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Objective: To compare the estimated glomerular filtration rate (eGFR) using the creatinine equation (eGFRcreat) or the cystatin C equation (eGFRcys) in people with HIV (PWH) under antiretroviral drugs. We specifically included patients with an eGFRcreat around 60 ml/min per 1.73 m2 to evaluate agreement on stage 2 and 3 chronic kidney disease (CKD) classification., Design: eGFRcreat, eGFRcys and resulting CKD staging were determined in 262 consecutive patients with HIV-1 (PWH) with a suppressed viral load (<200 copies/ml) under antiretroviral drugs and having impaired renal function (eGFRcreat between 45 and 80 ml/min per 1.73 m2). Antiretroviral drugs regimens were classified into eight groups: cobicistat (COBI)+elvitegravir (EVG), ritonavir (RTV)+protease inhibitor, dolutegravir (DTG), DTG+rilpivirine (RPV), RPV, raltegravir (RAL), bictegravir (BIC), and other antiretroviral drugs., Results: Mean eGFRcys was higher than mean eGFRcreat (77.7 ± 0.5 vs. 67.9  ± 7.9 ml/min per 1.73 m2, P < 0.0001). The differences were significant in five treatment groups with COBI/EVG; DTG; DTG+RPV; RPV; RAL. CKD classification was modified for 51% of patients when using eGFRcys instead of eGFRcreat, with reclassification to less severe stages in 37% and worse stages in 14%., Conclusion: This study highlighted significant differences in eGFR depending on the renal marker used in PWH, having a significant impact on CKD classification. eGFRcys should be an additive tool for patients having eGFRcreat around 60 ml/min per 1.73 m2 for better identification of renal impairment., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Psoriasis is a T-cell-mediated inflammatory disease with genetic factors involved in its etiopathogenesis. In non-HIV populations, HLA-B57:01 has been associated with a higher risk of psoriasis. The aim of this study was to investigate demographic and immunovirological characteristics associated with psoriasis, and to assess whether HLA-B57:01 is associated with psoriasis among people living with HIV (PLHIV) followed in a large French multicenter Dat'AIDS cohort., Methods: All PLHIV followed up from January 2000 to December 2018 with an available result for HLA-B57:01 were included. Logistic regression models were used to identify associations between psoriasis (outcome variable) and explanatory variables., Results: Among 31 076 PLHIV, the overall prevalence of psoriasis and HLA-B57:01 were 2.25 and 4.73%, respectively and varied according to ethnicity. By multivariate analysis, male gender [OR 1.81 (95% CI 1.46-2.24), P < 10], positive HLA-B57:01 [OR 2.66 (95% CI 2.12-3.33), P < 10], nadir CD4 cell count less than 200 cells/μl [OR 1.41 (95% CI 1.19-1.67), P < 10] and positive HCV serology [OR 1.45 (95% CI 1.20-1.76), P < 10] were significantly associated with a higher risk of psoriasis. Being born in West and Central Africa [OR 0.15 (95% CI 0.10-0.25), P < 10], the Caribbean islands [OR 0.14 (95% CI 0.05-0.45), P = 0.0008] or Latin America [OR 0.31 (95% CI 0.14-0.69), P = 0.004] was associated with a lower risk of psoriasis compared with patients born in mainland France., Conclusion: PLHIV carrying HLA-B57:01 have around a three-fold increased risk of psoriasis. This association might provide a possible explanation for the observed differences in psoriasis prevalence between ethnic groups.

Design: Current international guidelines recommend either boosted protease inhibitor (PI/r)-based or integrase inhibitors (INSTI)-based regimens during primary HIV infection (PHI), even though the latter have only demonstrated their superiority at the chronic stage. We compared the effectiveness of INSTI-based versus PI/r-based combined antiretroviral therapy (cART) initiated during PHI., Methods: This study was conducted among patients who initiated cART between 2013 and 2017, using data from the ANRS-PRIMO cohort and the Dat'AIDS study. Cumulative proportions of patients reaching viral suppression (HIV-1 RNA <50 copies/ml) were calculated using Turnbull's estimator for interval-censored data. CD4 cells and CD4/CD8 ratio increases were estimated using mixed linear models. Results were adjusted for the data source., Results: Among the 712 study patients, 299 received an INSTI-based cART. Patients' baseline characteristics were similar between groups. Viral suppression was reached more rapidly in INSTI-treated versus PI/r-treated patients (P < 0.01), with cumulative proportions of 32 versus 6% at 4 weeks, 72 versus 31% at 12 weeks, 91 versus 78% at 24 weeks and about 95% in both groups at 48 weeks. At 4 weeks, INSTI-treated patients had gained on average 40 CD4 cells/μl (P = 0.05) over PI/r-treated ones; mean CD4 counts were similar in the two groups at 48 weeks. The CD4/CD8 ratio followed the same pattern. Results were similar when restricted to a comparison between dolutegravir-based versus darunavir-based cART., Conclusion: On the basis of this study and available literature, we recommend the use of INSTI-based cART for treatment initiation during PHI, as it leads to faster viral suppression and immune restoration.

Objective: To assess determinants for histologically proven high-grade anal intraepithelial lesions (hHSIL) in HIV-positive men who have sex with men (MSM), a population at high-risk of HPV-related anal cancer., Design: APACHES is a prospective study of anal HPV and related-lesions in 513 HIV-positive MSM aged at least 35 years in six centres across France., Methods: At baseline, participants underwent high-resolution anoscopy (HRA) with biopsy of suspicious lesions, preceded by anal swabs for liquid-based cytology, p16/Ki67 immunostaining, and HPV DNA. hHSIL diagnosis was established by histopathological review panel consensus, and determinants assessed by logistic regression., Results: Baseline hHSIL prevalence was 10.4% and did not differ significantly by age, sexual behaviour or HIV/immunodeficiency markers. hHSIL prevalence was significantly elevated in participants who smoked (ORadj = 2.6, 95% CI 1.3-5.5) or who, in concurrent anal swabs, had ASCUS/LSIL (3.6, 95% CI 1.4-9.3) or ASC-H/HSIL (22.2, 95% CI 6.8-72.6) cytologic abnormalities, p16/Ki67 dual positivity (3.4, 95% CI 1.5-7.5), or non-HPV16 HR (13.0, 95% CI 1.7-102), but most notably, HPV16 (46.3, 95% CI 6.1-355) infection. Previous diagnosis of low-grade (2.3, 95% CI 1.0-5.4) or high-grade (3.8, 95% CI 1.5-9.9) anal lesion also conveyed higher hHSIL risk. After controlling for patient-specific determinants, there remained significant centre-specific effects, most clearly in higher risk groups (HPV16-positive participants: 31.3% hHSIL in centres A-D versus 5.1% in centres E and F, P < 0.01)., Conclusion: Anal cytology and HPV16 infection are potentially useful determinants of hHSIL risk in HIV-positive MSM, but HIV/immunodeficiency-related variables appear not to be. Controlling for patient-specific hHSIL determinants highlights variability in HRA practice across diverse clinical settings and the need for better standardization of this difficult procedure.

Objectives: To investigate efficacy and safety of a single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg vs. darunavir/cobicistat plus emtricitabine/tenofovir disoproxyl fumarate (TDF) (control) in antiretroviral-treatment-naive, HIV-1-infected adults., Design: Phase-3, randomized, active-controlled, double-blind, international, multicenter, noninferiority study (NCT02431247)., Methods: Seven hundred and twenty-five participants were randomized (1 : 1) to D/C/F/TAF (362) or control (363). The primary objective was to demonstrate noninferiority of D/C/F/TAF vs. control for percentage viral load less than 50 copies/ml (FDA-snapshot analysis) at 48 weeks (10% margin)., Results: At week 48, D/C/F/TAF was noninferior to control (91.4 vs. 88.4% achieved viral load <50 copies/ml, respectively; difference 2.7%; 95% CI -1.6 to 7.1; P < 0.0001), with 4.4 vs. 3.3% of patients, respectively, having viral load greater or equal to 50 copies/ml. No treatment-emergent mutations associated with darunavir or TAF/TDF resistance were observed in either group. One patient (D/C/F/TAF) was identified with M184I/V conferring resistance to emtricitabine. Incidences of grades 3 and 4 adverse events (5 vs. 6%), serious adverse events (5 vs. 6%) and adverse event-related discontinuations (2 vs. 4%) were low and similar between groups. Mean decrease in urine protein/creatinine ratio was greater with D/C/F/TAF than control (-22.42 vs. -10.34 mg/g, P = 0.033). Mean percentage change in bone mineral density with D/C/F/TAF vs. control was 0.21 vs. -2.73%, P < 0.0001 (hip), -0.68 vs. -2.38%, P = 0.004 (lumbar spine), and -0.26 vs. -2.97%, P < 0.0001 (femoral neck). Median change from baseline in total cholesterol/HDL-cholesterol ratio was 0.20 vs. 0.08, P = 0.036., Conclusion: D/C/F/TAF achieved a high virologic suppression rate (91.4%) and was noninferior to darunavir/cobicistat with F/TDF. D/C/F/TAF also demonstrated the bone and renal safety advantages of TAF in combination with darunavir/cobicistat.

Objectives: To assess the alcohol consumption, tobacco addiction and psychoactive substance use (PSU) of people living with HIV (PLHIV)., Design: Cross-sectional study in an HIV outpatient unit., Methods: Autoquestionnaire systematically proposed to all patients during their usual clinical care visit during a 6-months period, for alcohol (AUDIT test), tobacco (Short Fagerstrom Test) and PSU (ASSIST V3.0 test)., Results: Of 1334 distributed questionnaires, 1018 PLHIV responded: 76.8% were men [528 patients were MSM), and the median age was 49 years (interquartile range: 42-46). A prevalence of excessive alcohol drinking was found in 22% [95% confidence interval (CI) 19.5-24.7%] and 44.6% (CI 41.5-47.7%) were current smokers, with high dependence in 29.1% (CI 24.9-33.7%). The prevalence of PSU was 37.8% (CI 34.8-41%) in the past 3 months: cannabis 27.7%, poppers 16.4%, cocaine 8.9%, psychotropic medications 7.1%, gamma-hydroxybutyrate/gamma-butyrolactone (GHB/GBL) 4.7%, stimulants 3.1%, synthetic cathinones 2.7%, hallucinogens 1.5%. In the past 3 months, PSU was more prevalent in MSM than in non-MSM patients (46 versus 30%, P < 0.001). MSM consumed significantly more inhaled solvents (poppers) 31.0 versus 1.1%, GHB/GBL 7.8 versus 0.8%, stimulants 5.0 versus 1.1%, synthetic cathinones 4.9 versus 0.3%, and hallucinogens 2.3 versus 0.5%., Conclusion: Given the high prevalence of PSU and other addictions (alcohol and smoking) among PLHIV, and particularly among MSM, a systematic screening of PSU and other addictions should be part of routine clinical care.

Objective: High hepatitis C virus (HCV) treatment uptake combined with effective direct-acting antiviral-based regimens resulted in a dramatic decline of HCV infection in French people living with HIV (PLWH). We assessed the yearly incidence of new HCV infection in PLWH enrolled in the large French Dat'AIDS cohort from 2012 to 2016 with a specific focus on MSM., Methods: The incidence of new HCV infection was determined yearly in HCV-negative PLWH with serological follow-up during 2012-2016. The incidence of HCV reinfection was determined in patients who were cured of a previous infection., Results: Among 40 714 PLWH, HCV status was available in 38 217 (94%). A total of 5557 PLWH (15%) were HCV infected at first time-point, 82% of whom were cured of HCV by the end of 2016. Among 21 519 HCV-negative PLWH with serological follow-up (63 449 patient-years), 219 first HCV infections occurred (MSM: 188, others: 31). Similarly, among 3406 patients who were cured of a previous infection (10 602 patient-years), 73 reinfections occurred (MSM: 51, others: 22). From 2012 to 2016, the incidence of a first infection in MSM rose from 0.5 to 0.92% patient-years, whereas the incidence or reinfection remained stable (2.52-2.90% patient-years)., Conclusion: Despite a high HCV treatment uptake and cure rate, the incidence of first HCV infection regularly increased in French HIV-positive MSM between 2012 and 2016. The incidence of reinfection fluctuated but remained constantly higher than the incidence of first infection, suggesting that a subgroup of MSM pursued high-risk practices following cure of a first infection.

Objective: To explore whether airway obstruction is associated with HIV in a cohort of HIV-infected and uninfected smokers., Methods: People living with HIV (PLWHIV) participated in the ANRS EP48 HIV CHEST study, an early lung cancer diagnosis study with low-dose chest tomography. HIV-uninfected study participants were from the CONSTANCES cohort. Inclusion criteria were an age greater than 40 years, a smoking history of at least 20 pack-years, and for PLWHIV, a CD4 T-lymphocyte nadir less than 350/μl and last CD4 cell count more than 100 cells/μl. Two randomly selected HIV-uninfected study participants were matched by age and sex with one PLWHIV. Prebronchodilatator forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio was the primary outcome, and association of FEV1/FVC ratio less than 0.70 and FEV1 less than 80% of the theoretical value, as a proxy of chronic obstructive pulmonary disease, the secondary outcome., Results: In total, 351 PLWHIV and 702 HIV-uninfected study participants were included. Median age was 50 years, and 17% of study participants were women. Plasma HIV RNA was less than 50 copies/ml in 89% of PLWHIV, with a median CD4 cell count of 573 cells/μl. HIV (β -2.19), age (per 10 years increase; β -2.81), tobacco use (per 5 pack-years increase; β -0.34), and hepatitis C virus serology (β-2.50) were negatively associated with FEV1/FVC. HIV [odds ratio (OR: 1.72)], age (per 10 years increase; OR 1.77), and tobacco use (per 5 pack-years increase; OR 1.11) were significantly associated with the secondary outcome., Conclusion: Our study found a significant association of airway obstruction with HIV status in smokers aged more than 40 years with previous immunodeficiency.

Objective: Lung cancer screening with chest computed tomography (CT) is beneficial in smokers aged 55 to 74 years. We studied the risks, benefits and feasibility of early lung cancer diagnosis with CT in HIV-infected smokers., Design and Setting: French, multicentre, single round chest CT study in France, realized between February 2011 and June 2012., Participants: Patients were HIV-infected smokers at least 40 years, at least 20 pack-years, with a CD4 T-lymphocyte nadir count below 350 cells/μl., Intervention: Single chest CT with a proposed standardized workup algorithm of positive images., Main Outcome Measure: The outcome was the number of histologically proven lung cancers diagnosed by CT with a 2-year follow-up., Results: Median age of the 442 included patients was 49.8 years, 81.6% were under 55 years, 84% were men, median smoking was 30 pack-years, median nadir and last CD4 cell counts were 168 and 574 cells/μl, respectively, and 90% of patients had a plasma HIV RNA below 50 copies/ml. A positive image at baseline was reported in 94 (21%) patients, and 15 (3.4%) patients had 18 invasive procedures with no serious adverse events. Lung cancer was diagnosed in 10 patients (six at early stages), of which nine (2.0%, 95% confidence interval: 0.9-3.8) were CT detected, and eight in patients below 55 years., Conclusion: Early lung cancer diagnosis with CT in HIV-infected smokers was feasible, safe, and yielded a significant number of cancers. Lung cancer screening of HIV-infected smokers with an important history of immunodeficiency revealed a substantial number of cancers at younger ages than the targeted range in the general population.

Objective: WHO recommends ritonavir-boosted protease inhibitor with two nucleoside reverse transcriptase inhibitors in HIV-infected patients failing non-nucleoside reverse transcriptase inhibitor-based first-line treatment. Here, we aimed to provide more evidence for the choice of nucleoside reverse transcriptase inhibitor and boosted protease inhibitor., Design: ANRS 12169 is a 48-week, randomized, open-label, non-inferiority trial in three African cities, comparing efficacy and safety of three second-line regimens., Methods: Patients failing non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy with confirmed plasma HIV-1 viral load above 1000 copies/ml were randomly assigned to tenofovir/emtricitabine + lopinavir/ritonavir (control group as per WHO recommendations), abacavir + didanosine + lopinavir/ritonavir (ABC/ddI group) or tenofovir/emtricitabine + darunavir/ritonavir (DRV group) regimens. The primary endpoint was the proportion of patients with plasma vral load below 50 copies/ml at week 48 in the modified intention-to-treat population. Non-inferiority was pre-specified with a 15% margin., Results: Of the 454 randomized patients, 451 were included in the analysis. Globally, 294 (65.2%) and 375 (83.2%) patients had viral load below 50 and 200 copies/ml, respectively, at week 48. The primary endpoint was achieved in 105 (69.1%) control group patients versus 92 (63.4%) in the ABC/ddI (difference 5.6%, 95% confidence interval -5.1 to 16.4) and 97 (63.0%) in the DRV (difference 6.1%, 95% confidence interval -4.5 to 16.7) groups (non-inferiority not shown). Overall, less number of patients with baseline viral load at least 100 000 copies/ml (n = 122) had a viral load below 50 copies/ml at week 48 (37.7 versus 75.4%; P < 0.001)., Conclusions: The three second-line regimens obtained similar and satisfactory virologic control and confirmed the WHO recommendation (TDF/FTC/LPVr) as a valid option. However, the suboptimal response for patients with high viral load warrants research for improved strategies.

Objective: To evaluate the efficacy and safety/tolerability of dolutegravir (DTG, S/GSK1349572), a potent inhibitor of HIV integrase, through the full 96 weeks of the SPRING-1 study., Design: ING112276 (SPRING-1) was a 96-week, randomized, partially blinded, phase IIb dose-ranging study., Methods: Treatment-naive adults with HIV received DTG 10, 25, or 50 mg once daily or efavirenz (EFV) 600 mg once daily (control arm) combined with investigator-selected dual nucleos(t)ide reverse transcriptase inhibitor backbone regimen (tenofovir/emtricitabine or abacavir/lamivudine). The primary endpoint of the study was the proportion of participants with plasma HIV-1 RNA less than 50 copies/ml, based on time to loss of virologic response at 16 weeks (conducted for the purpose of phase III dose selection), with a planned analysis at 96 weeks. Safety and tolerability were also assessed., Results: Of 208 participants randomized to treatment, 205 received study drug. At week 96, the proportion of participants achieving plasma HIV-1 RNA less than 50 copies/ml was 79, 78, and 88% for DTG 10, 25, and 50 mg, respectively, compared with 72% for EFV. The median increase from baseline in CD4 cells was 338 cells/μl with DTG (all treatment groups combined) compared with 301 cells/μl with EFV (P  = 0.155). No clinically significant dose-related trends in adverse events were observed, and fewer participants who received DTG withdrew because of adverse events (3%) compared with EFV (10%)., Conclusion: Throughout the 96 weeks of the SPRING-1 study, DTG demonstrated sustained efficacy and favorable safety/tolerability in treatment-naive individuals with HIV-1.

Objective: To assess the frequency of glomerular and tubular proteinuria in a cohort of HIV-infected patients, and to determine the factors associated with each type of injury., Design: Cross-sectional study of 1210 consecutive HIV-infected adults followed in HIV outpatient unit (Montpellier/France)., Methods: Spot urine protein to creatinine (uPCR), albumin to creatinine (uACR) and albumin to protein (uAPR) ratios were assessed. Glomerular injury was defined as uACR at least 30 mg/g or uPCR at least 200 mg/g with uAPR at least 0.4. Tubular injury was defined as uPCR 200 mg/g or more with uAPR less than 0.4. Multivariate logistic regression identified independent factors of each type of proteinuria, in the 1158 patients with estimated glomerular filtration rate (eGFR) at least 60 ml/min per 1.73 m, using re-expressed modification of diet in renal disease equation., Results: Frequency of proteinuria was 18.2% among patients with eGFR at least 60 ml/min per 1.73 m consisting in tubular proteinuria for 50.7% of them. Factors associated with glomerular proteinuria were age [OR 1.34/10-year increment (95%CI: 1.08-1.66)], diabetes [OR 3.37 (95%CI: 1.53-7.44)], and arterial hypertension [OR 2.52 (95%CI: 1.36-4.66)]. Factors associated with tubular proteinuria were age [OR 1.43 (95%CI: 1.14-1.79)], current tenofovir use [OR 3.52 (95%CI: 1.86-6.65)], hepatitis C co-infection [OR 1.62 (95%CI: 1.00-2.65)], AIDS stage [OR 1.83 (95%CI: 1.18-2.82)], CD4 cell count less than 200 per μl [OR 2.48 (95%CI: 1.31-4.70)]., Conclusion: This study distinguished risk factors for tubular injury, mainly related to HIV disease and its treatment (tenofovir), and glomerular injury, linked to non HIV-related variables (age, diabetes, hypertension). Measuring uPCR, uACR and uAPR may help with the detection and specific management of early chronic kidney disease in HIV-infected patients having normal or sub-normal eGFR.

Management of relapsing or refractory immune reconstitution inflammatory syndromes (IRISs) despite corticosteroid therapy is yet to be defined. We describe three HIV-infected patients with corticosteroid-dependent and life-threatening paradoxical immune reconstitution inflammatory syndrome for whom thalidomide treatment induced rapid clinical remission and permitted complete corticosteroid withdrawal without clinical relapse.

Interferon-α administration during structured treatment interruptions (STIs) was studied in a phase III trial. We randomized 168 chronically infected HIV undetectable under combined antiretroviral therapy patients to have three STIs with or without α-interferon. The number of patients who had to resume treatment during post-STI follow-up was not significantly different between the two arms. Patients with a low CD4 nadir and a high baseline HIV-DNA had a higher risk of treatment resumption in the interferon arm.

The efficiency of CCR5 as an HIV coreceptor is strongly dependent on its level of cell surface expression. Therefore, it is of major importance to identify the factors that regulate cell surface density of CCR5. Among the chemokines that bind to CCR5, and induce its internalization, CCL5 is the most abundant in vivo. We show that the level of CCL5 production is a main factor determining CD4+ T cell surface CCR5 density.

To investigate the maintenance of long-term memory B cells specific for hepatitis B surface antigen (HBsAg), purified blood B cells were polyclonally stimulated and cells secreting antibodies directed to HBsAg (HBs-SC) enumerated by ELISpot. HBs-SC were found in 18/20 HIV-1-infected patients with either natural or vaccinal immunity to hepatitis B virus, including six subjects with serum anti-hepatitis B surface antibody levels less than 10 mIU/ml. A lower number of HBs-SC was found in HBsAg-vaccinated patients compared with vaccinated controls.

Objective: To determine antiviral activity, pharmacokinetic properties, and safety of vicriviroc, an orally available CCR5 antagonist, as monotherapy in HIV-infected patients., Design and Methods: An ascending, multiple dose, placebo-controlled study randomized within treatment group. Forty-eight HIV-infected individuals were enrolled sequentially to dose groups of vicriviroc: 10, 25 and 50 mg twice a day, and were randomly assigned within group to receive vicriviroc or placebo (16 total patients/group) for 14 days., Results: Significant reductions from baseline HIV RNA after 14 days were achieved in all active treatment groups. Suppression of viral RNA persisted 2-3 days beyond the end of treatment. Reductions of 1.0 log10 HIV RNA or greater were achieved in 45, 77 and 82% of patients in the three groups, respectively. Eighteen, 46 and 45% of subjects achieved declines of 1.5 log10 or greater in HIV RNA in the three groups, respectively. Vicriviroc was rapidly absorbed with a half-life of 28-33 h, supporting once-daily dosing. Pharmacokinetic parameters were dose linear; steady state was achieved by day 12. Two subjects experienced a transient detectable X4-tropic virus. Vicriviroc was well tolerated in all dose groups. The frequency of adverse events was similar in the vicriviroc and placebo groups: 72 and 62%, respectively. The most frequently reported adverse events included headache, pharyngitis, nausea and abdominal pain, which were not dose related., Conclusion: Whereas all doses were well tolerated and produced significant declines in plasma HIV RNA, total oral daily doses of 50 or 100 mg vicriviroc monotherapy for 14 days appeared to provide the most potent antiviral effect in this study.

Objective and Design: The intensity of replication of CCR5-using HIV-1 strains is highly dependent on the number of CCR5 molecules on the surface of CD4-positive T cells. The molecular mechanisms responsible for this phenomenon remained so far unclear. As CCR5 co-receptors are coupled to G alpha i and G alpha q proteins, we tested the hypothesis that the activation triggered through these proteins secondary to the interaction between the viral envelope and CCR5 could account for the effect of the level of CCR5 expression on HIV-1 production., Methods: We transduced the wild-type or a G-protein signalling-defective CCR5 gene into CD4/CCR5 HOS cells and peripheral blood mononuclear cells. The effect on cell activation in presence of a CCR5-binding chemokine and on HIV infection was monitored by measuring calcium mobilization and p24 antigen production, respectively. The role of G alpha i protein signalling was tested by adding pertussis toxin to the cell cultures or by transfecting small interfering (si) RNAs into the HOS cells., Results: The over-expression of the wild-type form, but not of a G-protein signalling-defective form of CCR5, on the surface of CCR5 expressing peripheral blood mononuclear cells markedly increased their infectability. In addition, both pertussis toxin and G alpha i 1-specific siRNA drastically inhibited R5 infection., Conclusions: The signalling through G alpha i-protein induced upon R5 virion binding to CCR5 is responsible for the difference in HIV-1 infectability between CD4-positive T cells expressing low or high levels of cell surface CCR5 density. This observation sheds new light on the physiopathology of HIV infection, and opens new therapeutic opportunities targeting G alpha i signalling.

We analysed the genetic changes in gp41 in a population of 30 heavily pretreated HIV-1-infected patients failing on a T-20-containing salvage therapy. This study confirms the key role of the number of drugs presumed to be still effective associated with T-20 in the magnitude of the virological response. Our results suggest that only HR-1 sequencing is necessary to characterize resistance to T-20, and that HR-2 domain sequencing is probably not required.

Background: Both highly potent antiretroviral drug rescue therapy and treatment interruption have been suggested to be effective in patients with multiple treatment failure., Objective: To assess both the benefits and risks of an 8-week treatment interruption associated with a six to nine-drug rescue regimen in patients with multiple treatment failures., Design: A randomized comparative controlled trial in 19 university hospitals in France., Patients: Sixty-eight HIV-infected patients with multiple previous treatment failures and CD4 cell counts less than 200 x 10(6) cells/l and plasma HIV-1-RNA levels of 50,000 copies/ml or greater., Measurements: The primary efficacy outcome was the proportion of patients with at least a 1 log10 decrease (copies/ml) in the plasma HIV-1-RNA level after 12 weeks of therapy., Results: Treatment interruption followed by multidrug salvage therapy led to a greater proportion of patients achieving virological success (i.e. 1 log10 decrease) at 12 weeks compared with patients receiving multidrug therapy alone (62 versus 26%, intent-to-treat analysis; P = 0.007). The median decrease in the HIV-1-RNA level was -1.91 and -0.37 log10 copies/ml (P = 0.008), respectively. Treatment interruption led to an increase in the number of sensitive drugs of the multidrug regimen (71 versus 35% of regimen with at least two sensitive drugs; P = 0.004). Factors associated with virological success were treatment interruption, the reversion of at least one mutation to wild type, adequate plasma drug concentration, and the use of lopinavir., Conclusion: Treatment interruption was beneficial for treatment-experienced HIV-infected patients with advanced HIV disease and multidrug-resistant virus.

Objectives: To examine whether polyclonal activation of circulating B cells, in a process that involves CD40-CD40 ligand and cytokine interactions, could induced HIV-1-specific memory B cells to synthesize HIV-1-specific antibodies., Methods: B cells from 26 HIV-1-infected patients were cultured with a CD40L-transfected cell line plus interleukins 2 and 10 and tested for their secretion of HIV-1- and Toxoplasma gondii-specific antibodies., Results: In vitro activated B lymphocytes from HIV-1-infected patients secreted anti-HIV-1-specific antibodies. B cells from HIV-1-infected patients as well as those from controls chronically infected by T. gondii synthesized T. gondii-specific antibodies. HIV-1-specific IgG-, IgA- or IgM-secreting B cells represented approximately 1 x 10(-4) to 1 x 10(-5) of total circulating B cells and 1 x 10(-2) to 1 x 10(-3) of immunoglobulin-secreting cells. HIV-1-specific memory B cells were found in 9/9 untreated patients and in 8/17 patients receiving highly active antiretroviral therapy (HAART). The other nine patients showed a normal CD40-CD40L B cell response and six of them produced T. gondii-specific antibody B cells. The follow-up of seven patients indicated that HIV-1-specific memory B cells became undetectable after 8 to 46 months of HAART, whereas T. gondii-specific memory B cells persisted in parasite coinfected patients., Conclusions: Circulating memory HIV-1-specific B cells were detected in untreated patients and in about half of the patients taking HAART, suggesting that persistent low-level ongoing viral replication is not sufficient to maintain HIV-1-specific memory B cells.

Objective and Design: Interferon alpha (IFNalpha), which is known to directly inhibit the HIV-1 replicative cycle and to increase the activity of cytotoxic T lymphocytes (CTL), is being tested as an anti-HIV agent. As CTL play a major role in immune defence against HIV, we wanted to further characterize CTL activity and the effect of IFNalpha on it., Methods: We followed by flow cytometry the intracellular expression of the key mediator of cytotoxicity, perforin, in peripheral blood T cells of patients treated with IFNalpha., Results: We observed that the percentage of T cells harbouring perforin was higher in infected subjects than in non-infected controls. Administration of IFNalpha2b attached to polyethylene glycol increased this perforin expression further and reduced viral load (P = 0.010). The increase in the percentage of T cells expressing perforin correlated with IFNalpha-induced decrease in viral load (r, 0.753; P = 0.003). In addition, the level of perforin expression before IFNalpha administration was inversely correlated with viral load remaining after IFNalpha administration (r, -0.647; P= 0.017)., Conclusion: The pre-therapeutic percentage of perforin-positive T cells might be a predictive marker of the virological response to IFNalpha in HIV-1-infected patients.

Objective: The percentage and the activity of natural killer (NK) cells are known to be decreased in HIV-infected patients. However, the mechanisms responsible for this NK deficiency are poorly understood. Because of the role of NK cells in the host defence against microbial infections, this defect contributes to the virus-induced immune deficiency. The aim of the present study was to better understand this defect in order to be able to restore NK function in HIV infection., Design and Methods: The expression of the cytolytic mediators perforin and granzyme A was analysed by flow cytometry, the lytic activity of peripheral blood NK cells of HIV-infected patients was analysed by cytotoxic assay, and the expression of perforin was followed during administration of interferon (IFN)alpha attached to polyethylene glycol (PEG)-IFNalpha., Results: The lytic activity and the expression of perforin and granzyme A was low in NK cells of infected individuals in comparison with normal control volunteers. In both groups NK cytotoxic capacity was linked to perforin expression. The low perforin expression in HIV-infected subjects negatively correlated with HIV RNA plasma level. administration of PEG-IFNalpha restored perforin expression even in patients whose viral load was not reduced by this treatment., Conclusions: These results suggest that HIV-induced NK deficiency could be partly mediated by a defect in perforin and granzyme A expression, and that PEG-IFNalpha could be used in infected subjects to directly improve their natural immunity in addition to eventually reducing their viraemia.

Objectives: As spontaneous anti-HIV-1 antibody and IgG secretion by peripheral blood mononuclear cells (PBMC) reflect immune system activation by HIV-1 antigens, we evaluated the impact of antiretroviral therapies on HIV-1 specific and non-specific B cell responses., Methods: Anti-HIV-1 antibody and non-specific IgG were measured by ELISA in supernatants of PBMC cultured during 7 day from 30 patients initiating an antiretroviral therapy at baseline, 8, 16, 24, 36 and 48 weeks., Results: An early and sustained fall in plasma viral load to below the detection limit (20 copies/ml) was observed in 17 sustained responder patients (SR), whereas HIV-1 RNA remained detectable in 13 others incomplete responders. In both groups, HIV-1 specific antibody secretion decreased significantly in parallel with plasma viral load and polyclonal immunoglobulin production became similar to that of PBMC controls. However, HIV-1 specific antibody production became negative in only six SR, exhibiting a greater increase of CD4 T-cell counts and higher levels of the spontaneous HIV-1 specific IgA secretion at baseline than the other SR., Conclusions: Antiretroviral therapy induced a rapid and dramatic decrease of spontaneous HIV-1 specific and non-specific B cell responses. These results pointed out that HIV-1 specific antibody secretion persisted in 11 out of 17 SR patients, suggesting persistent immune system activation by residual HIV-1 antigens., (Copyright 2002 Lippincott Williams & Wilkins)

Objective and Design: We have recently shown that the number of CCR5 molecules at the surface of peripheral blood CD4 T cells (CCR5 density) correlates with the viral RNA plasma level in HIV-1-infected individuals. As viral load is a strong predictor of outcome in HIV infection, the present study examines the correlation between CCR5 density and HIV-1 disease progression., Methods: Using a quantitative flow cytometry assay, we measured CCR5 density in HIV-1-infected adults and control healthy volunteers. The CCR5 genotype (presence of a Delta 32 allele) was also determined., Results: CCR5 density was stable over time on non-activated, HLA-DR(-)CD4 T cells of infected individuals. In a study cohort of 25 patients, asymptomatic and non-treated, we observed a correlation between CCR5 density on HLA-DR(-)CD4 T cells and the CD4 T cell slope (P = 0.026), which was independent of the presence or absence of the Delta 32CCR5 deletion. In particular, slow progressors expressed lower CCR5 densities than non-slow progressors (P = 0.004) and non-infected control subjects (P = 0.002)., Conclusion: These results are compatible with the hypothesis that CCR5 density, which is a key factor of HIV-1 infectability, determines in-vivo HIV production, and thereby the rate of CD4 cell decline. Consequently, CCR5 density quantitation could be a new valuable prognostic tool in HIV-1 infection. Moreover, these data emphasize the therapeutic potential of treatments that reduce functional CCR5 density.

Objective: Assessment of genotypic changes in the reverse transcriptase gene of HIV-1 occurring in antiretroviral naive patients treated by stavudine plus didanosine combination therapy., Methods: Sequence analysis (codons 1-230) was performed after amplification of the reverse transcriptase gene from plasma samples collected at baseline and at the end of treatment from 39 previously treatment-naive patients treated for 24-48 weeks., Results: At baseline, mutations associated with zidovudine resistance were detected in plasma from two patients: Asp67Asn/Lys219Gln and Leu210Trp. Among the 39 subjects, 18 (46%) developed mutations: one developed the Val75Thr/Ala mutation, four (10%) developed a Gln151Met multidrug-resistance mutation (MDR), associated in one of them with the Phe77Leu and the Phe116Tyr MDR mutations and 14 (36%) developed one or more zidovudine-specific mutations (Met41Leu, Asp67Asn, Lys70Arg, Leu210Trp, Thr215Tyr/Phe). The development of a Met41Leu zidovudine-specific mutation was associated with the development of a Gln151Met mutation in one patient. Other reverse transcriptase mutations known to confer resistance to nucleoside analogues were not detected. At inclusion, there was no statistical difference in HIV-1 load between patients who developed resistance mutations and those who did not. RNA HIV-1 load decrease was higher (P = 0.05) in patients who maintained a wild-type reverse transcriptase genotype (-2.22 log10 copies/ml) than in patients who developed resistance mutations (-1.14 log10 copies/ml)., Conclusion: Stavudine/didanosine combination therapy is associated with emergence of zidovudine-related resistance or MDR mutations in naive patients. These findings should be considered when optimizing salvage therapy for patients who have received a treatment including stavudine/didanosine combination.

Objective: This study was performed to investigate the hyporeactivity of purified B lymphocytes from HIV-1-infected patients., Design: Given the importance of the B-cell Ag receptor (BCR) and CD40 in B-lymphocyte activation, we assessed the capacity of purified peripheral blood B lymphocytes from HIV-1-infected patients to differentiate into Ig-secreting cells in a T-cell- and accessory-cell-independent system of BCR and CD40 costimulation., Methods: B lymphocytes from 21 HIV-1-infected patients were purified by immunomagnetic cell separation and costimulated with immobilized anti-CD40 monoclonal antibodies and Staphylococcus aureus Cowan I particles in the presence of interleukin (IL)-2 and IL-10. Homotypic aggregate formation, apoptosis, cell cycle entrance, proliferation and Ig secretion of B cells were analysed., Results: Costimulation by the BCR and CD40 induced proliferation and differentiation of B lymphocytes into Ig-secreting cells in 13 patients (group I) but not in eight patients (group II). For three patients in group II, the dual triggering induced apoptosis of B cells. The unexpected inability of these cells to differentiate was associated with a high CD38 expression and a weak spontaneous production of Ig or anti-HIV-1 antibodies in patients with a high viral load and a low CD4+ lymphocyte count. Despite this anomaly, the B cells from group II were able to progress through the cell cycle after stimulation with a combination of phorbol ester and ionomycin in complete medium, suggesting an impairment in BCR and CD40 early signal transduction., Conclusion: Intrinsic in vitro hyporeactivity of B lymphocytes to dual triggering of BCR and CD40 was observed in advanced HIV-1 disease and appeared to be related to in vivo hyperactivation of B cells.