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Background: The high effectiveness and safety of the two-drug (2DRs) strategy using dolutegravir (DTG) plus lamivudine (3TC) have led to international guidelines recommending their use for treatment-naive HIV patients. In virologically suppressed patients, de-escalating from 3DRs to DTG plus either rilpivirine (RPV) or 3TC has shown high rates of virological suppression., Objectives: This study aimed to compare the real-life data of two multicenter Spanish cohorts of PLWHIV treated with DTG plus 3TC (SPADE-3) or RPV (DORIPEX) as a switch strategy, not only in terms of virological suppression, safety, and durability but also in terms of immune restoration. The primary endpoint was the percentage of patients with virological suppression on DTG plus 3TC and DTG plus RPV at weeks 24 and 48. The secondary outcomes included the proportion of patients who experienced the protocol-defined loss of virological control by week 48; changes in immune status in terms of CD4+ and CD8+ T lymphocyte counts and the CD4+/CD8+ ratio; the rate, incidence, and reasons for discontinuation of treatment over the 48-week study period; and safety profiles at weeks 24 and 48., Methods: We conducted a retrospective, observational, multicenter study of 638 and 943 virologically suppressed HIV-1-infected patients in two cohorts who switched to 2DRs with DTG plus RPV or DTG plus 3TC., Results: The most frequent reasons for starting DTG-based 2DRs were treatment simplification/pill burden or drug decrease. The virological suppression rates were 96.9%, 97.4%, and 99.1% at weeks 24, 48, and 96, respectively. The proportion of patients with virological failure over the 48-week study period was 0.01%. Adverse drug reactions were uncommon. Patients treated with DTG+3TC increased CD4, CD8, and CD4/CD8 parameters at 24 and 48 weeks., Conclusions: We conclude that DTG-based 2DRs (combined with 3TC or RPV) in clinical practice were effective and safe as a switching strategy, with a low VF and high viral suppression rates. Both regimens were well tolerated, and ADR rates were low, including neurotoxicity and induced treatment discontinuations.

miRNAs dictate relevant virus-host interactions, offering new avenues for interventions to achieve an HIV remission. We aimed to enhance HIV-specific cytotoxic responses-a hallmark of natural HIV control- by miRNA modulation in T cells. We recruited 12 participants six elite controllers and six patients with chronic HIV infection on long-term antiretroviral therapy ("progressors"). Elite controllers exhibited stronger HIV-specific cytotoxic responses than the progressors, and their CD8+T cells showed a miRNA (hsa-miR-10a-5p) significantly downregulated. When we transfected ex vivo CD8 + T cells from progressors with a synthetic miR-10a-5p inhibitor, miR-10a-5p levels decreased in 4 out of 6 progressors, correlating with an increase in HIV-specific cytotoxic responses. The effects of miR-10a-5p inhibition on HIV-specific CTL responses were modest, short-lived, and occurred before day seven after modulation. IL-4 and TNF-α levels strongly correlated with HIV-specific cytotoxic capacity. Thus, inhibition of miR-10a-5p enhanced HIV-specific CD8 + T cell capacity in progressors. Our pilot study proves the concept that miRNA modulation is a feasible strategy to combat HIV persistence by enhancing specific cytotoxic immune responses, which will inform new approaches for achieving an antiretroviral therapy-free HIV remission., Competing Interests: Outside the submitted work, author SS-V reports personal fees from ViiV Healthcare, Janssen Cilag, Gilead Sciences, and MSD as well as non-financial support from ViiV Healthcare and Gilead Sciences and research grants from MSD and Gilead Sciences. Author SM reports grants, personal fees and non-financial support from ViiV Healthcare, personal fees and non-financial support from Janssen, grants, personal fees and non-financial support from MSD, grants, personal fees and non-financial support from Gilead. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Madrid-Elena, Serrano-Villar, Gutiérrez, Sastre, Morín, Luna, Martín, Santoyo-López, López-Huertas, Moreno, García-Bermejo, Moreno-Pelayo and Moreno.)

Changes in the microbiota have been linked to persistent inflammation during treated HIV infection. In this pilot double-blind study, we study 30 HIV-infected subjects on antiretroviral therapy (ART) with a CD4/CD8 ratio < 1 randomized to either weekly fecal microbiota capsules or placebo for 8 weeks. Stool donors were rationally selected based on their microbiota signatures. We report that fecal microbiota transplantation (FMT) is safe, not related to severe adverse events, and attenuates HIV-associated dysbiosis. FMT elicits changes in gut microbiota structure, including significant increases in alpha diversity, and a mild and transient engraftment of donor's microbiota during the treatment period. The greater engraftment seems to be achieved by recent antibiotic use before FMT. The Lachnospiraceae and Ruminococcaceae families, which are typically depleted in people with HIV, are the taxa more robustly engrafted across time-points. In exploratory analyses, we describe a significant amelioration in the FMT group in intestinal fatty acid-binding protein (IFABP), a biomarker of intestinal damage that independently predicts mortality. Gut microbiota manipulation using a non-invasive and safe strategy of FMT delivery is feasible and deserves further investigation. Trial number: NCT03008941.

Human immunodeficiency virus (HIV) infection impairs mucosal immunity and leads to bacterial translocation, fueling chronic inflammation and disease progression. While this is well established, questions remain about the compositional profile of the translocated bacteria, and to what extent it is influenced by antiretroviral therapy (ART). Using 16S ribosomal DNA targeted sequencing and shotgun proteomics, we showed that HIV increases bacterial translocation from the gut to the blood. HIV increased alpha diversity in the blood, which was dominated by aerobic bacteria belonging to Micrococcaceae (Actinobacteria) and Pseudomonadaceae (Proteobacteria) families, and the number of circulating bacterial proteins was also increased. Forty-eight weeks of ART attenuated this phenomenon. We found that enrichment with Lactobacillales order, and depletion of Actinobacteria class and Moraxellaceae and Corynebacteriacae families, were significantly associated with greater immune recovery and correlated with several inflammatory markers. Our findings suggest that the molecular cross talk between the host and the translocated bacterial products could influence ART-mediated immune recovery., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Human immunodeficiency virus (HIV) remains incurable due to latent viral reservoirs established in non-activated CD4 T cells that cannot be eliminated via antiretroviral therapy. Current efforts to cure HIV are focused on identifying drugs that will induce viral gene expression in latently infected cells, commonly known as latency reversing agents (LRAs). Some drugs have been shown to reactivate latent HIV but do not cause a reduction in reservoir size. Therefore, finding new LRAs or new combinations or increasing the round of stimulations is needed to cure HIV. However, the effects of these drugs on viral rebound after prolonged treatment have not been evaluated. In a previous clinical trial, antiretroviral therapy intensification with maraviroc for 48 weeks caused an increase in residual viremia and episomal two LTR-DNA circles suggesting that maraviroc could reactivate latent HIV. We amended the initial clinical trial to explore additional virologic parameters in stored samples and to evaluate the time to viral rebound during analytical treatment interruption in three patients. Maraviroc induced an increase in cell-associated HIV RNA during the administration of the drug. However, there was a rapid rebound of viremia after antiretroviral therapy discontinuation. HIV-specific T cell response was slightly enhanced. These results show that maraviroc can reactivate latent HIV in vivo but further studies are required to efficiently reduce the reservoir size.

Introduction: Neurocognitive impairment associated to human immunodeficiency virus (HIV) is a current problem despite the effectiveness of antiretroviral treatment. The screening tests which best suit to Spanish population are Brief Neuro-cognitive Scale (BNCS) and Neu Screening. We are unaware of our HIV population' neurocognitive impairment magnitude., Aims: To verify if association between HIV and neurocognitive impairment does exist and to know its prevalence., Subjects and Methods: An observational, descriptive and transversal study comparing 24 HIV-outpatients and 21 non-HIV-healthy control matched by age, gender and educational level. Hospital Anxiety and Depression Scale, Neu Screening and BNCS were used as neurocognitive impairment screening. Positive screening was considered with one or more abnormal test., Results: 33.3% of VIH+ and 33.3% of healthy controls had positive screening without significant difference between both populations. Positive screening was significantly associated with anxiety-punctuation and depression-punctuation. A lineal correlation between CD4-nadir-levels and Digit Symbol and between CD4-nadir-levels and verbal fluency results were found. There was no significant relationship between HIV serology and screening result., Conclusions: HIV-patients clinically controlled had no significantly different neurocognitive profile compared to control population. CD4-nadir levels may be a predictor variable in terms of neurocognitive impairment development. BNCS and Neu Screening are reasonable alternatives for neurocognitive impairment screening. A concomitant psychiatric and neuro-psychological assessment is necessary. Further studies with bigger samples are necessary in order to confirm the alternative hypothesis.

This study examines the relationship between regulatory B (Breg) and T (Treg) compartments, which play crucial roles in the maintenance of immune homeostasis in the context of HIV. Using flow cytometry, the phenotypes of different Breg and Treg subsets from HIV-infected and healthy individuals were analyzed, along with the suppressive capacity of Breg. Peripheral blood samples of thirteen HIV+ treatment-naïve individuals, fourteen treated-HIV+ individuals with undetectable viral load and twelve healthy individuals were analyzed. The absolute counts of Breg and Treg subsets were decreased in HIV+ treatment-naïve individuals in comparison to treated-HIV+ and healthy individuals. Interestingly, correlations between Breg subsets (CD24hiCD27+ and PD-L1+ B cells) and IL-10-producing Breg observed in healthy individuals were lost in HIV+ treatment-naïve individuals. However, a correlation between frequencies of CD24hiCD38hi or TIM-1+-Breg subsets and Treg was observed in HIV+ treatment-naïve individuals and not in healthy individuals. Therefore, we hypothesized that various Breg subsets might have different functions during B and T-cell homeostasis during HIV-1 infection. In parallel, stimulated Breg from HIV-infected treatment-naïve individuals presented a decreased ability to suppress CD4+ T-cell proliferation in comparison to the stimulated Breg from treated-HIV+ or healthy individuals. We demonstrate a dysregulation between Breg and Treg subsets in HIV-infected individuals, which might participate in the hyper-activation and exhaustion of the immune system that occurs in such patients., Competing Interests: The authors have declared that no competing interests exist.

Background: While nutritional interventions with prebiotics and probiotics seem to exert immunological effects, their clinical implications in human immunodeficiency virus (HIV)-infected subjects initiating antiretroviral therapy (ART) at advanced HIV disease remain unclear., Methods: This was a pilot multicenter randomized, placebo-controlled, double-blind study in which 78 HIV-infected, ART-naive subjects with <350 CD4 T cells/μL or AIDS were randomized to either daily PMT25341 (a mixture of synbiotics, omega-3/6 fatty acids and amino acids) or placebo for 48 weeks, each in combination with first-line ART. Primary endpoints were changes in CD4 T-cell counts and CD4/CD8 ratio from baseline to week 48 and safety. Secondary endpoints were changes in markers of T-cell activation, bacterial translocation, inflammation, and α and β microbiota diversity., Results: Fifty-nine participants completed the follow-up with a mean CD4+ T-cell count of 221 ± 108 cells/μL and mean CD4/CD8 ratio of 0.26 ± 0.19. PMT25341 was well tolerated, without grade 3-4 adverse effects attributable to the intervention. While most of the assessed biomarkers improved during the follow-up in both arms, PMT25341-treated subjects did not experience any significant change, compared to placebo-treated subjects, in mean CD4+ T-cell count change (278 vs 250 cells/μL, P = .474) or CD4/CD8 ratio change (0.30 vs 0.32, P = .854). Similarly, we did not detect differences between treatment arms in secondary endpoints., Conclusions: In HIV-infected patients initiating ART at advanced disease, the clear immunological benefits of ART were not enhanced by this nutritional intervention targeting the gut-associated lymphoid tissue and microbiota., Clinical Trials Registration: NCT00870363.

Maraviroc is a CCR5 antagonist used in the treatment of HIV-1 infection. We and others have suggested that maraviroc could reactivate latent HIV-1. To test the latency-reversing potential of maraviroc and the mechanisms involved, we performed a phase II, single-center, open-label study in which maraviroc was administered for 10 days to 20 HIV-1-infected individuals on suppressive antiretroviral therapy (EudraCT registration no. 2012-003215-66). All patients completed full maraviroc dosing and follow-up. The primary endpoint was to study whether maraviroc may reactivate HIV-1 latency, eliciting signaling pathways involved in the viral reactivation. An increase in HIV-1 transcription in resting CD4 + T cells, estimated by levels of HIV-1 unspliced RNA, was observed. Moreover, activation of the NF-κB transcription factor was observed in these cells. To elucidate the mechanism of NF-κB activation by maraviroc, we have evaluated in HeLa P4 C5 cells, which stably express CCR5, whether maraviroc could be acting as a partial CCR5 agonist, with no other mechanisms or pathways involved. Our results show that maraviroc can induce NF-κB activity and that NF-κB targets gene expression by CCR5 binding, since the use of TAK779, a CCR5 inhibitor, blocked NF-κB activation and functionality. Taking the results together, we show that maraviroc may have a role in the activation of latent virus transcription through the activation of NF-κB as a result of binding CCR5. Our results strongly support a novel use of maraviroc as a potential latency reversal agent in HIV-1-infected patients. IMPORTANCE HIV-1 persistence in a small pool of long-lived latently infected resting CD4 + T cells is a major barrier to viral eradication in HIV-1-infected patients on antiretroviral therapy. A potential strategy to cure HIV-1-infection is the use of latency-reversing agents to eliminate the reservoirs established in resting CD4 + T cells. As no drug has been shown to be completely effective so far, the search for new drugs and combinations remains a priority for HIV cure. We examined the ability of maraviroc, a CCR5 antagonist used as an antiretroviral drug, to activate latent HIV-1 in infected individuals on antiretroviral therapy. The study showed that maraviroc can activate NF-κB and, subsequently, induce latent HIV-1-transcription in resting CD4 + T cells from HIV-1-infected individuals on suppressive antiretroviral therapy. Additional interventions will be needed to eliminate latent HIV-1 infection. Our results suggest that maraviroc may be a new latency-reversing agent to interfere with HIV-1 persistence during antiretroviral therapy., (Copyright © 2018 American Society for Microbiology.)

Detection of virus in cerebrospinal fluid (CSF) in HIV-infected patients with HIV viral load (VL) undetectable in plasma has been termed viral escape. These leaks may be asymptomatic from a neurological point of view, similar to plasma blips, or associated with neurological disease, with discordant VL between plasma and CSF, and may be evidence of a compartmentalization of the virus and the possibility of identifying quasispecies with mutations that confer resistance to ART. We present the case of a man with AIDS and disseminated tuberculosis who presented neurological symptomatology evidenced by headache and convulsive syndrome, who presented a discordance between plasma and CSF HIV VL; the genotypic test of the virus, obtained by lumbar puncture, identified new mutations that determined a change in ART with subsequent satisfactory evolution.

Introduction: Red Salud UC is an Academic health network where HIV-infected patients from the public and private health system are followed by a multidisplinary team., Aim: To determine virologic and immunologic response after 144 weeks of starting first antiretroviral therapy in these patients., Methods: A retrospective analysis of adult HIV patients attended between 1992 and 2011 was performed. Demographic and clinical characteristics, antiretroviral therapies data and immunologic and virologic outcomes were collected. CD4 count and HIV viral load changes up to 144 weeks after initiation of antiretroviral therapy were analyzed., Results: 860 patients were included in the analyses. Median age was 42 years, 93% were men. Median CD4+ count at baseline was 202 cells/mm³. The most used ART regimen was zidovudine/lamivudine plus efavirenz. First line anti-retroviral therapy was changed in 42% patients, being the most common cause, drug toxicity. At week 144, median CD4+ lymphocyte cell count was 449 cells/mm³. Ninety percent and 96% had undetectable viral load measured as < 50 copies/mL or < 400 copies/mL respectively., Discussion: First report of a university cohort, with CD4 and viral load follow up for 144 weeks, including Chilean patients from public and private system. After initiation of ART, an excellent immunologic and virologic response was observed in this cohort.

Objective: The protein kinase C (PKC) agonist bryostatin-1 has shown significant ex-vivo potency to revert HIV-1 latency, compared with other latency reversing agents (LRA). The safety of this candidate LRA remains to be proven in treated HIV-1-infected patients., Methods: In this pilot, double-blind phase I clinical-trial (NCT 02269605), we included aviraemic HIV-1-infected patients on triple antiretroviral therapy to evaluate the effects of two different single doses of bryostatin-1 (10 or 20 μg/m) compared with placebo., Results: Twelve patients were included, four in each arm. Bryostatin-1 was well tolerated in all participants. Two patients in the 20 μg/m arm developed grade 1 headache and myalgia. No detectable increases of cell-associated unspliced (CA-US) HIV-1-RNA were observed in any study arm, nor differences in HIV-1 mRNA dynamics between arms (P = 0.44). The frequency of samples with low-level viraemia did not differ between arms and low-level viraemia did not correlate with CA-US HIV-1-RNA levels (P = 0.676). No changes were detected on protein kinase C (PKC) activity and in biomarkers of inflammation (sCD14 and interleukin-6) in any study arm. After the single dose of bryostatin-1, plasma concentrations were under detection limits in all the patients in the 10 μg/m arm, and below 50 pg/ml (0.05 nmol/l) in those in the 20 μg/m arm., Conclusion: Bryostatin-1 was safe at the single doses administered. However, the drug did not show any effect on PKC activity or on the transcription of latent HIV, probably due to low plasma concentrations. This study will inform next trials aimed at assessing higher doses, multiple dosing schedules or combination studies with synergistic drugs.

Antiretroviral therapy has significantly improved the life expectancy in HIV-infected people, but it cannot cure the disease by itself. Several barriers have been identified for the cure of HIV infection, including a reservoir of latently infected cells, persistent viral replication in tissues, and anatomical sanctuaries. The main strategy proposed for the cure of HIV consists on the administration of drugs that, through the reactivation of latent HIV, would eliminate the cell reservoir. Ongoing clinical trials have shown the proof of concept, but the efficacy of these drugs in decreasing the reservoir size has not been proved so far.

Objectives: We have analyzed the parameters (bacterial translocation, immune activation and regulation, presence of HCV coinfection) which could be implicated in an inappropriate immune response from individuals with chronic HIV infection. The influence of them on the evolution of CD4+ T cell count has been investigated., Patients and Methods: Seventy HIV-infected patients [monoinfected by HIV (n = 20), HCV-coinfected (with (n = 25) and without (n = 25) liver cirrhosis)] and 25 healthy controls were included. Median duration of HIV infection was 20 years. HIV- and HCV-related parameters, as well as markers relative to bacterial translocation, monocyte and lymphocyte activation and regulation were considered as independent variables. Dependent variables were the increase of CD4+ T cell count during the follow-up (12 months)., Results: Increased values of bacterial translocation, measured by lipopolysaccharide-binding protein, monocyte and lymphocyte activation markers and T regulatory lymphocytes were detected in HIV-monoinfected and HIV/HCV coinfected patients. Serum sCD14 and IL-6 were increased in HIV/HCV-coinfected patients with liver cirrhosis in comparison with those with chronic hepatitis or HIV-monoinfected individuals. Time with undetectable HIV load was not related with these parameters. The presence of cirrhosis was negatively associated with a CD4+ T cell count increase., Conclusion: In patients with a chronic HIV infection, a persistent increase of lipopolysaccharide-binding protein and monocyte and lymphocyte modifications are present. HCV-related cirrhosis is associated with more elevated serum concentrations of monocyte-derived markers. Cirrhosis influences the continued immune reconstitution of these patients.

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., (© 2014 British HIV Association.)

Objectives: Determine the association between the information received on high activity antiretroviral treatment (HAART) and the adherence to this treatment in patients with HIV / AIDS of a hospital of Lima, Peru., Materials and Methods: Cross-sectional analytical study. Through interviews were applied the questionnaire SIMS (Satisfaction with Information about Medicines Scale) to measure satisfaction with information received about medications and SMAQ (Simplified Medication Adherence Questionnaire) to determine adherence to HAART. By reviewing medical records sociodemographic and clinical data were collected., Results: 364 patients were interviewed. Satisfaction with the information received about drugs was not associated with adherence to HAART (p = 0.611). Factors associated with the satisfaction with information were: female (ORa = 0.52; 95% CI 0.30 to 0.90); level of higher education (ORa = 0.45; 95% CI 0.27 to 0.75) and age (ORa = 1.05; 95% CI 1.02 to 1.08). There were more satisfaction with the information received on the action and drug use compared with information about potential adverse events (48.9% vs. 43.1%; p = 0.0291)., Conclusions: Satisfaction with information received about drugs was not associated with adherence to HAART. This satisfaction increases with age and is lower in females and in the degree of higher education. There are desires for further information on the potential adverse reactions to HAART.

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.

Objective: Antiretroviral therapy (ART) intensification has been shown to reduce the reservoir of latently infected CD4 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 in chronically HIV-1-infected patients was assessed in two previous clinical trials. In this 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 T cells carrying replication-competent virus, 2-long terminal repeat (2-LTR) circles and CD4/CD8 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=0.004). After 24 weeks of drug discontinuation, the median size of the reservoir was still significantly lower than at baseline (P=0.008). 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=0.1). CD4 and CD8 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.

Objective: Analysis of the contribution of genetic (single nucleotide polymorphisms (SNP) at position -238 and -308 of the tumor necrosis factor alpha (TNF-α) and -592 of the interleukin-10 (IL-10) promotor genes) and of classical factors (age, alcohol, immunodepression, antirretroviral therapy) on the risk of liver cirrhosis in human immunodeficiency (HIV)-hepatitis C (HCV) virus coinfected patients., Patients and Methods: Ninety one HIV-HCV coinfected patients (50 of them with chronic hepatitis and 41 with liver cirrhosis) and 55 healthy controls were studied. Demographic, risk factors for the HIV-HCV infection, HIV-related (CD4+ T cell count, antiretroviral therapy, HIV viral load) and HCV-related (serum ALT concentration, HCV viral load, HCV genotype) characteristics and polymorphisms at position -238 and -308 of the tumor necrosis factor alfa (TNF- α) and -592 of the interleukin-10 (IL-10) promotor genes were studied., Results: Evolution time of the infection was 21 years in both patients' groups (chronic hepatitis and liver cirrhosis). The group of patients with liver cirrhosis shows a lower CD4+ T cell count at the inclusion in the study (but not at diagnosis of HIV infection), a higher percentage of individuals with previous alcohol abuse, and a higher proportion of patients with the genotype GG at position -238 of the TNF-α promotor gene; polymorphism at -592 of the IL-10 promotor gene approaches to statistical significance. Serum concentrations of profibrogenic transforming growth factor beta1 were significantly higher in healthy controls with genotype GG at -238 TNF-α promotor gene. The linear regression analysis demonstrates that the genotype GG at -238 TNF-α promotor gene was the independent factor associated to liver cirrhosis., Conclusion: It is stressed the importance of immunogenetic factors (TNF-α polymorphism at -238 position), above other factors previously accepted (age, gender, alcohol, immunodepression), on the evolution to liver cirrhosis among HIV-infected patients with established chronic HCV infections.

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 <40 copies/mL for at least 2 years and CD4 count >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., (Copyright © 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Objectives: To estimate HIV incidence in the adult population of Peru, 2010, and analyze its distribution based on risk behavior., Materials and Methods: The UNAIDS model was applied based on the modes of transmission (MoT). The information was obtained from the review detailed in 59 documents (1984 - 2008). National databases were also analyzed to obtain specific data. Final selection of data was validated by the technical group and a group of experts. After consultation with experts, values were corrected and an uncertainty analysis was conducted. The model was adjusted to 2009 national prevalence (0.45%)., Results: Incidence estimated for 2010 was 0.03%, (4346 new infections). 84% of new infections concentrate on higher risk groups: men who have sex with men (55%) and people who have casual sex with heterosexuals (6.2%). The remaining 16% corresponds to low-risk heterosexual population. Heterosexual transmission accounts for 43% of new cases, 18% of which corresponds to female partners of high risk individuals. Only 2.2% of cases is related to female sexual work and 1.0% to injection drug users., Conclusions: The model provides an estimation of the incidence and its distribution among risk groups according to the mode of transmission, consistent with the HIV case reporting. The model creates scenarios to help decision making and policy formulation, as well as surveillance and planning of prevention and control.

Background: Thymidine analogue resistance mutations (TAMs) selected under treatment with nucleoside analogues generate two distinct genotypic profiles in the HIV-1 reverse transcriptase (RT): (i) TAM1: M41L, L210W and T215Y, and (ii) TAM2: D67N, K70R and K219E/Q, and sometimes T215F. Secondary mutations, including thumb subdomain polymorphisms (e.g. R284K) have been identified in association with TAMs. We have identified mutational clusters associated with virological failure during salvage therapy with tenofovir/emtricitabine-based regimens. In this context, we have studied the role of R284K as a secondary mutation associated with mutations of the TAM1 complex., Results: The cross-sectional study carried out with > 200 HIV-1 genotypes showed that virological failure to tenofovir/emtricitabine was strongly associated with the presence of M184V (P < 10-10) and TAMs (P < 10-3), while K65R was relatively uncommon in previously-treated patients failing antiretroviral therapy. Clusters of mutations were identified, and among them, the TAM1 complex showed the highest correlation coefficients. Covariation of TAM1 mutations and V118I, V179I, M184V and R284K was observed. Virological studies showed that the combination of R284K with TAM1 mutations confers a fitness advantage in the presence of zidovudine or tenofovir. Studies with recombinant HIV-1 RTs showed that when associated with TAM1 mutations, R284K had a minimal impact on zidovudine or tenofovir inhibition, and in their ability to excise the inhibitors from blocked DNA primers. However, the mutant RT M41L/L210W/T215Y/R284K showed an increased catalytic rate for nucleotide incorporation and a higher RNase H activity in comparison with WT and mutant M41L/L210W/T215Y RTs. These effects were consistent with its enhanced chain-terminated primer rescue on DNA/DNA template-primers, but not on RNA/DNA complexes, and can explain the higher fitness of HIV-1 having TAM1/R284K mutations., Conclusions: Our study shows the association of R284K and TAM1 mutations in individuals failing therapy with tenofovir/emtricitabine, and unveils a novel mechanism by which secondary mutations are selected in the context of drug-resistance mutations.

Objective: The aim of this study was to assess whether measurement of hepatitis C virus RNA (HCV-RNA) at 12 weeks post-treatment could predict sustained virological response (SVR) to antiviral therapy for chronic hepatitis C (pegylated interferon alfa-2a and ribavirin) in HIV-co-infected patients., Patients and Methods: HIV-HCV co-infected patients were included if they completed a full course of anti-HCV therapy, achieved an end-of-treatment response and complied with the week +12 and +24 post-treatment follow-up schedule for serum HCV-RNA determination (Real-time HCV (Abbott, Wiesbaden, Germany) (lower limit of detection, 12 IU/ml)., Results: Forty out of 66 patients (61%) showed an end-of-treatment response. They were assessed in a follow-up visit at +12 and at +24 weeks post-treatment. Serum HCV-RNA was undetectable in 28 of them at +12 weeks, and 100% of these remained undetectable at 24 weeks post-treatment (the gold standard of (SVR). The positive predictive value was 100% (95% confidence interval, 98.21-100%)., Conclusion: Post-treatment follow-up to identify virological relapse could be shortened to 12 weeks, providing a new definition of sustained virological response., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

Objective: To analyze the evolution of published scientific articles on HIV/AIDS in Peru., Methods: A bibliometric analysis of papers on HIV/AIDS published in journals indexed in MEDLINE, SciELO and LILACS until October 2010. We selected research papers fully developed in Peru, and multicenter studies with participating Peruvian sites., Results: We identified 257 publications on HIV/AIDS, showing an increase since 2003. The average publication delay was 2.8±1.8 years. Only 94 (36.6 %) articles were published in Spanish. The most studied areas were epidemiology (36.6 %) and clinical topics (35.8 %). The cross-sectional design was the most frequent (56.8 %) followed by case series. According to the WHO classification, studies to learn more about the disease and risk factors predominated (85.6 %) and according to the intervention areas, 46.7 % focused on diagnosis and treatment. Most studies were conducted in Lima (65.9 %). 48.2 % of studies focused on people living with HIV/AIDS. Finally, Revista Peruana de Medicina Experimental y Salud Pública was the journal that published most articles on HIV/AIDS (9.7 %)., Conclusions: We found a growth in scientific production on HIV/AIDS in Peru; however, we believe that the research undertaken was not based on an agreed national agenda or national research priorities, which might have limitted its dissemination and application.

Background and Aims: Analysis of the influence of the effects of increased intestinal permeability on haemodynamic alterations in human immunodeficiency virus (HIV)-infected patients with decompensated hepatitis C virus (HCV)-related liver disease., Methods: Forty HIV/HCV co-infected patients and 40 HCV mono-infected patients, 20 of them with compensated cirrhosis and 20 with a previous decompensation, and 20 healthy controls, were studied. Intestinal permeability was determined by serum levels of lipopolysaccharide-binding protein (LBP). Monocyte expression of toll-like receptor 4 (TLR-4), serum levels of interleukin (IL)-6 and soluble receptors of tumour necrosis factor (sTNFRI) were analysed. Cardiac index, systemic vascular resistance (SVR), plasma renin activity (PRA) and aldosterone concentration were also determined in cirrhotic patients., Results: Serum levels of LBP, TLR-4, IL-6 and sTNFRI were significantly higher in HIV-HCV co-infected and HCV mono-infected patients with decompensated cirrhosis compared with those with compensated liver disease. Significantly lower values of SVR and higher values of cardiac index, PRA and aldosterone concentration were observed in patients with decompensated cirrhosis compared with those with compensated liver disease, particularly in those with elevated levels of IL-6. There were no significant differences between HIV/HCV co-infected and HCV mono-infected patients., Conclusions: Higher intestinal permeability and consequent macrophage activation is observed in patients with cirrhosis; this permeability is even higher in those with portal hypertension. Serum values of IL-6 are associated with the characteristic haemodynamic derangement observed in advanced phases of cirrhosis. HIV/HCV co-infected cirrhotic patients present inflammatory and systemic haemodynamic alterations similar to those observed in HCV mono-infected patients., (© 2011 John Wiley & Sons A/S.)

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.

Background: Variable progression towards AIDS has been described and has been related to viral and host factors. Around 10% of the HIV-1 infected patients are slow progressors (SP), not presenting with AIDS disease signs even after more than 10 years of infection. Viral gene defects have been associated with the disease progression but more studies are still needed., Methodology: The sequence of vif and nef were analyzed for HIV-1 infecting 14 SP and 46 normal progressors (NP) patients., Results: Co-circulation of a strain carrying vif deleted gene with the wild type strain was detected in an SP patient with more than 10 years of infection. Other mutations (insertion in aa 63 in one strain, two premature stop codons in another one) were found in viruses infecting two other patients. Except for the SP8 strain, which exhibited a premature stop codon in nef, no gross deletions or insertions were observed in nef genes of both NPs and SPs strains analyzed., Conclusions: Different kind of mutation: deletion, insertion and stop codon, were detected in 3/14 samples from SP, with co-circulation of a 195 bp vif deletion virus with a wild type in one of these patients. Although vif defects do not seem to be a frequent feature in SPs, this study illustrates the importance of analysing this gene, in addition to the multiple factors associated with the long-term non progression to AIDS.

Maraviroc is the first co-receptor antagonist to be approved for use in HIV infected patient. In a phase II trial, in which the drug was administered as a single therapy, the most suitable maintenance dose was 300 mg, once or twice per day. The MOTIVATE double blind, placebo-compared studies, were carried out on patients infected by HIV-1 with R5 tropism and resistant to drugs from three families of retrovirals. Maraviroc two times per day achieved < 50 copies/mL in 45.5% of the patients compared to 16.7% in the placebo group (p < 0.001). The CD4+ lymphocyte count had a mean of 63 cells/mm(3) higher with Maraviroc. The drug was shown to be superior in all patient groups regardless of the baseline viral load, the baseline CD4+ lymphocyte count or the number of accompanying active drugs. In the study on patients infected by HIV with X4/dual/mixed tropism, Maraviroc, was not virologically effective, but did produce a CD4 increase higher than the placebo. Maraviroc was compared with Efavirenz in the study on patients with no previous treatment and with R5-tropic virus. At 48 weeks, the percentage of patients with a viral load of <50 copies/mL was 69.3% in the group that received Efavirenz and 65.3% in the Maraviroc group. In conclusion, Maraviroc has demonstrated its increased efficacy in patients with CCR5-tropic virus and a long history of antiretroviral use and failure, and in patients with no previous treatment.

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-naïve 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 log(10) copies/mL in group 1 and 3.8 log(10) copies/mL in group 2. After 28 days, the mean HIV-1 RNA reduction was 0.99 log(10) copies/mL [95% confidence interval (CI) 0.45-1.53] for group 1 and 0.89 log(10) copies/mL (95% CI 0.38-1.40) for group 2. AUCMB/day values were 0.775 log(10) copies/mL (95% CI 0.33-1.22) and 0.774 log(10) 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 and Objectives: Polymorphisms in the genes that encode for the CCR2 chemokine receptor and its natural ligand CCL2 have been shown to influence the natural history of HIV-1 infection, although data are inconsistent. Our aim was to determine whether functionally active CCR2 and CCL2 genetic variants influence the risk of infection and disease progression in a cohort of white Spaniards., Patients and Methods: This was a multicenter genetic association case-control study. Two single nucleotide polymorphisms (SNPs), V64I (G > A) of the CCR2 gene and -2518 (A > G) of the CCL2 gene, were assessed in 318 individuals: 73 HIV-1-infected long-term nonprogressors (LTNPs) of >16 years duration, 109 HIV-1-infected usual progressors (UPs), 36 heavily exposed to HIV-1 but uninfected individuals (EUs), and 100 control subjects. The distribution of the CCR5Delta32 allele was also assessed. Genotyping was performed using polymerase chain reaction (PCR) restriction fragment length polymorphisms (RFLPs) or PCR and automatic sequencing analysis methods on white blood cell DNA. Genotype and allele frequencies were compared by the chi2 test and the Fisher exact test., Results: CCR2 genotype distribution and allele frequencies showed nonsignificant differences between groups. The distribution of CCL2 alleles showed no significant differences between groups. HIV-1-infected individuals had, however, a significantly higher prevalence of the variant homozygous CCL2 GG genotype compared with EUs (P = 0.02). This result persisted when we studied only individuals with wild-type CCR5. Genotype and allele distribution of CCL2 was similar in HIV-1-infected UPs and LTNPs., Conclusions: In our cohort of white Spaniards, homozygosity for the variant CCL2-2518GG genotype is overrepresented in HIV-1-infected subjects.

Interferon (IFN)-alpha induced CD4(+) T lymphopenia is a toxic effect of the treatment of chronic hepatitis C virus (HCV) in human immunodeficiency virus (HIV)-co-infected patients. To increase the knowledge about this secondary effect, we performed an analysis of the evolution of the T cell receptor excision circles (TRECs), CD4(+) and CD8(+) T cells and of their CD45RO(+) and CD45RA(+) subpopulations during the treatment of chronic hepatitis HCV with peginterferon alpha (pegIFN-alpha) + ribavirin. Twenty HCV/HIV-co-infected patients, with undetectable HIV load after highly active antiretroviral therapy (HAART), were treated with pegIFN-alpha + ribavirin. TRECs were determined using real-time polymerase chain reaction. CD4(+) and CD8(+) T cells and their CD45RO(+) and CD45RA(+) subpopulations were analysed by two-colour flow cytometry. Median baseline CD4(+) and CD8(+) T cells were 592 mm(3) and 874 mm(3), respectively. Median baseline CD45RO(+) subpopulation was 48% for CD4(+) T and 57% for CD8(+) T lymphocytes. A progressive decrease in both T cell populations, as well as of their CD45RO(+) and CD45RA(+) subpopulations, was detected, with a difference between the baseline and nadir levels approaching 50%. The evolution of T cell populations and TRECs was independent of the response to the treatment. T lymphocytes and their subpopulations returned to baseline levels at 24 weeks after the end of treatment, with the exception of the T CD4(+) CD45RA(+) subpopulation. The ratio of CD4(+) CD45RO(+)/CD4(+) CD45RA(+) increased from 0.89 (baseline) to 1.44 (24 weeks after the end of the therapy). TRECs/ml did not return to the basal values. In conclusion, a significant reduction of CD4(+) and CD8(+) T cells, and of their CD45RA(+) and CD45RO(+) subpopulations, in HIV/HCV co-infected patients treated with pegIFN-alpha was observed. Both subpopulations increased after the suppression of treatment, but the CD4(+) CD45RA subpopulation did not reach the basal levels as a consequence, at least in part, of a decrease in thymic production.

To examine whether polymorphisms of the RANTES chemokine gene promoter are associated with long-term nonprogressive HIV-1 infection in white Spanish subjects, we performed a cross-sectional genetic association case-control study. Two-hundred sixty-seven white Spaniards were studied: 58 were HIV-1-infected long-term nonprogressors (LTNPs) of more than 16 years, 109 were HIV-1-infected usual progressors (UPs), and 100 were control subjects. Three RANTES single nucleotide polymorphisms (SNPs) at positions -28C>G, -109T>C, and -403G>A were assessed. The prevalence of the CCR5Delta 32 allele was also examined. Genotyping was performed using polymerase chain reaction and automatic sequencing analysis methods. Genotype and allele frequencies between the 3 groups were compared by the chi2 test and the Fisher exact test. The distribution of allelic variants of RANTES in controls, UPs, and LTNPs, respectively, was 3%, 2%, and 5% for -28G; 4%, 2%, and 2% for -109C; and 18%, 18%, and 18% for -403A (P = not significant). The differences were still nonsignificant when we exclusively analyzed individuals not carrying the CCR5Delta32 allele. We conclude that LTNP of more than 16 years is not associated with SNPs in the RANTES gene promoter in white Spanish HIV-1-infected subjects.

Background and Objectives: The influence of the polymorphisms of the CX3CR1 chemokine receptor gene on the natural history of HIV-1 infection is controversial. This study aimed to determine whether functionally active CX3CR1 genetic variants are associated with long-term nonprogressive infection of >15 years in HIV-1-infected Spanish patients., Patients and Methods: Two single-nucleotide polymorphisms, V249I (G > A) and T280M (C > T), of the CX3CR1 gene were assessed in 271 Spaniards. These included 60 HIV-1-infected patients who were long-term nonprogressors (LTNPs) of >15 years, 109 HIV-1-infected patients who were usual progressors (UPs), and 102 control subjects. The CCR5Delta32 was also assessed. Genotyping was performed using polymerase chain reaction and automatic sequencing analysis methods on white cell DNA. Genotype and allele frequencies were compared by the chi test and the Fisher exact test., Results: The frequencies of the 249I variant allele were 42% for LTNPs, 24.5% for UPs, and 35% for healthy controls; the differences between LTNPs and UPs were significant (odds ratio 0.46; 95% CI: 0.27 to 0.75; P = 0.0017). For 280M the distribution was 16% for LTNPs, 14% for UPs, and 17% for healthy controls (P = NS). The haplotype 249I280T was significantly more common in LTNPs than in UPs (P = 0.0007). These results persisted after excluding from the analysis the individuals carrying the CCR5Delta32., Conclusions: CX3CR1 249I variant allele is more frequent in Spanish HIV-1-infected LTNPs of >15 years. This effect is independent of the presence of the CCR5Delta32 allele.

Purpose: To compare outcomes of nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine or efavirenz versus abacavir-based regimens with a backbone of zidovudine and lamivudine as initial therapy of treatment-naive adults with HIV-1 infection in routine clinical care., Method: All patients starting their first antiretroviral therapy with any of the studied regimens from January 1999 to December 2002 were included in the analysis. Rates of viral suppression (HIV-RNA below 50 copies/mL) and discontinuation of any component of the regimen were compared at 48 weeks., Results: Fifty-one patients started with one of the two NNRTI-based regimens and 49 started with the triple nucleoside regimen (3-NRTI). After 48 weeks, more patients in the NNRTI regimens (76.5%) than in the 3-NRTI (51.1%) regimen achieved a HIV-1 RNA level below the limit of detection (<1.7 log10 copies/mL; p = .008). Time to change the antiretroviral regimen was shorter with 3-NRTI (median [range]: 234 [139-329] days) than with NNRTI (346 [0-756] days) (p = .0901). More withdrawals related to drug toxicity or intolerance occurred with the 3-NRTI-based regimen., Conclusion: In a routine clinical care setting, initial antiretroviral treatment with an NNRTI (nevirapine or efavirenz) plus zidovudine and lamivudine was virologically superior and safer than a 3-NRTI therapy (abacavir with the same NRTI backbone).

We studied the frequency of the SDF-1 3'A allelic variant (801G-->A) in a cohort of white Spaniards made up of (1) HIV-1-infected long-term nonprogressors (LTNPs) older than 16 years of age (n = 57), (2) HIV-1-infected usual progressors (UPs; n = 107), and (3) a group of healthy controls (n = 100). The mutant SDF-1 3'A allele was observed in 28% of LTNPs, 19% of UPs, and 26% of healthy controls (P = not significant). Homozygosity for the 3'A mutation was detected in 7%, 4%, and 3% of LTNPs, UPs, and healthy controls, respectively (P = not significant). Polymorphism at the SDF-1 locus is not associated with LTNP disease of longer than 16 years in Spanish HIV-1-infected patients. This effect is independent of the CCR5Delta32 allele.

Therapy with interferon and ribavirin for hepatitis C virus (HCV) infection induces a decrease in several haematological population counts. It is unclear whether haematological toxicity is more severe in patients co-infected with HCV and human immunodeficiency virus (HIV). This study analysed the evolution of haematological population counts during and after interferon and ribavirin therapy for chronic HCV infection. Eleven patients co-infected with HIV and HCV and treated with pegylated interferon plus ribavirin, and ten treated with standard interferon plus ribavirin, were analysed. With reference to baseline values, neutrophil counts decreased by an average of 45% (range 18-67%), total lymphocytes by 50% (16-63%), CD4 lymphocytes by 54% (16-61%), haemoglobin by 9% (5-16%) and platelets by 31% (16-45%). The nadir of the decrease was reached in the first weeks of therapy and was maintained while patients were receiving treatment. The reduction in all series was higher with pegylated interferon. Patients recovered their baseline counts after finishing the treatment. No cases of haemorrhage or outstanding infection were detected during follow-up.

The objective of this study was to assess the factors implicated in an increased or decreased risk of pneumonia, with particular attention to the response to highly active antiretroviral therapy (HAART) and the effect of the polysaccharide 23-valent pneumococcal vaccination in 300 human immunodeficiency virus (HIV)-infected adults followed-up for a median of 35.6 months. Pneumococcal pneumonia occurred in 12 patients and all bacterial pneumonia (pneumonia caused by Streptococcus pneumoniae or other bacteria, as well as those with negative cultures but presumably bacterial in origin) in 40 patients. In the univariate analysis, immunodepressed patients (defined as those with less than 200 CD4+ T cell/microl), those without immunological response to HAART (defined as an increase of 25% of CD4+ T lymphocyte count), patients with previous admissions to hospital and those with cotrimoxazole or Mycobacterium avium intracellulare prophylaxis showed a higher incidence of both pneumococcal and all bacterial pneumonia. Multivariate analysis demonstrated that the presence of pneumococcal pneumonia was associated with a CD4+ lymphocyte count at the time of HIV diagnosis <200 cells/microl. The multivariate model that was more valid for prediction of all bacterial pneumonia included a CD4+ T cell count <200 cells/microl and absence of immunological response to HAART. Only in patients with a baseline CD4+ T cell count lower than 200/microl and immunological response to HAART, a near significant lower incidence of all bacterial pneumonia was observed after vaccination. Thus, these results do not support an important additional protective effect of 23-valent pneumococcal vaccine in HIV-patients with immunological response to HAART., (Copyright 2004 Wiley-Liss, Inc.)

Objectives: This work analyses the influence of immune status, serum human immunodeficiency virus (HIV) load and hepatitis C virus (HCV) genotypes on the probability of resolution of HCV infection in HIV-co-infected patients, as well as the evolution of HCV viremia after antiretroviral therapy., Patients and Methods: Forty-five patients with anti-HIV and anti-HCV antibodies were classified into two groups as a function of the positivity or persistent negativity of HCV RNA detection (active or recovered HCV infection, respectively). They were treated with highly active antiretroviral therapy (HAART). Serum HCV RNA was quantified by the reverse transcription-polymerase chain reaction. HCV genotypes were detected by line probe assay or by detection of type-specific antibodies., Results: HCV RNA was detectable in 30 (66.6%) out of 45 HIV-infected patients. CD4+ T-cell counts, HIV viremia, or HCV genotypes were similar in patients with active or recovered HCV infection. Patients with active HCV infection had a non-significant decrease of HCV viremia during a follow-up of 12 months (from 6.15 +/- 6.32 to 5.96 +/- 6.05 log copies/mL). This was not influenced by baseline HCV or HIV viral load, HCV genotype, or CD4+ T-cell count. The non-significant decrease was present in patients with or without an immunological response to HAART., Conclusion: HCV genotypes, immune status, or serum HIV load did not influence the resolution or chronicity of HCV infection in HIV-co-infected individuals. A non-significant decrease of HCV viremia in these patients treated with combinations including antiproteases could be expected.

A 1-year prospective analysis of patient adherence to antiretroviral therapy (zidovudine plus zalcitabine [55 patients] or zidovudine plus zalcitabine plus saquinavir [32 patients]) was performed in human immunodeficiency virus (HIV)-infected patients attended at a tertiary care hospital. Adherence to therapy was measured jointly by pharmacy records, patients' self-recording, and an increase in mean corpuscular volume. Likewise, the effects of therapy on clinical parameters, HIV load, CD4+ cell count, and serum levels of tumor necrosis factor alpha (TNF-alpha) and its soluble receptors were analyzed. Twenty-seven patients of those on a double-agent regimen and 12 of those on a triple-agent regimen adhered to the treatment. Ten opportunistic events occurred in noncompliant patients versus none in compliant individuals. A significant increase in CD4+ cell count and a decrease in HIV viral load were observed only in patients who adhered to therapy. TNF and its soluble receptors remained elevated at the end of follow-up, even in patients in whom the HIV viral load decreased to < 400 copies/ml. In conclusion, adherence to therapy must be considered a major factor influencing the results of antiretroviral therapy. Although these treatments have been demonstrated to be efficacious, they are not able to normalize the immune activation markers. These data suggest a suboptimal effect of antiretroviral therapy on the eradication of HIV-1.

Aims/background: This study was undertaken to examine the relationship of hepatitis C (HCV) viremia to human immunodeficiency virus (HIV) infection and to investigate the evidence of infection by specific hepatitis C genotypes., Patients and Methods: The analysis of HCV viremia was performed by reverse transcription-polymerase chain reaction in serum samples from 186 patients' selected by their positivity for anti-HCV antibodies. All samples were tested for HIV infection. In those patients with sera positivity for HCV RNA, isolates were genotyped by line probe assay. In those patients whose sera were negative for HCV RNA, antibodies specific for genotypes implicated in past HCV infection were detected by ELISA., Results: HCV RNA was detected in 117 patients with anti-HCV antibodies (62.9%). There was no statistically significant association between HCV RNA and HIV positivity (Odds ratio, O.R.: 1.75, Confidence interval 95%, C.I.: 0.92-3.33, p = 0.095). A positive association was demonstrated between infection by HCV genotype 3 and HCV viremia (O.R.: 10.67, C.I.: 1.51-458.05, p = 0.015) in HIV-infected patients, as well as between infection by HCV genotype 1 and HCV viremia (O.R.: 4.71, C.I.: 1.65-13.75, p = 0.002) in HIV-non infected individuals. In both groups, a negative association was observed between past HCV infection by multiple genotypes and HCV viremia (HIV-infected patients, O.R.: 0.10, C.I.: 0.00-1.11, p = 0.033. HIV-non infected patients, O.R.: 0.05, C.I.: 0.00-0.41, p = 0.001)., Conclusions: Infection by specific HCV genotypes (type 3 in HIV-infected patients and by type 1 in HIV-non infected ones) implies a higher risk of HCV viremia, whereas multiple HCV types infection is negatively associated with this probability. HIV coinfection does not influence the probability of HCV viremia.

In order to analyze the etiology, cytological and biochemical characteristics, and outcome of pleural disease in patients infected with HIV, the medical records of 86 HIV-positive patients with pleural effusion were reviewed. Controls were 106 HIV-negative patients with parapneumonic or tuberculous effusion. Most HIV-positive patients were intravenous drug abusers (95.3%). Pleural effusions in HIV-positive patients were caused by infections in 76 (89.4%) cases. Parapneumonic effusion was diagnosed in 59 patients and tuberculous pleuritis in 15 patients. Staphylococcus aureus was the most frequently isolated bacteria. Parameters for differentiating complicated cases of parapneumonic exudate from uncomplicated cases, such as pleural fluid pH < 7.20 (sensitivity 80% vs. 84.3%), pleural fluid glucose < 35 mg/dl (sensitivity 45% vs. 56.25%) pleural fluid LDH > 1600 UI/l (sensitivity 85% vs. 62.50%), showed similar sensitivity in HIV-positive and HIV-negative patients. Monocytes in pleural fluid were significantly decreased in tuberculous pleuritis in HIV-positive patients (506 +/- 425 vs. 1014 +/- 1196 monocytes/ml, p < 0.05). No significant differences were detected in the outcome of HIV-positive and HIV-negative patients with pleural disease. It can be concluded that the pleural effusion was of predominantly infectious etiology in HIV-positive patients from populations with a high prevalence of intravenous drug abuse. Neither the biochemical parameters in pleural fluid nor the outcome differed significantly between HIV-positive and HIV-negative patients.