorphism was an unfavorable factor in the majority of cases (65%). Baseline liver fibrosis data was collected in all patients except for 14 cases. A liver biopsy was available in three of these cases and the rest had either clinical signs of cirrhosis, had previously received interferon and ribavirin or had obesity-related technical difficulties.

Table 1 Baseline epidemiological, clinical and laboratory characteristics of the study population 

IQR: Interquartile range; HIV: Human immunodeficiency virus; HCV: Hepatitis C virus; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: Gammaglutamyl transpeptidase; INR: International normalized ratio; HBV: Hepatitis B virus; CDC: Centers for Disease Control and Prevention; kPa: Kilopascals; MSM: Males who have sex with males. aMeasured in patients with baseline liver cirrhosis. bPortal hypertension diagnosed via upper GI endoscopy or an imaging study. cLiver rigidity determined via transient elastography. dDrinking habit sometime during the patient's history.

Table 2 shows the antiretroviral therapy regimens used by researchers. The most widely used regimens included tenofovir disoproxil fumarate and integrase inhibitors (mainly raltegravir). Sustained viral response was reached by 91.7% of patients (intention-to-treat analysis) and 95.6% had undetectable HCV VL levels after treatment completion. No variables were identified that predicted virologic or therapeutic failure with regard to SVR (Fig. 1). The univariate analysis found no association between SVR and other variables such as platelet count, albumin, or Child-Pugh classification in cirrhotic patients. DAA therapy strategies are summarized in figure 2 and 48% of regimens also included ribavirin. Treatment duration was variable: 65.9% completed 12-week regimens, 30.1% completed 24-week schemes and only 3.9% received shorter 8-week dose schedules.

Table 2 Antiretroviral treatment regimens used during DAA administration 

NRTI: Nucleoside reverse-transcriptase inhibitor; NNRTI: Non-nucleoside reverse-transcriptase inhibitor; HIV: Human immunodeficiency virus; TDF: Tenofovir disoproxil fumarate; ABC: Abacavir.

Fig. 1 Univariate analysis: variables that predict an unfavorable outcome. The graph illustrates the main variables included in the univariate analysis. No variable was shown to predict an unfavorable outcome (OR: Odds ratio; CI: Confidence interval; HIV: Human immunodeficiency virus; TDF: Tenofovir disoproxil fumarate; ABC: Abacavir; IFN: Pegylated interferon; Rib: Ribavirin). 

Fig. 2 Direct-acting antiviral strategies. The figure shows the direct-acting antiviral strategies that were used and the percentage of patients receiving ribavirin within each group (SMV: Simprevir; LDV: Ledipasvir; SOF: Sofosbuvir; DCV: Daclatasvir; OBV: Ombitasvir; PTV: Paritaprevir; DSV: Dasabuvir; RTV: Ritonavir). 

SVR according to the various subgroups is summarized in figure 3. No statistically significant differences were found with regard to DAA therapy strategies. There were 19 therapy failures and these included ten relapses (distributed among all groups except for paritaprevir/ritonavir/ombitasvir), one breakthrough (in the sofosbuvir/ledipasvir group, relating to poor patient adherence) and three dropouts due to toxicity (two in the sofosbuvir/simeprevir group and one in the sofosbuvir/daclatasvir group). The relapsed patients had the same genotype after a repeat test, although reinfection cannot be definitely excluded as a phylogenetic study was not performed. In addition to the non-adherent patient, five patients dropped out due to causes unrelated to treatment: two died (one had sepsis and one had hepatorenal syndrome with hydropic decompensation after therapy onset) and three were lost to follow-up. Another individual died after reaching SVR and was diagnosed with advanced-stage lung adenocarcinoma. One further subject discontinued therapy due to toxicity without ever reaching SVR. Most reported adverse events included asthenia and gastrointestinal disorders. No baseline resistance tests were performed and only one test was carried out with the patient with breakthrough failure and no resistance-associated substitutions were found.

Fig. 3 Sustained viral response in the various subgroups. *Sustained viral response was recorded for the various DAA treatment groups. a) PTV/RTV/OBV; b) PTV/RTV/OBV/DSV; c) SOF/LDV; d) SOF/SMV; e) SOF/DCV; and f) SOF (DAA: Direct-acting antiviral; VL: Viral load; HCV: Hepatitis C virus; SMV: Simprevir; LDV: Ledipasvir; SOF: Sofosbuvir; DCV: Daclatasvir; OBV: Ombitasvir; PTV: Paritaprevir; DSV: Dasabuvir; RTV: Ritonavir). 

A multivariate analysis was performed with logistic regression using backwards stepwise exclusion. SVR was the dependent variable whereas sex, age, cirrhosis, genotype 1 or 4 vs 3 and over 800,000 copies/ml of HCV VL were used as independent variables. No independent predictor of SVR was found.

DISCUSSION

Data from clinical trials of HCV treatment with DAAs in coinfected patients have shown similar effectiveness as compared to studies in mono-infected subjects ^{11) (12) (13) (14}. Studies from mono-infected Spanish cohorts have been published ^{15) (16) (17) (18}, however, there are few reports on the effectiveness of these therapies in prospective coinfected cohorts ¹⁹. This paper reports real-life SVR data obtained from a multicenter cohort. Patients in this cohort study had a median age of almost 50 years and were predominantly male. The proportion of patients with detectable HIV V (> 50 copies/ml) was < 10%. Strikingly, almost 45% of patients had fewer than 200 CD4 T-cells.

HCV/HIV coinfection is strongly associated with parenteral drug use. However, HCV epidemiology has changed over the years. There are recent reports of HCV microepidemics in populations that engage in risky sexual practices such as chemsex, particularly among men who have sex with men (MSM) ^{20) (21}. This highlights the importance of ongoing health education for at risk groups in order to inform them of the steps to be taken to prevent virus transmission and to highlight the need for frequent serology tests. The latter remains a primary goal for the Plan estratégico para el abordaje de la hepatitis C en el Sistema Nacional de Salud, approved in Spain in 2015. Similarly, these data also warrant a proactive therapeutic approach towards patients, either with or without mild fibrosis (F0-F1).

HCV infection in this cohort mostly results from genotypes 1a and 4. This was also seen in other Spanish series and stems from the fact that these are the most common genotypes associated with parenteral drug use. Historically, this is the primary HCV transmission route in our study setting. Genotypes 2 and 1b were the least common and these genotypes have been linked to minor transmission routes (blood products transfusion). Data from our study are consistent with those of other Spanish series ²². This cohort also includes genotype-3 patients, the least common genotype with very limited evidence.

In contrast to specifically designed clinical trials in coinfected patients, our study had in excess of 45% of patients who met elastographic criteria for cirrhosis (Metavir F4) ^{13) (14}. The vast majority of patients had a recent elastographic study of liver rigidity and no significant differences in SVR were observed between the cirrhosis and pre-cirrhosis groups or between the mild and moderate stiffness groups. No statistically significant differences were found among the various genotypes. In contrast to other studies ^{13) (14)}, relapse rates were similar when patients were stratified according to baseline HCV RNA; the cut-off was 800,000 copies/ml. Data from our cohort are similar to those reported by other observational studies in coinfected subjects, such as the French HEPAVIH cohort ²³.

The prospective studies performed to analyze real-life DAA effectiveness have yielded similar results to those reported in clinical trials ^{24) (25}. The therapy regimens recommended for these patients are essentially the same for mono-infected individuals, with the potential drug-drug interactions between ARDs and DAAs. There were differences with regard to effectiveness among the various DAA regimens in this study. The multivariate analysis attempted to identify variables that were potentially associated with an unfavorable outcome. No variable was independently associated with the prediction of a poor outcome in a statistically significant manner.

Our cohort's findings support the excellent results seen in clinical trials. DAA real-life effectiveness in patients with HCV/HIV coinfection is outstanding. Toxicity is exceptional, as are toxicity-related therapy discontinuations. This suggests that the high potency and safety shown by these drugs by far exceeds the predictors of poor outcome described in other studies.

CONCLUSIONS

HCV treatment in patients with HIV infection reached very high sustained viral response rates. Real-life data and the clinical trials involved were excellent. Safety and tolerability are significant benefits of these drugs. No specific factors that predicted an unfavorable outcome were identified in this study.