Ignacio Santos

Delayed diagnosis of HIV infection in a multicenter cohort: prevalence, risk factors, response to HAART and impact on mortality.

To study the prevalence of Delayed HIV Diagnosis (DHD) and its associated risk factors, to evaluate the effect of DHD on virological and immunological responses to HAART and to estimate the impact of DHD on all-causes mortality. Prospective cohort of 2, 564 HIV-positive HAART-naïve subjects attending 19 hospitals in Spain, 2004-2006. Estimations were made by logistic regression and survival analyses by Cox regression models. Prevalence of DHD was 37.3% (35.0-39.6). DHD was related to low educational level (OR:1.31, 95% CI:1.0-1.7). Compared to men who have sex with men (MSM), DHD was more frequent in heterosexuals (OR:1.9 95% CI:1.5-2.5) and injection drug users (IDUs) (OR:2.0 95% CI:1.5-2.8). An interaction between age and sex was found. Although risk of having DHD did not increase after age 30 in women, it increased linearly with age in men. No differences in virological (OR 1.2 95% CI: 0.8-1.8) and CD4 T cell (OR 1.1 95% CI: 0.7-1.8) responses to HAART were seen. The adjusted hazard ratio for death in patients with DHD was 5.2, (95% CI: 1.9-14.5). DHD is very common, especially in older men, heterosexuals and IDUs. Although we did not find differences in virological and immunological responses to HAART, we did observe higher mortality in people with DHD. Increased efforts to early diagnose HIV infection are urgently needed.

Risk, predictors, and mortality associated with non-AIDS events in newly diagnosed HIV-infected patients: role of antiretroviral therapy

Objective:We aimed to characterize non-AIDS events (NAEs) occurring in newly diagnosed HIV-infected patients in a contemporary cohort. Methods:The Cohort of the AIDS Research Network (CoRIS) is a prospective, multicenter cohort of HIV-infected adults antiretroviral naive at entry, established in 2004. We evaluated the incidence of and the mortality due to NAEs and AIDS events through October 2010. Poisson regression was used to investigate factors associated with a higher incidence of NAEs. Results:Overall, 5185 patients (13.306 person-years of follow-up), median age (interquartile range) 36 (29–43) years, participated in the study. A total of 86.5% patients had been diagnosed in 2004 or later. The incidence rate of NAEs was 28.93 per 1000 person-years [95% confidence interval (CI) 26.15–32.07], and of AIDS-defining events 25.23 per 1000 person-years (95% CI 22.60–28.16). The most common NAEs were psychiatric, hepatic, malignant, renal, and cardiovascular related. After adjustment, age, higher HIV-viral load, and lower CD4 cell count at cohort entry were associated with the occurrence of NAEs, whereas likelihood significantly decreased with sexual transmission and higher educational level. Additionally, antiretroviral therapy was inversely associated with the development of some NAEs, specifically of psychiatric [incidence rate ratio (95% CI) 0.54 (0.30–0.96)] and renal-related [incidence rate ratio (95% CI) 0.31 (0.13–0.72)] events. One hundred and seventy-three (3.33%) patients died during the study period. NAEs contributed to 28.9% of all deaths, with an incidence rate (95% CI) of 3.75 (2.84–4.94) per 1000 person-years. Conclusion:In patients newly diagnosed with HIV infection, NAEs are a significant cause of morbidity and mortality. Our results suggest a protective effect of antiretroviral therapy in the occurrence of NAEs, in particular of psychiatric and renal-related events.

Pegylated interferon α2a plus ribavirin versus pegylated interferon α2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients

OBJECTIVES The two currently available types of pegylated interferon (peg-IFN) used to treat hepatitis C have different pharmacokinetic properties. It is unclear how these differences affect response to therapy. We compared the effectiveness and safety of peg-IFN-alpha2a and peg-IFN-alpha2b, both with ribavirin, against chronic hepatitis C virus (HCV) infection in HIV-infected patients. METHODS From the GESIDA HIV/HCV cohort, we analysed patients treated with peg-IFN-alpha2a (n = 315) or peg-IFN-alpha2b (n = 242). The primary endpoint was a sustained virological response (SVR). RESULTS Both groups were well matched in baseline characteristics except for a higher frequency of injection drug users in the peg-IFN-alpha2b group than in the peg-IFN-alpha2a group (85% versus 76%; P = 0.01) and a higher frequency of bridging fibrosis and cirrhosis (F3-F4) in the peg-IFN-alpha2b group than in the peg-IFN-alpha2a group (42% versus 33%; P = 0.04). End-of-treatment response was significantly lower among patients treated with peg-IFN-alpha2b [40% versus 52%; odds ratio (OR), 1.63; 95% confidence interval (95% CI), 1.16-2.29; P < 0.01]. However, no significant differences were found in SVR between patients treated with peg-IFN-alpha2b and those treated with peg-IFN-alpha2a (31% versus 33%; OR, 1.09; 95% CI, 0.75-1.59; P = 0.655). Therapy was interrupted due to adverse events in 33 (14%) patients treated with peg-IFN-alpha2b and 47 (15%) patients treated with peg-IFN-alpha2a. CONCLUSIONS No differences in effectiveness and safety were found between peg-IFN-alpha2b and peg-IFN-alpha2a for the treatment of chronic HCV infection in HIV-infected patients.

Response to Liposomal Doxorubicin and Clinical Outcome of HIV-1–Infected Patients with Kaposi’s Sarcoma Receiving Highly Active Antiretroviral Therapy

Abstract Purpose: HIV-associated Kaposi’s sarcoma (KS) may not resolve despite highly active antiretroviral therapy (HAART). Moreover, the therapeutic goal has shifted from palliative care to long-term durable complete remission. The objective of the study was to assess the impact of liposomal doxorubicin in the treatment of HIV-associated KS in the HAART era. Method: In this prospective, noncomparative, multicenter study, patients with more than 10 cutaneous lesions or visceral disease were treated with 20 mg/m2 of liposomal doxorubicin (Caelyx®) every 3 weeks in addition to their antiretroviral therapy. In addition to tumor measurements and laboratory tests, human herpes virus 8 (HHV-8) polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMC) was performed. Results: Out of 79 participants enrolled in the study, 47 (59%) had stage T1 , 41 (52%) I1 , and 32 (40%) S1 . Nine individuals were not evaluable for response, 32 (40%) had complete response, 30 (38%) partial response, 5 (6%) stable disease, and 3 (4%) progression. Regression analysis did not find any statistically significant factor predicting response. HHV-8 PCR was positive in 37/53 (70%) patients with available PBMC samples, and HHV-8 viremia cleared in 14/27 (52%) without correlation with clinical response. Eleven (14%) participants experienced a relapse of KS, while at the last update of data, 49 (62%) remained stable. The only risk factor for recurrence identified was the follow-up time (odds ratio [OR] 1.21, 95% CI 1.07-1.36; p = .002). Conclusion: The response rate of AIDS-associated KS to liposomal doxorubicin administered with HAART was high, and most often the response was durable. HHV-8 viremia did not correlate well with clinical outcome.

Early lipid changes with atazanavir/ritonavir or darunavir/ritonavir.

Ritonavir‐boosted atazanavir and darunavir are protease inhibitors that are recommended for initial treatment of HIV infection because each has shown better lipid effects and overall tolerability than ritonavir‐boosted lopinavir. The extent to which lipid effects and overall tolerability differ between treatments with atazanavir and darunavir and whether atazanavir‐induced hyperbilirubinaemia may result in more favourable metabolic effects are issues that remain to be resolved.

Clinical effects of viral relapse after interferon plus ribavirin in patients co-infected with human immunodeficiency virus and hepatitis C virus

BACKGROUND & AIMS Sustained viral response (SVR) after therapy with interferon-ribavirin (IF-RB) reduces liver-related (LR) complications and mortality in HIV/HCV-co-infected patients. Here, we assess the impact of end-of-treatment response with subsequent relapse (REL) on LR events (LR death, liver decompensation, hepatocellular carcinoma, or liver transplantation), and liver stiffness (LS) by transient elastography. METHODS We analyzed the GESIDA 3603 Cohort (HIV/HCV-co-infected patients treated with IF-RB in 19 centers in Spain). Response to IF-RB was categorized as SVR, REL, and no response (NR). The study started when IF-RB was stopped and ended at death or the last follow-up visit. Multivariate regression analyses were adjusted for age, sex, HIV category of transmission, CDC clinical category, nadir CD4+ cell count, HCV genotype, HCV-RNA viral load, and liver fibrosis. RESULTS Of 1599 patients included, response was categorized as NR in 765, REL in 250 and SVR in 584. Median follow-up was more than 4 years in each group. Taking the group of patients with NR as reference, we found that the adjusted hazard ratios (95% confidence interval) of liver-related events (liver-related death, liver decompensation, hepatocellular carcinoma, liver transplantation) for patients with REL and for patients with SVR were 0.17 (0.05; 0.50) and 0.03 (0; 0.20), respectively. We also found that SVR was followed by less liver stiffness than both REL and NR. However, REL was associated with less liver stiffness than NR. CONCLUSIONS Best outcomes were achieved with an SVR. However, REL was associated with less LR mortality, decompensation, and liver stiffness than NR.

Effects of sustained viral response in patients with HIV and chronic hepatitis C and nonadvanced liver fibrosis.

Objective:We assessed the effects of sustained viral response (SVR), after treating with interferon–ribavirin (IF-RB), on mortality, liver-related (LR) events (decompensation, hepatocellular carcinoma), HIV progression, and liver stiffness in HIV/hepatitis C virus (HCV)-coinfected patients with nonadvanced liver fibrosis. Methods:From a cohort of HIV/HCV-coinfected patients treated with IF-RB, we selected those with baseline liver fibrosis stages F0, F1, or F2 according to METAVIR. The study started when IF-RB was stopped and ended at death or at the last follow-up visit. Results:A total of 695 patients were included (HCV genotype 1 or 4, 431; F0, 77; F1, 290; and F2, 328), and 274 patients achieved SVR. After a median follow-up of 4.9 years, the adjusted hazard ratio (aHR) [95% confidence interval (CI)] of LR events or overall death, for patients with SVR taking the group of patients with no SVR as a reference was 0.217 (0.079 to 0.599) (P = 0.003) for the whole cohort with F0 to F2. For patients with F0, the aHR (95% CI) was 0.514 (0.040 to 6.593) (P = 0.609), for patients with F1, the aHR (95% CI) was 0.305 (0.053 to 1.762) (P = 0.185), and for patients with F2, it was 0.075 (0.009 to 0.662) (P = 0.020). We also found that, in comparison with no SVR, SVR was followed by less frequent HIV progression for the entire population (F0 to F2) and less frequent liver stiffness across all categories of fibrosis. Conclusions:SVR in HIV/HCV-coinfected patients with moderate stages of liver fibrosis is associated with a reduction of mortality and LR events, and with a reduction of progression of HIV and liver fibrosis.

Differential Body Composition Effects of Protease Inhibitors Recommended for Initial Treatment of HIV Infection: A Randomized Clinical Trial

BACKGROUND It is unclear whether metabolic or body composition effects differ between protease inhibitor-based regimens recommended for initial treatment of human immunodeficiency virus (HIV) infection. METHODS ATADAR is a phase 4, open-label, multicenter, randomized clinical trial. Stable antiretroviral-naive HIV-infected adults were randomly assigned to atazanavir/ritonavir 300/100 mg or darunavir/ritonavir 800/100 mg in combination with tenofovir/emtricitabine daily. Predefined endpoints were treatment or virological failure, drug discontinuation due to adverse effects, and laboratory and body composition changes at 96 weeks. RESULTS At 96 weeks, 56 (62%) atazanavir/ritonavir and 62 (71%) darunavir/ritonavir patients remained free of treatment failure (estimated difference 8.2%; 95% confidence interval [CI], -.6 to 21.6) and 71 (79%) atazanavir/ritonavir and 75 (85%) darunavir/ritonavir patients remained free of virological failure (estimated difference 6.3%; 95% CI, -.5 to 17.6). Seven patients discontinued atazanavir/ritonavir and 5 discontinued darunavir/ritonavir due to adverse effects. Total and high-density lipoprotein cholesterol similarly increased in both arms, but there was a greater increase in triglycerides in the atazanavir/ritonavir arm. At 96 weeks, body fat (estimated difference 2862.2 gr; 95% CI, 726.7 to 4997.7; P = .0090), limb fat (estimated difference 1403.3 gr; 95% CI, 388.4 to 2418.2; P = .0071), and subcutaneous abdominal adipose tissue (estimated difference 28.4 cm(2); 95% CI, 1.9 to 55.0; P = .0362) increased more in the atazanavir/ritonavir arm than in darunavir/ritonavir arm. Body fat changes in the atazanavir/ritonavir arm were associated with higher insulin resistance. CONCLUSIONS We found no major differences between atazanavir/ritonavir and darunavir/ritonavir in efficacy, clinically relevant side effects, or plasma cholesterol fractions. However, atazanavir/ritonavir led to higher triglycerides and more total and subcutaneous fat than darunavir/ritonavir. Also, fat gains with atazanavir/ritonavir were associated with insulin resistance. Clinical Trials Registration. NCT01274780.

Liver toxicity of initial antiretroviral drug regimens including two nucleoside analogs plus one non-nucleoside analog or one ritonavir-boosted protease inhibitor in HIV/HCV-coinfected patients.

Abstract Objective: To evaluate the incidence and risk factors for grade 3 or 4 ALT or AST elevations (TE) and grade 4 total bilirubin elevations (TBE) among HIV/HCV- coinfected treatment-naïve patients with an initial regimen including 2 nucleoside analogs plus efavirenz (EFV), nevirapine (NVP), or a ritonavir-boosted protease inhibitor (PI/r).Patients and Methods: This was a retrospective multicenter observational cohort study that recruited 745 HIV-infected drug-naïve patients with detectable plasma HCV RNA who started a regimen including EFV, NVP, or PI/r.Results: EFV was prescribed in 323 (43%), NVP in 126 (17%), and a PI/r in 296 (40%) patients. Grade 3 or 4 TE were observed in 19 (5.9%) individuals receiving EFV compared with 14 (11%) on NVP (P = .056) and 31 (10.5%) on PI/r (P = .036). Grade 4 TBE were identified in 7 (2.2%) patients on EFV, 1 (0.8%) on NVP, and 11 (3.7%) on PI/r (P = .19). Therapy was discontinued due to liver toxicity in 13 (4%) patients on EFV, 16 (13%) on NVP, and 17 (6%) on PI/r (P = .003).Conclusions: Regimens including EFV, NVP, or PI/r are generally safe in treatment-naïve HIV/HCV-coinfected patients. Grade 3-4 TE are less commonly seen with EFV than with PI/r. Discontinuations due to hepatotoxicity were less frequent for patients receiving EFV than for those treated with NVP.

Baseline serum low-density lipoprotein cholesterol levels predict response to hepatitis C virus therapy in HIV/hepatitis C virus coinfected patients.

Background:High levels of serum low-density lipoprotein cholesterol are associated with better response to pegylated interferon and ribavirin in hepatitis C virus monoinfected patients. There are no data concerning this topic in HIV/hepatitis C virus coinfected patients in whom lipid disorders are particularly common. Objective:To assess the association between baseline lipid levels and sustained virologic response to pegylated interferon and ribavirin in coinfected patients. Methods:A total of 260 HIV/hepatitis C virus coinfected patients under treatment with pegylated interferon and ribavirin and who had a baseline serum lipid profile were included in this retrospective study. Results:Thirty-eight (24%) patients with genotypes 1–4 and 64 (63%) with genotypes 2–3 achieved sustained virologic response. Forty-nine (44%) patients with serum low-density lipoprotein cholesterol levels 100 mg/dl or more showed sustained virologic response compared with 53 (36%) with lower values [adjusted odds ratio: 2.51; 95% confidence interval: 1.40–4.87; P = 0.003]. This association was independent of the remaining predictors of sustained virologic response which were genotypes 2–3, plasma hepatitis C virus RNA 600 000 IU/ml or less, exposure to at least 80% of the planned therapy and lack of concomitant antiretroviral therapy. The rate of sustained virologic response in patients with genotype 1 and low-density lipoprotein cholesterol at least 100 mg/ml was 31% compared with 17% in those with lower values (adjusted odds ratio: 2.19; 95% confidence interval: 1.04–4.66; P = 0.040). The corresponding figures in subjects with genotypes 2–3 were 73 and 58% [2.71 (0.99–7.46); P = 0.054]. No other lipid was associated with response. Conclusion:Higher low-density lipoprotein cholesterol levels predict sustained virologic response to pegylated interferon and ribavirin in HIV/hepatitis C virus coinfected patients. This might be used to improve the rate of sustained virologic response in this setting.