Surabhi Dangi-Garimella, PhD

A combined analysis of data gathered from the Canadian Health Measures Survey (CHMS) and the US—National Health and Nutrition Examination Survey (NHANES) found a 2.5% to 3.5% increase in the 10-year risk of cardiovascular disease (CVD) in patients with a hepatitis C virus (HCV) infection.  

In addition to liver complications, such as fibrosis, cirrhosis, liver cancer, and liver failure, HCV infection has also been found responsible for extrahepatic complications that affect the hematologic, neurologic, and renal functions. Several studies have also documented cause-specific cardiovascular mortality in patients who are positive for HCV.

The current cross-sectional study included 10,115 participants from CHMS (2007-2015) and 16,668 participants from NHANES (2007-2016), who were between 30 and 74 years old and had no prior history of CVD.

 A Framingham Risk Score (FRS) algorithm was developed for this population. Exclusion criteria also included missing data on any of the required FRS data: age, gender, blood pressure, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), smoking status, diabetes, and antihypertensive medication. Lack of information on HCV status was also an exclusion criterium.

HCV-positive participants had a very distinct sociodemographic profile, but cardiometabolic risk factors, inflammatory markers, and serum levels of micronutrients were comparable with the HCV-negative population. Additionally, the HCV-positive participants had a significantly higher rate of intravenous recreational drug use in both the NHANES (33% vs 1%) and CHMS (53% vs 1%) populations.

HCV-positive participants had significantly lower levels of triglycerides, low-density lipoprotein cholesterol, TC:HDL-C, and ApoB, compared with the noninfected controls. In the CHMS group, viral infection was associated with higher TC (4.50 ± 0.97 vs 3.94 ± 1.27 mmol/L; 

 <.001), as opposed to the HCV-positive NHANES participants, who had lower TC (4.67 ± 1.0 vs 5.17 ± 1.1 mmol/L; 

<.001). There was no association between HCV status and diabetes (either self-reported or glycated hemoglobin levels).

Liver enzyme levels were much higher in the presence of active HCV infection, unsurprisingly, and FRS value among the HCV-positive NHANES participants was much higher in the HCV RNA-positive cases (15.3% ± 10.4%; 

 = .047) compared with the HCV-negative cases (12.1% ± 9.8%). HCV-positive cases had a significantly higher 10-year risk of CVD in both the NHANES (14.7 ± 10.3 vs 10.0 ± 10.0; 

 <.001) and CHMS (10.5 ± 8.8 vs 8.0 ± 6.6; 

 = .008) groups. Interestingly, the overall CVD risk was higher in the US population, independent of their infection status.

HCV-infected individuals in the NHANES population had a 4.21% (

 <.001) greater 10-year CVD risk compared with the noninfected population. Similarly, the HCV-positive CHMS US population (3.5%; 

 <.001) had a greater risk compared with the Canadian population (2.5%; 

“The expansion of anti-HCV therapy may also contribute to reduced CVD risk and burden in patients with chronic HCV infection and should be explored further in other datasets and population modelling studies,” the authors conclude.

1. Kristiansen MG, Løchen ML, Gutteberg TJ, Mortensen L, Eriksen BO, Florholmen J. Total and cause-specific mortality rates in a prospective study of community-acquired hepatitis C virus infection in northern Norway. 

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2. Lee MH, Yang HI, Wang CH, et al. Hepatitis C virus infection and increased risk of cerebrovascular disease. 

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3. Badawi A, Di Giuseppe G, Arora P. Cardiovascular disease risk in patients with hepatitis C infection: results from two general population health surveys in Canada and the United States (2007-2017). 

. 2018;13(12):e0208839. doi: 10.1371/journal.pone.0208839.

Articles

A combined analysis of data gathered from the Canadian Health Measures Survey and the US–National Health and Nutrition Examination Survey found a 2.5% to 3.5% increase in the 10-year risk of cardiovascular disease in patients with a hepatitis C virus (HCV) infection.  

Study Finds HCV Infection Increases 10-Year Risk of Cardiovascular Disease

A median 19-month follow-up of the JULIET trial—a single-arm, open-label, multicenter, global, pivotal phase 2 trial of the chimeric antigen receptor (CAR)-T cell therapy tisagenlecleucel directed against CD19-expressing B cells&mdash;has found a 40% complete response (CR) and a manageable safety profile in adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

Tisagenlecleucel (Kymriah) was FDA approved in May 2018 for the treatment of adult patients with R/R large B-cell lymphoma following at least 2 prior line of therapy.

Conducted across 27 sites in 10 countries, the JULIET trial enrolled 167 patients with R/R DLBCL at the cutoff date of May 21, 2018, and 115 of them received an infusion of CD19-directed CAR T cells (dose range 0.1 x 10

 cells). Eligibility criteria included at least 18 years of age; at least 2 lines of prior therapy, including an anti-CD20 antibody and an anthracycline; and were ineligible for or had failed autologous stem cell transplant (ASCT). Primary trial endpoint was overall response rate (ORR), as a sum total of the CR and partial response as assessed by an independent review committee. Secondary endpoints included duration of response, overall survival, and safety.

About 90% of infused patients received bridging therapy and 93% received lymphodepleting chemotherapy. Median time from infusion to data cutoff was 19.3 months. Median age was 56 years (range, 22-76 years); 23% were aged ≥65 years. At study entry, 77% of infused patients had stage III/IV disease; 55% and 43% had germinal center and activated B-cell molecular subtypes, respectively. Over half of the patients had received at least 3 prior lines of antineoplastic therapy (range, 1-6) and about the same number had undergone a prior ASCT.

Of the 99 patients who were evaluated who had at least 3 months of follow-up, ORR was 54% (95% CI, 43%-64%), with 40% CR. Further, ORR was consistent across prognostic subgroups that were evaluated, including prior ASCT, gender, age, and molecular subtype.

Median duration of response (DOR) was not reached at the time of data analysis, and DOR was not influenced by age or R/R status, the study found. No relapses were observed beyond 11 months after infusion. The median OS for all infused patients was 11.1 months (95% CI, 6.6 months-not evaluable [NE]) and was not reached for patients in CR (95% CI, 21 months-NE). The OS probability was 48% (95% CI, 38%-57%) at 12 months and 43% (95% CI, 33%-53%) at 18 months, and, similar to DOR, was not influenced by the patient’s age or R/R status.

“These findings are consistent with what we’ve shown in our single-site studies here at Penn, which is that the majority of patients who go into remission stay in remission,” said Stephen J. Schuster, MD, director of the Lymphoma Program at the Abramson Cancer Center of the University of Pennsylvania, who is the principle investigator for the JULIET trial.

The authors compared the survival curves from their current study with those of the SCHOLAR-1 study

 and found that patients enrolled in JULIET performed much better in terms of overall survival. The OS probability was about 30% and 25% for SCHOLAR-1 and CORAL at 12 months, respectively, and 25% and 20% at 24 months, respectively.

More than half (57%) of patients experienced cytokine release syndrome, 34% of which were grade 3/4. Prolonged (>28 days) cytopenias were observed in 45% patients, 34% of which were high-grade (3/4); a majority (17%) of infections in 37% of patients were grade 3. Twenty percent of treated patients experienced neurological adverse events, including a single case of grade 2 cerebral edema, which was detected without a contrast computed tomography (CT) scan, which disappeared following a contrast CT scan after 24 hours.

The authors report that there were no treatment-related deaths following their last data presentation at the Congress of the European Hematology Association in June this year.

Schuster SJ, Bishop MR, Tam C, et al. Sustained disease control for adult patients with relapsed or refractory diffuse large B-Cell lymphoma: an updated analysis of Juliet, a global pivotal phase 2 trial of tisagenlecleucel. In: Proceedings from the American Society of Hematology; December 1-3, 2018; San Diego, CA. Abstract 1684.

Global trial shows CAR T therapy can lead to durable remissions in non-Hodgkin’s lymphoma [press release]. Philadelphia, PA: Penn Medicine; November 30, 2018. 

newswise.com/articles/view/704664/?sc=dwhr&xy=10014716

Crump M, Neelapu SS2, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study.

. 2017;130(16):1800-1808. doi: 10.1182/blood-2017-03-769620.

Gisselbrecht C, Schmitz N, Mounier N, et al. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. 

. 2012;30(36):4462-4469. doi: 10.1200/JCO.2012.41.9416.

Borchmann P, Tam CS, Ulrich Jager, et al. An updated analysis of Juliet, a global pivotal phase 2 trial of tisagenlecleucel in adult patients with relapsed or refractory (r/r) diffuse large b-cell lymphoma (DLBCL). In: Proceedings from the 23rd Congress of the European Hematology Association; June 14-17, 2018; Stockholm, Sweden. Abstract S799.

A median 19-month follow-up of the JULIET trial&mdash;a single-arm, open-label, multicenter, global, pivotal phase 2 trial of the chimeric antigen receptor-T cell therapy tisagenlecleucel directed against CD19-expressing B cells&mdash;has found a 40% complete response and a manageable safety profile in adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

Longer-Term JULIET Results Confirm Sustained Response With Tisagenlecleucel in Relapsed/Refractory DLBCL

A kidney transplant patient treated with direct-acting antivirals (DAAs) for a chronic hepatitis C virus (HCV) infection showed reactivation of the hepatitis B virus (HBV), which proved fatal. The authors of the report recommend a call to action for including HBV testing as part of the patient’s work-up in transplant recipients who are on immunosuppressants, especially in the context of abnormal liver tests.

There are 4 classes of DAAs that target different proteins in the HCV virus:

NS3/4A protease inhibitors: block the viral protease, which inhibits survival and replication in the host cell (galexos, grazoprevir, sunvepra)

NS5B polymerase inhibitors: inhibit replication in the liver by binding viral RNA (sofosbuvir)

NS5A inhibitors: prevent viral replication and infection process (daclatasvir, elbasvir, ledipasvir, ombitasvir)

Non-nucleoside NS5B polymerase inhibitors: inhibit viral replication (dasabuvir)

Of these, the discovery of second-generation DAAs revolutionized the treatment landscape of HCV and introduced a potential for a cure. However, according to the new study published in the 

International Journal of Infectious Diseases

, there are certain complications associated with these treatments that may be associated with patient comorbidities.

The authors of the report describe a 48-year-old male kidney transplant recipient with a chronic HCV infection who was treatment-naïve. On immunosuppressants (tacrolimus, mycophenolate mofetil, and prednisone), he developed end-stage renal disease and was evaluated for a third transplant. Following a panel of metabolic and liver-function tests, the patient was started on a combination of 2 DAAs: grazoprevir (100 mg/day) and elbasvir (50 mg/day) for 12 weeks.

Following a reduction in the dose of tacrolimus in the first few weeks, HCV-RNA was below the limit of detection (LOD) 6-weeks after DAA treatment was initiated. However, the patients had persistent elevated aminotransferase levels that were significant even till week 9. The patient was subsequently taken off of grazoprevir, which is known to cause liver toxicity and treated with valganciclovir for a cytomegaloviral load that was detected.

When the patient was readmitted to the hospital with fever and jaundice 2 months later, the HCV-RNA remained below LOD but the HBsAg antigen was detected, indicative of infection with HBV. A subsequent retrospective analysis of frozen serum samples found both HBsAg and HBV-DNA before DAA treatment was initiated, but the biomarkers peaked within a few weeks of treatment initiation.

The patient was started on entecavir for the HBV, but that did not prevent his liver deterioration and subsequent death a month later.

“This is a case of severe hepatitis B reactivation during anti-HCV therapy with grazoprevir and elbasvir,” the authors wrote, adding that a septic shock associated with profound immunosuppression may have had a significant role to play in the patient’s deterioration. They further highlight the need to test for HBV in immunosuppressed patients with the hope that earlier diagnosis and can help alter untoward outcomes.

Sastre L, Ruiz P, Costa J, Forns X. Severe hepatitis B reactivation during direct-acting antiviral treatment in “the absence” of hepatitis B surface antigen. 

. 2018;pii: S1201-9712(18)34593-4. doi: 10.1016/j.ijid.2018.11.014.

HBV Reactivation a Serious Adverse Effect of DAAs in the Treatment of HCV

Ibrutinib combined with obinutuzumab had better progression-free survival (PFS) at 30 months than the standard chemoimmunotherapy regimen, chlorambucil plus obinutuzumab, regardless of high-risk genomic features in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who had never been treated. These results from the iLLUMINATE study were presented at the 60th American Society of Hematology Annual Meeting & Exposition, being held December 1-4, in San Diego, California.

Ibrutinib is a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase and was approved in 2016 in the United States as a single-agent, chemotherapy-free regimen for patients with CLL. The 

is a phase 3, open-label, multicenter trial that was designed to test the efficacy of ibrutinib with obinutuzumab versus chlorambucil with obinutuzumab in treatment-naïve patients with CLL/SLL.

Eligibility criteria included treatment-naïve CLL/SLL, ≥65 years or <65 years with coexisting conditions (Cumulative Illness Rating Scale score >6, creatinine clearance <70 mL/min, and/or del(17p) or TP53 mutation).

One set of patients received 6 cycles of 420 mg ibrutinib once daily, combined with obinutuzumab 1000 mg on days 1/2, 8, and 15 of cycle 1, and day 1 of subsequent 28-day cycles. The other set of patients was treated with 6 cycles of chlorambucil (0.5 mg/kg on days 1 and 15 of each 28-day cycle) combined with obinutuzumab, in the same dose and frequency as above. PFS was the primary endpoint and secondary endpoints included PFS in a high-risk population—del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV&mdash;rate of undetectable minimal residual disease, overall response rate (ORR), overall survival (OS), and safety.

The trial allowed crossover of patients with confirmed progression in the chlorambucil—obinutuzumab arm to single-agent ibrutinib.

The trial enrolled 229 patients, 113 of whom were randomized to the ibrutinib-obinutuzumab arm and 116 to the chlorambucil-obinutuzumab arm. Median age was 71 years (range, 40-87) and 65% of patients had the above listed high-risk genomic features.

With a median follow-up of 31.3 months, patients who were treated with ibrutinib—obinutuzumab had a significantly better PFS compared with the comparator arm (median not reached [NR] vs 19.0 months; hazard ratio [HR], 0.231; 95% CI, 0.145-0.367; 

 <.0001). At 30 months, the PFS rates were 79% with ibrutinib—obinutuzumab and 31% with chlorambucil–obinutuzumab. These were PFS results as assessed by an independent review committee (IRC), the authors reported.

Investigator (INV)-assessed PFS showed a similar trend for ibrutinib—obinutuzumab versus chlorambucil–obinutuzumab (median PFS NR vs 21.9 months; HR, 0.260; 95% CI, 0.163 to 0.415; 

 <.0001). Further, the improvements in PFS seen among patients receiving ibrutinib—obinutuzumab were independent of their genomic status compared with the comparator arm (median NR vs 14.7 months; HR, 0.154; 95% CI, 0.087-0.270; 

Both IRC- and INV-assessed ORR were better for the ibrutinib-obinutuzumab arm. IRC-assessed ORR was 88% with ibrutinib—obinutuzumab vs 73% with the comparator, while INV-assessed ORRs were 91% and 81%, respectively. Similar trends were observed with the IRC-assessed complete response (CR) rate, which was higher with ibrutinib-obinutuzumab (19% vs 8%). INV-assessed CR rates were 41% and 16%, respectively.

The authors report similar 30-month OS rates: 86% in the ibrutinib—obinutuzumab arm and 85% in the chlorambucil-obinutuzumab arm, with 40% of patients randomized to chlorambucil–obinutuzumab receiving single-agent ibrutinib as second-line therapy. Over a median follow-up of 31.3 months, 4% of patients in the ibrutinib–obinutuzumab arm and 44% in the chlorambucil–obinutuzumab arm initiated subsequent therapy.

The most frequent (≥3%) serious adverse events (AEs) among patients in the ibrutinib—obinutuzumab arm were pneumonia (5%), atrial fibrillation (4%), febrile neutropenia (4%), and pyrexia (4%). The more common serious AEs in the chlorambucil–obinutuzumab were infusion-related reactions (IRRs; 7%), febrile neutropenia (6%), pneumonia (4%), tumor lysis syndrome (4%), and pyrexia (3%). While no patients discontinued obinutuzumab due to IRRs with in the ibrutinib–obinutuzumab arm, 7 patients in the comparator stopped obinutuzumab.

AEs leading to discontinuation of ibrutinib or chlorambucil occurred in 18 (16%) and 11 patients (9%), respectively, and AEs leading to discontinuation of obinutuzumab occurred in 10 patients (9%) in the ibrutinib—obinutuzumab arm and 15 (13%) in the chlorambucil–obinutuzumab arm.

At about the 3-year follow-up mark, 70% of patients in the ibrutinib—obinutuzumab arm are on single-agent ibrutinib.

Based on their findings, the authors conclude that the ibrutinib—obinutuzumab combination therapy was tolerable among treatment-naïve patients with CLL/SLL with no new safety signals identified and that it represents an effective chemotherapy-free treatment option for first-line CLL/SLL including among the high-risk population.

Moreno C, Greil R, Demirkan F, et al. Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL): results from phase 3 iLLUMINATE. In: Proceedings from the American Society of Hematology; December 1-4, 2018; San Diego, CA. Abstract 691.

Ibrutinib combined with obinutuzumab had better progression-free survival (PFS) at 30 months than the standard chemoimmunotherapy regimen, chlorambucil plus obinutuzumab, regardless of high-risk genomic features in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who had never been treated.

Surabhi Dangi-Garimella, PhD

Articles

Study Finds HCV Infection Increases 10-Year Risk of Cardiovascular Disease

Longer-Term JULIET Results Confirm Sustained Response With Tisagenlecleucel in Relapsed/Refractory DLBCL

HBV Reactivation a Serious Adverse Effect of DAAs in the Treatment of HCV

iLLUMINATE: Superior PFS With Ibrutinib–Obinutuzumab Even in High-Risk, Untreated CLL/SLL