Daniel Gillor

Antibody 10-1074 suppresses viremia in HIV-1-infected individuals

Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection.

Poor outcome of HIV-infected patients with plasmablastic lymphoma: results from the German AIDS-related lymphoma cohort study.

Out of 302 AIDS-related lymphoma (ARL) patients enrolled in the German ARL cohort study, 18 patients had plasmablastic lymphoma (PBL). Twelve out of 18 patients (67%) have died with a median survival of 4 months (range 0–11 months). In univariate analysis, an intermediate or high international prognostic index score was associated with a significantly lower overall survival and progression-free survival. The predominant cause of death was progressive lymphoma (67%). Our data indicate that the outcome of AIDS-related PBL is still very poor.

Treatment of AIDS-related lymphomas: rituximab is beneficial even in severely immunosuppressed patients.

Objective:AIDS-related lymphomas (ARLs) significantly contribute to mortality in HIV-infected patients. Optimal chemotherapy treatment and the use of rituximab remain controversial. The aim of the present cohort study was to analyze the outcome of HIV-infected patients diagnosed with ARL, with regard to the use of rituximab, clinical characteristics and histopathological markers. Methods and design:This observational uncontrolled multicenter cohort study included 163 HIV-infected patients with ARL diagnosed between January 2005 and December 2008 in Germany. Results:Patients with CD20-positive ARL had a significantly better overall survival (OS) and progression-free survival (PFS) than patients with CD20-negative ARL [hazard ratio 0.28, 95% confidence interval (CI) 0.15–0.53 and hazard ratio 0.29, 95% CI 0.16–0.53]. In CD20-positive cases, the use of rituximab was associated with better OS and PFS (n = 128, hazard ratio 0.48, 95% CI 0.25–0.93 and hazard ratio 0.47, 95% CI 0.26–0.86), even in patients with severe immune deficiency at ARL diagnosis (CD4 T-cell count<100 cells/&mgr;l, n = 33; OS: hazard ratio 0.25, 95% CI 0.07–0.90). In multivariate analysis, CD4 T-cell counts more than 100 cells/&mgr;l and the use of rituximab were associated with better OS and PFS. In total, there were 12 polychemotherapy-associated deaths, which were not related to specific therapy regimens or to the use of rituximab. Conclusion:In patients with CD20-positive ARL, CD4 T-cell count at ARL diagnosis and the use of rituximab had strong impact on survival. Rituximab was beneficial in ARL even in the setting of severe immune deficiency and was not associated with an increased risk of fatal infections.

Survival of AIDS-related diffuse large B-cell lymphoma, Burkitt lymphoma, and plasmablastic lymphoma in the German HIV Lymphoma Cohort

Overall survival (OS) of patients with acquired immunodeficiency syndrome (AIDS)‐related Burkitt lymphoma (BL), diffuse large B‐cell lymphoma (DLBCL) and plasmablastic lymphoma (PBL) was analysed in the German AIDS‐related‐Lymphoma‐Cohort‐Study. Of 291 patients prospectively included between January 2005 and December 2012, 154 had DLBCL, 103 BL and 34 PBL. Two‐year OS rates were similar between BL (69%) and DLBCL patients (63%) but lower for PBL patients (43%). Intermediate (Hazard ratio [HR] 4·1 95% confidence interval [CI] 1·98–8·49) or high (HR 4·92 95% CI 2·1–11·61) International Prognostic Index, bone marrow involvement (HR 1·69 95% CI 1·00–2·84) and PBL histology (HR 2·24 95% CI 1·24–4·03) were independent predictors of mortality.

Hodgkin lymphoma is as common as non-Hodgkin lymphoma in HIV-positive patients with sustained viral suppression and limited immune deficiency: a prospective cohort study

The incidence of HIV‐related non‐Hodgkin lymphoma (NHL) but not that of Hodgkin lymphoma (HL) has been declining. The aim of the study was to compare HIV‐infected patients with NHL and HL with respect to antiretroviral therapy (ART) exposure at the time of lymphoma diagnosis.

Aerosolized Ribavirin for Patients With Cancer and Respiratory Syncytial Virus Infection

TO THE EDITOR—In a recent issue of the Journal of Infectious Diseases, Chemaly et al report the results of their randomized clinical trial, which compared an intermittent (ISR) versus a continuous dosing schedule (CSR) of ribavirin in patients with respiratory syncytial virus (RSV) infection and cancer [1]. The premature discontinuation of another randomized study because of slow accrual after 5 years [2] demonstrates the challenges associated with clinical research in this field. Thus, Chemaly et al should be congratulated for successfully accomplishing this difficult trial. The authors claim, as the main result of the study, that ISR was more efficacious than CSR in the prevention of progression from upper respiratory tract to lower respiratory tract RSV infection. Unfortunately, this result is not plausible from a clinical perspective, since daily doses of ribavirin (6 g) were identical in both groups, and tolerability and safety were also not different. The authors hypothesize that the higher success rate in the ISR arm could be explained by better compliance, but their tolerability and safety findings do not substantiate this explanation: 1 discontinuation occurred in each arm, and no other data supporting their hypothesis are provided. We challenge the authors’ statement regarding the superior efficacy of ISR. The authors have put together an impressive list of patient risk factors: coinfections were more common in the CSR group (P= .03); the rate of graft versus host disease, which is associated with increased immunosuppression, was (not significantly) higher in the CSR group; and the rate of autologous transplantation was (not significantly) higher in the ISR group. Although we cannot claim that bias introduced by these factors influenced the study’s main result, the list of items demonstrates several sources for bias. The randomization process was changed to adapted randomization after enrollment of 10 patients. Estimating a priori probabilities from only 10 treated patients in a highly variable population is prone to bias but critical for all further computations. We challenge the use and value of the a priori and a posteriori probabilities given by the authors in this complicated and highly variable patient cohort. The adaptive randomization process is very sensitive to the characteristics of the first few patients included, and so are all calculations of the accompanying probabilities. No other result from the trial, such as the finding that mortality was the most important end point or that viral shedding was a surrogate marker, supports the authors’ claim. In addition, the crude rates of progression in both groups are not statistically different. Since no completed clinical trial comparing aerosolized ribavirin with placebo is available, it is still not known whether ribavirin in any dosing form is beneficial in this setting. Although the authors argue that published reports on this issue indicate some efficacy of ribavirin [3], all informationrelies on noncontrolled studies with varying methodological quality. Others have used oral ribavirin for treatment of RSV infection in adult cancer patients, but again the results are inconclusive [4]. In conclusion, the study by Chemaly et al should not be regarded as proof for the efficacy of aerosolized ribavirin in general or ISR specifically in the treatment of RSV infections in adult cancer patients. Therefore, decisions regarding treatment of RSV infection in these patients should still be made on a case-bycase basis until results of more-rigorous clinical trials are available.

Performance of the inFLUenza Patient-Reported Outcome (FLU-PRO) diary in patients with influenza-like illness (ILI)

Background The inFLUenza Patient Reported Outcome (FLU-PRO) measure is a daily diary assessing signs/symptoms of influenza across six body systems: Nose, Throat, Eyes, Chest/Respiratory, Gastrointestinal, Body/Systemic, developed and tested in adults with influenza. Objectives This study tested the reliability, validity, and responsiveness of FLU-PRO scores in adults with influenza-like illness (ILI). Methods Data from the prospective, observational study used to develop and test the FLU-PRO in influenza virus positive patients were analyzed. Adults (≥18 years) presenting with influenza symptoms in outpatient settings in the US, UK, Mexico, and South America were enrolled, tested for influenza virus, and asked to complete the 37-item draft FLU-PRO daily for up to 14-days. Analyses were performed on data from patients testing negative. Reliability of the final, 32-item FLU-PRO was estimated using Cronbach’s alpha (α; Day 1) and intraclass correlation coefficients (ICC; 2-day reproducibility). Convergent and known-groups validity were assessed using patient global assessments of influenza severity (PGA). Patient report of return to usual health was used to assess responsiveness (Day 1–7). Results The analytical sample included 220 ILI patients (mean age = 39.3, 64.1% female, 88.6% white). Sixty-one (28%) were hospitalized at some point in their illness. Internal consistency reliability (α) of FLU-PRO Total score was 0.90 and ranged from 0.72–0.86 for domain scores. Reproducibility (Day 1–2) was 0.64 for Total, ranging from 0.46–0.78 for domain scores. Day 1 FLU-PRO scores correlated (≥0.30) with the PGA (except Gastrointestinal) and were significantly different across PGA severity groups (Total: F = 81.7, p<0.001; subscales: F = 6.9–62.2; p<0.01). Mean score improvements Day 1–7 were significantly greater in patients reporting return to usual health compared with those who did not (p<0.05, Total and subscales, except Gastrointestinal and Eyes). Conclusions Results suggest FLU-PRO scores are reliable, valid, and responsive in adults with influenza-like illness.

Reliability, Validity, and Responsiveness of InFLUenza Patient-Reported Outcome (FLU-PRO©) Scores in Influenza-Positive Patients

OBJECTIVES To assess the reliability, validity, and responsiveness of InFLUenza Patient-Reported Outcome (FLU-PRO©) scores for quantifying the presence and severity of influenza symptoms. METHODS An observational prospective cohort study of adults (≥18 years) with influenza-like illness in the United States, the United Kingdom, Mexico, and South America was conducted. Participants completed the 37-item draft FLU-PRO daily for up to 14 days. Item-level and factor analyses were used to remove items and determine factor structure. Reliability of the final tool was estimated using Cronbach α and intraclass correlation coefficients (2-day reliability). Convergent and known-groups validity and responsiveness were assessed using global assessments of influenza severity and return to usual health. RESULTS Of the 536 patients enrolled, 221 influenza-positive subjects comprised the analytical sample. The mean age of the patients was 40.7 years, 60.2% were women, and 59.7% were white. The final 32-item measure has six factors/domains (nose, throat, eyes, chest/respiratory, gastrointestinal, and body/systemic), with a higher order factor representing symptom severity overall (comparative fit index = 0.92; root mean square error of approximation = 0.06). Cronbach α was high (total = 0.92; domain range = 0.71-0.87); test-retest reliability (intraclass correlation coefficient, day 1-day 2) was 0.83 for total scores and 0.57 to 0.79 for domains. Day 1 FLU-PRO domain and total scores were moderately to highly correlated (≥0.30) with Patient Global Rating of Flu Severity (except nose and throat). Consistent with known-groups validity, scores differentiated severity groups on the basis of global rating (total: F = 57.2, P < 0.001; domains: F = 8.9-67.5, P < 0.001). Subjects reporting return to usual health showed significantly greater (P < 0.05) FLU-PRO score improvement by day 7 than did those who did not, suggesting score responsiveness. CONCLUSIONS Results suggest that FLU-PRO scores are reliable, valid, and responsive to change in influenza-positive adults.

Incidence and risk factors for relapses in HIV-associated non-Hodgkin lymphoma as observed in the German HIV-related lymphoma cohort study

Outcome of HIV-infected patients with AIDS-related lymphomas has improved during recent years. However, data on incidence, risk factors, and outcome of relapses in AIDS-related lymphomas after achieving complete remission are still limited. This prospective observational multicenter study includes HIV-infected patients with biopsy- or cytology-proven malignant lymphomas since 2005. Data on HIV infection and lymphoma characteristics, treatment and outcome were recorded. For this analysis, AIDS-related lymphomas patients in complete remission were analyzed in terms of their relapse- free survival and potential risk factors for relapses. In total, 254 of 399 (63.7%) patients with AIDS-related lymphomas reached a complete remission with their first-line chemotherapy. After a median follow up of 4.6 years, 5-year overall survival of the 254 patients was 87.8% (Standard Error 3.1%). Twenty-nine patients relapsed (11.4%). Several factors were independently associated with a higher relapse rate, including an unclassifiable histology, a stage III or IV according to the Ann Arbor Staging System, no concomitant combined antiretroviral therapy during chemotherapy and R-CHOP-based compared to more intensive chemotherapy regimens in Burkitt lymphomas. In conclusion, complete remission and relapse rates observed in our study are similar to those reported in HIV-negative non-Hodgkin lymphomas. These data provide further evidence for the use of concomitant combined antiretroviral therapy during chemotherapy and a benefit from more intensive chemotherapy regimens in Burkitt lymphomas. Modifications to the chemotherapy regimen appear to have only a limited impact on relapse rate.