A 4-days-on and 3-days-off maintenance treatment strategy for adults with HIV-1 (ANRS 170 QUATUOR): a randomised, open-label, multicentre, parallel, non-inferiority trial.

BACKGROUND: Intermittent (on 4 days per week) antiretroviral therapy (ART) for patients with HIV-1 might be more convenient, better tolerated, and cheaper than continuous treatment. We aimed to establish the efficacy and safety of a 4-days-on and 3-days-off (intermittent) maintenance regimen versus a standard 7 day (continuous) maintenance regimen. METHODS: In a randomised, open-label, multicentre, parallel, non-inferiority trial, we randomly assigned (1:1) adults with HIV-1 infection with a plasma viral load (pVL) of less than 50 copies per mL for more than 12 months and no drug-resistance mutations to either the intermittent regimen or their existing continuous maintenance regimen, with stratification according to third therapeutic agent (protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or integrase-strand transfer inhibitor). Participants were recruited from 59 hospitals throughout France. The main exclusion criteria were CD4 cell count lower than 250 cells per µL and chronic hepatitis B virus infection. The primary endpoint was the proportion of participants in the modified intention-to-treat (mITT) population who started the study strategy presenting treatment success at week 48 (pVL <50 copies per mL without strategy modification), estimated using the US Federal Drug Administration snapshot approach, with a 5% non-inferiority margin. The study was registered with ClinicalTrials.gov (NCT03256422) and EudraCT (2017-000040-17). The trial is now closed. FINDINGS: From Sept 7, 2017, to Jan 22, 2018, 850 potential participants were screened for eligibility. 647 participants were enrolled and randomly assigned (1:1) to either the intermittent or the continuous treatment group. The mITT population included 636 participants (318 per group). At week 48, in the mITT population, treatment success was recorded in 304 (96%) of 318 participants in the intermittent treatment group and 308 (97%) of 318 in the continuous treatment group (adjusted difference -1·3%, 95% CI -4·2 to 1·7). Six (2%) participants in the intermittent treatment group and four (1%) participants in the continuous treatment group had virological failure. Grade 3-4 adverse events were reported in 29 (9%) participants in the intermittent treatment group and 39 (12%) participants in the continuous treatment group (p=0·320). Daily life satisfaction improved in 153 (59%) of 258 participants in the intermittent treatment group versus 19 (7%) of 255 in the continuous treatment group (p<0·0001). ART costs were 43% lower in the intermittent treatment group than in the continuous treatment group (p<0·0001). INTERPRETATION: These findings show the non-inferiority of the treatment strategy of 4-consecutive-days-on and 3-days-off strategy maintenance regimen relative to standard continuous ART triple therapy over 48 weeks. 4 days on and off treatment represents a workable, effective alternative strategy for patients with high adherence to ART, and using a drug combination with a high genetic barrier to resistance. FUNDING: Institut National de la Santé et de la Recherche Médicale Agence Nationale de Recherche sur le Sida et les Hépatites Virales, Maladies Infectieuses Emergentes.

Very low utility of surveillance imaging in early-stage classic Hodgkin lymphoma treated with a combination of doxorubicin, bleomycin, vinblastine, and dacarbazine and radiation therapy.

BACKGROUND: This study evaluated the need for surveillance imaging in early-stage classic Hodgkin lymphoma (cHL) after planned combined-modality therapy (CMT). METHODS: Primary early-stage cHL patients who underwent CMT were included. Positron emission tomography (PET)/computed tomography (CT), CT, or both were performed at the initial staging, during or after chemotherapy, and for at least 2 years during follow-up. Imaging studies and medical records were reviewed to determine if and when relapse had occurred. Radiation doses and costs were also calculated from follow-up imaging. RESULTS: The study included 78 patients with a median follow-up of 46 months; 85% of the patients had stage II disease (32% with bulky disease). Four of 77 interim PET scans were positive; none of these patients relapsed during follow-up, which ranged from 24 to 80 months. After a total of 466 follow-up imaging studies (91% with CT and 9% with PET/CT), no cHL relapse was detected. Eleven abnormal findings were noted on surveillance imaging: 9 were false-positives, and 2 were second primary malignancies. The average cumulative dose per patient from follow-up imaging was 107 mSv, which translated into an estimated lifetime excess cancer risk of 0.5%; the estimated total costs were $296,817 according to Medicare reimbursements. CONCLUSIONS: Surveillance imaging with either CT or PET/CT can be omitted safely for early-stage cHL treated with a combination of doxorubicin, bleomycin, vinblastine, and dacarbazine and radiation therapy because the risk of relapse is extremely low. This observation also applies to patients with bulky disease. The elimination of surveillance imaging will also reduce healthcare expenses and cumulative radiation doses in these predominantly young patients.

The tyrosine kinase inhibitor Dasatinib blocks in-vitro HIV-1 production by primary CD4+ T cells from HIV-1 infected patients.

HIV reservoirs persistence despite antiretroviral therapy (ART) might be related to persistent immune activation and residual HIV production, requiring further therapeutic strategies. We demonstrated that the tyrosine kinase inhibitor (TKI) Dasatinib, used for chronic myeloid leukaemia, significantly blocks in vitro HIV1 production by 3.4 logs in HIV1-infected primary CD4 T lymphocytes, by inhibiting cell activation and proliferation, without cell toxicity. This molecule deserves to be investigated further for HIV cure strategies to hinder persistent immune activation and residual viral production.

Improving out-of-hours intravenous fluid prescribing for junior doctors: a prescription label.

Junior doctors are routinely asked to prescribe intravenous fluids (IVF) out-of-hours. Given time constraints and the number of unfamiliar patients, there is uncertainty about their prescription accuracy and safety, particularly in patients who have specific fluid balance requirements. An IVF prescription label was devised for the fluids section of the adult drug chart indicating important patient identifiers and diagnoses such as chronic heart/renal failure. The audit was carried out over a 16 day period, covering three weekends. A qualitative pre- and post-audit questionnaire assessed the confidence of junior doctors in out-of-hours IVF prescribing. All doctors based on the ward during that specific time period were targeted for the post-audit questionnaire. Post-audit, 58% (n=7) saw the label. 86% of those seven doctors stated the label had prompted them to do the following: a) examine the patient b) check blood results and c) urine output. 100% stated that the label improved their confidence in prescribing IVF. In addition, 71% felt the label made them more cautious in prescribing IVF and 43% felt they prescribed less. Overall, all seven (100%) doctors stated that the IVF prescription label was a useful addition to the drug chart. In conclusion, pressurised junior doctors would feel more confident prescribing IVF for unfamiliar patients if crucial information was readily visible on the drug chart. This would improve the accuracy of fluid prescribing and patient safety.

ABVD alone and a PET scan complete remission negates the need for radiologic surveillance in early-stage, nonbulky Hodgkin lymphoma.

BACKGROUND: Patients with early-stage, nonbulky classic Hodgkin lymphoma (cHL) undergo intensive posttreatment radiologic surveillance despite having a low risk of disease recurrence. The current study attempted to evaluate the risk of disease recurrence and the value of radiologic surveillance in patients treated with the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone who achieved a complete remission (CR) as noted on posttreatment positron emission tomography (PET). METHODS: Forty-seven patients who underwent therapy with interim and/or posttreatment PET scans were evaluated for disease recurrence during ≥ 24 months of follow-up. Their presenting characteristics and imaging results were assessed and interpreted in relation to clinical outcome. RESULTS: All 47 patients were eligible for analysis. The majority of patients were female (35 patients) with a median age of 28 years (range, 17 years-65 years.). The nodular sclerosing subtype was the predominant histology (41 patients). A total of 34 patients were staged with IIA disease, 6 with IA disease, 6 with IIB disease, and 1 with IIEA disease (lung) (according to Cotswolds modification of the Ann Arbor staging system). All patients completed 6 cycles of planned ABVD therapy and achieved a CR. Two had a positive PET scan (1 interim scan and 1 posttreatment scan); both were biopsy-proven sarcoidosis. Two patients developed disease recurrence at 7 months and 24 months, respectively, after negative interim and posttreatment imaging. One case of recurrence was identified through surveillance imaging and the other was identified simultaneously by the patient and surveillance scan. A total of 45 patients experienced a durable CR; 21 had additional unscheduled imaging/workup during surveillance to investigate symptoms or imaging signs of concern. CONCLUSIONS: Because of a low risk of disease recurrence, posttreatment radiologic surveillance appears to be unnecessary in patients with early-stage, nonbulky (CD20 negative) cHL who achieve a PET-detected CR with the ABVD combination alone. This will reduce cumulative radiation exposure and health care costs in a predominantly young patient population.

E138K and M184I mutations in HIV-1 reverse transcriptase coemerge as a result of APOBEC3 editing in the absence of drug exposure.

BACKGROUND: Recent clinical trials with rilpivirine combined with emtricitabine and tenofovir revealed that patients failing treatment, frequently, harbored viruses encoding resistance-associated mutations in the HIV-1 reverse transcriptase at position E138K and M184I. We show here that APOBEC3 proteins play a role in the emergence of these drug resistance mutations. METHODS: We used a Vif mutant that has suboptimal activity against APOBEC3 to assess the in-vitro frequency of APOBEC3-induced resistance mutations in reverse transcriptase. To assess the degree of in-vivo G-to-A viral hypermutation, a large amount of data of HIV-1 RT proviral sequences from peripheral blood mononuclear cells (PBMCs) recovered from infected patients under HAART was analyzed. RESULTS: In-vitro replication experiments in cell lines with and without APOBEC3 expression suggest that APOBEC3-driven mutagenesis contributes to the generation of both M184I and E138K within HIV proviral repository in the absence of drug exposure. Additionally, analysis of 601 patients PBMCs sequences revealed that the copresence of mutations E138K and M184I were never detected in nonhypermutated sequences, whereas these mutations were found at a high frequency (24%) in the context of APOBEC3 editing and in the absence of exposure to etravirine-rilpivirine. CONCLUSION: We demonstrate using in-vitro experiments and analyzing patients PBMCs sequences that M184I and E138K resistance-associated mutations may pre-exist in proviral reservoir at a high frequency prior to drug exposure, as a result of APOBEC3 editing. Thus, incomplete neutralization of one or more APOBEC3 proteins may favor viral escape to rilpivirine-emtricitabine.

Hepatitis C and non-Hodgkin lymphoma: the clinical perspective.

Hepatitis C virus (HCV) is a commonly transmitted infection that has both hepatic and extrahepatic repercussions. These range from the inflammatory to the oncologic with an undisputed link to hepatitis, liver cirrhosis, and hepatocellular carcinoma. Its role in the development of B cell non-Hodgkin lymphoma (B-NHL) is becoming better understood, leading to opportunities for research, therapy, and even prevention. Research in the field has progressed significantly over the last decade, with the number of patients diagnosed with HCV and B-NHL rising incrementally. It is therefore becoming crucial to fully understand the pathobiologic link of HCV in B cell lymphomagenesis and its optimal management in the oncologic setting.

Humidified high-flow nasal oxygen utilization in patients with cancer at Memorial Sloan-Kettering Cancer Center.

BACKGROUND: Respiratory signs and symptoms are commonly encountered by physicians who care for cancer patients. Supplemental oxygen (SOx) has long been used for treatment of hypoxic respiratory insufficiency, but data reveal mixed efficacy results. The use and outcome patterns of technologically advanced oxygen delivery devices, such as humidified high-flow nasal oxygen (HHFNOx), are incompletely understood. METHODS: Institutional database search of the number of patient cases in which the current HHFNOx device was used, and abstraction of 183 patient medical records for usage characteristics. RESULTS: Patients have been treated with HHFNOx at Memorial Sloan Kettering Cancer Center (MSKCC) since 2008. Of the 183 patients randomly selected for our study, 72% received HHFNOx in the intensive care unit (ICU) because of hypoxia. Patients usually improved (41%) or remained stable (44%) while on the device, whereas 15% declined. At study completion, 45% of patients were living, and 55% had died. The median time on HHFNOx was 3 days (range: 1-27). A do not resuscitate (DNR) order was present in 101 (55%) patients, either before (12%) or after (43%) device utilization. The majority (78%) of these 101 patients died at MSKCC. CONCLUSION: Dyspnea is a common and important symptom in cancer patients for which SOx traditionally has had no clear basis except in select cases of hypoxia and patient preference. Our institutional experience with HHFNOx contributes to the understanding of the applications and challenges surrounding the use of new medical devices in the cancer population. Physiologic and quality-of-life benefits of HHFNOx compared with traditional oxygen delivery methods should be studied prospectively.

HIV-1 X4/R5 co-receptor in viral reservoir during suppressive HAART.

As immune recovery during HAART is mainly caused by the expansion of X4-naive cells, we studied the evolution of HIV tropism in the reservoir of 34 patients receiving 48 weeks of HAART. No change in virus tropism was observed over time, but patients with X4 viruses had higher HIV-1 proviral DNA levels than patients with R5 viruses. This suggests that CCR5 antagonist activity should not be compromised in patients harbouring R5 viruses before starting HAART.