Real-world evidence of the effectiveness of ombitasvir-paritaprevir/r ± dasabuvir ± ribavirin in patients monoinfected with chronic hepatitis C or coinfected with human immunodeficiency virus-1 in Spain.

AIM: We describe the effectiveness and safety of the interferon-free regimen ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (OBV/PTV/r ± DSV ± RBV) in a nationwide representative sample of the hepatitis C virus (HCV) monoinfected and human immunodeficiency virus-1/hepatitis C virus (HIV/HCV) coinfected population in Spain. MATERIAL AND METHODS: Data were collected from patients infected with HCV genotypes 1 or 4, with or without HIV-1 coinfection, treated with OBV/PTV/r ± DSV ± RBV at 61 Spanish sites within the initial implementation year of the first government-driven "National HCV plan." Effectiveness was assessed by sustained virologic response at post-treatment week 12 (SVR12) and compared between monoinfected and coinfected patients using a non-inferiority margin of 5% and a 90% confidence interval (CI). Sociodemographic and clinical characteristics or patients and adverse events (AEs) were also recorded. RESULTS: Overall, 2,408 patients were included in the intention-to-treat analysis: 386 (16%) were patients with HIV/HCV. Patient selection reflected the real distribution of patients treated in each participating region in Spain. From the total population, 96.6% (95% CI, 95.8-97.3%) achieved SVR12. Noninferiority of SVR12 in coinfected patients was met, with a difference between monoinfected and coinfected patients of -2.2% (90% CI, -4.5% - 0.2%). Only genotype 4 was associated with non-response to OBV/PTV/r ± DSV ± RBV treatment (p<0.001) in the multivariate analysis. Overall, 286 patients (11.9%) presented AEs potentially related to OBV/PTV/r ± DSV, whereas 347 (29.0%) presented AEs potentially related to ribavirin and 61 (5.1%) interrupted ribavirin. CONCLUSIONS: Our results confirm that OBV/PTV/r ± DSV ± RBV is effective and generally well tolerated in a representative sample of the HCV monoinfected and HCV/HIV coinfected population in Spain within the experience of a national strategic plan to tackle HCV.

Optimal Use of Transient Elastography and Acoustic Radiation Force Impulse to Stage Liver Fibrosis in HIV/HCV-Coinfected Patients in Clinical Practice.

OBJECTIVES: Liver fibrosis (LF) is crucial for the individualized management of patients with hepatitis C virus (HCV). We evaluated the concordance between two noninvasive methods for staging LF, transient elastography (TE) and acoustic radiation force impulse (ARFI), in patients coinfected with human immunodeficiency virus and HCV. We propose an algorithm for optimal use of both techniques in routine clinical practice. METHODS: A total of 89 human immunodeficiency virus/HCV-coinfected patients underwent TE and ARFI on the same day. The kappa index was used to assess concordance between the techniques. An algorithm combining ARFI and TE was proposed based on the independent factors associated with a kappa index greater than or equal to 0.70, obtained from a multiple regression analysis. We performed a cost-effectiveness analysis. The study was approved by our institutional review board and all patients signed the informed consent. RESULTS: Concordance between TE and ARFI for F2, F3, and F4 was 0.55, 0.59, and 0.69, respectively. Ultrasound normal spleen size (odds ratio [OR], 0.20; 95% confidence interval [CI], 0.05-0.91) and high viral load (OR, 0.36; 95% CI, 0.17-0.77) reduced the probability of agreement between TE and ARFI, whereas ultrasound normal left liver lobe size (OR, 3.32; 95% CI, 1.21-9.10) increased this probability. The algorithm revealed that LF was adequately assessed in 74.16%, with 25.84% of patients misclassified. The incremental cost-effectiveness ratio of TE compared with ARFI to increase concordance by 1% was €8.86. CONCLUSIONS: Concordance between TE and ARFI was moderate. In the algorithm we proposed, ARFI was cost-effective as a first technique for the staging of LF in the study population.

Evaluation of the Innate Immune Modulator Acitretin as a Strategy To Clear the HIV Reservoir.

The persistence of HIV despite suppressive antiretroviral therapy is a major roadblock to HIV eradication. Current strategies focused on inducing the expression of latent HIV fail to clear the persistent reservoir, prompting the development of new approaches for killing HIV-positive cells. Recently, acitretin was proposed as a pharmacological enhancer of the innate cellular defense network that led to virus reactivation and preferential death of infected cells. We evaluated the capacity of acitretin to reactivate and/or to facilitate immune-mediated clearance of HIV-positive cells. Acitretin did not induce HIV reactivation in latently infected cell lines (J-Lat and ACH-2). We could observe only modest induction of HIV reactivation by acitretin in latently green fluorescent protein-HIV-infected Jurkat cells, comparable to suboptimal concentrations of vorinostat, a known latency-reversing agent (LRA). Acitretin induction was insignificant, however, compared to optimal concentrations of LRAs. Acitretin failed to reactivate HIV in a model of latently infected primary CD4+ T cells but induced retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signaling (MAVS) expression in infected and uninfected cells, confirming the role of acitretin as an innate immune modulator. However, this effect was not associated with selective killing of HIV-positive cells. In conclusion, acitretin-mediated stimulation of the RIG-I pathway for HIV reactivation is modest and thus may not meaningfully affect the HIV reservoir. Stimulation of the RIG-I-dependent interferon (IFN) cascade by acitretin may not significantly affect the selective destruction of latently infected HIV-positive cells.

Short-term Treatment With Interferon Alfa Diminishes Expression of HIV-1 and Reduces CD4+ T-Cell Activation in Patients Coinfected With HIV and Hepatitis C Virus and Receiving Antiretroviral Therapy.

Long-term treatment with interferon (IFN) alfa plus ribavirin decreases the proviral human immunodeficiency virus type 1 (HIV) DNA level. However, the short-term impact of IFN alfa on persistent HIV and its effects on immune activation after antiretroviral therapy remain unknown. Our study showed that the cell-associated HIV RNA level and CD4(+) T-cell activation decreased in the IFN group (n = 10). No changes were detected in levels of residual plasma viremia, replication-competent reservoirs, proviral DNA, or 2-long-terminal repeat circles, although APOBEC3G, TRIM5α, BST2, and TRIM22 were upregulated in the IFN group. These data suggest that short-term treatment with IFN alfa combined with RBV decreases HIV expression, in part through inhibition of HIV transcription by TRIM22 and decrease in T-cell activation.

Prevalence and factors associated with liver steatosis as measured by transient elastography with controlled attenuation parameter in HIV-infected patients.

OBJECTIVE: To assess the prevalence and factors associated with significant hepatic steatosis (SHS, steatosis involving ≥10% hepatocytes) in HIV-infected patients. DESIGN: A prospective, cross-sectional study. METHODS: Five hundred and five HIV-infected patients were included in this study. All patients underwent a transient elastography examination with the controlled attenuation parameter (CAP). SHS was defined using the previously identified CAP cut-off of 238 dB/m. We analysed the associations between SHS and demographics, metabolic data, coinfections and drug therapy. RESULTS: SHS was detected in 201 (40%) patients. Individuals with and without plasma HIV RNA of 50 copies/ml or less presented SHS in 168 (42%) and 33 (31%) cases, respectively (P = 0.030). Patients with SHS compared with those without SHS presented higher median (IQR) BMI [BMI, 25.6 (22.5-28) vs. 22.3 (20.3-24.2) kg/m; P < 10], DBP [79 (72-85) vs. 74 (68-81) mmHg; P = 0.0001], fasting plasma glucose [95 (87-106) vs. 91 (84-97) mg/dl; P = 0.002] and triglycerides [128 (92-189) vs. 109 (80-167) mg/dl; P = 0.002], and lower HDL cholesterol [44 (37-54) vs. 48 (40-59), mg/dl; P = 0.004]. In multivariate analysis, the only factor associated with SHS was BMI [per unit increase, adjusted odds ratio (95% confidence interval) 1.34 (1.22-1-47); P < 10]. CONCLUSION: SHS measured by CAP is highly prevalent among HIV-infected patients. High BMI is the main predictor of SHS in this setting.

Incidence of hepatocellular carcinoma in HIV-infected patients with cirrhosis: a prospective study.

: This study assesses the incidence of hepatocellular carcinoma (HCC) in a prospective cohort of HIV-infected patients, the majority receiving antiretroviral therapy, with liver cirrhosis from different etiologies, enrolled between 2004 and 2005 with median follow-up of 5 years. We followed 371 patients, 25.6% with decompensated cirrhosis at baseline. The incidence rate of HCC was 6.72 per 1000 person-years [95% confidence interval (CI): 2.6 to 10.9]. There was a trend toward a higher cumulative probability of developing HCC at 6 years of follow-up (considering death and liver transplant as competing risks) in patients with decompensated versus compensated cirrhosis at baseline (6% vs. 2%, P < 0.06).

Pulse wave velocity as index of arterial stiffness in HIV-infected patients compared with a healthy population.

BACKGROUND: Chronic HIV infection leads to premature atherosclerosis. Arterial stiffness is considered a subclinical marker of cardiovascular disease. METHODS: Pulse wave velocity (PWV) was determined in 254 individuals (174 HIV-infected patients and 80 healthy controls, 2:1 matched by age and gender) to compare the prevalence of arterial stiffness and to identify associated factors. PWV was determined using noninvasive automated device (Complior). Factors associated with impaired PWV were assessed among cardiovascular risk factors, HIV infection parameters, and laboratory data. Logistic regression analyses were performed to determine differences between groups and factors associated to arterial stiffness. RESULTS: Overall, 81.4% of participants were male, median age was 46.54 [interquartile range (IQR): 41-52] years. Higher percentages of HIV-infected subjects showed dyslipemia (P = 0.012) and smoking habit (P = 0.002). The median time from HIV diagnosis was 13 (IQR: 6-18) years and the median time on antiretroviral therapy was 11 (IQR: 5-15) years. Nearly, all patients were virologically suppressed (89.7%) at the time of PWV. Arterial stiffness in the global population was 20.5%, 18.9% in HIV-infected group, and 23.8% in controls (P = 0.405). High diastolic blood pressure and high levels of triglycerides at time of PWV were associated with increased PWV (P = 0.009 and P = 0.023, respectively). CONCLUSIONS: Virologically suppressed HIV-infected patients showed similar arterial elasticity to non-HIV-infected patients. HIV-related conditions were not associated with arterial stiffness, probably because of the good immunologic and virological status of this group. However, high diastolic pressure at the time of PWV and high levels of triglycerides were associated risk factors.

Early but limited effects of raltegravir intensification on CD4 T cell reconstitution in HIV-infected patients with an immunodiscordant response to antiretroviral therapy.

BACKGROUND: Immune hyperactivation in immunodiscordant patients can induce residual HIV replication and limit CD4 T cell recovery. We assessed the impact of raltegravir intensification on CD4 T cell recovery and viral persistence. METHODS: We performed a randomized, controlled, pilot trial. Patients with CD4 T cell counts <350 cells/mm(3) despite suppressive antiretroviral therapy were randomized (2 : 1) to intensify with raltegravir (intensified arm, n = 30) or to continue with the same regimen (control arm, n = 14) for 48 weeks. Then, the control individuals intensified their treatment for 24 weeks (delayed-intensification arm). We analysed changes in CD4 T cell counts, total and episomal HIV DNA in peripheral blood mononuclear cells and predictive factors for response. RESULTS: Raltegravir intensification induced a rapid increase in CD4 T cell counts (week 12) (P = 0.007), although this was not sustained over time. Control patients maintained constant but slow increases in CD4 T cell counts (present in the pre-study period), reaching CD4 T cell counts similar to those of patients in the intensification arm at week 48. This effect was confirmed by the analysis of the delayed-intensification arm. Proviral DNA levels remained stable in both arms over time; episomal DNA forms and ultrasensitive plasma viral load were barely detected during the study. Increases in CD4 T cell counts were associated with low baseline CD95 expression in CD4 and CD8 T cells (P = 0.020). CONCLUSIONS: Raltegravir intensification modestly impacts viral dynamics and induces a rapid but limited gain in CD4 T cell counts in immunodiscordant patients. Residual viral replication does not seem to be the main cause of unsatisfactory CD4 T cell recovery in these patients.

Sustained virological response to interferon plus ribavirin reduces non-liver-related mortality in patients coinfected with HIV and Hepatitis C virus.

BACKGROUND: Sustained virological response (SVR) after therapy with interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). We assessed the effect of SVR on HIV progression and mortality not related to liver disease. METHODS: An observational cohort study including consecutive HIV/HCV-coinfected patients treated with interferon plus ribavirin between 2000 and 2008 in 19 centers in Spain. RESULTS: Of 1599 patients, 626 (39%) had an SVR. After a median follow-up of approximately 5 years, we confirmed that failure to achieve an SVR was associated with an increased risk of liver-related events and liver-related death. We also observed higher rates of the following events in nonresponders than in responders: AIDS-defining conditions (rate per 100 person years, 0.84 [95% confidence interval (CI), .59-1.10] vs 0.29 [.10-.48]; P= .003), non-liver-related deaths (0.65 [.42-.87] vs 0.16 [.02-.30]; P = .002), and non-liver-related, non-AIDS-related deaths (0.55 [.34-.75] vs 0.16 [.02-.30]; P = .002). Cox regression analysis showed that the adjusted hazard ratios of new AIDS-defining conditions, non-liver-related deaths, and non-liver-related, non-AIDS-related deaths for nonresponders compared with responders were 1.90 (95% CI, .89-4.10; P = .095), 3.19 (1.21-8.40; P = .019), and 2.85 (1.07-7.60; P = .036), respectively. CONCLUSIONS: Our findings suggest that eradication of HCV after therapy with interferon plus ribavirin in HIV/HCV-coinfected patients is associated not only with a reduction in liver-related events but also with a reduction in HIV progression and mortality not related to liver disease.

Effect of liver fibrosis on long-term mortality in HIV/hepatitis C virus-coinfected individuals who are evaluated to receive interferon therapies in the highly active antiretroviral therapy era.

The factors associated with overall mortality and liver decompensation in HIV and hepatitis C virus (HCV)-coinfected patients who are evaluated to receive HCV antiviral therapy with a known liver histological fibrosis stage were evaluated in a prospective cohort study. A total of 387 consecutive HIV/HCV-coinfected patients attending an outpatient clinical unit between January 1997 and December 2007 who fulfilled criteria to be treated with interferon and to whom liver biopsy was performed were included and followed every 6 months from time of liver biopsy to death or to December 2008. The follow-up period was 6.2 years (IQR: 3.5-9.2). The median age at time of liver biopsy was 38 years. This included 73% men; 28% had advanced liver fibrosis (F3-F4) and a CD4 cell count of 556 cells/mm(3), 72% had HIV RNA <400 copies/ml and a mean CD4 nadir of 207 cell/mm(3), 21% had a previous diagnosis of AIDS, and 92% were on antiretroviral therapy. During follow-up 48% underwent HCV antiviral therapy, with a sustained virological response in 33%. The overall mortality rate and the incidence of liver decompensation or liver-related death were 1.17 and 0.72 per 100 patients-year, respectively. End stage liver disease (9/28 patients) and non-AIDS-related cancer (6/28) were the main causes of death. F3-F4 (HR: 3.74, 95% CI: 1.69-8.26, p=0.001) and previous AIDS diagnosis (HR: 3.04, 95% CI: 1.36-6.81) were the factors independently associated with death. Mortality rates in patients who received and who did not receive HCV antiviral therapy were 0.44 and 2.04 per 100 patients-year, respectively (p=0.003). In addition to the low mortality rate observed, HIV/HCV-coinfected patients with poor predictors of survival are candidates for intensive clinical management.

Changes in T-cell subsets in HIV-HCV-coinfected patients during pegylated interferon-alpha2a plus ribavirin treatment.

BACKGROUND: We evaluated the effect of different doses of pegylated interferon (PEG-IFN)-alpha2a/ribavirin (RBV) on several T-cell activation markers in HIV-HCV-coinfected patients and their relationship with changes in plasma HCV RNA. METHODS: Frozen peripheral blood mononuclear cells (PBMCs) from 22 patients receiving two different PEG-IFN-alpha2a schedules were analysed by six-colour flow cytometry. Cell-surface expression of CD38 was quantified. HIV and HCV viral loads, as well as absolute CD4+ and CD8+ T-cell counts, were recorded during the follow up (72 weeks). RESULTS: PEG-IFN-alpha2a/RBV treatment decreased the absolute numbers of CD8+ and CD4+ T-cells. The decrease in CD8+ T-cells was more pronounced, resulting in increased percentages of CD4+ T-cells. Percentages of naive/memory CD4+ T-cell subsets remained unchanged, although the percentage of CD38+CD45RO+ cells significantly increased. By contrast, the CD8+ T-cell compartment significantly reduced the percentage of CD45RO+ cells and HLA-DR+ cells, whereas the percentage of CD38 expressing cells was increased because of a significant increase in cell-surface CD38 expression. Changes in CD8+ T-cells were similar for both PEG-IFN-alpha2a/RBV doses, but high doses induced more severe perturbations in CD4+ T-cells. All changes returned to baseline levels after treatment cessation and, except for the loss of naive CD4+ T-cells, were not associated with virological response. CONCLUSIONS: Transient lymphopaenia induced by PEG-IFN-alpha2a/RBV differentially affects T-cell subsets. Activated HLA-DR+ and CD45RO+ cells were selectively reduced in peripheral blood, whereas CD38 expression was up-regulated mainly in memory cells. Increasing PEG-IFN-alpha2a/RBV doses mainly affect CD4+ T-cells but failed to modify clinical outcome.

Ability of treatment week 12 viral response to predict long-term outcome in genotype 1 hepatitis C virus/HIV coinfected patients.

OBJECTIVE: Guidelines recommendation to extend treatment duration in genotype 1 hepatitis C virus (HCV)/HIV-coinfected patients who clear the virus later than treatment week 4 is not evidence-based. Our main objective was to study the ability of week 12 viral response [early virologic response (EVR)] to predict long-term outcome in patients treated for 48 weeks. DESIGN: Multicenter retrospective cohort analysis. METHODS: Genotype 1 HCV treatment-naive, HIV-coinfected adult patients with compensated liver disease who started combination therapy with fixed-dose pegylated-interferon (pegIFN) alfa-2a or weight-based pegIFN alfa-2b plus ribavirin were included. Univariate and forward stepwise logistic regression analysis were used to identify predictors of sustained viral response (SVR) and relapse. RESULTS: By intention-to-treat analysis, 31.3% (87/278) of patients achieved an SVR. SVR rate was more than three-fold higher in patients who cleared the virus by week 12 of treatment compared with late responders. Among 123 end-of-treatment responders, 36 (29.3%) relapsed. Relapse risk increased in patients with cirrhosis, in those with ribavirin dose reductions and in late responders: more than 65% of patients who cleared the virus between weeks 12 and 24 relapsed following 48 weeks of treatment compared with 10% of those attaining a complete EVR (<15 IU/ml) at treatment week 12 (risk ratio 6.4, 95% confidence interval 2.9-14.4). CONCLUSION: Viral response at treatment week 12 is a strong predictor of long-term outcome. Genotype 1 HCV/HIV-coinfected patients who achieve a complete EVR (<15 IU/ml) are at low risk of viral relapse after completing the standard 48 weeks of therapy.

Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with human immunodeficiency virus infection and long-lasting viral suppression / Impacto virológico, inmunológico y clínico del cambio de inhibidores de proteasa a terapia con nevirapina o efavirenz en pacientes infactados con el VIH que presentan una supresión viral prolongada

Seventy-seven subjects infected with human immunodeficiency virus were randomized to switch from protease inhibitor (PI) therapy to nevirapine therapy (group A; n=26) or to efavirenz therapy (group B; n=25) or to continue PI therapy (group C; n=26), At month 12, viral suppression had been maintained in 96 of patients in group A, 92 of patients in group B, and 92 of patients in group C. A significant increase in the CD4(+) level was observed in all 3 groups, In group A, lipid profiles improved, whereas levels of gamma-glutamiltransferase and alanine aminotransferase significantly increased; 1 subject interrupted treatment because of hepatotoxicity. In group B, an increase in gamma-glutamiltransferase levels was also observed, and 3 patients interrupted treatment because of central nervous system symptoms, Two patients in group C withdrew therapy, Quality of life significantly improved for groups A and B, In patients receiving effective PI-based therapy, the replacement of the PI with either nevirapine or efavirenz is safe and virologically effective(AU)

Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with human immunodeficiency virus infection and long-lasting viral suppression.

Seventy-seven subjects infected with human immunodeficiency virus were randomized to switch from protease inhibitor (PI) therapy to nevirapine therapy (group A; n=26) or to efavirenz therapy (group B; n=25) or to continue PI therapy (group C; n=26). At month 12, viral suppression had been maintained in 96% of patients in group A, 92% of patients in group B, and 92% of patients in group C. A significant increase in the CD4(+) level was observed in all 3 groups. In group A, lipid profiles improved, whereas levels of gamma-glutamiltransferase and alanine aminotransferase significantly increased; 1 subject interrupted treatment because of hepatotoxicity. In group B, an increase in gamma-glutamiltransferase levels was also observed, and 3 patients interrupted treatment because of central nervous system symptoms. Two patients in group C withdrew therapy. Quality of life significantly improved for groups A and B. In patients receiving effective PI-based therapy, the replacement of the PI with either nevirapine or efavirenz is safe and virologically effective.