VIH y salud ósea / HIV and bone health

Con el advenimiento de la terapia antirretroviral, el pronóstico y la sobrevida de los pacientes infectados con el virus de la inmunodeficiencia humana (VIH) han cambiado de manera radical, por lo cual en la actualidad se evidencia un aumento en el riesgo de padecer enfermedades no relacionadas con el VIH como, por ejemplo, la osteoporosis. La disminución de la densidad mineral ósea (DMO) se observa en el 40-90% de las personas infectadas por el VIH, con una prevalencia de osteopenia y osteoporosis del 52 y 15%, respectivamente. Esta población de pacientes tiene un mayor riesgo de fracturas (60%) en comparación con personas no infectadas y un riesgo de fracturas vertebrales 2,3 veces mayor que en la población general. El tenofovir fumarato se asoció con un aumento de pérdida renal de fósforo e hiperparatiroidismo secundario. El efavirenz y los inhibidores de proteasas (IP) afectan el metabolismo de la vitamina D; actúan a nivel enzimático aumentando la expresión de la enzima CYP24 que lleva a producción de vitamina D inactiva. El FRAX es una herramienta sencilla y accesible, por lo que su uso está recomendado en pacientes con VIH. Además de las medidas higiénico-dietéticas, actividad física, calcio y vitamina D, el uso de bifosfonatos está indicado en el tratamiento de la osteoporosis en estos pacientes. (AU)

With the advent of antiretroviral therapy, the prognosis and survival of patients infected with the human immunodeficiency virus (HIV) have radically changed, which is why there is now evidence of an increased risk of suffering from diseases not related to HIV such as osteoporosis. The decrease in bone mineral density (BMD) is observed in 40-90% of people infected with HIV, with a prevalence of osteopenia and osteoporosis of 52 and 15%, respectively. This patient population has a 60% higher risk of fractures compared to uninfected people and a risk of vertebral fractures 2.3 times higher than in the general population. Tenofovir fumarate administration is associated with increased renal phosphorus loss and secondary hyperparathyroidism. Efavirenz and protease inhibitors (IP) affect the metabolism of vitamin D, they act at the enzymatic level by increasing the expression of the CYP24 enzyme that leads to the production of inactive vitamin D. The FRAX is a simple and accessible tool, so its use is recommended in patients with HIV and in addition to dietary hygiene measures, physical activity, calcium, and vitamin D, the use of bisphosphonates is indicated in the treatment of osteoporosis in these patients. (AU)

First-wave protease inhibitors for hepatitis C genotype 1 treatment: a real-life experience in Brazilian patients

Abstract INTRODUCTION: Licensed for chronic hepatitis C treatment in 2011, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), which have high sustained viral responses (SVR), ushered a new era characterized by the development of direct-action drugs against the hepatitis C virus (HCV). The aim of this study was to analyze the effectiveness and safety of BOC and TVR administered with pegylated interferon and ribavirin and to share the experience of a Brazilian reference center. METHODS: A retrospective descriptive study was conducted in patients with HCV genotype 1 infection who started treatment between July 2013 and December 2015. Data were collected using a computerized system. RESULTS: A total of 115 subjects were included, of which 58 (50.4 %) had liver cirrhosis and 103 (89.6 %) used TVR. The overall SVR rate was 61.7 % (62.1 % for TVR and 58.3 % for BOC). The presence of cirrhosis was associated with a lower SVR rate, whereas patients who relapsed after prior therapy had a greater chance of showing SVR than did non-responders. The incidence of adverse drug reactions (ADRs) was high. Almost all patients (~100 %) presented with hematologic events. Furthermore, treatment had to be discontinued in 15 subjects (13 %) due to severe ADRs. CONCLUSIONS: In conclusion, the SVR rates in our study were lower than those reported in pre-marketing studies but were comparable to real-life data. ADRs, particularly hematological ADRs, were more common compared to those in previous studies and resulted in a high rate of treatment discontinuity.

Curing Chronic Hepatitis C: A Cost Comparison of the Combination Simeprevir Plus Sofosbuvir vs. Protease-Inhibitor-Based Triple Therapy

ABSTRACT Introduction. Interferon-free, multi-direct acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection is highly effective and well tolerated, but costly. To gain perspective on the evolving economics of HCV therapy, we compared the cost per cure of a multi-DAA regimen with the prior standard of triple therapy. Material and methods. Patients infected with HCV genotype 1 who were treated through the University of Colorado Hepatology Clinic between May 2011 and December 2014 comprised the study population. The multi-DAA regimen of simeprevir plus sofosbuvir (SMV/SOF) was compared to the triple therapy regimen consisting of peginterferon and ribavirin, with either boceprevir or telaprevir (TT). Sustained-virologic response (SVR) rates, total costs per treatment and adverse events were recorded. Total cost per SVR were compared for the two treatments, controlling for patient demographics and clinical characteristics. Results. One hundred eighty-three patients received SMV/SOF (n = 70) or TT (n = 113). Patients receiving SMV/SOF were older, more treatment experienced, and had a higher stage of fibrosis. SVRs were 86% and 59%, average total costs per patient were $152,775 and $95,943, and average total costs per SVR were $178,237 vs. $161,813.49 for SMV/SOF and TT groups, respectively. Medication costs accounted for 98% of SMV/SOF and 85% of TT treatment costs. Conclusion. The high cure rate of multi-DAA treatment of HCV is offset by the high costs of the DAAs, such that the cost per cure from TT to multi-DAA therapy has been relatively constant. In order to cure more patients, either additional financial resources will need to be allocated to the treatment of HCV or drug costs will need to be reduced.

Aplastic Anemia and Severe Myelosuppression with Boceprevir or Simeprevir-Containing Hepatitis C Virus Treatment

ABSTRACT The addition of the new protease inhibitors (PIs) to peg-interferon (IFN) and ribavirin (RBV), approved for chronic hepatitis C, has clearly improved sustained virological response (SVR) rates although several adverse events have been reported with this regimens, including mild hematological toxicity. Moreover, severe pancytopenia and aplastic anemia during triple therapy with telaprevir has recently been described in seven patients. We report here two cases of severe agranulocytosis/aplastic anemia using boceprevir or simeprevir in interferon-based combination and 2 additional cases of severe myelosupression in IFN-free therapy with sofosbuvir and simeprevir plus RBV. Our observations suggest that PIs could have a sort of class-effect in developing severe hematologic toxicity or, at least, an additive interaction with other potentially myelotoxic agents such as IFN or RBV that are used in the classical regimens against HCV. Unfortunately, the mechanisms behind this phenomenon are currently unknown. In conclusion, given the lifethreatening character of these complications, close monitoring is mandatory in patients under PIs based therapy to promptly detect serious hematological toxicities and to carefully evaluate treatment discontinuation. Prospective studies assessing the usefulness of RBV in the era of new IFN-free combinations are needed.

Predictors of early treatment discontinuation and severe anemia in a Brazilian cohort of hepatitis C patients treated with first-generation protease inhibitors

The aim of this study was to determine risk factors for adverse events (AE)-related treatment discontinuation and severe anemia among patients with chronic hepatitis C virus (HCV) genotype 1 infection, treated with first-generation protease inhibitor (PI)-based therapy. We included all patients who initiated treatment with PI-based therapy at a Brazilian university hospital between November 2013 and December 2014. We prospectively collected data from medical records using standardized questionnaires and used Epi Info 6.0 for analysis. Severe anemia was defined as hemoglobin ≤8.5 mg/dL. We included 203 patients: 132 treated with telaprevir (TVR) and 71 treated with boceprevir (BOC). AE-related treatment discontinuation rate was 19.2% and anemia was the main reason (38.5%). Risk factors for treatment discontinuation were higher comorbidity index (OR=1.85, CI=1.05-3.25) for BOC, and higher bilirubin count (OR=1.02, CI=1.01-1.04) and lower BMI (OR=0.98, CI=0.96-0.99) for TVR. Severe anemia occurred in 35 (17.2%) patients. Risk factors for this outcome were lower estimated glomerular filtration rate (eGFR; OR=0.95, CI=0.91-0.98) for patients treated with TVR, and higher comorbidity index (OR=2.21, CI=1.04-4.67) and ribavirin dosage (OR=0.84, CI=0.72-0.99) for those treated with BOC. Fifty-five (57.3%) patients treated with TVR and 15 (27.3%) patients treated with BOC achieved sustained virological response (SVR). Among patients who received TVR and interrupted treatment due to AE (n=19), only 26.3% (n=5) achieved SVR (P=0.003). Higher number of comorbidities, lower eGFR and advanced liver disease are associated with severe anemia and early treatment cessation, which may compromise SVR achievement.

Safety aspects of protease inhibitors for chronic hepatitis C: adverse events and drug-to-drug interactions

The standard of care therapy of chronic hepatitis C with the combination of pegylated interferon and ribavirin for 24 or 48 weeks was a remarkable accomplishment of the past decade. However, sustained virological responses rates of about 80% (genotypes 2-3) and 50% (geno 3 type 1) were not satisfactory especially for patients infected with genotype 1. Important advances in the biology of HCV have made possible the development of the direct-acting antiviral agents boceprevir and telaprevir with substantial increase in the rates of sustained virological response with shorter duration of therapy for a large number of patients. However, the complexity of triple therapy is higher and several new side effects are expected suggesting greater expertise in the patient management. Anemia and disgeusia are frequent with boceprevir while cutaneous rash, ranging from mild to severe, is expected with telaprevir. Higher risk of drug-drug interactions demand further clinical consideration of the previous well-known adverse events of pegylated interferon and ribavirin. Identification and prompt management of these potential new problems with boceprevir and telaprevir are crucial in clinical practice for optimizing treatment and assuring safety outcomes to HCV-genotype 1 patients.

Antiretroviral treatment for HIV infection/AIDS and the risk of developing hyperglycemia and hyperlipidemia

A cross-sectional study with internal comparison groups was conducted to describe sociodemographic characteristics, as well as verify the association between the type of antiretroviral treatment used and hyperglycemia and hyperlipidemia, with special attention to the use of HIV protease inhibitors. The data was obtained through an interview questionnaire, as well as blood and urine samples that were collected for the laboratory exams. A total of 418 patients were interviewed. 46 of these, however, met the exclusion criteria. The sample was therefore composed by 372 HIV positive patients, attended at the laboratory of the Correia Picanço State Hospital for the collection of blood, to estimate the HIV viral load and/or TCD4 cell counts from August to November 2000. The association between the variables was tested using the chi-square test and the p-value. A multiple logistic regression analysis was carried out to adjust for potential confounding factors. A greater frequency of patients with high glucose levels was observed among those making use of antiretroviral therapy without protease inhibitors, but the number of patients limited the comparisons. An association was verified between the total serum cholesterol level and the use of HIV protease inhibitors (p = 0.047) even after controlling for age. An association was also observed between the triglyceride levels and the use of HIV protease inhibitors, which remained after adjustment for age, sex and creatinine levels (p < 0.001). The levels of glucose and TSH, the presence of proteinuria and the practice of physical activity were not associated either with the levels of cholesterol or with the levels of tryglicerides thus they were not confounders of the associations described.

Um estudo epidemiológico transversal, com caráter analítico, foi realizado para descrever características sócio-demográficas bem como verificar a associação entre o tipo de tratamento antiretroviral empregado e hiperglicemia e hiperlipidemia, com especial atenção aos pacientes em uso de inibidores da protease do HIV. As informações foram obtidas a partir de um questionário e da coleta de sangue e urina para a execução dos exames laboratoriais. Foram entrevistados 418 pacientes, sendo que 46 indivíduos foram excluídos do estudo. A amostra foi então composta por 372 pacientes soropositivos para o HIV atendidos no ambulatório do Hospital Correia Picanço da Secretaria Estadual de Saúde, no período de agosto a novembro de 2000. O teste do Qui-quadrado foi usado para testar as associações e a regressão logística múltipla para ajustar pelos potenciais fatores de confusão. Observou-se uma maior frequência de pacientes com níveis elevados de glicose entre aqueles que faziam uso de terapia antiretroviral sem inibidores da protease, mas o pequeno número de indivíduos limitou as comparações. Verificou-se uma associação entre o colesterol total e o uso de inibidores da protease (p = 0,047) mesmo após o ajuste por idade. Verificou-se também uma associação entre os níveis de triglicerídeos e o uso de inibidores da protease que permaneceu estatisticamente significante mesmo após o ajuste por idade, sexo e níveis de creatinina (p < 0,001). Os níveis de glicose, de TSH, a presença de proteinúria e a pratica de exercícios físicos não estiveram associados com os níveis de colesterol ou com os níveis de triglicerídeos, não se caracterizando como fatores de confusão das associações descritas.

Osteonecrosis en pacientes infectados por HIV / Osteonecrosis in HIV-infected patients

Según la literatura, la osteonecrosis tiene una mayor incidencia en los pacientes infectados con HIV que en la población general. Ello sería resultado de la confluencia de factores de riesgo clásicos y de otros propios de esta población o más prevalentes en ella, como el tratamiento con inhibidores de proteasa, la dislepemia producto de su consumo, la presencia de anticuerpos anticardiolipina séricos, la hipercoagulabilidad, la restauración inmune y las vasculitis. Presentamos una serie de 13 pacientes infectados con HIV con osteonecrosis. El motivo de consulta fue dolor en grandes articulaciones. Cuatro eran alcoholistas, 8 tabaquistas y 9 tenían dislipemia. Once habían recibido esteroides en algún momento de la vida aunque sólo uno estaba reciciéndolos al momento de inicio del dolor. En 2 se detectaron anticuerpos anticardiolipina séricos. Doce tenían sida y recebían tratamiento antirretroviral de alta eficacia (11 con inhibidores de proteasa). Ellos lograron una adecuada recuperacíon inmunológica. Consideramos necesario incluir la osteonecrosis como diagnóstico diferencial de artralgia persistente en pacientes infectados con HIV e investigar infección por HIV en todo paciente con osteonecrosis sin claros factores predisponentes.

Immune recovery vitritis presenting as panuveitis following therapy with protease inhibitors.

Immune reconstitution in acquired immunodeficiency syndrome (AIDS) patients on highly active anti-retroviral therapy (HAART) with cytomegalovirus (CMV) retinitis manifested as posterior segment intraocular inflammation has been reported. We report an adult HIV-positive Indian male with clinically inactive CMV retinitis who developed panuveitis with hypopyon. This was related to immune recovery mediated by combination anti-retroviral treatment, including protease inhibitors.

Lipodistrofia secundaria al uso de antirretrovirales inhibidores de proteasas / Lipodistrophy secondary to the use of antiretrovirals pretease inhibitors

El uso de inhibidores de proteasas en el tratamiento de la infección por HIV-1, ha revolucionado la sobrevida de éstos enfermos. Pero también se lo ha asociado a diabetes mellitus de nuevo comienzo, hiperlipidemia y lipodistrofia. Presentamos tres pacientes con lipodistrofia secundaria y comentamos la fisiopatogenia y tratamiento

Tratamiento antirretroviral / Antiretroviral therapy

En el presente trabajo se analizan los beneficios y limitaciones de la terapia antirretroviral de alta eficacia (HAART). Los objetivos de esta terapia son reducir la carga viral plasmática lo máximo posible y durante el mayor tiempo posible. Esto implica alcanzar niveles de carga viral no detectables con técnicas ultrasensibles. Se evalúan los resultados obtenidos con los principales esquemas de tratamiento asi como sus indicaciones y efectos adversos.

Fatores antinutricionais: inibidores de proteases e lectinas / Antinutritional factors: protease inhibitors and lectins

Os fatores antinutricionais presentes em alimentos podem provocar efeitos fisiológicos adversos ou diminuir a biodisponibilidade de nutrientes. A maior questão sobre os riscos à saúde provocados por antinutrientes é o desconhecimento dos níveis de tolerância, do grau de variação do risco individual e da influência de fatores ambientais sobre a capacidade de detoxificação do organismo humano. Dentre os fatores antinutricionais os inibidores de proteases e as lectinas são considerados instáveis ao tratamento térmico. A hipertrofia pancreática causada pelos inibidores de tripsina tem sido relatada em alguns estudos com animais. As alterações da função fisiológica em animais causadas por ação de lectinas no intestino parecem estar relacionadas à especificidade destas substâncias com as células da mucosa intestinal. Os possíveis efeitos adversos dos inibidores de proteases e das lectinas na maioria das vezes são inferidos somente de experimentos com animais de laboratório

Acute myocardial infarction in a 34-year-old HIV-positive female patient while undergoing active antiretroviral therapy containing a protease inhibitor

We describe the case of a young HIV-positive patient undergoing three-drug antiretroviral therapy that included a protease inhibitor for 9 months, who was admitted to the hospital with an acute myocardial infarction. A coronary angiogram revealed occlusion caused by a thrombus in the proximal third of the anterior descending artery. Complete recanalization was obtainedafter an angioplasty was performed. At the time of the infarction, only the triglyceride levels were found to be high. Metabolic alterations associated with the prolonged use of protease inhibitors have been described such as an increase in the triglyceride and the cholesterol serum levels, diabetes, resistence to insulin, lipodystrophy, and pancreatitis. The consequences of chronic hyperlipidemia are well known in the medical literature, especially premature coronary artery disease. No family history of coronary disease was identified in this patient. Whether the genesis of this localized thrombosis was due to a change in the metablism of the vascular endothelium caused by the protease inhibitors, or by related dyslipidemia, is still to be determined. In this case, the data suggest a strong link between coronary insufficiency and prolonged use of the protese inhibitor.

Associaçäo entre inibidores de protease e urolitíase / Indinavir associated nephrolithiasis

Introduction: The use of protease inhibitors, mainly the indinavir, drug recently introduced for the treatment of patients with the human immunodeficiency virus (HIV), has shown formations of crystals and urinary calculi as side effects. Surch conditions are found in 4 percent of patients using indinavir. Case Report: An HIV positive 32 years old male patient taking indinavir and AZT is presented. During treatment, the patient presented left flank pain and left uretero-hydronephrosis at renal ultrasound. Retrograde pyelography showed an image compatible with ureteral calculi. Six month later the patient presented for consultation and an intravenous pyelography and renal ultrasound were normal. Probably, the calculous had passed spontaneously. Conclusions: The benefits of the protease inhibitors for HIV positive patients are enormous and their use are rapidly increasing. Thus, physicians should be aware of this benign complication. Most of these cases are benign and the treatment should be analgesia and oral and parenteral hydration. Patients using indinavir must be advised to maintain adequate hydration