Use of Generic Antiretroviral Drugs and Single-Tablet Regimen De-Simplification for the Treatment of HIV Infection in Spain.

The present study sought to describe the use of generic drugs and single-tablet regimen (STR) de-simplification for the treatment of human immunodeficiency virus (HIV) infection among 41 hospitals from the cohort of the Spanish HIV/AIDS Research Network (CoRIS). In June 2018, we collected information on when generic antiretroviral drugs (ARVs) were introduced in the different hospitals, how the decisions to use them were made, and how the information was provided to the patients. Most of the nine available generic ARVs in Spain by June 2018 had been introduced in at least 85% of the participating hospitals, except for zidovudine (AZT)/lamivudine (3TC) and AZT. The time difference between the effective marketing date of each generic ARV and its first dispensing date in the hospitals was much shorter for the more recently approved generic ARV since the year 2017. However, only up to 20% of the hospitals de-simplified efavirenz (EFV)/tenofovir disoproxil (TDF)/emtricitabine (FTC), dolutegravir (DTG)/abacavir (ABC)/3TC, and rilpivirine (RPV)/TDF/FTC (to generic EFV+TDF/FTC, DTG+generic ABC/3TC, and RPV+generic TDF/FTC, respectively), whereas the generic STR EFV/TDF/FTC was introduced in 87.8% of the centers. The median times between the date of effective marketing of generic TDF/FTC and the date of de-simplification of EFV/TDF/FTC and RPV/TDF/FTC were 723 [interquartile range (IQR): 369-1,119] and 234 (IQR: 142-264) days, respectively; this time was 155 (IQR: 28-287) days for de-simplification of DTG/ABC/3TC. In conclusion, despite the widespread use of generic ARVs, STRs de-simplification was only undertaken in <20% of the hospitals. There was wide variability in the timing of the introduction of each generic ARV after they were available in the market.

Clinical characteristics and outcome of Spanish patients with ANCA-associated vasculitides: Impact of the vasculitis type, ANCA specificity, and treatment on mortality and morbidity.

The aim of this study was to describe the clinical characteristics of ANCA-associated vasculitides (AAV) at presentation, in a wide cohort of Spanish patients, and to analyze the impact of the vasculitis type, ANCA specificity, prognostic factors, and treatments administered at diagnosis, in the outcome.A total of 450 patients diagnosed between January 1990 and January 2014 in 20 Hospitals from Spain were included. Altogether, 40.9% had granulomatosis with polyangiitis (GPA), 37.1% microscopic polyangiitis (MPA), and 22% eosinophilic granulomatosis with polyangiitis (EGPA). The mean age at diagnosis was 55.6 ±â€Š17.3 years, patients with MPA being significantly older (P < 0.001). Fever, arthralgia, weight loss, respiratory, and ear-nose-throat (ENT) symptoms, were the most common at disease onset. ANCAs tested positive in 86.4% of cases: 36.2% C-ANCA-PR3 and 50.2% P-ANCA-MPO. P-ANCA-MPO was significantly associated with an increased risk for renal disease (OR 2.6, P < 0.001) and alveolar hemorrhage (OR 2, P = 0.010), while C-ANCA-PR3 was significantly associated with an increased risk for ENT (OR 3.4, P < 0.001) and ocular involvement (OR 2.3, P = 0.002). All patients received corticosteroids (CS) and 74.9% cyclophosphamide (CYC). The median follow-up was 82 months (IQR 100.4). Over this period 39.9% of patients suffered bacterial infections and 14.6% opportunistic infections, both being most prevalent in patients with high-cumulated doses of CYC and CS (P < 0.001). Relapses were recorded in 36.4% of cases with a mean rate of 2.5 ±â€Š2.3, and were more frequent in patients with C-ANCA-PR3 (P = 0.012). The initial disease severity was significantly associated with mortality but not with the occurrence of relapses. One hundred twenty-nine (28.7%) patients (74 MPA, 41 GPA, 14 EGPA) died. The mean survival was 58 months (IQR 105) and was significantly lower for patients with MPA (P < 0.001). Factors independently related to death were renal involvement (P = 0.010), cardiac failure (P = 0.029) and age over 65 years old (P < 0.001) at disease onset, and bacterial infections (P < 0.001). An improved outcome with significant decrease in mortality and treatment-related morbidity was observed in patients diagnosed after 2000, and was related to the implementation of less toxic regimens adapted to the disease activity and stage, and a drastic reduction in the cumulated CYC and CS dose.

[Interruption of antiretroviral therapy in chronically HIV-infected patients]. / Interrupción del tratamiento antirretroviral en pacientes con infección crónica por el virus de la inmunodeficiencia humana.

BACKGROUND AND OBJECTIVE: To describe the immunological, virological and clinical outcomes of HIV-infected patients who stop antiretroviral therapy (ART) and to identify the factors related to durability. PATIENTS AND METHOD: Retrospective study of patients who interrupt therapy after six months without clinical events, level of CD4+ > or = 500 cells/microl and HIV RNA > or = 5,000 copies/ml (3.7 log10). RESULTS: In October 2004, 44 patients were included, 32 (72%) of them were stables after one year of ART cessation (group A) and 12 (28%) patients had to restart therapy due to a decreased CD4+ count < 300 cells/microl (group B). Both groups were compared. CD4 cell count nadir (414 cells/microl [199] versus 171 cells/microl [107]; p = 0.000) and CD4+ count level at time of ART stop (920 [302] cells/microl versus 633 cells/microl [177] p = 0.004) showed differences with statistical significance. The most important CD4+ count fall was observed at third month after stopping ART; 588 cells/microl (288) on group A and 382 cells/microl (167) on group B. The mean time without ART was 27 months on group A and 7 months on group B. Two patients had acute retroviral syndrome, and one had Pneumocystis jiroveci pneumonia. Cholesterol levels were 199 mg/dl (42) and triglycerides 257 mg/dl (271) on ART and during interruption decreased to 155 (38) and 165 (122) mg/dl respectively. After multivariate analysis, a CD4+ count nadir > 200 cells/microl (p = 0,0005; OR = 0,12; 95% CI, 0.036-0,398) and a CD4+ count at time of ART stop > 800 cells/microl (p = 0,04; OR: 0,11; CI 95%: 0,015-0,936) were independently related to durability of therapy interruption. CONCLUSIONS: Prolonged discontinuation of ART guided by CD4+ response causes a low morbi-mortality. The cell count CD4+ nadir and the CD4+ count at time of ART cessation are protective factors of durability. An improvement of metabolic parameters is observed during the discontinuation of ART.

Whipple's disease diagnosed during anti-tumor necrosis factor alpha treatment: two case reports and review of the literature.

INTRODUCTION: Whipple's disease is a rare infectious disease caused by Tropheryma whipplei with protean clinical manifestations. This infection may mimic chronic inflammatory rheumatisms. CASE PRESENTATION: We report two cases of Whipple's disease diagnosed in the context of an inflammatory disease with anti-tumor necrosis factor alpha failure. The first patient was a 58-year-old white man with psoriatic spondylarthritis, who was treated with adalimumab, etanercept, infliximab, tocilizumab and golimumab. The second was a 73-year-old white man with rheumatoid arthritis, who received treatment with infliximab, then etanercept and rituximab. CONCLUSIONS: Whipple's disease should be suspected in all patients diagnosed with chronic inflammatory rheumatism, partially controlled or not controlled by treatment with tumor necrosis factor alpha blockers, whose condition worsens after treatment.

Once-a-day highly active antiretroviral therapy: a systematic review.

We analyzed the available evidence about the efficacy and tolerability of once-a-day highly active antiretroviral therapy (HAART), searching databases, conference proceedings, and journals. Two reviewers independently selected 6 uncontrolled and 2 randomized clinical trials of at least 24 weeks duration and with 80% participant follow-up. Regimens included didanosine (ddI), emtricitabine (FTC), and efavirenz (EFV) (2 studies, 326 patients); ddI, lamivudine (3TC), and EFV (3 studies, 147 patients); ddI, 3TC, EFV, and adefovir dipivoxil (1 study, 11 patients); ddI, nevirapine, and EFV (1 study, 15 patients); and ddI, 3TC, indinavir, and ritonavir (1 study, 10 patients). Virological efficacy ranged between 70% and 91%. Preliminary randomized clinical trials showed that once-a-day regimens (ddI, 3TC, and EFV or ddI, FTC, and EFV) had a virological efficacy at least similar to that of conventional HAART. The overall CD4 cell increase was at least 114 lymphocytes/microL. Tolerability was good, with a low discontinuation rate.

Risk and determinants of developing severe liver toxicity during therapy with nevirapine-and efavirenz-containing regimens in HIV-infected patients.

We examined the risk and determinants of developing severe liver toxicity in 108 HIV-infected patients showing adherence to nevirapine- and efavirenz-containing regimens. Between January 1997 and December 2000, 70 patients were treated with nevirapine- and 38 patients with efavirenz-containing regimens, for a median period of 127 days (interquartile range 65-240). Severe liver toxicity was defined as grade 3-4 elevations (>5 x upper limit of normal) of aminotransferases AST or ALT. A total of 22 (20%) patients showed severe liver toxicity, 17 of them were treated with nevirapine- and five with efavirenz-containing regimens (relative risk [RR]: 1.85, 95% confidence intervals [CIs] 0.74-4.61; P=not significant). Multivariate analysis showed the association of severe liver toxicity with hepatitis C antibody positive (RR 7.64; 95% CI: 1.48-39.52; P=0.01), nevirapine- or efavirenz-containing regimens combined with a protease inhibitor (RR: 3.07, 95% CI: 1.01-9.32, P=0.04) and alcohol intake greater than 40 g per day (RR: 3.09, 95% CI: 1.27-7.54, P=0.01). These findings have potential implications for selecting and monitoring antiretroviral therapy in HIV-infected patients with hepatitis C virus coinfection and for avoiding alcohol intake during antiretroviral therapy.

[Abnormal body fat distribution and type of antiretroviral therapy as predictors of cardiovascular disease risk in HIV-infected patients]. / Distribución anormal de la grasa corporal y tipo de tratamiento antirretroviral como predictores de riesgo de enfermedad cardiovascular en pacientes infectados por el virus de la inmunodeficiencia humana.

BACKGROUND AND OBJECTIVE: Dyslipidemia, insulin resistance and body fat redistribution are respectively short and long-term complications of protease inhibitor-containing antiretroviral regimens. To establish whether differences in the type of antiretroviral therapy (protease-containing or protease-sparing) or the presence and severity of body fat redistribution, explained differences in cardiovascular risk, we undertook a cross-sectional study. PATIENTS AND METHOD: The study was carried out in 219 consecutive HIV-infected patients attending an outpatient HIV clinic between February and April, 2002. Age, sex, smoking status, weight, height, waist circumference, blood pressure, antihypertensive treatment, total cholesterol, HDL cholesterol, triglycerides, and glucose concentrations, in addition to changes in body fat distribution were measured in 31 HIV-infected patients with no antiretroviral therapy, 35 HIV-infected patients treated with protease inhibitor-sparing regimens, and 153 HIV-infected patients treated with protease inhibitor-containing regimens. A ten-year cardiovascular disease risk was estimated according to the Framingham score. RESULTS: Patients treated with protease inhibitor-containing regimens as well as patients treated with protease inhibitor-sparing agents showed higher concentrations of cholesterol (p < 0.001), triglycerides (p = 0.004), glucose (p = 0.028), and greater changes in body fat distribution (p = 0.001) than patients with no antiretroviral therapy. An abnormal body fat distribution score was more strongly associated (p < 0.001) with the estimated 10-year cardiovascular disease risk than the type of HAART (p = 0.036). Ten-year cardiovascular disease risk increased linearly from 7.48% to 11.16% and to 19.50% in patients with no or mild, moderate and severe lipodystrophy scores, respectively. CONCLUSIONS: The results of this study encourage the use of cardiovascular preventive strategies in HIV-infected patients with severe lipodystrophy.

Screening for subclinical Leishmania infection in HIV-infected patients living in eastern Spain.

BACKGROUND: We anticipated that patients with HIV infection living in endemic areas were at greater risk of infection which can reactivate due to immunosuppression; therefore, we analyzed the prevalence of latent Leishmania infantum infection in patients infected with HIV. METHODS: A total of 179 patients with HIV infection were screened for the presence of anti-Leishmania antibodies using indirect immunofluorescent antibody test (IFAT) (Leishmania-spot IF; bioMérieux, Marcy l'Etoile, France). All patients were followed up for at least 1 year. The primary end-point was to confirm the presence of Leishmania infection. RESULTS: Significant titer of antibodies to Leishmania was detected in six (3%; 95% confidence interval: 0.5-5.5%) asymptomatic patients. Two of them had visceral leishmaniasis that was confirmed by parasite visualization in clinical samples, the presence of Leishmania promastigotes in Novy-MacNeal-Nicolle culture, polymerase chain reaction (PCR)-based methods, and/or urinary antigen test. Among 173 patients with indirect immunofluorescent antibody test below 1:40, one HIV-infected patient severely immunosuppressed, confirmed negative by IFAT, was diagnosed of visceral leishmaniasis. CONCLUSION: The use of indirect immunofluorescent antibody test for Leishmania screening is not justified in asymptomatic patients with HIV infection living in endemic areas due to the small rate of significant antibody titer and the low frequency of clinical disease.

Pharmacological and clinical evidence of nevirapine immediate- and extended-release formulations.

We reviewed the current information available on nevirapine immediate- and extended-release formulations and its role in single-dose and combination antiretroviral therapy. Nevirapine was approved in 1996 and was the first non-nucleoside reverse-transcriptase inhibitor available for the treatment of HIV-1 infection. Nevirapine has demonstrated good efficacy and a well-characterized safety profile. A major drawback is the low genetic barrier, allowing the emergence of resistance in the presence of single mutations in the reverse-transcriptase gene. This shortcoming is particularly relevant when nevirapine is administered in a single dose to prevent mother-to-child transmission of HIV-1 infection, compromising the efficacy of future non-nucleoside reverse transcriptase-inhibitor regimens. Studies published recently have probed the noninferiority of nevirapine compared to ritonavir-boosted atazanavir with both tenofovir disoproxil fumarate and emtricitabine in antiretroviral treatment-naïve patients. In 2011, a new formulation of nevirapine (nevirapine extended release) that allowed once-daily dosing was approved by the Food and Drug Administration and by the European Medicines Agency. VERxVe, a study comparing nevirapine extended release with nevirapine immediate release in antiretroviral treatment-naïve patients, and TRANxITION, a study carried out in antiretroviral treatment-experienced patients who switched therapy from nevirapine immediate release to nevirapine extended release, provided data on the noninferiority of the new formulation of nevirapine compared with nevirapine immediate release in terms of efficacy and safety. Nevirapine extended release will further increase the durability and persistence of nevirapine-containing antiretroviral therapy, allowing once-daily dosing regimens.

Cross-sectional epidemiology of hepatitis C virus detection and treatment in HIV-infected patients.

BACKGROUND: Sustained virologic response to peginterferon plus ribavirin reduces liver-related complications and mortality in patients co-infected with HIV and hepatitis C virus. Therefore, the presence of any barriers to start hepatitis C virus therapy should be identified and eliminated in order to recruit all eligible patients. METHODS: Cross-sectional study. In a HIV referral clinic we assessed the proportion of patients eligible for hepatitis C virus evaluation and treatment according to consensus guidelines. RESULTS: We identified 134 patients with hepatitis C virus and HIV co-infection. Twenty-one patients were excluded from the analysis due to never attending the HIV clinic (n=12) or having hepatitis C virus RNA not detectable (n=9). In the remaining 113 patients, only 61% had identification of hepatitis C virus genotype and quantification of hepatitis C viral load. Thirty-six patients started peginterferon plus ribavirin, and 16 (44%) achieved sustained virologic response. Seventy-seven patients did not receive treatment for hepatitis C virus due to the presence of medical contraindications (n=22), provider barriers (n=15), or patient barriers (n=40). Multivariate analysis identified lower education degree (odds ratio: 4.53; 95% confidence intervals: 1.36-15.16, p=0.014) and patient civil status single, separated or widower (odds ratio: 4.81; 95% confidence intervals: 1.54-14.99, p=0.007) as the independent determinants associated to not initiating therapy for hepatitis C virus infection in patients with barriers. CONCLUSION: A minor proportion of HIV-infected patients received appropriate assessment and treatment for hepatitis C virus infection. Social disadvantages require multidisciplinary models of health care to improve hepatitis C virus treatment initiation and success.

Net benefits of resistance testing directed therapy compared with standard of care in HIV-infected patients with virological failure: A meta-analysis.

BACKGROUND: We incorporated the latest available information to evaluate the net benefit of using resistance testing in HIV-infected patients with virological failure. METHODS: Meta-analysis of randomized controlled trials comparing the clinical impact of selecting antiretroviral therapy according to results of resistance testing (phenotype or genotype) or according to the standard of care. The population studied included HIV-infected patients with virological failure. The outcome measures were the proportion of patients with HIV-RNA below the detection limit, and the decline in HIV-RNA and increase in CD4 lymphocyte count at the end of follow-up (< or = 24 weeks). Clinical trials were identified through searches in MEDLINE, EMBASE and proceedings from major infectious diseases meetings. RESULTS: Eight trials including a total of 1810 patients were eligible. Therapy guided by resistance testing resulted in a higher percentage of patients with HIV-1 RNA below the detection limit at the end of follow-up (< or = 24 weeks) as compared with the standard of care (40.2% vs. 32.9%). The pooled risk ratio was 1.23; 95% CI 1.09-1.40, p = 0.0009; test for heterogeneity I(2)=0%; p = 0.46). The number needed to treat [NNT] was 13 (95% CI: 9-25). Subgroup analysis showed greater benefits in therapy guided by genotype testing with expert interpretation, when compared with standard of care (NNT: 5; 95% CI: 3-9; p = 0.06). The heterogeneity among trials for evaluating HIV-1 RNA decline and CD4 lymphocyte cell count increase made unfeasible pooling the results across studies. CONCLUSION: Genotype testing with expert interpretation showed the greatest benefit for guiding therapy in patients with HIV infection and virological failure.