Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies.

INTRODUCTION: This pooled analysis of nine phase I and II trastuzumab deruxtecan (T-DXd) monotherapy studies described drug-related interstitial lung disease (ILD)/pneumonitis in patients treated with T-DXd. METHODS: Patients who received T-DXd across nine studies were included. Investigator-assessed ILD/pneumonitis events were retrospectively reviewed by an independent adjudication committee; events adjudicated as drug-related ILD/pneumonitis are summarized. RESULTS: The analysis included 1150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%; other cancer, 3.0%). Median treatment duration was 5.8 (range, 0.7-56.3) months, with a median of 4 (range, 1-27) prior lines of therapy. The overall incidence of adjudicated drug-related ILD/pneumonitis was 15.4% (grade 5, 2.2%). Most patients with ILD/pneumonitis experienced low-grade events (grade 1 or 2, 77.4%); 87.0% had their first event within 12 months [median, 5.4 (range, <0.1-46.8) months] of their first dose of T-DXd. Based on data review, adjudicated ILD/pneumonitis onset occurred earlier than identified by investigators for 53.2% of events [median difference in onset date, 43 (range, 1-499) days]. Stepwise Cox regression identified several baseline factors potentially associated with increased risk of adjudicated drug-related ILD/pneumonitis: age <65 years, enrollment in Japan, T-DXd dose >6.4 mg/kg, oxygen saturation <95%, moderate/severe renal impairment, presence of lung comorbidities, and time since initial diagnosis >4 years. CONCLUSIONS: In this pooled analysis of heavily treated patients, the incidence of ILD/pneumonitis was 15.4%, with most being low grade and occurring in the first 12 months of treatment. The benefit-risk of T-DXd treatment is positive; however, some patients may be at increased risk of developing ILD/pneumonitis, and further investigation is needed to confirm ILD/pneumonitis risk factors. Close monitoring and proactive management of ILD/pneumonitis are warranted for all.

Gene expression analysis in serial liver fine needle aspirates.

No method with low morbidity presently exists for obtaining serial hepatic gene expression measurements in humans. While hepatic fine needle aspiration (FNA) has lower morbidity than core needle biopsy, applicability is limited due to blood contamination, which confounds quantification of gene expression changes. The aim of this study was to validate FNA for assessment of hepatic gene expression. Liver needle biopsies and FNA procedures were simultaneously performed on 17 patients with chronic hepatitis C virus infection with an additional FNA procedure 1 week later. Nine patients had mild/moderate fibrosis and eight advanced fibrosis. Gene expression profiling was performed using Affymetrix microarrays and TaqMan qPCR; pathway analysis was performed using Ingenuity. We developed a novel strategy that applies liver-enriched normalization genes to determine the percentage of liver in the FNA sample, which enables accurate gene expression measurements overcoming biases derived from blood contamination. We obtained almost identical gene expression results (ρ = 0.99, P < 0.0001) comparing needle biopsy and FNA samples for 21 preselected genes. Gene expression results were also validated in dogs. These data suggest that liver FNA is a reliable method for serial hepatic tissue sampling with potential utility for a variety of preclinical and clinical applications.

Genomic variability associated with the presence of occult hepatitis B virus in HIV co-infected individuals.

Occult hepatitis B virus (O-HBV) infection is characterized by the presence of HBV DNA without detectable hepatitis B surface antigen (HBV DNA+/HBsAg-) in the serum. Although O-HBV is more prevalent during HBV/HIV co-infection, analysis of HBV mutations in co-infected patients is limited. In this preliminary study, HBV PreSurface (PreS) and surface (S) regions were amplified from 33 HIV-positive patient serum samples - 27 chronic HBV (C-HBV) and six O-HBV infections. HBV genotype was determined by phylogenetic analysis, while quasispecies diversity was quantified for the PreS, S and overlapping polymerase regions. C-HBV infections harboured genotypes A, D and G, compared to A, E, G and one mixed A/G infection for O-HBV. Interestingly, nonsynonymous-synonymous mutation values indicated positive immune selection in three regions for O-HBV vs one for C-HBV. Sequence analysis further identified new O-HBV mutations, in addition to several previously reported mutations within the HBsAg antigenic determinant. Several of these O-HBV mutations likely contribute to the lack of detectable HBsAg in O-HBV infection by interfering with detection in serologic assays, altering antigen secretion and/or decreasing replicative fitness.

Characterization of hepatitis E-specific cell-mediated immune response using IFN-gamma ELISPOT assay.

In developing countries, hepatitis E (HEV) and hepatitis A (HAV) are the major causes of acute viral hepatitis with similar feco-oral modes of transmission. In contrast to the high seroprevalence of hepatitis A infection, a low seroprevalence of HEV among children in endemic areas has been reported. These data suggest the possibility that silent HEV infection is undiagnosed by the current available methods. Many of the serological tests used for HEV diagnosis have poor specificity and are unable to differentiate among different genotypes of HEV. Moreover, the RT-PCR used for HEV isolation is only valid for a brief period during the acute stage of infection. Cell-mediated immune (CMI) responses are highly sensitive, and long lasting after sub-clinical infections as shown in HCV and HIV. Our objective was to develop a quantitative assay for cell-mediated immune (CMI) responses in HEV infection as a surrogate marker for HEV exposure in silent infection. Quantitative assessment of the CMI responses in HEV will also help us to evaluate the role of CMI in HEV morbidity. In this study, an HEV-specific interferon-gamma (IFN-gamma) ELISPOT assay was optimized to analyze HEV-specific CMI responses. We used peripheral blood mononuclear cells (PBMC) and sera from experimentally infected chimpanzees and from seroconverted and control human subjects to validate the assay. The HEV-specific IFN-gamma ELISPOT responses correlated strongly and significantly with anti-HEV ELISA positive/negative results (rho=0.73, p=0.02). Moreover, fine specificities of HEV-specific T cell responses could be identified using overlapping HEV ORF2 peptides.

Response rates to pegylated interferon and ribavirin in HCV/HIV coinfection: a research synthesis.

Several recent trials have determined varying rates of response to pegylated interferon plus ribavirin (peg-IFN + RIB) in hepatitis C virus (HCV)/human immunodeficiency virus-coinfected patients. We sought to identify a pooled response rate and sources of interstudy variability. A literature search was conducted to identify randomized or prospective studies evaluating response rates to peg-IFN + RIB in coinfected patients. A Bayesian hierarchical model was used to estimate overall response rate. Between-study variance was calculated and sensitivity analyses were conducted. Meta-regression was employed to identify sources of between-study variability. The literature search yielded seven studies of 146, which matched keywords and inclusion criteria. The combined patient total was 784. Individual intention-to-treat response rates ranged from 27.3% to 44.2%. The pooled Bayesian estimate of percent response was 33.3%. Significant interstudy heterogeneity was detected. Meta-regression yielded no significant effects of covariates on response rate. Subanalyses by CD4+, HCV viral load and genotype yielded sustained virological response (SVR) odds ratios of 0.73 for low CD4+, 0.41 for high viral load and 0.30 for genotype 1/4. The pooled response rate is not attributable to any one study. Response is poor compared with HCV-monoinfected patients. Interstudy variability is not satisfactorily explained by factors influencing individual response, but may be due to differences between studies unavailable for inclusion in this analysis. However, both genotype 1/4 and high HCV viral load at baseline were significantly associated with a reduction in odds of SVR in pooled subanalysis. Improved treatments are needed in coinfected patients, especially with genotype 1/4 and high viral load.

Human immunodeficiency virus-infected patients with prior Pneumocystis pneumonia exhibit increased serologic reactivity to several major surface glycoprotein clones.

Recombinant clones of the carboxyl terminus of the major surface glycoprotein (MsgC) of Pneumocystis jirovecii are useful for analyzing serologic responses in humans. However, there is no standardized set of antigens in general use, which could lead to conflicting results. We have previously shown that human immunodeficiency virus type 1 (HIV-1)-infected patients with prior Pneumocystis pneumonia (PcP+) responded more frequently and more strongly to a clone of MsgC than did HIV-1-infected patients without PcP (PcP-). Here we test three new clones of MsgC to determine the effect of antigenic sequence variation on immune reactivity in blood donors and HIV-infected patients previously analyzed for reactivity to our original MsgC clone. In Western blot analyses, PcP+ patients exhibited the highest frequency of reactivity to each MsgC clone, and the frequency of reactivity with all four MsgC clones together was significantly higher in sera from PcP+ patients than in sera from the other patient groups. Furthermore, in an enzyme-linked immunosorbent assay we found that the PcP+ population had the highest level of reactivity to two of the four clones tested. One of the new clones could distinguish between PcP+ and PcP- populations, and two MsgC clones could distinguish blood donors from the other patient populations. The results show that inherent differences in MsgC amino acid sequence can affect recognition by antibodies independently of variations in protein length or patient population, and the utility of a clone depends on its sequence and on the populations tested.

Management of hepatitis B virus in HIV-positive patients.

High rates of coinfection with human immunodeficiency virus-1 (HIV) and the hepatitis B virus (HBV) are commonly found in at risk populations due to their shared parenteral route of transmission. Although the increasingly widespread use of highly active antiretroviral therapy (HAART) has prolonged survival for those with HIV, it has also increased the potential for morbidity and mortality from other diseases and opportunistic infections. Liver-related illness is a leading cause of morbidity and mortality in those infected with HIV and HBV is responsible for a vast proportion of this, especially in regions of high HBV prevalence. HIV/HBV coinfected patients may exhibit atypical serological markers of HBV infection, hindering appropriate diagnosis. They may experience faster progression to cirrhosis, decompensation, and hepatocellular carcinoma than HBV-monoinfected patients. Rates of response to vaccine against HBV are abrogated in those with HIV, facilitating the spread of the virus. Treatment of HBV must be monitored for resistance, although newer agents appear to have less risk of resistance development. Moreover, treatment of HIV with antivirals must be monitored closely for liver toxicity. Because liver damage with HBV occurs via the immune response to the virus, liver damage is possible with HAART-mediated immune reconstitution. Although liver transplant is not commonly undertaken in HIV-positive patients, centers undertaking transplantation report improved survival and low rates of HBV recurrence.

The importance of clinical parameters when differentiating cholestatic hepatitis C virus from allograft rejection.

BACKGROUND: The exact cause and appropriate treatment for cholestasis following liver transplantation in recipients with hepatitis C virus recurrence (RHCV) are difficult to determine. Our objective was to determine the diagnostic accuracy of clinical and histological parameters in liver transplant recipients with RHCV and concurrent cholestasis. METHODS: A retrospective analysis from June 1996 to May 2003 was performed on adult liver transplant (OLT) recipients with hepatitis C virus. Patients with cholestasis (bilirubin >5 mg/dL, 6 months after OLT) were selected. Demographics, etiology, immune suppression, clinical and histologic outcomes, and virologic features were evaluated. Patients were divided into two groups based on clinical and histological criteria: (1) patients with parameters suggestive of cholestatic HCV; and (2) patients with parameters consistent with acute cellular rejection. RESULTS: Thirty-seven patients met study criteria (20 males). The average age was 54 years (range = 14-72), and time from transplant to jaundice was 769 days (range = 48-2981). The groups were comparable regarding HCV viral load, age, gender, time from transplant, and United Network of Organ Sharing status at time of transplant. Retransplantation was performed in two patients in group 1, neither of whom survived, and in three patients in group 2, all of whom survived. Clinical parameters correlated well with diagnosis of cholestasis (r = 0.85, P < .001) whereas histological evaluation did not (r = 0.11, P = .53). Mortality in group 1 was 78% (7 of 9) vs. 50% (13 of 26) in group 2. Median duration of survival following liver transplantation in group 1 was 132 days versus 435 days in group 2. CONCLUSION: Clinical diagnosis parameters for RHCV with cholestasis appear more accurate than histology parameters and should be the primary consideration in directing therapy. Despite timely diagnosis, cholestatic RHCV LTx recipients have a poor prognosis.

The long-term effects of immune suppression on liver transplant recipients with recurrent hepatitis C viral infection.

INTRODUCTION: Adequate immune suppression following liver transplantation in recipients with recurrence of hepatitis C virus (HCV) is not standardized. The aim of this study was to evaluate the association between immune suppression protocol and the clinical/histological parameters in HCV transplant recipients with an HCV recurrence. METHODS: A retrospective analysis was performed on recipients of liver transplants from June 1998 to October 2003 who experienced HCV recurrence. Only patients with liver biopsies at 3 to 5 years following liver transplantation were included in the analysis. The data set included: patient demographics, immune suppression, antiviral therapies, as well as histology to evaluate ductopenia and chronic rejection. Patients divided into groups of high, medium, and low immune suppression were subdivided by treatment with versus without interferon. A control group with similar demographics suffering from cryptogenic cirrhosis was used for comparison. RESULTS: During this period 45 patients had liver biopsies at 3 to 5 years posttransplantation. Their mean age was 56.5 years and mean time from transplant to biopsy was 1543 days. Their average posttransplant survival was 1964 days. There was no difference among the three groups with respect to HCV RNA levels (log(10) IU/mL), age, gender, time from transplant, donor age, and UNOS status. Median HCV RNA levels within the three groups were comparable at various time periods pre- and posttransplant. CONCLUSION: The development of chronic allograft damage following transplantation in recipients with recurrent HCV tended to be worse among patients with low levels of immune suppression, suggesting the importance of therapy to maintain allograft function.

Topical testosterone treatment for chronic allograft failure in liver transplant recipients with recurrent hepatitis C virus.

INTRODUCTION: Liver transplant recipients with allograft failure due to recurrent hepatitis C virus (HCV) infection often develop marked muscle wasting and ascites prior to death and are denied repeat liver transplantation. We sought to determine whether topical testosterone therapy is associated with improved muscle mass and survival in patients with chronic allograft failure post-liver transplant. METHODS: We performed a retrospective review of liver transplant recipients with chronic allograft failure. Group 1 patients were treated for >6 months with testosterone gel 1%; group 2 patients were untreated. RESULTS: Fourteen patients were identified with stage 3 or 4 fibrosis, muscle wasting, and allograft failure due to recurrent HCV. Group 1 (n=9) patients had statistically significant improvement in albumin, testosterone, muscle strength, well-being, and MELD/CTP scores, while there was no improvement seen for any of these parameters in group 2 (n=5). There were no deaths in group 1, while four of five patients in group 2 died on average 84 days posttransplant. Adverse effects of testosterone treatment included lower extremity edema (which resolved upon dose adjustment), hypertension, and pruritus. CONCLUSIONS: Topical testosterone gel appears to increase muscle strength, stimulate albumin synthesis, and improve survival in patients with allograft failure post-liver transplant.