Does transient cART started during primary HIV infection undermine the long-term immunologic and virologic response on cART resumption?

BACKGROUND: We explored the impact of transient cART started during the primary HIV-infection (PHI) on the long-term immunologic and virologic response on cART resumption, by comparison with treatment initiation during the chronic phase of HIV infection (CHI). METHODS: We analyzed data on 1450 patients enrolled during PHI in the ANRS PRIMO cohort between 1996 and 2013. "Treatment resumption" was defined as at least 3 months of resumed treatment following interruption of at least 1 month of treatment initiated during PHI. "Treatment initiation during CHI" was defined as cART initiated ≥6 months after PHI. The virologic response to resumed treatment and to treatment initiated during CHI was analyzed with survival models. The CD4 cell count dynamics was modeled with piecewise linear mixed models. RESULTS: 136 patients who resumed cART for a median (IQR) of 32 (18-51) months were compared with 377 patients who started cART during CHI for a median of 45 (22-57) months. Most patients (97%) achieved HIV-RNA <50 cp/mL after similar times in the two groups. The CD4 cell count rose similarly in the two groups during the first 12 months. However, after 12 months, patients who started cART during CHI had a better immunological response than those who resumed cART (p = 0.01); therefore, at 36 months, the gains in √CD4 cells/mm(3) and CD4% were significantly greater in patients who started treatment during CHI. CONCLUSION: These results suggest that interruption of cART started during PHI has a significant, albeit modest negative impact on CD4 cell recovery on cART resumption.

Early loss of bone mineral density is correlated with a gain of fat mass in patients starting a protease inhibitor containing regimen: the prospective Lipotrip study.

BACKGROUND: HIV-infected patients starting antiretroviral treatment (ART) experience deep and early disorders in fat and bone metabolism, leading to concomitant changes in fat mass and bone mineral density. METHODS: We conducted a prospective study in treatment-naive HIV-infected patients randomized to receive two nucleoside reverse transcriptase inhibitors in combination with either a protease inhibitor (PI) or a non-nucleosidic reverse transcriptase inhibitor (NNRTI), to evaluate early changes in body composition, bone mineral density and metabolic markers as differentially induced by antiretroviral therapies. We measured changes in markers of carbohydrate, of fat and bone metabolism, and, using dual-emission X-ray absorptiometry (DXA), body composition and bone mineral density (BMD). Complete data on changes between baseline and after 21 months treatment were available for 35 patients (16 in the PI group and 19 in the NNRTI group). RESULTS: A significant gain in BMI and in total and lower limb fat mass was recorded only in patients receiving PI. A loss of lumbar BMD was observed in both groups, being higher with PI. Plasma markers of bone metabolism (alkaline phosphatase, osteocalcin, collagen crosslaps) and levels of parathormone and of 1,25diOH-vitamin D3 significantly increased in both groups, concomitant with a decline in 25OH-vitamin D3. Lipids and glucose levels increased in both groups but rise in triglyceride was more pronounced with PI. A correlation between loss of BMD and gain of fat mass is observed in patients starting PI. CONCLUSIONS: We evidenced an early effect of ART on lipid and bone metabolisms. PI lead to a significant gain in fat mass correlated with a sharp drop in BMD but active bone remodelling is evident with all antiretroviral treatments, associated with low vitamin D levels and hyperparathyroidism. In parallel, signs of metabolic restoration are evident. However, early increases in lean and fat mass, triglycerides, waist circumference and leptin are much more pronounced with PI.

Longitudinal study of body composition of 101 HIV men with lipodystrophy: dual-energy X-ray criteria for lipodystrophy evolution.

The aim of this study was to define evolution profiles of body composition among human immunodeficiency virus (HIV)-infected men with lipodystrophy. The design is a retrospective analysis using observational data collected longitudinally. We included 101 HIV-infected men with lipodystrophy managed in routine practice and who had 2 dual energy X-ray absorptiometry scans within a minimum interval of 18 mo. Lipodystrophy was defined as a fat mass ratio (FMR, defined as the ratio of the percentage of the trunk fat mass over the percentage of the lower limbs fat mass) equal or superior to 1.5. Patients were classified in "improved" group (IG: increase of lower limbs fat mass >/= 10%) or "nonimproved" group (NIG). Body composition, immunovirological and epidemiological data were collected and compared between the 2 groups. In the whole population, over a 4-yr period, a significant increase was observed for total fat mass, trunk fat mass, and lower limbs fat mass, whereas total lean mass was stable. Total body mineral density decreased. Fifty-nine patients (IG), less exposed to zidovudine than the NIG, had an increase of lower limbs fat mass higher than 10%. But only 13 (22%) regained a normal distribution of fat mass (FMR < 1.5), showing that lipodystrophy was slowly reversible. Among the NIG, 5 patients (11.9%), less exposed to zidovudine and with a higher mean of viral load, reached an FMR below 1.5. It was mainly because of a loss of trunk fat mass, which could be the sign of a lipodystrophy worsening. Lipodystrophy improved for 58.4% of men. The improvement was very slow. Recovery was observed only in patients with an earlier intervention. No correlation was observed between lipodystrophy and total body bone mineral density. The loss of trunk fat mass without gain of lower limbs fat mass may indicate a worsening of HIV disease.

Effects of discontinuing stavudine or protease inhibitor therapy on human immunodeficiency virus-related fat redistribution evaluated by dual-energy x-ray absorptiometry.

STUDY OBJECTIVE: To determine whether discontinuation of stavudine or protease inhibitor therapy improves human immunodeficiency virus (HIV)-related fat distribution in men. DESIGN: Observational, retrospective study consisting of a cross-sectional (part 1) and a longitudinal (part 2) study. DATA SOURCE: Medical records from Purpan University Hospital and La Grave University Hospital, Toulouse, France. Subjects. Eighty men with HIV infection treated with antiretrovirals and 151 healthy male controls matched for age. MEASUREMENTS AND MAIN RESULTS: In part 1, body composition and fat distribution of the HIV-infected men were compared by dual energy x-ray absorptiometry (DEXA) with those of the controls to determine whether body fat distribution is altered in HIV-infected men. In part 2, we analyzed modifications of body composition and fat distribution in 45 of the 80 patients. These 45 had been exposed to antiretroviral drugs, including stavudine and a protease inhibitor, for at least 5 months before the first of two DEXA assessments. They received three different treatment strategies for several months. In group 1, stavudine was withdrawn; in group 2, protease inhibitor was discontinued, and in group 3, stavudine plus protease inhibitor were continued. Group 1 showed a significant fat gain in the lower extremities 31.7 +/- 5.9 months after stavudine discontinuation (p<0.0001). Group 2 did not show any significant modification of total body, lower limb, or trunk fat despite protease inhibitor discontinuation for 35.2 +/- 6.6 months. Findings were similar for group 3, who continued receiving stavudine-protease inhibitor therapy for 21.2 +/- 12.8 months. CONCLUSION: These data suggest that long-term withdrawal of stavudine from the antiretroviral therapy regimen may be associated with significant improvement in lipoatrophy in the lower extremities, whereas long-term protease inhibitor withdrawal did not modify fat distribution.

Persistence of distinct HIV-1 populations in blood monocytes and naive and memory CD4 T cells during prolonged suppressive HAART.

OBJECTIVE: Reservoirs of HIV-1 are a major obstacle to virus eradication. There is therefore a need to clearly understand the molecular nature of the virus populations that persist in patients with sustained suppression of plasma viraemia on highly active antiretroviral therapy (HAART). DESIGN: We performed a detailed analysis of the genotypes of HIV-1 quasispecies isolated from highly purified blood cell types taken from three selected patients with sustained undetectable viral loads on HAART for 7 years. METHODS: We used polychromatic flow cytometry to sort naive and memory CD4 T cells, CD14 monocytes, and CD56+CD3- natural killer (NK) cells from the total peripheral blood mononuclear cells after 7 years of HAART. Clonal analysis was used to determine coreceptor use and drug-resistance genotypes of HIV-1 quasispecies in the sorted blood cell types. RESULTS: We detected HIV-1 DNA in memory and naive CD4 T cells and in CD14 monocytes, but not in the CD56+CD3- NK cells. Phylogenetic analysis demonstrated that the various blood cells types of two of the three patients harboured genetically distinct HIV-1 quasispecies. Drug-resistance mutations were also distributed differently from one cell type to another. This compartmentalization suggests a minimal virus trafficking between blood cell types during suppressive HAART. CONCLUSIONS: We observed a cell-specific compartmentalization of the residual virus populations during prolonged suppressive HAART. The coexistence of numerous HIV-1 quasispecies with different resistance genotypes and coreceptor use in cellular reservoirs may be relevant for future antiretroviral treatment strategies.

Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman's disease: ANRS 117 CastlemaB Trial.

PURPOSE: Single-agent chemotherapy is usually effective in HIV-associated multicentric Castleman's disease (MCD). However, in most patients, chemotherapy cannot be discontinued. PATIENTS AND METHODS: To evaluate the efficacy of four weekly rituximab infusions (375 mg/m(2)) after discontinuation of chemotherapy in HIV-associated MCD, 24 patients were enrolled onto a prospective open-label trial. RESULTS: At study entry, the median time from MCD diagnosis was 21 months. All patients had stable disease on chemotherapy and were dependent on chemotherapy for a median time of 13 months. The median CD4 cell count was 270 x 10(6)/L, and the plasma HIV RNA was less than 50 copies/mL in 18 patients. One patient died with progressive disease at day 15, and 23 patients completed the four cycles of rituximab. Sustained remission (SR) off treatment at day 60 (primary end point) was achieved in 22 patients (92%). From day 60 to day 365, one patient died with acute respiratory failure of undetermined origin, and four patients experienced relapse. Seventeen patients (71%) were alive in SR at day 365 without specific treatment, and the overall survival rate was 92% (95% CI, 71% to 98%). Rituximab was well tolerated, and the majority of adverse events were mild to moderate infections. Mild exacerbation of Kaposi's sarcoma (KS) lesions was observed in eight of 12 patients with previous KS. CONCLUSION: Rituximab was both effective and safe in HIV-infected patients with chemotherapy-dependent MCD.

Virological and immunological effects of salvage therapy following treatment interruption and a shift in HIV-1 resistance genotype.

The circulating human immunodeficiency virus type 1 (HIV-1) population of patients in whom many prior therapy regimens have failed often undergo a shift from a drug-resistant virus to a wild-type virus following interruption of treatment. This study analyses the virological and immunological effects of salvage therapy following treatment interruption and a shift from a drug-resistance genotype. Twenty-one HIV-1 infected patients who had genotype reversion by population-based sequencing after 3 months of treatment interruption were given a new salvage regimen consisting of 3-5 drugs selected according to their treatment history. Seven (33%) of 21 patients who had fewer than 200 HIV-1 RNA copies/ml until month 12 were defined as virological responders. Four patients were transient responders and 10 were nonresponders. The virological responders were more frequently CDC group A and had higher CD4 + T lymphocyte counts at the time of treatment resumption. The peripheral blood T CD4 + and T CD8 + lymphocyte populations of the patients declined significantly during treatment interruption. Only virological responders showed significant increases in their CD4 + T lymphocyte count 12 months after treatment resumption and these counts rapidly returned to pre-interruption baseline values in most of these patients. Treatment interruption could be useful for optimising salvage therapy for patients previously given many failing regimens. However, controlled trials are needed to assess the clinical benefit of this strategy.