The efficacy and safety of systemic corticosteroids as first line treatment for granulomatous lymphocytic interstitial lung disease.

BACKGROUND: Granulomatous and lymphocytic interstitial lung disease (gl-ILD) is a major cause of morbidity and mortality among patients with common variable immunodeficiency. Corticosteroids are recommended as first-line treatment for gl-ILD, but evidence for their efficacy is lacking. OBJECTIVES: This study analyzed the effect of high-dose corticosteroids (≥0.3 mg/kg prednisone equivalent) on gl-ILD, measured by high-resolution computed tomography (HRCT) scans, and pulmonary function test (PFT) results. METHODS: Patients who had received high-dose corticosteroids but no other immunosuppressive therapy at the time (n = 56) and who underwent repeated HRCT scanning or PFT (n = 39) during the retrospective and/or prospective phase of the Study of Interstitial Lung Disease in Primary Antibody Deficiency (STILPAD) were included in the analysis. Patients without any immunosuppressive treatment were selected as controls (n = 23). HRCT scans were blinded, randomized, and scored using the Hartman score. Differences between the baseline and follow-up HRCT scans and PFT were analyzed. RESULTS: Treatment with high-dose corticosteroids significantly improved HRCT scores and forced vital capacity. Carbon monoxide diffusion capacity significantly improved in both groups. Of 18 patients, for whom extended follow-up data was available, 13 achieved a long-term, maintenance therapy independent remission. All patients with relapse were retreated with corticosteroids, but only one-fifth of them responded. Two opportunistic infections were found in the corticosteroid treatment group, while overall infection rate was similar between cohorts. CONCLUSIONS: Induction therapy with high-dose corticosteroids improved HRCT scans and PFT results of patients with gl-ILD and achieved long-term remission in 42% of patients. It was not associated with major side effects. Low-dose maintenance therapy provided no benefit and efficacy was poor in relapsing disease.

Evolution of Major Amputation Risk in Patients Hospitalized in France for Critical Limb Ischemia: The COPART Registry.

Over the past decade, improvements in medical treatment and revascularization techniques have been beneficial for patients with peripheral artery disease in the late stage of critical limb ischemia (CLI). We evaluated the putative reduction in the number of major amputees in the Cohorte des Patients ARTeriopathes (COPART) cohort over time. Patients were selected from this multicenter cohort, from 2006 to 2016, for CLI according to Trans-Atlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease II criteria. Patients included before and after 2011 were compared. Patients were followed for 1 year. Primary outcome was the rate of major amputations. Secondary outcomes were minor amputations, deaths from all causes, cardiovascular deaths; 989 patients were included, 489 before 2011 and 450 after 2011. There was a significant decrease in rates of major amputation after 2011 (17% vs 25%), confirmed in multivariate analysis (odds ratio [OR]: 1.5 [1.1-2.2]), an increase in revascularization, particularly distal angioplasty (OR: 2.7 [1.7-4.4]) and increased statin intake (OR: 1.6 [1.1-2.1]). For secondary outcomes, there was no significant difference. Limb prognosis of CLI patients has improved over the past decade, possibly due to more revascularizations, particularly distal ones, and increased statin use.

Characterization of contact force during endocardial and epicardial ventricular mapping.

BACKGROUND: The optimal contact force (CF) for ventricular mapping and ablation remains unvalidated. We assessed CF in different endocardial and epicardial regions during ventricular tachycardia substrate mapping using a CF-sensing catheter (Smartouch; Biosense-Webster) and compared the transseptal versus retroaortic approach. METHODS AND RESULTS: In total, 8979 mapping points with CF, and force vector orientation (VO) were recorded in 21 patients, comprising 13 epicardial, 12 left ventricular (6 transseptal and 6 retroaortic approach), and 12 right ventricular endocardial maps. VO was defined as adequate when the vector was directed toward the myocardium. During epicardial mapping, 46% of the points showed an adequate VO and a median CF of 8 (4-13) g, however, with significant differences among the 8 regions. When VO was inadequate, median CF was higher at 16 (10-24) g (P<0.0001). During left ventricular and right ventricular endocardial mapping, 94% of VO were adequate. Median CF of adequate VO was higher in the left ventricular and right ventricular endocardium than in the epicardium (15 [8-25] and 13 [7-22] g versus 8 [4-13] g, respectively; both P<0.001). Global median left ventricular CF with transseptal approach was not statistically different from retroaortic approach, but CF in the apicoinferior and apicoseptal regions was higher with transseptal approach (P<0.001). CONCLUSIONS: Ventricular mapping demonstrates important regional variations in CF, but in general, CF is higher endocardially than epicardially where poor catheter orientation is associated with higher CF. A transseptal approach may lead to improved contact particularly in the apicoseptal and inferior regions.

Transmission of HIV-1 minority-resistant variants and response to first-line antiretroviral therapy.

BACKGROUND: The transmission of drug-resistant HIV-1 can impair the virological response to antiretroviral therapy. Minority-resistant variants have been detected in acute seroconverters. We investigated the clinical relevance of the detection of majority and minority-resistant variants in an observational study in antiretroviral therapy naive, recently infected patients. METHODS: We included patients infected between 1996 and 2005, with a plasma sample obtained less than 18 months after seroconversion and prior to antiretroviral therapy initiation. Majority-resistant variants were determined by direct population sequencing. Minority-resistant variants were searched by allele-specific PCR for the mutations K103N and M184V in reverse transcriptase and L90M in protease. The association between resistance and viroimmunological response to antiretroviral therapy was estimated by using a piecewise linear mixed model. RESULTS: Majority-resistant variants were detected in 23/172 (13.4%) patients. Patients with majority-resistant variants had a lower mean plasma viral load and higher mean CD4 cell count at baseline compared with those without resistance. The decrease in viral load between 1 and 6 months on antiretroviral therapy was significantly steeper in patients with sensitive viruses compared with those with majority-resistant variants (P = 0.029). Minority-resistant variants were detected in 21/73 (29%) patients with wild-type viruses at sequencing analysis. The presence of minority-resistant variants did not modify baseline viral load and CD4 cell count and did not affect the changes in viral load and CD4 cell count. CONCLUSION: The transmission of majority-resistant variants, but not minority-resistant variants, influenced the response to antiretroviral therapy in this prospective study. The detection of the transmission of minority-resistant variants warrants further clinical validation.

Reduced bone mineral density in HIV-infected patients: prevalence and associated factors.

BACKGROUND: There is a high prevalence of bone demineralization among HIV-infected patients but mechanisms of alteration of bone turnover are still unclear and it is thought to be multifactorial. METHODS: A cross-sectional survey of 492 HIV-infected patients within the Aquitaine cohort estimated the prevalence of osteoporosis/osteopenia and investigated associated factors. Bone mineral density of total body, lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. Multivariable analyses of the association with HIV disease status, treatment and anthropometric parameters were stratified according to gender. RESULTS: Median age was 43 years (interquartile range, 38-50); 73% were male; 19.7% patients had reached AIDS, 93.1% were treated with HAART; and 28.5% had lipodystrophy. Based on World Health Organization criteria, osteopenia was diagnosed in 54.6% of men [95% confidence interval (CI), 49.4-59.7) and 51.1% of women (95% CI, 42.6-59.6) and osteoporosis in 33.7% of men (95% CI, 28.8-38.6) and 8.3% of women (95% CI, 3.6-13.9). Using a polytomous logistic regression, older age, homosexual transmission group, low body mass index and low HIV plasma viral load were associated with the diagnosis of bone abnormalities in men, whereas older age and low CD4 lymphocyte count nadir were independently associated with osteoporosis/osteopenia in women. The use of HAART was not related to osteoporosis after adjustment (P = 0.58). CONCLUSIONS: This cohort-based survey showed a high prevalence of osteopenia and osteoporosis of multifactorial origin. Mechanisms and consequences of these bone disorders need to be investigated.

Susceptibility to antiretroviral drugs of CRF01_AE, CRF02_AG, and subtype C viruses from untreated patients of Africa and Asia: comparative genotypic and phenotypic data.

Non-B HIV-1 viruses are predominant in developing countries where access to antiretroviral drugs (ARVs) is progressively being intensified. It is important to obtain more data on the susceptibility of these viruses to available ARVs. CRF01_AE, CRF02_AG, and subtype C strains of HIV-1 obtained from untreated patients from Vietnam, Cote d'Ivoire, and India were analyzed for their in vitro susceptibility to NRTIs, NNRTIs, PIs, and an entry inhibitor (T-20) using a recombinant viral assay (PHENOSCRIPT). The corresponding viruses, which had been previously sequenced in reverse transcriptase (RT), protease (prot), plus envelope (env) C2/V3 genes and had therefore been fully characterized, were further sequenced in env HR1 + HR2 regions. CRF01_AE isolates are sensitive to NRTIs and NNRTIs with the exception of one isolate that exhibits a decreased susceptibility to NNRTIs associated with a I135T substitution in RT. CRF02_AG and subtype C viruses are sensitive to NRTIs and NNRTIs but some CRF02_AG isolates tend to be resistant to abacavir, potentially related to associated substitutions of RT at positions 123 (D123N) plus 135 (I135V). Whereas all but one CRF01_AE isolates are fully susceptible to PIs, some CRF02_AG and, more frequently, some subtype C isolates are resistant to atazanavir. The role of substitutions in prot at positions of secondary resistance mutations 20, 36, 63, and 82 is raised with a potentially crucial role of the V82I substitution. Finally, all viruses tested, regardless of the CRF or subtype, are fully susceptible to T-20.

Antiretroviral efficacy and virological profile of a zidovudine/lamivudine/tenofovir disoproxil fumarate combination therapy in antiretroviral-naive patients.

OBJECTIVE: To study the antiviral efficacy and the mutations selected by a triple therapy with zidovudine (AZT), lamivudine (3TC) and tenofovir disoproxil fumarate (TDF). METHODS: Antiretroviral-naive patients received 300 mg AZT/150 mg 3TC twice a day plus 300 mg TDF once a day in an open pilot study. Follow-up was assessed at baseline therapy (MO) and at months 1, 3, 6, 9 and 12. Reverse transcriptase (RT) genotypic resistance analysis and in selected cases, a recombinant drug susceptibility and replication capacity assay were performed from plasma RNA at baseline and in case of virological failure (VF); that is, rebound of viral load >50 copies/microl on therapy. RESULTS: Twenty-four patients were included. At baseline, the median CD4+ T-cell count was 443 cells/microl and the median plasma viral load (VL) was 4.38 log10 copies/ml. RT resistance mutations were observed at MO in 4 patients. At M12, the proportion of patients with a VL <50 copies/ml reached 88% using an on-treatment analysis and 67% with an intent-to-treat analysis. The median increase in CD4+ T cells at M12 was 94 cells/microl. Four patients had a VF on therapy: two with wild-type viruses, one with selection of M184V and thymidine analogue mutations (TAMs) on a background of TAMs, and one with selection of K65R and M184V, with a replication capacity at 2.4%/o. CONCLUSION: The virological response in our study demonstrates the antiviral efficacy of the AZT/3TC/TDF combination therapy, which needs further evaluation. The moderate frequency of selection of K65R could be due to the presence of AZT in the regimen.