Eric Billaud

Phase II Trial of CHOP Plus Rituximab in Patients With HIV-Associated Non-Hodgkin's Lymphoma

PURPOSE To evaluate the safety and efficacy of rituximab adjunction to the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen in patients with newly diagnosed AIDS-related non-Hodgkins lymphoma. PATIENTS AND METHODS HIV-seropositive patients with high-grade lymphoma of B-cell origin were eligible if they had no more than one of the following characteristics: CD4 cell count less than 100/microL, prior AIDS, or performance status less than 2. This multicenter phase II trial evaluated the response rate and disease-free survival after six courses of rituximab plus CHOP. Results Sixty-one patients were enrolled. All the patients were assessable for safety and 52 were assessable for the tumor response after treatment completion. Characteristics of patients were median age, 41 years; median CD4 cells, 172/microL; histology, diffuse large B-cell lymphoma (n = 42), immunoblastic (n = 2), Burkitt lymphoma (n = 16), and plasmablastic (n = 1); 42 patients with stage III to IV; International Prognostic Index 0 to 1 (n=31), and 2 to 3 (n = 27). Grade 3 or 4 toxicity consisted of febrile neutropenia in nine patients, anemia in 16 patients, and thrombocytopenia in five patients. Complete remission (CR) or unconfirmed CR was achieved in 40 of the 52 assessable patients, partial remission was achieved in five patients, and seven patients experienced progression. Forty-three patients were alive after a median follow-up of 33 months. The estimated 2-year overall survival rate was 75% (95% CI, 64% to 86%). Eighteen patients died: 16 as a result of lymphoma, one as a result of infection, and one as a result of encephalitis. CONCLUSION Rituximab adjunction to CHOP produced a CR rate of 77% and a 2-year survival rate of 75% in patients with AIDS-related non-Hodgkins lymphoma, without increasing the risk of life-threatening infections.

Detection of Microsporidia and Identification of Enterocytozoon bieneusi in Surface Water by Filtration Followed by Specific PCR.

Microsporidiosis due to species from five different genera, Enterocytozoon, Eiiceplialitozoori, Nosema. Vittafoma and Trachipleistophora, has emerged as an opportunistic infection in immunocompromised patients. Up to now, the source of contamination remains unknown, especially for E. bieneusi, the most common species found in humans. As for other parasitic diseases with fecal excretion of infective stages, the presence of parasites in the environment is likely and surface water may represent a possible source of contamination or a vehicle of transmission. We report on the development of a filtration and PCR-based method for detection of microsporidial spores and we demonstrated the presence of E. bieneusi in one sample of surface water from the river Seine. Experimental studies using water spiked with spores obtained from infected stools (E. bieneusi), or tissue cultures inikted with E. cunicrrli, E. hellem and E. intestinalis (kindly provided by E. Canning and T. Van Gool) were performed to assess for efficiency and sensitivity of the filtration and PCR methods. The filtration comprised two sequential steps. The first step consisted in a concentration of the sample. Water was flushed at 4 litershin. through a filtration cartridge wluch retains all particles of more than 1 micron size (Fulflo. M39R10A, Parker Filtration, France) ; then the collected material was eluted from the cartridge into 2 liters of distilled water. In the second step, this eluate was submitted to three sequential filtrations at 200 d m i n . on 180, 60, 11 microns pore-size nylon filters (47 mm of diameter) (Millipore, France) then finally filtered on a 0.4 micron pore-size polycarbonate filter (Millipore). Each filter was examined by PCR and one part of the 0.4 micron filters was examined by light microscopy using Uvitex 2B staining. DNA extraction of the material colIected from the filters was pertormed using guanidine thiocyanate, according to Boom et al. [l], then identification of parasitic DNA was performed by hvo sequential PCR directed against different DNA fragments of the small sirbunit rRNA gene of microsporidia. The first PCR used generic primers designed for detecting human infecting microsporidia [2] for a 35 cycles amplification, then the resulting products were submitted to a second amplification (35 cycles), using primers specific for E. bieneusi [3], E. intestinalis [ 3 ] , E. cuniculi and E. hellem (kindly provided by ARJ Schuitema). The 1265 bp DNA fragments obtained with E. bieneusi specific PCR primers from 4 filters were sequenced (E.S.G.S., Montigny le Bretonneux, France) and analyzed comparatively to previously published sequences of microsporidia (Genbank). For field studies, five 200400 liters samples were collected : one sample of surface water from the river Seine, 15 km down-stream to Paris, three Goni the river Loire, 25 km up-stream to Nantes, and one sample of ground water collected near Paris. Two liters of each sample were directly filtered (without concentration) and the remaining was concentrated then filtered as described above. Experimental studies using spiked distilled water showed that the spores of the different species of microsporidia were retained by the 0.4 micron filter and could be detected by light microscopy and by PCR. When increasing dilutions of spores of E. cuniculi, E. liellem or E. intestinalis were tested, they were no longer detectable by microscopy but generic and specific PCR were positive, allowing the detection of approximatively 1-3 spores in 2 liters of distilled MATERIAL, AND METHODS.

Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors

OBJECTIVE To estimate the change in survival of patients with AIDS-related progressive multifocal leukoencephalopathy (PML), in relation to the introduction of protease inhibitors (PI). DESIGN The French Hospital Database on HIV (FHDH) is a prospective cohort of 70 224 HIV-infected subjects. This study included the patients diagnosed with PML between 1 July 1995 and 30 June 1997. PML diagnosis was both presumptive and confirmed. We compared the survival probability according to the diagnosis period (period 1 or 2, before or after introduction of PI in France on 1 April 1996). Coxs model was used to calculate the relative hazards of death according to the antiretroviral regimen. RESULTS The study included 246 patients, 109 diagnosed during period 1 and 137 during period 2. In all, 131 patients received an antiretroviral combination that included PI. By 31 December 1997, a total of 131 deaths had been reported. The probability of survival at 6 months for patients from period 2 was nearly twice as high as for patients from period 1 (60.5 versus 34.5%). In comparison with patients receiving no treatment, the risk of death in patients on combination therapy not including PI was reduced by 38% [relative hazard (RH) 0.62, 95% confidence interval (CI) (0.41; 0.95), P = 0.026] and in patients on combination therapy with PI, by 63% [RH 0.37, 95% CI (0.22; 0.64), P = 0.0004]. CONCLUSION This study of a large cohort of patients diagnosed with PML (n = 246), provides evidence that a combination antiretroviral regimen, especially one including PI, confers marked survival benefits.

Risk factors for osteonecrosis in HIV-infected patients: impact of treatment with combination antiretroviral therapy.

Background:Osteonecrosis was increasingly associated with HIV infection in the 1990s. It is unclear whether its risk increases with the duration of HIV infection, the duration of combination antiretroviral therapy (cART) or both. Objective:To analyse factors associated with the rate of symptomatic osteonecrosis, particularly the relative impacts of the duration of HIV infection and the duration of cART, using the French Hospital Database on HIV, which comprises a large number of subjects with substantial follow-up. Methods:Poisson regression model was used to identify factors associated with the rate of osteonecrosis among patients enrolled in 1996–2002. Results:The study involved 56 393 subjects with a total follow-up of 229 031 person-years. Symptomatic osteonecrosis was diagnosed in 104 subjects with an incidence rate of 4.5/10 000 person-years. Multivariate analysis identified three factors associated with the rate of osteonecrosis: prior AIDS-defining illnesses [adjusted relative rate (RR), 3.1; 95% confidence interval (CI), 2.0–4.9], the CD4 cell nadir [RR, 1.6 (95% CI, 0.9–2.9) for CD4 cell count 50–199 cells/μl; RR, 1.8 (95% CI, 1.0–3.3) for CD4 cell count < 50 cells/μl; both relative to CD4 cell count ≥ 200 cells/μl] and exposure to cART. Compared with unexposed patients, the RR of osteonecrosis ranged from 2.6 (95% CI, 1.2–5.9) in patients treated with cART for < 12 months to 5.1 (95% CI, 2.1–12.6) in patients treated for ≥ 60 months. Conclusions:Osteonecrosis appears to be a complication of both HIV infection and cART.

Cohort Profile: French hospital database on HIV (FHDH-ANRS CO4)

The French Hospital Database on HIV (FHDH) is a hospital-based multicentre open cohort with inclusions ongoing since 1989. The research objectives focus mainly on mid- and long-term clinical outcomes and therapeutic strategies, as well as severe AIDS and non-AIDS morbidities, and public health issues relative to HIV infection. FHDH also serves to describe HIV-infected patients receiving hospital care in France. FHDH includes data on more than 120,000 HIV-infected patients from 70 French general or university hospitals distributed throughout France. Patients are eligible for inclusion if they are infected by HIV-1 or HIV-2 and give their written informed consent. Standardized variables are collected at each outpatient visit or hospital admission during which a new clinical manifestation is diagnosed, a new treatment is prescribed or a change in biological markers is noted, and/or at least every 6 months. Since its inception, variables collected in FHDH include demographic characteristics, HIV-related biological markers, the date and type of AIDS and non AIDS-defining events, antiretroviral treatments and the date and causes of death, as reported in the medical records. Since 2005, data have also been collected on: co-infection with hepatitis B or C virus; alcohol and tobacco use; and non HIV-related biomarkers. Anyone can submit a research project by completing a standardized form available on the FHDH website (http://www.ccde.fr/_fold/fl-1385734776-429.pdf) or from the corresponding author, describing the context and objectives of the study. All projects are reviewed by the scientific committee.

All-oral Direct-acting Antiviral Regimens in HIV/Hepatitis C Virus–coinfected Patients With Cirrhosis Are Efficient and Safe: Real-life Results From the Prospective ANRS CO13–HEPAVIH Cohort

BACKGROUND Human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients with cirrhosis have long been considered to be difficult to treat, and real-life efficacy and tolerance data with all-oral direct-acting antiviral (DAA) combinations in these patients are scarce. METHODS Cirrhotic HIV/HCV-coinfected patients enrolled in the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) CO13 HEPAVIH cohort initiating an all-oral DAA regimen were consecutively included. A negative HCV RNA result at 12 weeks of follow-up or thereafter was assumed as a sustained virologic response (SVR12). Adjusted exact logistic regression was used to study factors associated with treatment outcome. RESULTS We included 189 patients who initiated an all-oral DAA regimen with the following characteristics: median age 53.2 years; 74.6% male; Centers for Disease Control and Prevention classification A/B/C: 37%/31%/32%; Child-Pugh class A/B/C: 91%/8%/1%; 87% with HIV RNA <50 copies/mL; 99% on antiretrovirals; median CD4 count: 489 cells/µL; HCV treatment naive 29%; HCV genotype 1/2/3/4: 58%/4%/17%/21%. Sofosbuvir (SOF) + daclatasvir ± ribavirin (RBV) was used in 123 patients, SOF + RBV in 30, SOF + simeprevir in 11, and SOF + ledipasvir in 23. An SVR12 was reported in 93.1% of the patients (95% confidence interval, 88.5%-96.3%). In adjusted analyses, no difference was found between 12 or 24 weeks of treatment, in patients receiving RBV or not, and in treatment-naive vs experienced patients. Premature stop of DAA was reported for 8 patients. One patient died during treatment (unknown cause), and 12 other patients developed liver-related events. CONCLUSIONS In this prospective real-life cohort, all-oral DAA regimens were well tolerated and associated with a high virologic efficacy in cirrhotic HIV/HCV-coinfected patients. This should not alleviate the surveillance for liver-related events in these patients.

Risk factors for anaemia in human immunodeficiency virus/hepatitis C virus-coinfected patients treated with interferon plus ribavirin

Summary.  The most frequent and the most troublesome adverse effect of interferon plus ribavirin‐based therapy is anaemia. The aim of this analysis was to determine the incidence and risk factors of anaemia (Hb < 10 g/dL) in human immunodeficiency virus/hepatitis C virus (HCV)‐coinfected patients receiving anti‐HCV therapy. We reviewed all cases of anaemia occurring among 416 patients participating in a randomized, controlled 48‐week trial comparing peginterferon (peg‐IFN) alpha 2b plus ribavirin with interferon alpha‐2b plus ribavirin. Univariate and multivariate analyses were used to identify links with antiretroviral treatments, HCV therapy and clinical and laboratory findings. Sixty‐one (15.9%) of the 383 patients who received at least one dose of anti‐HCV treatment developed anaemia. In multivariate analysis the risk of anaemia was significantly associated with zidovudine (OR, 3.27 95% CI, 1.64–6.54, P = 0.0008) and peg‐IFN (OR, 2.35; 95% CI, 1.16–4.57, P = 0.0179). The risk of anaemia was lower in patients with higher baseline haemoglobin levels (OR, 0.35 95% CI, 0.26–0.49, P < 0.0001) and in patients receiving protease inhibitor‐based antiretroviral therapy (OR, 0.51 95% CI, 0.30–0.86, P = 0.0114). Zidovudine discontinuation could help to avoid anaemia associated with anti‐HCV therapy.

Potential for Drug-Drug Interactions between Antiretrovirals and HCV Direct Acting Antivirals in a Large Cohort of HIV/HCV Coinfected Patients

Objectives Development of direct acting antivirals (DAA) offers new benefits for patients with chronic hepatitis C. The combination of these drugs with antiretroviral treatment (cART) is a real challenge in HIV/HCV coinfected patients. The aim of this study was to describe potential drug-drug interactions between DAAs and antiretroviral drugs in a cohort of HIV/HCV coinfected patients. Methods Cross-sectional study of all HIV/HCV coinfected patients attending at least one visit in 2012 in the multicenter French Dat’AIDS cohort. A simulation of drug-drug interactions between antiretroviral treatment and DAAs available in 2015 was performed. Results Of 16,634 HIV-infected patients, 2,511 had detectable anti-HCV antibodies, of whom 1,196 had a detectable HCV-RNA and were not receiving HCV treatment at the time of analysis. 97.1% of these patients were receiving cART and 81.2% had a plasma HIV RNA <50 copies/mL. cART included combinations of nucleoside reverse transcriptase inhibitors with a boosted protease inhibitor in 43.6%, a non-nucleoside reverse transcriptase inhibitor in 17.3%, an integrase inhibitor in 15.4% and various combinations or antiretroviral drugs in 23.7% of patients. A previous treatment against HCV had been administered in 64.4% of patients. Contraindicated associations/potential interactions were expected between cART and respectively sofosbuvir (0.2%/0%), sofosbuvir/ledipasvir (0.2%/67.6%), daclatasvir (0%/49.4%), ombitasvir/boosted paritaprevir (with or without dasabuvir) (34.4%/52.2%) and simeprevir (78.8%/0%). Conclusions Significant potential drug-drug interactions are expected between cART and the currently available DAAs in the majority of HIV/HCV coinfected patients. Sofosbuvir/ledipasvir and sofosbuvir/daclatasvir with or without ribavirin appeared the most suitable combinations in our population. A close collaboration between hepatologists and HIV/AIDS specialists appears necessary for the management of HCV treatment concomitantly to cART.

Safety and immunogenicity of double-dose versus standard-dose hepatitis B revaccination in non-responding adults with HIV-1 (ANRS HB04 B-BOOST): a multicentre, open-label, randomised controlled trial

BACKGROUND Revaccination with double-dose hepatitis B vaccine has been recommended in HIV-infected patients who do not respond to standard vaccination, but has not yet been assessed. We aimed to compare the safety and immunogenicity of a reinforced hepatitis B revaccination protocol with the standard revaccination schedule in HIV-infected patients not responding to primary vaccination. METHODS We did this multicentre, open-label, randomised controlled trial, at 53 centres in France. HIV-infected adults (aged ≥18 years), with CD4 counts of 200 cells per μL or more and no response to a previous hepatitis B vaccination or a 20 μg booster dose, were randomly assigned (1:1), according to a computer-generated randomisation list with permuted blocks (block sizes of two to six), to receive either standard-dose (20 μg) or double-dose (40 μg) recombinant hepatitis B vaccine at weeks 0, 4, and 24. Randomisation was stratified by baseline CD4 count (200-349 vs ≥350 cells per μL). Patients and treating physicians were not masked to treatment allocation, but the randomisation list was concealed from the investigators who assigned participants to the vaccination groups. The primary endpoint was the proportion of responders, defined as patients with hepatitis B surface antibody (anti-HBs) titres of 10 mIU/mL or more, at week 28. We did analysis by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00670839. FINDINGS Between May 19, 2008, and May 8, 2011, 178 participants were randomly assigned to the standard-dose group (n=90) or the double-dose group (n=88), of whom 176 (98%) participants were included in the primary efficacy analysis. At week 28, we recorded a response in 60 patients (67%, 95% CI 57-77) in the standard-dose group versus 64 patients (74%, 63-82) in the double-dose group (p=0·334). Except for more frequent local reactions in the double-dose group than the standard-dose group (13 [15%] vs four [4%] patients; p=0·020), there was no difference in safety between groups. INTERPRETATION In adults with HIV-1 who have not responded to previous hepatitis B vaccination, double-dose revaccination did not achieve a higher response rate than did revaccination with standard single-dose regimen. However, the safety profile was similar between treatment groups. Our results should be assessed in future studies before double-dose vaccine can be considered for the standard of care of vaccine non-responders. FUNDING French National Institute for Medical Research-French National Agency for Research on AIDS and Viral Hepatitis.

Efficacy and safety of stavudine and didanosine combination therapy in antiretroviral-experienced patients

Objectives:To assess the efficacy, tolerance, and safety of combination antiretroviral therapy with didanosine and stavudine in HIV-infected patients with CD4+ cell counts >100 × 106/l and HIV plasma RNA >104 copies/ml previously treated with other antiretroviral agents for at least 3 months. Design:In this open, multicentre, non-randomized, Phase II pilot study, adult patients were administered didanosine (200 mg twice daily) plus stavudine (40 mg twice daily) for 6 months. Patients for whom the first regimen had led to undetectable HIV RNA levels were offered a second 6-month course of treatment; those who had achieved insufficient immunological and virological gains in the first 6 months were given a new combination. Methods:Primary evaluation of efficacy was based on viral load measured by branched DNA second-generation testing (lower limit of detection, 500 copies/ml) and CD4+ cell counts; secondary evaluations included AIDS-defining events and clinical side-effects. Results:Sixty-five patients with median prior antiretroviral therapy of 24 months (65 with zidovudine, 29 with zalcitabine) were included in the study. At baseline, median CD4+ cell count was 198 × 106/l and median plasma HIV RNA was 80 000 copies/ml (4.9 log10 copies/ml). In this heavily pretreated population, an increase in the mean CD4+ cell count was observed (+70 × 106/l at 24 weeks). In addition, rapid and prolonged antiviral activity was seen, with a mean maximal decrease of 1.1 log10 copies/ml at week 4, a mean decrease of 0.89 log10 copies/ml at week 24, and a plasma RNA viraemia <500 copies/ml achieved in 14% of patients at week 24. Conclusions:Combination therapy with stavudine and didanosine is safe and leads to a sustained antiviral effect, even in patients with prolonged prior antiretroviral exposure and low CD4+ cell counts.