François Boué

Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study

BACKGROUND The relative roles of immunodeficiency, HIV viral load, and combination antiretroviral therapy (cART) in the onset of individual cancers have rarely been examined. We examined the effect of these factors on the risk of specific cancers in patients infected with HIV-1. METHODS We investigated the incidence of both AIDS-defining cancers (Kaposis sarcoma, non-Hodgkin lymphoma, and cervical cancer) and non-AIDS-defining cancers (Hodgkins lymphoma, lung cancer, liver cancer, and anal cancer) in 52 278 patients followed up in the French Hospital Database on HIV cohort during 1998-2006 (median follow-up 4.9 years, IQR 2.1-7.9; 255 353 person-years). We tested 78 models with different classifications of immunodeficiency, viral load, and cART with Poisson regression. FINDINGS Current CD4 cell count was the most predictive risk factor for all malignancies apart from anal cancer. Compared with patients with CD4 count greater than 500 cells per microL, rate ratios (RR) ranged from 1.9 (95% CI 1.3-2.7) for CD4 counts 350-499 cells per microL to 25.2 (17.1-37.0) for counts less than 50 cells per microL for Kaposis sarcoma (p<0.0001), from 1.3 (0.9-2.0) to 14.8 (9.7-22.6) for non-Hodgkin lymphoma (p<0.0001), from 1.2 (0.7-2.2) to 5.4 (2.4-12.1) for Hodgkins lymphoma (p<0.0001), from 2.2 (1.3-3.6) to 8.5 (4.3-16.7) for lung cancer (p<0.0001), and from 2.0 (0.9-4.5) to 7.6 (2.7-20.8) for liver cancer (p<0.0001). For cervical cancer, we noted a strong effect of current CD4 (RR 0.7 per log(2), 95% CI 0.6-0.8; p=0.0002). The risk of Kaposis sarcoma and non-Hodgkin lymphoma increased for current plasma HIV RNA greater than 100 000 copies per mL compared with patients with controlled viral load (RR 3.1, 95% CI 2.3-4.2, p<0.0001; and 2.9, 2.1-3.9, p<0.0001, respectively), whereas cART was independently associated with a decreased incidence (0.3, 0.2-0.4, p<0.0001; and 0.8, 0.6-1.0, p=0.07, respectively). The RR of cervical cancer for those receiving cART was 0.5 (0.3-0.9; p=0.03). The risk of anal cancer increased with the time during which the CD4 count was less than 200 cells per microL (1.3 per year, 1.2-1.5; p=0.0001), and viral load was greater than 100 000 copies per mL (1.2 per year, 1.1-1.4, p=0.005). INTERPRETATION cART would be most beneficial if it restores or maintains CD4 count above 500 cells per microL, thereby indicating an earlier diagnosis of HIV infection and an earlier treatment initiation. Cancer-specific screening programmes need to be assessed in patients with HIV. FUNDING Agence Nationale de Recherches sur le SIDA et les hépatites (ANRS), INSERM, and the French Ministry of Health.

Incidence of non-AIDS-defining cancers before and during the highly active antiretroviral therapy era in a cohort of human immunodeficiency virus-infected patients

PURPOSE To determine incidence of non-AIDS-defining cancers (NADC) in HIV-infected patients before (P1) and during (P2) the use of highly active antiretroviral therapy (HAART) relative to that observed in the French general population (FGP) of the same age and sex. PATIENTS AND METHODS Sex- and age-adjusted NADC standardized incidence ratios (SIR), with FGP as reference, were estimated in 1992 to 1995 (P1) and in 1996 to 1999 (P2) in a French Hospital Database on HIV prospective hospital cohort study. RESULTS NADCs were diagnosed in 260 patients during P1 and 391 patients during P2 among the 77,025 patients included in the database between January 1, 1992, and December 31, 1999. Estimated incidence of all cancers was higher in HIV-infected men than in FGP during both periods (P1 SIR = 2.36 and P2 SIR = 1.91). No excess of cancers was observed among HIV-infected women in either period. Incidence of all cancers did not change from P1 to P2 in either sex (SIR = 0.96 for men and 1.00 for women). In contrast, incidence of Hodgkins disease (HD) was higher than in FGP in both sexes and both periods and increased in P2 as compared with P1; incidence of lung cancer was higher in both sexes during P2. CONCLUSION Relative to FGP, the overall incidence of NADCs was increased in HIV-infected men but not in women and did not differ between P1 and P2. Only HD was much more common in HIV infection, and the potential role of HAART on HD cannot be excluded.

Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment

HIV infection results in CD4+ T cell deficiency, but efficient combination antiretroviral therapy (c-ART) restores T cells and decreases morbidity and mortality. However, immune restoration by c-ART remains variable, and prolonged T cell deficiency remains in a substantial proportion of patients. In a prospective open-label phase I/IIa trial, we evaluated the safety and efficacy of administration of the T cell regulator IL-7. The trial included 13 c-ART-treated HIV-infected patients whose CD4+ cell counts were between 100 and 400 cells/microl and plasma HIV RNA levels were less than 50 copies/ml. Patients received a total of 8 subcutaneous injections of 2 different doses of recombinant human IL-7 (rhIL-7; 3 or 10 microg/kg) 3 times per week over a 16-day period. rhIL-7 was well tolerated and induced a sustained increase of naive and central memory CD4+ and CD8+ T cells. In the highest dose group, 4 patients experienced transient increases in viral replication. However, functional assays showed that the expanded T cells responded to HIV antigen by producing IFN-gamma and/or IL-2. In conclusion, in lymphopenic HIV-infected patients, rhIL-7 therapy induced substantial functional and quantitative changes in T cells for 48 weeks. Therefore, patients may benefit from intermittent therapy with IL-7 in combination with c-ART.

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.

Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection

BACKGROUND Pneumocystis carinii pneumonia and toxoplasmic encephalitis are frequent life-threatening opportunistic infections in patients with human immunodeficiency virus (HIV) infection. Primary prophylaxis against P. carinii pneumonia is now common, but there are few data on regimens for primary prophylaxis against toxoplasmosis. METHODS We conducted a randomized trial that compared two prophylactic regimens: dapsone (50 mg per day) plus pyrimethamine (50 mg per week) was compared with aerosolized pentamidine (300 mg per month). The patients had symptomatic HIV infection, no history of P. carinii pneumonia or symptomatic toxoplasmosis, and CD4+ counts below 200 per cubic millimeter (0.2 x 10(9) per liter). RESULTS In an intention-to-treat analysis, after a median follow-up of 539 days P. carinii pneumonia developed in 10 patients in each group, whereas toxoplasmosis developed in 32 of 176 patients in the pentamidine group and 19 of 173 patients in the dapsone-pyrimethamine group. Those assigned to pentamidine had a risk of P. carinii pneumonia that was similar to the risk in those assigned to dapsone-pyrimethamine (adjusted relative risk, 1.13; 95 percent confidence interval, 0.44 to 2.92; P = 0.79), but a higher risk of toxoplasmosis (adjusted relative risk, 1.81; 95 percent confidence interval, 1.12 to 2.94; P = 0.02). Among the 262 patients with serologic evidence of past exposure to Toxoplasma gondii, the relative risk of symptomatic toxoplasmosis was 2.37 times higher in those assigned to pentamidine (95 percent confidence interval, 1.3 to 4.4; P = 0.006). More patients discontinued dapsone-pyrimethamine than pentamidine because of toxicity (42 vs. 3; P < 0.001). Survival was similar in the two groups. CONCLUSIONS For primary prevention of P. carinii pneumonia, dapsone-pyrimethamine is as effective, though not as well tolerated, as aerosolized pentamidine. Dapsone-pyrimethamine also prevents first episodes of toxoplasmosis.

Structural analogy between aqueous and oily magnetic fluids

In this paper, we compare the structure and the phase behavior of two kinds of magnetic fluids, also called ferrofluids. They are constituted of the same maghemite particles, the diameters of which lie around 8 nm, dispersed either in water or in cyclohexane. Both systems are constructed to get the same interparticle interactions and differ only through the nature of the repulsion. Repulsion is either electrostatic, due to the charges of citrate molecules adsorbed on the particles surface in water, or steric, due to the alkyl chains of adsorbed surfactants in cyclohexane. Small angle neutron scattering (SANS) experiments show that both systems are highly repulsive and that the structure factors are very similar. This is confirmed by stability measurements: the samples are stable if temperature is decreased and if a magnetic field is applied. If the repulsion is decreased by the addition of electrolyte in water or bad solvent in cyclohexane, a gas–liquid-like transition is observed in both systems. However...

Smart Foams: Switching Reversibly between Ultrastable and Unstable Foams†

Ultrastable foams with an optimal foamability have been obtained using hydroxyl fatty acids tubes. The stabilization results from the adsorption of monomers at the air-water interface preventing coalescence and coarsening and from the presence of tubes in the Plateau borders limiting the drainage. Upon heating, tubes transit to micelles, which induces foam destabilization. Such foams are thus the first to have a temperature tunable stability.

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.

Prolonged survival without neurological improvement in patients with AIDS-related progressive multifocal leukoencephalopathy on potent combined antiretroviral therapy.

To evaluate the benefit of combined antiretroviral therapy including protease inhibitors (CART) on survival time and neurological progression in patients with AIDS-related progressive multifocal leukoencephalopathy (PML), 81 consecutive PML cases, collected between January 1990 and June 1998, were reviewed. Fifteen patients were neuropathologically proven. JC virus detection in CSF was positive in 59 patients. At PML diagnosis, median CD4 cell count was low (median, 35 cells/microL) and plasma HIV load, determined in 41 patients, was high (median, 4.8 log10 copies/ml). Following PML diagnosis, there was a significant difference (P<10(-4)) in survival between patients who were untreated or treated with nucleoside analogs (n=50, median: 80 days) and patients who were started early on CART (n=23, median: 246 days). A third group of eight patients who received CART late during the course of PML was considered separately. At the study endpoint, 18 of all the CART-treated patients (n=31) were still alive. Plasma HIV load was undetectable in 67% of them. The median increase in CD4 cell count was 112 cells/microL from CART onset. In contrast, no significant improvement in neurological status was observed. Our results demonstrate a benefit of CART on survival of AIDS-related PML patients and suggest the need for an early, specific anti-JC virus treatment to limit the neurological deterioration.

Determinants of delayed diagnosis of HIV infection in France, 1993–1995

Objective:To describe the circumstances of the first HIV-positive test and to study the determinants of a delayed diagnosis of HIV infection. Methods:In a retrospective study among adult AIDS patients diagnosed between July 1993 and May 1995 in two French districts, data on socioeconomic characteristics, circumstances of first HIV-positive test and attitudes and behaviours regarding medical care were collected in a confidential interview and analysed for potential association with a late test, defined as a first HIV-positive test within 6 months of AIDS diagnosis. Results:Of the 359 AIDS patients studied, 69 (19.2%) had a late test. Late testers were more likely than other patients to have had an HIV-positive test because of clinical symptoms (89.7 versus 38.9%, P < 0.001) and not to perceive themselves as being at risk of infection with HIV (53.6 versus 39.3%, P < 0.05). The proportion of late testers was 34.6% among heterosexually infected patients, 12.7% among homo-/ bisexual men and 9.6% among injecting drug users. Factors independently associated with a late test were male gender [adjusted odds ratio (aOR), 5.6; 95% confidence interval (CI), 1.7–18.9] and absence of earned income (aOR, 5.2; 95% CI, 1.4–19) among heterosexually infected patients; high education (aOR, 3.1; 95% CI, 1.0–9.6) and having consulted a person practising alternative medicine (aOR, 3.4; 95% CI, 1.2–10) in homo-/bisexual men. Conclusions:Despite incentives to be tested for HIV, many individuals in France are still tested too late, even if they are in known high-risk groups. Efforts to test HIV-infected people as early as possible should be made by increasing the perception of HIV risk and decreasing the level of missed opportunities for testing. Current case management approaches make this recommendation critically important from both public health and an individual perspective.