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Background: The proportion of HIV controllers developing virologic, immunological or clinical progression and the baseline predictors of these outcomes have not been assessed in large cohorts., Methods: A multicenter cohort of HIV controllers was followed from baseline (the first of the three HIV-1 RNA levels < 50 in elite controller or from 50 to 2000 copies/ml in viremic controllers) up to August 2011, to the development of a progression event (loss of viral load control, CD4 decline, AIDS or death) or to the censoring date (lost to follow-up or initiation of antiretroviral therapy). Predictive models of progression at baseline and a risk score for the combined HIV-1 progression end point were calculated., Results: Four hundred and seventy-five HIV-1 controllers of whom 204 (42.9%) were elite controller with 2972 person-years of follow-up were identified. One hundred and forty-one (29.7%) patients lost viral load control. CD4 cell count declined in 229 (48.2%) patients. Thirteen patients developed an AIDS event and four died. Two hundred and eighty-seven (60.4%) developed a combined HIV-1 progression. Baseline predictors for the progression end points and for elite and viremic controller patients were very similar: risk for HIV-1 acquisition, baseline calendar year, CD4 nadir, viral load before baseline and hepatitis C virus coinfection. The probability of a combined HIV-1 progression at 5 years was 70% for elite controllers with the highest score compared with 13% for those with the lowest., Conclusion: HIV-1 disease progression in elite and viremic controllers is frequent. We propose a baseline clinical score to easily classify these patients according to risk of progression. This score could be instrumental for taking clinical decisions and performing pathogenic studies.

Administering raltegravir once daily would make adherence to antiretroviral treatment easier, especially if the concomitant drugs are also administered once daily. We report our experience on the use of raltegravir, both once- and twice-daily.Retrospective review of HIV-infected patients on treatment with raltegravir 800 mg once or 400 mg twice a day plus 2 analogs. Patients were classified as group A (subjects switched to raltegravir due to adverse events on a previous regimen or drug-drug interactions) and group B (subjects who restarted antiretroviral treatment after a previous drop-out). The primary clinical endpoint was the percentage of subjects with virological suppression after 96 weeks. Treatment's effectiveness (noncomplete/missing equals failure) was also evaluated. Pharmacokinetic study was performed in unselected patients. Plasma raltegravir concentrations were determined by high-performance liquid chromatography coupled with mass spectrometry.A total of 133 patients were included in the study (74 and 59 on raltegravir once- and twice-daily). There were only 4 virological failures in the entire cohort during the follow-up. Thus, the Kaplan-Meier estimation of efficacy by on-treatment analysis was 96.3% (CI95, 92.8-99.8) at week 96, independently of the dosing regimen and of the raltegravir concentrations. Similar exposures to raltegravir based on AUC0-τ, but higher Cmax and significantly lower Ctrough were observed when raltegravir was given once daily compared with 400 mg twice daily. In fact, 14 out of 56 Ctrough concentrations (25%) from patients taking raltegravir once daily were below the IC95 of wild-type HIV-1 clinical isolates while only 2 samples from patients receiving 400 mg twice a day were below this value, although no relationship between Ctrough and efficacy was found. The main limitations of the study are that the raltegravir dosing regimen was not randomized and more than 50% of the patients were virologically suppressed at baseline.Regimens comprising raltegravir 800 mg once daily plus 2 nucleos(t)ide reverse transcriptase inhibitors can be an efficacious and safe option, particularly in virologically suppressed patients and those with a viral load <100,000 copies/mL.

The purpose of this article is to evaluate the evolution of microbial translocation (MT) and its role in CD4 and CD8 T cells immune activation (IA) in HIV-1-infected patients on ritonavir-boosted darunavir monotherapy (mtDRV/rtv).Prospective study of consecutive HIV-1-infected patients switched to mtDRV/rtv as a simplification regimen. Subjects were classified according to the virological behavior during a 24-month follow-up as continuous undetectable viral load, blips, intermittent viremia, and virological failure (VF). MT was evaluated by plasma LPS and 16S genomic rDNA (16S rDNA) levels, whereas IA was assessed by the coexpression of HLA-DR and CD38 in CD4 and CD8 T cells, and plasma sCD14 levels.Seventy-one patients were included in this substudy of the MonDar cohort (ClinicalTrials.gov: NCT01505722). At baseline, CD4 (ρ = -0.352, P = 0.01) and CD8 T-cell activation (ρ = -0.468, P < 0.001) were correlated with time with viral suppression, but not with MT markers. A significant decrease in plasma LPS levels was found only in patients without VF (baseline, 77.8 vs month 24, 60.4 pg/mL; P < 0.001]. Both plasma 16S rDNA and sCD14 levels were unchanged irrespective of the viral behavior. The only variable independently associated with a decrease in CD4 and CD8 T cells activation was an undetectable HIV-1 viremia (β = 4.78, P < 0.001 and β = 2.93, P = 0.005, respectively).MT does not have a pivotal role in T-cell activation, at least in patients with long-term viral suppression. The viremic episodes and VF are the main factors related to CD4 and CD8 T-cells IA, even during mtDRV/rtv.

Objective: To assess the impact of blips and persistent viremia episodes on cell-associated HIV-DNA reservoir in extensively pretreated patients receiving ritonavir-boosted darunavir monotherapy (MtDRV/rtv) for 24 months., Design and Methods: Patients from the MonDAR prospective study (NCT01606722) who received at least 6 months of MtDRV/rtv and had at least two available peripheral blood mononuclear cells (PBMCs) samples were selected and classified according to the viral outcome as continuous undetectable viremia (cUV; n = 40), blips (n = 31), intermittent viremia (IV; n = 23), and virological failure (VF, two consecutive viral loads >200 copies/ml; n = 20). Proviral HIV-DNA was quantified by real-time PCR in PBMCs samples at baseline, and months 6, 12, 18 and 24. Additionally, HIV-DNA levels were exhaustively analyzed at virological failure and blip episodes., Results: The HIV-DNA levels remained constant during the 24 months in every group. Neither blips nor intermittent viremia influenced the HIV-DNA levels at short-term or at middle term. By contrast, virological failure episodes gave rise to a significant increase in proviral DNA (2.15 vs. 2.32 log10 HIV-DNA copies/10 PBMCs; P = 0.042). Basal proviral DNA levels more than 2 log10 copies/10 PBMCs predicted the time to viral rebound at any given cut-off point (>20, >50, and >200 copies/ml. HR: 3.02, 2.61, and 3.02, respectively; P ≤ 0.03. Besides, an adherence less than 95% was also strongly associated with virological failure (HR, 3.17; P = 0.021)., Conclusion: Blip episodes and intermittent viremia did not affect the cellular HIV reservoir dynamic during MtDRV/rtv. Higher adherence and an HIV-DNA levels less than 2 log10 copies/10 PBMCs at baseline were associated with a lower risk of virological failure.

The efficacy of low-dose, ritonavir-boosted saquinavir (SQV/rtv) once daily plus 2 nucleoside retrotranscriptase inhibitors (NRTIs) in pregnant human immunodeficiency virus (HIV)-1-infected women was prospectively evaluated, ensuring a SQV minimum concentration (Cmin) >/=100 ng/mL with a therapeutic drug monitoring strategy. The primary clinical endpoint was the percentage of women with an HIV-RNA viral load (VL) of <50 copies/mL at the time of delivery. Forty-nine pregnancy episodes were included, with a median CD4 count and VL of 441/muL and 3710 copies/mL, respectively. Two patients were lost to follow-up and 1 patient discontinued treatment because of abdominal discomfort. SQV levels were in excess of the target Cmin in 43 of 46 episodes (93.4%) in which the end of pregnancy was reached on 1200/100 mg daily. The dosage was increased to 1600/100 mg in the remaining 3 episodes to achieve the target levels. By an intention-to-treat analysis, VL was undetectable at delivery in 43 episodes (87.7%; 95% confidence interval, 78.5-96.9) after a median of 18 weeks of treatment (range, 3-39). In the 3 episodes remaining, VLs of 110,400 copies/mL and no available data were observed after only 3 weeks of treatment. Mild adverse events attributable to SQV/rtv occurred in 6 of 49 pregnancies (12.2%). No cases of HIV vertical transmission were observed. The pharmacokinetics, efficacy, and tolerability of this regimen suggest that once-daily low-dose boosted SQV may be considered an appropriate option in PI-naive or limited-PI-experienced HIV-infected pregnant women. Nevertheless, therapeutic drug monitoring is advisable to maintain appropriate levels throughout pregnancy.

Background: We recently observed a significant CD4 cell count decline in patients receiving didanosine (ddI) 400 mg, tenofovir (TDF) and nevirapine (NVP), despite virological suppression., Methods: We identified from our computerized patient database subjects who initiated combinations containing ddI and/or TDF for reasons other than virological failure, including simplification or intolerance. Changes in total, CD4+ and CD8+ lymphocyte counts since the initiation of therapy were analysed retrospectively. Plasma concentration of ddI was prospectively determined in eight of these patients receiving ddI 400 mg + TDF + NVP and 3 weeks after a ddI dosage reduction., Results: A total of 302 patients were studied. A significant decrease in CD4 and CD8 and in total lymphocyte counts was only seen in subjects receiving ddI standard dose + TDF-containing regimens, despite the maintenance of viral suppression. More than 50% of these patients showed a decline of more than 100 CD4 cells at 48 weeks. In contrast, subjects not receiving ddI + TDF together experienced the expected progressive increase in CD4 T-cell counts. Plasma levels of ddI were elevated in all patients receiving the standard ddI dose + TDF. DdI plasma levels significantly decreased when patients weighting > 60 kg reduced ddI dose to 250 mg, achieving similar levels to those generated by ddI 400 mg without TDF., Conclusions: Co-administration of ddI at standard doses plus TDF appears to exert a deleterious effect on CD4 and CD8 counts. Although lymphocyte toxicity related to excessive ddI plasma levels could explain our findings, other mechanisms cannot be excluded. Pharmacokinetic data suggest ddI dose reduction when coadministered with TDF.

Objective: To determine whether HIV-1 genotyping and expert advice add additional short-term virologic benefit in guiding antiretroviral changes in HIV+ drug-experienced patients., Design: A two factorial (genotyping and expert advice), randomized, open label, multi-center trial. The patients were stratified according to the number of treatment failures., Patients and Methods: HIV-1 infected patients on stable antiretroviral therapy who presented virological failure were included into the study. Genotypic testing was performed by using TrueGene HIV Genotyping kit and the results were interpreted by a software package (RetroGram, version 1.0). An expert advisory committee suggested the new therapeutic approach based on clinical information alone or on clinical information plus HIV-1 genotyping results. Plasma HIV-1 RNA load, CD4+ cell count and adverse events were recorded at baseline and every 12 weeks., Results: A total of 326 patients were included. The baseline CD4+ cell count and plasma HIV-1 RNA were 387 (+/- 224) x 10(6) cells/l and 4 (+/- 1) log(10) respectively. The proportion of patients with plasma HIV-1 RNA < 400 copies/ml at 24 weeks differed between genotyping and no genotyping arms (48.5 and 36.2%, P < 0.05). Factors associated with a higher probability of plasma HIV-1 RNA < 400 copies/ml were HIV-1 genotyping [odds ratio (OR), 1.7; 95% confidence interval (CI), 1.1-2.8; P = 0.016] and the expert advice in patients failing to a second-line antiretroviral therapy (OR, 3.2; 95% CI, 1.2-8.3; P = 0.016)., Conclusions: HIV-1 genotyping interpreted by a software package improves the virological outcome when it is added to the clinical information as a basis for decisions on changing antiretroviral therapy. The expert advice also showed virologic benefit in the second failure group.

Objective: To investigate the epidemiological, clinical and biological features of visceral leishmaniasis (VL) in patients with HIV-1 infection., Design: Retrospective study., Setting: Three university hospitals in southern Spain., Patients: Forty-seven adult patients with VL and HIV-1 infection diagnosed between January 1986 and November 1991., Results: Forty-five out of the 47 (96%) cases were diagnosed in the last 2 years. Fever (87%), hepatomegaly (74%), splenomegaly (72%) and pancytopenia (77%) were the most common presenting features. Most patients (79%) were strongly immunocompromised when VL was diagnosed, and were in stage IV of the Centers for Disease Control classification; 87% had a CD4 lymphocyte count < 200 x 10(6)/l. However, VL was the first severe infection diagnosed in 10 cases. Significant titres (> 1:40) of antileishmanial antibodies were detected by indirect immunofluorescence in five out of 16 (31%) cases only. Clinical response to the therapy was difficult to assess. Microbiological response was achieved in only 38% of the patients evaluated., Conclusions: Leishmaniasis is a relatively common infection in HIV-1-infected individuals in southern Spain. Its clinical picture is quite uniform and it can be the first opportunistic infection in individuals with HIV-1. In endemic areas, a high index of clinical suspicion should be maintained in order to avoid underdiagnosis of leishmaniasis.

Objective: To study the pharmacokinetics of zidovudine (ZDV) and its glucoronide metabolite (G-ZDV) in a patient with end-stage renal disease in haemodialysis., Design: Pharmacokinetics study performed during and between haemodialysis sessions., Methods: The patient was treated with oral ZDV (100 mg every 8 h). Concentrations of ZDV and G-ZDV were measured by radioimmunoassay. A monocompartmental model was used to calculate pharmacokinetic parameters., Results: The peak plasma concentrations of ZDV and G-ZDV after drug administration between haemodialysis sessions were 0.57 and 10.01 micrograms/ml, respectively. The half-lives of ZDV and G-ZDV rose to 3.2 and 14.2 h, respectively. The total body clearance for ZDV in the period between haemodialysis sessions (0.44 l/kg/h) was 66% lower than normal values. The ZDV half-life was normalized by haemodialysis, the total body clearance of ZDV increased (1.12 l/kg/h) and the G-ZDV half-life shortened (5.9-7.9 h). Neither G-ZDV accumulation nor derived ZDV toxicity occurred., Conclusions: Our data suggest that ZDV is safe and an efficient drug when administered at a dosage of 100 mg three times daily in patients with end-stage renal disease in haemodialysis sessions, and that ZDV and G-ZDV are cleared by haemodialysis.