Research Spotlight

Posted January 27th 2016

Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis.

Jacqueline O'Leary M.D.

Jacqueline O’Leary, M.D.

Curry, M. P., J. G. O’Leary, N. Bzowej, A. J. Muir, K. M. Korenblat, J. M. Fenkel, K. R. Reddy, E. Lawitz, S. L. Flamm, T. Schiano, L. Teperman, R. Fontana, E. Schiff, M. Fried, B. Doehle, D. An, J. McNally, A. Osinusi, D. M. Brainard, J. G. McHutchison, R. S. Brown, Jr. and M. Charlton (2015). “Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis.” New England Journal of Medicine 373(27): 2618-2628.

Full text of this article.

BACKGROUND: As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase. METHODS: We conducted a phase 3, open-label study involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir-velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin. CONCLUSIONS: Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. (Funded by Gilead Sciences; ASTRAL-4 ClinicalTrials.gov number, NCT02201901.).


Posted January 27th 2016

The Three-Month Readmission Rate Remains Unacceptably High in a Large North American Cohort of Cirrhotic Patients.

Jacqueline O'Leary M.D.

Jacqueline O’Leary, M.D.

Bajaj, J. S., K. R. Reddy, P. Tandon, F. Wong, P. S. Kamath, G. Garcia-Tsao, B. Maliakkal, S. W. Biggins, P. J. Thuluvath, M. B. Fallon, R. M. Subramanian, H. Vargas, L. R. Thacker and J. G. O’Leary (2015). “The Three-Month Readmission Rate Remains Unacceptably High in a Large North American Cohort of Cirrhotic Patients.” Hepatology. 2015 Dec 21. [Epub ahead of print].

Full text of this article.

In smaller single-center studies, cirrhotic patients are at a high readmission risk but a multi-center perspective study is lacking. AIM: To evaluate the determinants of 3-month readmissions in cirrhotic inpatients using the prospective 14-center NACSELD (North American Consortium for the Study of End-Stage Liver Disease) cohort. METHODS: Cirrhotics hospitalized for non-elective indications were consented and followed for 3-months post-discharge. The number of 3-month readmissions and their determinants on index admission and discharge were calculated. We used multivariable logistic regression for all readmissions, and for hepatic encephalopathy (HE), renal/metabolic and infection-related readmissions. A score was developed using admission/discharge variables for the total sample, which was validated on a random half of the total population. RESULTS: 1353 patients were enrolled, 1177 were eligible on discharge and 1013 had 3-month outcomes. Readmissions occurred in 53% (n=535;316 with one, 219 with >/=2), with consistent rates across sites. The leading causes were liver-related (n=333, HE, renal/metabolic and infections). Cirrhotics with worse MELD, diabetes, those taking prophylactic antibiotics and with prior HE, were more likely to be readmitted. The admission model included MELD and diabetes (c-statistic=0.64; after split-validation 0.65). The discharge model included MELD, proton pump inhibitor use and lower length-of-stay (c-statistic=0.65; after split-validation 0.70). 30% of readmissions could not be predicted. Patients with liver-related readmissions consistently had index-stay nosocomial infections as a predictor for HE, renal/metabolic and infection-associated readmissions (OR 1.9-3.0). CONCLUSIONS: Three-month readmissions occurred in about half of discharged cirrhotics, which were associated with cirrhosis severity, diabetes and nosocomial infections. Close monitoring of advanced cirrhotics and prevention of nosocomial infections could reduce this burden.


Posted January 27th 2016

Variations in albumin use in patients with cirrhosis: An AASLD members survey.

Jacqueline O'Leary M.D.

Jacqueline O’Leary, M.D.

Bajaj, J. S., J. G. O’Leary, F. Wong and P. S. Kamath (2015). “Variations in albumin use in patients with cirrhosis: An AASLD members survey.” Hepatology 62(6): 1923-1924.

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The quantitative and qualitative impacts of hypoalbuminemia are critically important in patients with cirrhosis.1 Therefore, to evaluate the practice patterns regarding ascites management and albumin use, a brief electronic survey was sent to 757 US-based clinical American Association for the Study of Liver Diseases (AASLD) members, which resulted in a 30% (n = 225) response rate: 77% were hepatologists at transplant centers, 13% were hepatologists at nontransplant centers, and 10% were gastroenterologists. The majority (82%) were in academic centers, followed by community hospitals (13%) and Veterans Affairs hospitals (8%). Most respondents saw six to 25 (27%), 26-75 (37%), and >75 (33%) patients with cirrhosis/month. Approximately half of the respondents had more than seven patients requiring paracentesis/month, while 33% had three to six patients/month requiring paracentesis. Interestingly, interventional radiology performed the majority of paracenteses in outpatients (56%) and slightly fewer in inpatients (45%). Most practitioners (72%) were satisfied with the paracentesis done outside their supervision. (Excerpt from text.)


Posted January 27th 2016

Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancerdagger.

Joyce O'Shaughnessy M.D.
Joyce O’Shaughnessy, M.D.

O’Shaughnessy, J., M. Campone, E. Brain, P. Neven, D. Hayes, I. Bondarenko, T. W. Griffin, J. Martin, P. De Porre, T. Kheoh, M. K. Yu, W. Peng and S. Johnston (2016). “Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancerdagger.” Annals of Oncology 27(1): 106-113.

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BACKGROUND: Androgen receptor (AR) signaling and incomplete inhibition of estrogen signaling may contribute to metastatic breast cancer (MBC) resistance to a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole). We assessed whether combined inhibition of androgen biosynthesis with abiraterone acetate plus prednisone and estradiol synthesis with exemestane (E) may be of clinical benefit to postmenopausal patients with NSAI-pretreated estrogen receptor-positive (ER+) MBC. PATIENTS AND METHODS: Patients (N = 297) were stratified by the number of prior therapies for metastatic disease (0-1 versus 2) and by prior NSAI use (adjuvant versus metastatic), and randomized (1 : 1 : 1) to receive oral once daily 1000 mg abiraterone acetate plus 5 mg prednisone (AA) versus AA with 25 mg E (AAE) versus 25 mg E alone (E). Each treatment arm was well balanced with regard to the proportion of patients with AR-positive breast cancer. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, clinical benefit rate, duration of response, and overall response rate. RESULTS: There was no significant difference in PFS with AA versus E (3.7 versus 3.7 months; hazard ratio [HR] = 1.1; 95% confidence interval [CI] 0.82-1.60; P = 0.437) or AAE versus E (4.5 versus 3.7 months; HR = 0.96; 95% CI 0.70-1.32; P = 0.794). Increased serum progesterone concentrations were observed in both arms receiving AA, but not with E. Grade 3 or 4 treatment-emergent adverse events associated with AA, including hypokalemia and hypertension, were less common in patients in the E (2.0% and 2.9%, respectively) and AA arms (3.4% and 1.1%, respectively) than in the AAE arm (5.8% for both). CONCLUSIONS: Adding AA to E in NSAI-pretreated ER+ MBC patients did not improve PFS compared with treatment with E. An AA-induced progesterone increase may have contributed to this lack of clinical activity. CLINICALTRIALSGOV: NCT01381874.


Posted January 27th 2016

Predictive Biomarker Profiling of > 6000 Breast Cancer Patients Shows Heterogeneity in TNBC, With Treatment Implications.E

Joyce O'Shaughnessy M.D.

Joyce O’Shaughnessy, M.D.

Millis, S. Z., Z. Gatalica, J. Winkler, S. Vranic, J. Kimbrough, S. Reddy and J. A. O’Shaughnessy (2015). “Predictive Biomarker Profiling of > 6000 Breast Cancer Patients Shows Heterogeneity in TNBC, With Treatment Implications.” Clinical Breast Cancer 15(6): 473-481.e473.

Full text of this article.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive disease without established targeted treatment options for patients with metastatic disease. This study was undertaken to evaluate potentially actionable biomarkers in a large cohort of TNBC and compare them with non-TNBCs. MATERIALS AND METHODS: We evaluated 6341 (2111 TNBC and 4230 non-TNBC) breast cancer samples at a central laboratory for biomarkers of potential drug response across multiple platforms, including gene sequencing, protein expression, and gene copy number. RESULTS: TNBC expresses androgen receptor (AR) in a significantly (P < .05) lower percentage of cases (17%) than hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-positive breast carcinomas (59% and 79%, respectively), and gene comutations were differentially associated with AR-positive versus AR-negative cases. Higher AR expression levels in TNBC predicted for lower Ki-67 levels. Seventy percent of TNBC harbored a phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), v-akt murine thymoma viral oncogene homolog 1 (AKT1), or phosophatase and tensin homolog (PTEN) aberration. TNBC patients had a significantly lower PIK3CA mutation rate (13%) than all other subtypes (P < .05) and a higher tumor protein p53 (TP53) mutation rate (64%) than the estrogen receptor (ER)-positive cases (approximately 30%; P < .05). Topoisomerase 2 (TOP2A) amplification was observed in 1.3% of TNBC and in 1.6% of HER2-negative, HR-positive cancers; in contrast, HER2-positive, HR-negative or HR-positive cancers exhibited TOP2A amplification in 19% and 40% of cases, respectively (P <.05). CONCLUSION: Multi-platform molecular profiling identifies subgroups of TNBC with different biomarker profiles, suggesting numerous potentially targetable alterations in TNBC. TNBC is further characterized by different gene mutations and proliferative activity relative to AR expression, highlighting a need for comprehensive pathologic examination with potential to develop different, individualized treatment options.