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Objectives In view of the fact that mucosal damage associated with HIV-1 infection leads to microbial translocation despite successful antiretroviral treatment, we analysed microbial translocation and expression of the gut-homing β7 receptor on peripheral T cells in HIV-1-infected individuals. Methods Fifteen long-term suppressed HIV-1-infected patients, of whom seven had their treatment intensified with maraviroc and eight with raltegravir, were included in the study. Samples at baseline, at week 48 of intensification, and at weeks 12 and 24 after deintensification were analysed for soluble CD14, lipopolysaccharide (LPS), LPS-binding protein, gut-homing β7 receptor and T-cell subsets. Results The increases in both microbial translocation and expression of the gut-homing β7 receptor on activated CD8 T cells found during maraviroc intensification were reduced after deintensification. Moreover, the correlations between activated β7+ T cells and LPS levels found during intensification with maraviroc (P = 0.036 and P = 0.010, respectively) were lost during deintensification. In contrast, microbial translocation was stable during raltegravir intensification, with the exception of decreased LPS levels and activated CD4 β7+ T cells, which reverted to baseline values after deintensification. Conclusions Microbial translocation is an important factor in gut immune activation and mucosa inflammation, as evidenced by the association between the dynamics of microbial translocation and activated T cells expressing the gut-homing β7 receptor. The recruitment of activated β7+ T cells to the gut tract when alteration of microbial translocation is maximum may be the major mechanism for recovery of mucosal integrity.

Objectives We compared reasons for the choice of regimen, time to and reasons for third drug modification, virological response and change in CD4 T-cell counts in patients started on atazanavir/ritonavir (ATV/r)- vs. efavirenz (EFV)-based first-line regimens. Methods We included patients from the Cohort of the Spanish HIV Research Network (CoRIS), a multicentre cohort of HIV-positive treatment-naive subjects, in the study. We used logistic regression to assess factors associated with choosing ATV/r vs. EFV, proportional hazards models on the subdistribution hazard to estimate subdistribution hazard ratios (sHRs) for third drug modification, logistic regression to estimate odds ratios (ORs) for virological response and linear regression to assess mean differences in CD4 T-cell count increase from baseline. Results Of 2167 patients, 10.7% started on ATV/r. ATV/r was more likely than EFV to be prescribed in injecting drug users [adjusted OR 1.85; 95% confidence interval (CI) 1.03–3.33], in 2009–2010 (adjusted OR 1.63; 95% CI 1.08–2.47) and combined with abacavir plus lamivudine (adjusted OR 1.53; 95% CI 0.98–2.43). Multivariate analyses showed no differences, comparing ATV/r vs. EFV, in the risk of third drug modification (sHR 1.04; 95% CI 0.74–1.46) or in virological response (OR 0.81; 95% CI 0.46–1.41); differences in mean CD4 T-cell count increase from baseline were at the limit of statistical significance (mean difference 29.8 cells/μL; 95% CI −4.1 to 63.6 cells/μL). In patients changing from EFV, 48% of changes were attributable to toxicity/adverse events, 16% to treatment failure/resistance, 3% to simplification, and 8 and 12%, respectively, to patients' and physicians' decisions; these percentages were 24, 6, 12, 14 and 24%, respectively, in those changing from ATV/r. Conclusions ATV/r- and EFV-based regimens meet the requirements of both efficacy and safety for initial combination antiretroviral regimen, which relate to better durability.

OBJECTIVES To describe raltegravir pharmacokinetics at steady-state in HIV/hepatitis C virus (HCV)-coinfected patients under antiretroviral (ARV) treatment with (n = 5) and without (n = 5) advanced liver cirrhosis (Child-Pugh C). METHODS This was a non-randomized, Phase I, parallel-assignment, open-label pharmacokinetic study in HIV/HCV-coinfected patients with Child-Pugh grade C hepatic cirrhosis. We recruited clinically stable HIV/HCV-coinfected adult patients with controlled HIV viraemia (

Objective: Antiretroviral therapy (ART) intensification has been shown to reduce the reservoir of latently infected CD4 þ T cells. However, it is currently unknown whether this effect is maintained after discontinuation of the intensifying drug. Design: The effect of ART intensification during 48 weeks with maraviroc or raltegravir inchronicallyHIV-1-infectedpatientswasassessedintwopreviousclinicaltrials.Inthis study, we analysed this effect at week 24 after discontinuation of the intensifying drugs, at baseline and 48 weeks of intensification. Methods: We measured the latently infected memory CD4 þ T cells carrying replication-competent virus, 2-long terminal repeat (2-LTR) circles and CD4 þ /CD8 þ T cells activation. Results: Fifteen patients were evaluated. After 48 weeks of intensification, HIV-1 reservoir size significantly decreased from 1.1 to 0.0 infectious units per million (IUPM) (P ¼0.004). After 24 weeks of drugdiscontinuation, the median size of the reservoir was still significantly lower than at baseline (P ¼0.008). 2-LTRs were undetectable in all individuals at baseline and after 48 weeks of intensification, continuing undetectable in all patients except two at week 24 after discontinuation (P ¼0.1). CD4 þ and CD8 þ T-cell activation significantly decreased at 48 weeks after intensification, without further increase after discontinuation. Conclusion: The effects of ART intensification with maraviroc or raltegravir persist at least 24 weeks after discontinuation of the drug. In a global strategy, ART intensification should be considered as part of a combination approach to achieve a functional cure or HIV eradication. 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2013, 27:2081‐2088

Summary Objectives HIV-infected subjects on antiretroviral therapy often fail to normalize the CD4/CD8 ratio despite CD4 count normalization. We aimed to analyze the biological significance of this finding. Methods Cross-sectional analysis in 20 HIV-infected subjects on stable triple-ART, plasma HIV RNA 350 cells/mm 3 . Laboratory measurements included T-cell activation (HLADR + , CD38 + ) and senescence (CD57 + ), lipopolysaccharide (LPS), sCD14 and the HIV latent reservoir (number of latently infected memory CD4 cells carrying replication-competent virus). Results CD4/CD8 ratio was positively correlated with CD4 nadir ( r = 0.468, p = 0.038) and accumulated ART exposure ( r = 0.554, p = 0.0011), and negatively with viral load before ART initiation ( r = −0.547, p = 0.013), CD4 + HLADR + CD38 + T-cells ( r = −0.428, p = 0.086) and CD8 + CD57 + T-cells ( r = −0.431, p = 0.084). No associations with LPS, sCD14 or HIV latent reservoir were found. After the multivariate analyses, the CD4/CD8 ratio remained independently associated with CD4 + HLADR + CD38 + T-cells and CD8 + HLADR + T-cells. Conclusions In our study in subjects on suppressive ART the CD4/CD8 ratio was independently associated with T-cell activation. Our results must be confirmed in larger studies, as this parameter might be a useful clinical tool to identify subjects with ongoing immune activation despite long-term viral suppression.

OBJECTIVES The stability of the reservoir of latently infected memory CD4 T-cells may be associated with continuous replenishment from residual HIV-1, not completely eliminated by otherwise successful antiretroviral therapy (ART). Treatment intensification could help to control residual virus and to modify the latent reservoir. The objective of this work is to assess the effect of intensifying therapy with raltegravir on the HIV-1 cell reservoir. DESIGN A pilot open-label phase-II clinical trial was performed to analyze ART intensification with raltegravir after 48 weeks in chronically HIV-1-infected patients on stable ART. METHODS We measured the number of latently infected memory CD4 T cells, residual viremia, 2-long terminal repeat circles, CD4/CD8 T-cell activation, lymphocyte subpopulations, gut homing receptor, and bacterial translocation. RESULTS A significant decay of HIV-1 latent reservoir was observed after intensification in the nine patients included (P = 0.021). No variation was found in either residual viremia or 2-long terminal repeat circles, whereas CD8 T-cell activation decreased at week 36 (P = 0.028). No differences were found in naive T-cell or effector memory cell counts, and the frequencies of gut homing receptor on activated or effector memory CD8 T cells. Bacterial translocation was stable, with the exception of a late decrease in lipopolysaccharide levels. CONCLUSIONS In this pilot noncomparative trial, treatment intensification with raltegravir significantly decreased the latent cellular HIV-1 reservoir and CD8 T-cell activation. Despite the limitations inherent to trial design, our results suggest that ART intensification should be considered as an adjuvant strategy to eradicate HIV-1 infection.

Although atazanavir is widely used in hepatitis C virus (HCV)-HIV-1 patients, little is known about its safety in advanced liver disease. We studied 34 HCV-HIV-1 patients with cirrhosis receiving atazanavir. After 551.2 patient-months of follow-up, there were no cases of serious liver toxicity or cirrhosis decompensation, and only 18.5% discontinued the drug. Despite median bilirubin level at inclusion was 1.5 mg/ml, increases in bilirubin level were mild. Model for end-stage liver disease score (MELD) increased to 1.35 points (95% confidence interval 0.13-2.6), but no patient changed their pretreatment situation after atazanavir introduction. Atazanavir is a well tolerated option in cirrhosis, and significant alterations in bilirubin or MELD were not observed.

We aimed to evaluate whether virological response to a short course of maraviroc monotherapy could predict HIV-1 tropism.A clinical trial was performed in HIV-1 treatment-naive patients infected with R5- or non-R5-tropic virus determined using the Trofile(®) assay, with1000 HIV-1 RNA copies/mL. Maraviroc was administered for 10 days. Viral load was measured at baseline and days 4, 7, 10 and 28. The main outcome measurement was the decline in HIV-1 RNA at day 10. The trial was registered in the ClinicalTrials.gov database (NCT01060618; TROPISMVC).Forty patients [30 R5 and 10 dual/mixed (D/M)] were recruited. There was a significant decrease in HIV-1 RNA after 10 days of maraviroc treatment in patients with R5-tropic virus (median 1.52 log10 RNA copies/mL; 95% CI 1.23-1.63; P 0.0001), but also in patients with D/M-tropic virus (median 1.62 log(10) RNA copies/mL; 95% CI 0.33-1.88; P = 0.00024). The difference in the HIV-1 RNA decrease (-0.16 log(10) RNA copies/mL; 95% CI -0.53 to 0.22) was not significant (P = 0.410). A decrease0.5 log(10) RNA copies/mL was found in 96.3% of patients with R5-tropic virus and in 70% of patients with D/M-tropic virus (P = 0.052). The differences were not significant when a decline of 1 log(10) RNA copies/mL was considered (92.6% versus 70%; P = 0.11).Treatment-naive patients infected with R5- or D/M-tropic virus have similar virological responses to a short course of maraviroc monotherapy. This clinical test thus cannot be used as a surrogate marker of viral tropism in this population.

INTRODUCTION Microbial translocation (MT) has been proposed as one of the triggering mechanisms of persistent immune activation associated to HIV-1 infection. Our objectives were to determine the correlation between different measurements of MT in suppressed HIV-1-infected individuals and to evaluate its correlation with immune activation. METHODS Eighteen suppressed HIV-1-infected patients with CD4+ T-cell count above 350 cells per cubic millimeter and undetectable plasma viral load, included in antiretroviral treatment intensification clinical trials, were evaluated. Samples obtained at baseline and at established time points during the trials were analyzed. Lipopolysaccharide (LPS), lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14), and bacterial 16S ribosomal DNA (16S rDNA), and markers of immune activation were determined. RESULTS We analyzed 126 plasma samples from the 18 patients. LPS significantly correlated with sCD14 (P < 0.001, r = 0.407) and LBP (P = 0.042, r = 0.260). Also, a significant correlation was found between sCD14 and LBP (P = 0.009, r = 0.325) but not between bacterial 16S rDNA and LPS, sCD14, or LBP (P = 0.346, P = 0.405, and P = 0.644). On the other hand, no significant correlation was found between LPS, sCD14, or LBP and CD4 (P = 0.418, P = 0.619, and P = 0.728) or CD8 T-cell activation (P = 0.352, P = 0.275, and P = 0.124). Bacterial 16S rDNA correlated with activated CD4 T cells (P = 0.005, r = 0.104) but not with activated CD8 T cells (P = 0.171). CONCLUSIONS There is a good correlation in the quantification of LPS, sCD14, and LBP levels, but not with bacterial 16S rDNA, as measurements of MT. We are unable to ensure that MT directly triggers T-cell immune activation at least among these patients with relatively good immune recovery and under treatment intensification.

Raltegravir (RAL) constitutes the first available integrase strand transfer inhibitor (INSTI) available in clinical practice. Three independent pathways have been described to confer resistance to RAL. Secondary mutations with little effect on INSTI susceptibility and additional substitutions with an uncertain role have also been described especially in HIV-1 non-B variants.We evaluated the prevalence of primary, secondary, and additional resistance mutations to INSTIs in patients naïve to RAL or elvitegravir (EGV) carrying different HIV-1 variants.A total of 83 patients infected by B HIV-1 subtype (64%) or non-B HIV-1 variants (36%) were evaluated. No primary mutations to RAL or EGV were found in the inte-grase sequences analyzed. Secondary mutations were detected in only 5 patients. Additional mutations were found in both in B and non-B variants. According to the geno2pheno algorithm, some of the secondary mutations detected (L74V, E138K, G163RS, and V151I) have been associated with a reduced estimated susceptibility to RAL and only the E138K mutation has been associated with a decreased estimated susceptibility to EGV. No virological failure was observed after RAL was administrated in 17 patients carrying 1 or more additional substitutions in the absence of primary or secondary mutations.No primary resistance mutations to INSTI were found in treatment-naïve or -experienced patients infected with B or non-B HIV-1 variants. The vast majority had some polymorphic and non-polymorphic substitutions; however response to RAL was excellent in patients who harbored one or more of these mutations. We could not identify any clinical factors associated with the presence of any of these mutations.

We estimated the effect of sexual behavior, age, and immunodeficiency on the number of high-risk human papillomavirus (HR-HPV) types in the anal canal among human immunodeficiency virus-positive men who have sex with men (MSM). Anal samples were genotyped with the Linear Array HPV Genotyping Test, and risk factors were investigated with Poisson regression. Of 586 MSM, 69% were Spanish, and 25.6% were Latin American; the median age was 34.9 years (interquartile range [IQR], 30.1-40.8). The median number of recent sex partners was 6 (IQR, 2-24 sex partners), and the median CD4(+) T-cell count was 531.5 cells/mm(3) (IQR, 403-701 cells/mm(3)). The prevalence of any and multiple HR-HPV infections was 83.4% and 60.5%, respectively. The most common types were HPV-16 (42%), HPV-51 (24%), HPV-39 (23.7%), and HPV-59 (23.5%). Age had a statistically significant, nonlinear association with the number of types, with the highest number detected around 35 years of age (P

Objective: The primary objective was to assess the effect of MVC intensification on latently infected CD4 + T cells in chronically HIV-1-infected patients receiving antiretroviral therapy. Methods: We performed an open-label pilot phase II clinical trial involving chronically HIV-1-infected patients receiving stable antiretroviral therapy whose regimen was intensified with 48 weeks of maraviroc therapy. We analyzed the latent reservoir, the residual viremia and episomal 2LTR DNA to examine the relationship between these measures and the HIV-1 latent reservoir, immune activation, lymphocyte subsets (including effector and central memory T cells), and markers associated with bacterial translocation. Results: Overall a non significant reduction in the size of the latent reservoir was found (p = 0.068). A mean reduction of 1.82 IUPM was observed in 4 patients with detectable latent reservoir at baseline after 48 weeks of intensification. No effect on plasma residual viremia was observed. Unexpectedly, all the patients had detectable 2LTR DNA circles at week 24, while none of them showed those circles at the end of the study. No changes were detected in CD4 + or CD8 + counts, although a significant decrease was found in the proportion of HLA-DR + /CD38 + CD4 + and CD8 + T-cells. LPS and sCD14 levels increased. Conclusions: Intensification with MVC was associated with a trend to a decrease in the size of the latent HIV-1 reservoir in memory T cells. No impact on residual viremia was detected. Additional studies with larger samples are needed to confirm the results. Trial Registration: ClinicalTrials.gov NCT00795444

We aimed to evaluate immunological, virological and clinical response to HAART, as well as all-cause mortality, in treatment-naive patients with a diagnosis of tuberculosis (TB) in the prior 6 months, compared to subjects with another AIDS-defining illness (ADI) or event-free individuals in an open, prospective and multicenter hospital-based cohort of HIV-infected naive adults (2004-2008). All cause mortality rates were calculated by Cox regression models. Among 4407 patients, 2400 (54.5%) started HAART: 110 (4.6%) had had previous TB and 414 (17.3%) another ADI. Median time from TB diagnosis to inititation of HAART was 53 days (IQR: 25.75-83.25), and for other ADI was 22 days (IQR: 8-42). Overall, 151 (6.3%) patients developed a new ADI during follow-up; 63% reached virological suppression and 69.4% had increases of ≥50 CD4+/µl, at 6 months. No statistically significant differences were found according to a previous history of TB or another ADI. Overall, 85 subjects died in 4031 person-years of follow-up with a mortality rate of 2.1 (95%CI: 1.7-2.6). When compared to subjects who started HAART in the absence of a previous ADI (HR 1), a prior diagnosis of an ADI other than TB was significantly associated with an increased risk of death. (HR 1.6; 95%CI: 1.1-2.3), but not a diagnosis of TB (HR 1.15; 95%CI: 0.5-2.5). In conclusion, a previous diagnosis of TB or another ADI before HAART did not compromise short-term virological and immunological response to treatment. A prior diagnosis of an ADI different to TB significantly increased all cause mortality.

Objectives To determine the effect of food on the antiviral activity of enteric-coated (EC) capsules of didanosine (ddI). Methods We conducted a pilot, randomized, open-label study of 28-day ddI-EC capsules monotherapy-administered in a fasted state (group 1, n=11) or with food (group 2, n=10) to treatment-naive chronically HIV-1-infected individuals. To assess the antiviral efficacy, HIV-1 RNA was determined at baseline, day 3, day 7 and weekly thereafter. The area under the HIV-1 RNA curve minus baseline weighted by time (AUCMB/day) was calculated. Results Mean baseline HIV-1 RNA was 4.2 log10 copies/mL in group 1 and 3.8 log10 copies/mL in group 2. After 28 days, the mean HIV-1 RNA reduction was 0.99 log10 copies/mL [95% confidence interval (CI) 0.45–1.53] for group 1 and 0.89 log10 copies/mL (95% CI 0.38–1.40) for group 2. AUCMB/day values were 0.775 log10 copies/mL (95% CI 0.33–1.22) and 0.774 log10 copies/mL (95% CI 0.48–1.07), respectively, showing no difference in the rate of decrease of HIV-1 RNA (P=0.995). Mean ddI plasma levels at day 28 were 0.0234 mg/L for group 1 and 0.0227 mg/L for group 2 (P=0.96). Conclusions In this pilot study, the administration of food did not have any significant effect on the antiviral activity of ddI-EC capsules.

Background Evaluation of the diagnostic value of anal cytology versus HRA in detecting anal intraepithelial neoplasia (AIN) and the added value of molecular markers in a multicenter cohort of HIV positive MSM (CoRIS-HRA). Methods: Concomitant anal liquid cytology and HRA with biopsy of acetowhite lugol-negative lesions if observed. Concordance was evaluated by the Kappa index. Dual staining for p16INK4a and Ki-67 (CINtec® PLUS, Roche) was done in cytology samples. Taking biopsy as the ‘gold standard’ for AIN diagnosis, the sensitivity and specificity of anal cytology and p16INK4/Ki-67 dual positivity was calculated. Results: Since November 2012, 172 patients were recruited in five Spanish hospitals. In 56 patients, no biopsies were performed as no lesions were observed. In the remaining 116 patients, 142 biopsies were obtained. Among 172 cytologies, 10.5% were inadequate, 27.9% negative, 1.1% ASCUS, 45.3% LSIL and 15.2% HSIL. Histology showed inadequacy in 3.5% of cases, negativity in 25.3%, LG-AIN in 35.2% and HG-AIN in 35.9%. In 116 patients, cytology and biopsy results were available (the highest lesion grade was used if multiple biopsies existed); the strength of agreement was fair (Kappa 0.351; 95% CI 0.232–0.470). Sensitivity and specificity of anal cytology versus HRA guided biopsy was 88.3% and 66.7%, respectively. In 67 cases, results from dual staining for p16INK4a/Ki-67 were available, rendering a sensitivity of 47.3% and a specificity of 66.7% compared with histology results. Conclusions: Although preliminary, our results show that in our setting dual staining for p16INK4a/Ki-67 did not improve the operational characteristics of anal liquid cytology.

Background: It has been suggested that the stability of the CD4 cell reservoir could be related to the continuous replenishment from plasma-residual HIV-1. Intensification with an entry inhibitor could help eliminate the detectable levels of ongoing viral replication and accelerate the decay of the reservoir by inhibiting the entry of the virus into the cells. Methods: The intensification study with an entry inhibitor (maraviroc-MVC) included patients with stable antiretroviral therapy (ART) with three or more drugs, viral load (VL) of 350 cells/mm3 and CCR5-tropism. Latently infected resting CD4 cells were determined at baseline, week 12 and week 24, with further analyses planned at week 36 and week 48. Highly purified resting CD4 cells were isolated using magnetic beads rendering ~20 million and plated in replicate dilutions and stimulated in a limiting dilution culture assay, with irradiated PBMCs from a seronegative donor. Cells containing HIV-replication-competent were quantified by HIV-1 p24 Antigen Assay (results in infective units per million). Results: Nine patients have been included. Median time of HIV-1 diagnosis was 103 months [IQR 58-240], ART was administered for a median of 75 months [IQR 38-144], and the median baseline CD4 count was 711 cells/mm3 [IQR 547-793]. At baseline, the reservoir could be quantified in six out of nine patients. One patient has left the study, and the other eight patients continue with VL of