Joaquín Portilla

Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and two nucleosides for maintenance therapy of HIV.

Background:Prior attempts to reduce the number of drugs needed to maintain viral suppression in patients with suppressed HIV replication while receiving three antiretroviral drugs have been unsuccessful. Methods:In 205 patients with suppressed HIV replication on lopinavir-ritonavir and two nucleosides, this randomized, open-label, non-inferiority clinical trial compared the strategies of continuation of triple therapy versus lopinavir-ritonavir monotherapy followed by reinduction with two nucleosides if virological rebound occurred without genotypic resistance to lopinavir-ritonavir. The primary endpoint was proportion of patients without therapeutic failure, defined as confirmed HIV RNA higher than 500 copies/mL (with exclusion of patients receiving monotherapy who resuppressed to < 50 copies/mL after resuming baseline nucleosides), or loss to follow-up, or change of randomized therapy other than reinduction. Results:At week 48, the percentage of patients without therapeutic failure was 94% in the monotherapy group versus 90% in the triple therapy group (difference,-4%; upper limit of 95% confidence interval for difference, 3.4%). The percentage of patients with HIV RNA 50 copies/mL at 48 weeks by intention-to-treat, missing data or reinductions considered as failures, were 85% in the monotherapy group versus 90% in the triple therapy group (P = 0.31; 95% upper limit of 95% confidence interval for difference, 14%). Conclusion:In this trial, 48 weeks of lopinavir-ritonavir monotherapy with reintroduction of nucleosides as needed was non-inferior to continuation of two nucleosides and lopinavir-ritonavir in patients with prior stable suppression. However, episodes of low level viremia were more common in patients receiving monotherapy. (ClinicalTrials. gov number, NCT00114933).

Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis.

Background:The OK04 trial has shown that 48 weeks of lopinavir-ritonavir monotherapy with reintroduction of nucleosides as needed was noninferior to continuation of triple therapy with 2 nucleosides and lopinavir-ritonavir in patients with prior stable suppression. However, it is still uncertain if this experimental strategy can maintain suppression in the long term. Methods:Patients entered this noninferiority trial (upper limit 95% confidence interval: +12%) with no history of virological failure while receiving a protease inhibitor and receiving 2 nucleosides plus lopinavir/ritonavir, with HIV RNA <50 copies per milliliter for more than 6 months. Primary end point was percent of patients without therapeutic failure, defined as confirmed HIV RNA >500 copies per milliliter with exclusion of monotherapy patients who resuppressed to <50 copies per milliliter after resuming baseline nucleosides, or loss to follow-up, or change of randomized therapy other than reinduction. Results:Through 96 weeks, percentage of patient without therapeutic failure was 87% (monotherapy, n = 100) vs. 78% (triple therapy, n = 98; 95% confidence interval: −20% to +1.2%). Percentage with HIV RNA <50 copies per milliliter (intention to treat, missing = failure, reinduction = failure): 77% (monotherapy) vs. 78% (triple therapy). Low-level viral rebound was more frequent in the monotherapy group. Twelve patients in the monotherapy group (12%) needed reinduction with nucleosides. Discontinuations due to adverse events were significantly more frequent in the triple therapy group (8%) than in the monotherapy group (0%); P = 0.003. Conclusions:At 96-week lopinavir/ritonavir monotherapy with reintroduction of nucleosides as needed was noninferior to continuation of triple therapy. Incidence of adverse events leading to treatment discontinuation was significantly lower with monotherapy. (ClinicalTrials.gov number, NCT00114933).

Dual treatment with lopinavir–ritonavir plus lamivudine versus triple treatment with lopinavir–ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial

BACKGROUND Our objective was to assess therapeutic non-inferiority of dual treatment with lopinavir-ritonavir and lamivudine to triple treatment with lopinavir-ritonavir plus two nucleos(t)ides for maintenance of HIV-1 viral suppression. METHODS In this randomised, open-label, non-inferiority trial, we recruited patients from 32 HIV units in hospitals in Spain and France. Eligible patients were HIV-infected adults (aged ≥18 years) with HIV-1 RNA of less than 50 copies per mL, for at least 6 months on triple treatment with lopinavir-ritonavir (twice daily) plus lamivudine or emtricitabine and a second nucleos(t)ide, with no resistance or virological failure to these drugs, and no positive hepatitis B serum surface antigen. Investigators at each centre randomly assigned patients (1:1; block size of four; stratified by time to suppression [<1 year or >1 year] and nadir CD4 cell count [<100 cells per μL or >100 cells per μL]; computer-generated random sequence) to continue triple treatment or switch to dual treatment (oral lopinavir 400 mg and oral ritonavir 100 mg twice daily plus oral lamivudine 300 mg once daily). The primary endpoint was response to treatment in the intention-to-treat population (all randomised patients) at 48 weeks. The non-inferiority margin was 12%. This study is registered with ClinicalTrials.gov, number NCT01471821. FINDINGS Between Oct 1, 2011, and April 1, 2013, we randomly assigned 250 participants to continue triple treatment (127 [51%] patients) or switch to dual treatment (123 [49%] patients). In the intention-to-treat population, 110 (86·6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87·8%) of 123 in the dual-treatment group (difference -1·2% [95% CI -9·6 to 7·3]; p=0·92), meeting the criteria for non-inferiority. Serious adverse events occurred in eight (7%) patients in the triple-treatment group and five (4%) in the dual-treatment group (p=0·515), and study drug discontinuations due to adverse events occurred in four (3%) in the triple-treatment group and one (1%) in the dual-treatment group (p=0·223). INTERPRETATION Dual treatment with lopinavir-ritonavir plus lamivudine has non-inferior therapeutic efficacy and is similarly tolerated to triple treatment. FUNDING AbbVie and Red Temática Cooperativa de Investigación en Sida.

Increasing Incidence of Hepatocellular Carcinoma in HIV-Infected Patients in Spain

BACKGROUND To report the clinical and epidemiological characteristics of hepatocellular carcinoma (HCC) diagnosed in a cohort of human immunodeficiency virus (HIV)-infected patients in Spain. METHODS All HIV-infected patients diagnosed of HCC in 18 hospitals in Spain before 31 December 2010 were included. The main characteristics of HCC cases are described and comparisons between cases according to the year of diagnosis are presented. RESULTS Eighty-two cases of HCC in HIV-infected patients were included, all of them related to viral hepatitis coinfection: hepatitis C virus (HCV) in 66 (81%), hepatitis B virus (HBV) in 6 (7%), and HBV/HCV in 10 (12%). From 1999, when the first case of HCC was diagnosed, a progressive increment in the incidence of HCC in the cohort has occurred. In patients coinfected with HIV/HCV-coinfected patients, the incidence HCC increased from 0.2 to 2.8 cases per 1000 person-years between 2000 and 2009. Death occurred in 65 patients (79%), with a median survival of 91 days (interquartile range, 31-227 days). Three of 11 patients (28%) who received potentially curative therapy died, compared with 62 of 71 patients (87%) who did not receive curative therapy (P = .0001). Compared with cases of HCC diagnosed before 2005, cases diagnosed later did not show a higher survival rate. CONCLUSIONS HCC is an emerging complication of cirrhosis in HIV-infected patients. A sharp increase in its incidence has occurred in those also infected by HCV in the recent years. Unfortunately, HCC is frequently diagnosed at an advanced stage, and mortality continues to be very high, with no significant changes in recent years. Earlier diagnosis, which may allow potentially curative therapy, is necessary.

Low-level HIV viremia is associated with microbial translocation and inflammation.

Background:Decrease in HIV viral load (VL) is accompanied by decrease in microbial translocation (MT) and chronic inflammation, but the behavior of these markers in patients with HIV-VL <20 copies per milliliter is unknown. The aim of this study was to determine whether strict control of HIV-VL is associated with MT and chronic inflammation. Methods:Observational cross-sectional study. Inclusion criteria: HIV patients receiving antiretroviral therapy and HIV-VL <200 copies per milliliter for more than 6 months. Exclusion criteria: chronic liver disease, active infection, or antibiotic consumption. Recruitment: patients who consecutively visited the outpatient clinic in November 2011. Primary endpoint: molecular MT as determined by detection in plasma of 16S ribosomal DNA. Secondary variables: lipopolysaccharide, soluble CD14, tumor necrosis factor &agr;, and interleukin 6. Primary explanatory variable: HIV-VL (COBAS AmpliPrep/COBAS TaqMan HIV-1 test, version 2.0) with a detection limit of 20 copies per milliliter. Results:Fifty-two patients were included: 65% men, median age 45 years, HIV acquired predominantly through sex (75%), 40% Centers for Disease Control and Prevention stage C, and median CD4 lymphocyte count 552 cells per cubic millimeter (range, 126–1640 cells/mm3). Molecular MT was observed in 46% and 18% of patients with low-level (20–200 copies/mL) and negative (<20 copies/mL) HIV-VL, respectively (P < 0.05). Plasma levels of inflammatory markers (tumor necrosis factor &agr; and interleukin 6) were higher in patients with molecular MT (P < 0.01) and were not influenced for HIV-VL. Conclusions:Patients with HIV infection receiving treatment and negative HIV-VL (<20 copies/mL) present less frequently MT than patients with low-level HIV viremias (20–200 copies/mL). MT is associated with higher levels of inflammation markers, independent of HIV-VL.

Anal Human Papillomavirus Genotype Distribution in HIV-Infected Men Who Have Sex with Men by Geographical Origin, Age, and Cytological Status in a Spanish Cohort

ABSTRACT Knowledge of human papillomavirus (HPV) type distribution in populations at risk for anal cancer is needed. Here, we describe the anal HPV genotype distribution in a large Spanish cohort (Cohort of the Spanish HIV Research Network HPV [CoRIS-HPV]) of HIV-positive men who have sex with men (MSM) according to geographical origin, age, and cytological status. A cross-sectional analysis of baseline data from 1,439 HIV-infected MSM (2007 to 2012) was performed. Anal HPV genotyping was performed using the Linear Array HPV genotyping test. Descriptive analyses of subject characteristics, prevalences, and 95% confidence intervals (CI) were performed. The global prevalences of HPV, high-risk HPV (HR-HPV), and low-risk HPV (LR-HPV) types were 95.8%, 83.0%, and 72.7%, respectively. Among the HR-HPV types, HPV16 was the most common, followed by HPV59, -39, -51, -18, and -52. The prevalence of multiple HR-HPV infections was 58.5%. There were no differences in the crude analyses between Spanish and Latin-American MSM for most HPV types, and a peak in prevalence for most HPV types was seen in patients in their late thirties. Globally and by specific HPV groups, men with abnormal anal cytologies had a higher prevalence of infection than those with normal cytologies. This study has the largest number of HIV-positive MSM with HPV genotype data analyzed according to cytological status as far as we know. The information gained from this study can help with the design of anal cancer prevention strategies in HIV-positive patients.

Association between il28b gene polymorphisms and plasma Hcv-rna levels in Hiv/hcv-co-infected patients

Background:IL28B polymorphisms influence both the rate of spontaneous hepatitis C virus (HCV) clearance and response to interferon α (IFNα)-based therapy. This observation has been reproduced in HIV-co-infected individuals. Controversy exists about the impact of IL28B alleles on HCV load. Methods:CoRIS is a nationwide, open cohort of newly diagnosed HIV-1 adults in Spain. In the subset of HCV-co-infected individuals, the relationship between plasma HCV-RNA and IL28B (rs12979860) genotypes was evaluated. Results:A total of 4670 HIV-1-infected patients had been included in CoRIS up to June 2010. All were naive for IFNα. HCV antibodies were reactive in 895 (19%). Of them, 289 specimens were available and tested positive for plasma HCV-RNA, with median values of 959 900 IU/ml. The rs12979860 genotype distribution in HCV viremic patients was CC 45%, CT 42.2% and TT 12.8%. The median plasma HCV-RNA according to IL28B genotypes was: CC 1 385 000, CT 848 939 and TT 251 189 IU/ml (P = 0.006). The percentage of patients with HCV-RNA more than 600 000 IU/ml was: CC 67.7%, CT 56.6% and TT 35.1% (P = 0.001). In multivariate analysis, IL28B CC/CT genotypes, infection with HCV genotypes 1/4 and prior intravenous drug users were independent predictors of HCV-RNA more than 600 000 IU/ml. Conclusion:HIV/HCV-co-infected patients with the C allele (CC/CT) at rs12979860 show significantly higher plasma HCV-RNA load than TT carriers. Notably, plasma HCV-RNA levels associated with poorer response to IFNα-based therapy are significantly more frequent in CC/CT than TT carriers. Hypothetically, patients harboring the rs12979860 allele C could display a lower activity of endogenous IFNα, allowing higher HCV replication while keeping an enhanced susceptibility to exogenous IFNα therapy.

Functional status determined by Barthel Index predicts community acquired pneumonia mortality in general population

BACKGROUND Barthel Index (BI) measures functional status. Our aim was to analyze if BI and other factors not included in Pneumonia Severity Index (PSI) predict mortality in general population with community acquired pneumonia (CAP). METHODS Prospective observational study including all patients with CAP diagnosed in 2006. Endpoint of study: 30-day mortality. Variables not included in PSI as BI were analyzed. Strength of association was determined by odds ratio (OR) with 95% confidence interval. RESULTS 550 patients, mean age of 60.3 ± 20.8, were included. 32 were lost during follow-up and 518 patients were finally analyzed. 44 (8.5%) patients died in the first 30 days after CAP diagnosis. In bivariate analysis, mortality was significantly more frequent in patients with PSI ≥ IV (19.2% vs 1.9%), BI≤80 points (23.9% vs 2.9%), multilobar infiltrate (20% vs 6%), diabetes mellitus (14.9% vs 6.5%), influenza vaccination (11.9% vs 6.6%) and pneumococcal vaccination (16.7% vs 6%). In multivariate analysis, mortality independently associated factors were: BI ≤80, OR: 3.9(CI95% 1.4-10.5; p < 0.001); PSI ≥ IV OR: 3.9(1.2-12.7; p < 0.05); and multilobar infiltrate OR: 2.9(1.1-7.3; p = 0.05). CONCLUSION A BI score ≤80 is associated with a higher mortality in patients with CAP independently of the PSI. BI can be a useful tool to predict CAP mortality in general population.

Clinical Utility of Maraviroc

Maraviroc belongs to the family of chemokine (C-C motif) receptor 5 (CCR5) antagonists that prevent the entry of human immunodeficiency virus (HIV) into host CD4+ T cells by blocking the CCR5 co-receptor R5. Maraviroc is currently the only CC5R co-receptor inhibitor that has been approved for clinical use in HIV-1-infected patients carrying the CCR5 tropism who are antiretroviral-na:?ve or have experienced therapeutic failure following traditional antiretroviral therapies. This article is a review of the main characteristics of maraviroc and the latest data regarding its clinical application.Maraviroc is effective and well tolerated in pre-treated and antiretroviral-naïve patients with HIV-1 infections carrying the CCR5 tropism. Data from the phase III programme of maraviroc, which includes the MOTIVATE 1 and 2 studies and the MERIT study, indicate that maraviroc significantly (p < 0.001) increases CD4+ cell counts compared with placebo in pre-treated patients and to a similar extent as efavirenz in antiretroviral-naïve patients. Even in cases where viral load is not completely suppressed, maraviroc improves immunological response compared with placebo. In addition, promising research suggests that maraviroc has favourable pharmacokinetic and safety profiles in patients with high cardiovascular risk or those co-infected with tuberculosis or hepatitis and could be considered an option for treatment of HIV-infected patients with these co-morbidities.Resistance to maraviroc is low and mainly related to the presence of chemokine (C-X-C motif) receptor 4 (CXCR4) tropism HIV-1-infections or to mutations in the V3 region of glycoprotein (gp) 120; however, the exact mechanisms by which resistance is acquired and their genotypic and phenotypic pattern have not yet been established. It is recommended that a tropism test should be performed when considering maraviroc as an alternate drug in HIV-1-infected patients. Current tropism assays have increased sensitivity to reliably detect CXCR4 HIV with rapid turn-around and at a low cost. Improved detection together with positive data on the drug’s efficacy and safety profiles should help physicians to identify more accurately the appropriate candidates for commencement of treatment with maraviroc.In summary, maraviroc improves immunological response and has shown favourable pharmacokinetic and safety profiles in patients with high cardiovascular risk or in those co-infected with tuberculosis or hepatitis. Long-term studies are needed to confirm whether therapeutic expectations resulting from clinical trials with maraviroc translate into a real benefit for HIV-1-infected patients for whom traditional antiretroviral therapies have failed or are not suitable.

What Drives the Number of High-Risk Human Papillomavirus Types in the Anal Canal in HIV-Positive Men Who Have Sex With Men?

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 < .001). The number of recent sex partners had a statistically significant, fairly linear association on the log scale (P = .033). The high prevalence of HR-HPV types is associated with recent sexual behavior and age.