Immune reconstitution inflammatory syndrome in HIV-infected patients with Pneumocystis jirovecii pneumonia / Síndrome inflamatorio de reconstitución inmune en pacientes con infección por VIH y neumonía por Pneumocystis jirovecii

INTRODUCTION: The incidence of immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients after an episode of Pneumocystis jirovecii pneumonia (PJP) seems to be lower than with other opportunistic infections. We conducted an observational study in order to determine the incidence, clinical characteristics and outcome of patients diagnosed with PJP-related IRIS. METHODS: We conducted an observational study of HIV patients diagnosed with PJP-related IRIS from January 2000 to November 2015. We analyzed epidemiological and clinical characteristics as well as laboratory findings. We also carried out a systematic review of published cases. RESULTS: Six cases of IRIS out of 123 (4.9%) HIV-infected patients with PJP who started ART were diagnosed. All six cases were men with a median age of 34 (IQR: 8) years. The six patients developed paradoxical IRIS. Subjects younger than 40 years old (p = 0.084) and with an HIV-RNA viral load >100000 copies/ml (p = 0.081) at diagnosis showed a tendency to develop IRIS. Thirty-seven published cases of PJP-related IRIS were identified. Although 51% of cases involved respiratory failure, no deaths were reported. CONCLUSIONS: PJP-related IRIS is rare condition compared to other opportunistic infections. It can lead to a severe respiratory failure in a significant proportion of cases, although no deaths have been reported

INTRODUCCIÓN: La incidencia del síndrome inflamatorio de reconstitución inmune (SIRI) en pacientes infectados por el virus de la inmunodeficiencia humana (VIH) después de un episodio de neumonía por Pneumocystis jirovecii (PJP) parece ser menor que con otras infecciones oportunistas. Hemos realizado un estudio observacional con el objetivo de conocer la incidencia, las características clínicas y la evolución de los pacientes diagnosticados de SIRI asociado con la PJP. MÉTODOS: Se ha realizado un estudio observacional de pacientes con VIH diagnosticados de SIRI asociado a PJP desde enero del 2000 hasta noviembre de 2015. Fueron analizadas características epidemiológicas y clínicas, así como hallazgos de laboratorio. Asimismo, se ha llevado a cabo una revisión sistemática de los casos publicados previamente. RESULTADOS: Se identificaron 6 casos de SIRI en 123 pacientes con VIH (4,9%) con PJP que comenzaron TAR. Los 6 casos eran varones con una edad media de 34 (IQR :8) años. En los 6 casos se trató de una SIRI paradójico. Los sujetos menores de 40 años (p = 0,084) y con VIH-ARN al diagnóstico mayor de 100.000 copias/ml (p = 0,081) mostraron una tendencia a desarrollar SIRI. Se identificaron 37 casos publicados de SIRI relacionado con PJP en la literatura. Aunque el 51% de los casos presentaron insuficiencia respiratoria, no se reportaron muertes. CONCLUSIONES: El SIRI asociado con PJP es una entidad infrecuente comparada con el relacionado con otras infecciones oportunistas. Puede provocar insuficiencia respiratoria grave en un porcentaje importante de casos, si bien no se han reportado muertes

Immune reconstitution inflammatory syndrome in HIV-infected patients with Pneumocystis jirovecii pneumonia.

INTRODUCTION: The incidence of immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients after an episode of Pneumocystis jirovecii pneumonia (PJP) seems to be lower than with other opportunistic infections. We conducted an observational study in order to determine the incidence, clinical characteristics and outcome of patients diagnosed with PJP-related IRIS. METHODS: We conducted an observational study of HIV patients diagnosed with PJP-related IRIS from January 2000 to November 2015. We analyzed epidemiological and clinical characteristics as well as laboratory findings. We also carried out a systematic review of published cases. RESULTS: Six cases of IRIS out of 123 (4.9%) HIV-infected patients with PJP who started ART were diagnosed. All six cases were men with a median age of 34 (IQR: 8) years. The six patients developed paradoxical IRIS. Subjects younger than 40 years old (p=0.084) and with an HIV-RNA viral load >100000 copies/ml (p=0.081) at diagnosis showed a tendency to develop IRIS. Thirty-seven published cases of PJP-related IRIS were identified. Although 51% of cases involved respiratory failure, no deaths were reported. CONCLUSIONS: PJP-related IRIS is rare condition compared to other opportunistic infections. It can lead to a severe respiratory failure in a significant proportion of cases, although no deaths have been reported.

Population pharmacokinetics of lopinavir/ritonavir (Kaletra) in HIV-infected patients.

BACKGROUND: A relationship between plasma concentrations and viral suppression in patients receiving lopinavir (LPV)/ritonavir (RTV) has been observed. Therefore, it is important to increase our knowledge about factors that determine interpatient variability in LPV pharmacokinetics (PK). METHODS: The study, designed to develop and validate population PK models for LPV and RTV, involved 263 ambulatory patients treated with 400/100 mg of LPV/RTV twice daily. A database of 1110 concentrations of LPV and RTV (647 from a single time-point and 463 from 73 full PK profiles) was available. Concentrations were determined at steady state using high-performance liquid chromatography with ultraviolet detection. PK analysis was performed with NONMEM software. Age, gender, height, total body weight, body mass index, RTV trough concentration (RTC), hepatitis C virus coinfection, total bilirubin, hospital of origin, formulation and concomitant administration of efavirenz (EFV), saquinavir (SQV), atazanavir (ATV), and tenofovir were analyzed as possible covariates influencing LPV/RTV kinetic behavior. RESULTS: Population models were developed with 954 drug plasma concentrations from 201 patients, and the validation was conducted in the remaining 62 patients (156 concentrations). A 1-compartment model with first-order absorption (including lag-time) and elimination best described the PK. Proportional error models for interindividual and residual variability were used. The final models for the drugs oral clearance (CL/F) were as follows: CL/F(LPV)(L/h)=0.216·BMI·0.81(RTC)·1.25(EFV)·0.84(ATV); CL/F(RTV)(L/h) = 8.00·1.34(SQV)·1.77(EFV)·1.35(ATV). The predictive performance of the final population PK models was tested using standardized mean prediction errors, showing values of 0.03 ± 0.74 and 0.05 ± 0.91 for LPV and RTV, and normalized prediction distribution error, confirming the suitability of both models. CONCLUSIONS: These validated models could be implemented in clinical PK software and applied to dose individualization using a Bayesian approach for both drugs.

Utilidad clínica de atazanavir / Clinical utility of atazanavir

Atazanavir (ATV) es un inhibidor de la proteasa (IP) cuyas principales cualidades en comparación con los otros IP son la cómoda dosificación, la buena tolerabilidad y el excelente perfil metabólico. Estas características hacen que se asemeje más a un no nucleósido que a un IP, pero con la elevada barrera genética propia de los IP. Está indicado en el tratamiento inicial, en la simplificación del tratamiento o el cambio por toxicidad, y en las primeras líneas de rescate. En Europa se ha aprobado la administración de ATV potenciado con ritonavir (300/100 mg/día) en todos los escenarios clínicos. En pacientes naïve se ha combinado con prácticamente todas la parejas de análogos de los nucleósidos y ha demostrado ser tan eficaz como lopinavir/ritonavir e incluso como efavirenz. En Estados Unidos, esta indicación está aprobada desde hace casi 5 años y ATV se ha convertido en el IP más prescrito, mientras que la Asociación Europea del Medicamento (EMEA) la ha aprobado este año. ATV es un fármaco óptimo para sustituir a otros antirretrovirales en estrategias de simplificación o cambios por toxicidad. En varios estudios se ha demostrado que en pacientes con buen control virológico puede sustituir a lopinavir/r o a otro IP, manteniéndose la eficacia terapéutica, con una excelente tolerabilidad y una mejoría del perfil lipídico, y con una disminución del riesgo cardiovascular. Esta estrategia es ampliamente utilizada en España. En este escenario, algunos pacientes podrían beneficiarse del tratamiento con ATV no potenciado (400 mg/día). ATV es una opción eficaz y muy atractiva en las primeras líneas de rescate en que el virus muestra escasa o nula resistencia a los IP, pues su simplicidad y tolerabilidad pueden mejorar los problemas de adhesión, principal causa de los fracasos terapéuticos. En pacientes con resistencia moderada a los IP, ATV es tan eficaz como LPV/r. La supervivencia de los pacientes con infección por el virus de la inmunodeficiencia humana (VIH) es cada vez más prolongada y cobran mayor importancia factores como la tolerabilidad, el riesgo cardiovascular y la adaptabilidad del tratamiento a la vida del paciente, por lo cual ATV debe desempeñar un importante papel en el tratamiento de la infección por el VIH

Atazanavir (ATV) is a protease inhibitor (PI) in which its main qualities, compared to other PI are dosing convenience, good tolerability and excellent metabolic profile. These characteristics makes it more like a nonnucleoside than a PI, but with the increased genetic barrier common to PI. It is indicated in initial treatment, simplification treatment or a change due to toxicity and in first line rescue treatment. The administering of ATV boosted with ritonavir (300/100 mg/d) has been approved in Europe in all clinical situations. In naïve patients it has been combined with practically all the nucleoside analogue pairs and has shown to be as effective as lopinavir/ritonavir and even efavirenz. In the USA, this indication has been approved for almost 5 years and ATV has become the most prescribed PI, while the EMEA has approved it this year. ATV is an optimal drug to replace other antiretrovirals in simplification strategies or changes due to toxicity. In several studies it has been shown that, in patients with good virological control, it can LPV/r or another PI, the therapeutic efficacy being maintained, with excellent tolerance and an improved lipid profile, and decreasing the cardiovascular risk. This strategy is widely used in Spain. In this scenario some patients could benefit from non-boosted ATV treatment (400 mg/d). ATV is an effective and very attractive option in first line rescue treatments in which the virus shows little or no resistance to PI, as its simplicity and tolerability can improve problems with compliance, the main cause of therapeutic failure. In patients with moderate resistance to PI, ATV is as effective as LPV/r. The survival of patients with HIV infection is increasingly longer and factors such as tolerability, cardiovascular risk and the adaptability of the treatment to the lifestyle of the patient, become more important, therefore ATV must play an important role in the treatment of HIV-infection

[Clinical utility of atazanavir]. / Utilidad clínica de atazanavir.

Atazanavir (ATV) is a protease inhibitor (PI) in which its main qualities, compared to other PI are dosing convenience, good tolerability and excellent metabolic profile. These characteristics makes it more like a nonnucleoside than a PI, but with the increased genetic barrier common to PI. It is indicated in initial treatment, simplification treatment or a change due to toxicity and in first line rescue treatment. The administering of ATV boosted with ritonavir (300/100 mg/d) has been approved in Europe in all clinical situations. In naïve patients it has been combined with practically all the nucleoside analogue pairs and has shown to be as effective as lopinavir/ritonavir and even efavirenz. In the USA, this indication has been approved for almost 5 years and ATV has become the most prescribed PI, while the EMEA has approved it this year. ATV is an optimal drug to replace other antiretrovirals in simplification strategies or changes due to toxicity. In several studies it has been shown that, in patients with good virological control, it can LPV/r or another PI, the therapeutic efficacy being maintained, with excellent tolerance and an improved lipid profile, and decreasing the cardiovascular risk. This strategy is widely used in Spain. In this scenario some patients could benefit from non-boosted ATV treatment (400 mg/d). ATV is an effective and very attractive option in first line rescue treatments in which the virus shows little or no resistance to PI, as its simplicity and tolerability can improve problems with compliance, the main cause of therapeutic failure. In patients with moderate resistance to PI, ATV is as effective as LPV/r. The survival of patients with HIV infection is increasingly longer and factors such as tolerability, cardiovascular risk and the adaptability of the treatment to the lifestyle of the patient, become more important, therefore ATV must play an important role in the treatment of HIV-infection.

[Current role of tenofovir in clinical medicine]. / Papel actual de tenofovir en la clínica.

Standard antiretroviral therapy (ART) consists of a combination of three active drugs. The selection of these drugs varies considerably according to the clinical scenario. The "gold standard" in patients initiating ART is tenofovir (TDF)/emtricitabine (FTC)/efavirenz. TDF/FTC is also considered a combination of choice when, for various reasons, ART is initiated with a boosted protease inhibitor. Abacavir and lamivudine (ABC/3TC) is also considered a combination of choice in most clinical practice guidelines. HLA-B*5701 determination minimizes the possibility of hypersensitivity of ABC and is a positive datum for the use of ABC/3TC. However, negative findings from the data collection on Adverse Events of Anti-HIV drugs (DAD) and ACTG5202 studies on this combination should be bourne in mind. TDF can also be a good choice for substituting another nucleoside analogue to avoid or reverse certain toxicities in patients with good virological control. Substituting thymidine analogues for TDF improves lipid profile and produces partial recuperation of subcutaneous fat. Because of the profile of resistance to TDF, this drug continues to be active in most patients with one, or even several, therapeutic failures. TDF plays and especially important role in patients coinfected with hepatotrophic viruses. In summary, TDF is a widely used drug in clinical practice due to its excellent combination of effectiveness, durability and tolerability, in addition to its ease of administration in a single daily dose, whether in its individual formation (Viread), or associated with FTC (Truvada), or with FTC and efavirenz (Atripla).

[Delayed diagnosis of HIV infection in the Spanish VACH cohort [1997-2002]]. / Diagnóstico tardío de la infección por el virus de la inmunodeficiencia humana en la Cohorte VACH (1997-2002).

OBJECTIVE: To study the prevalence of delayed diagnosis of HIV infection and associated factors. METHODS: A cross sectional study of patients included in the Spanish VACH cohort who had been diagnosed with HIV infection between 1997 and 2002 was performed. Delayed diagnosis was defined as patients diagnosed with HIV infection and AIDS simultaneously or within the first month after the first positive serologic test, or those with a first CD4+ cell count below 200/ml. The epidemiological characteristics of these patients were compared with those of the remaining patients RESULTS: Of 2,820 new cases of HIV infection, delayed diagnosis was found in 506 (18%). These patients differed from the remaining patients in their lower mean age and higher HIV viral load, as well as in their distribution by sex (higher proportion of males), occupational status, history of incarceration in prison, and HIV-risk transmission group. The median survival during follow-up was significantly lower among AIDS patients with a delayed diagnosis. CONCLUSIONS: Delayed diagnosis remains a cause for concern in our environment, due to its magnitude and its association with mortality. Some epidemiological characteristics provide clues to guide future programs directed at increasing information and improving prevention.

Diagnóstico tardío de la infección por el virus de la inmunodeficiencia humana en la Cohorte VACH (1997-2002) / Delayed diagnosis of HIV infection in the Spanish VACH cohort [1997-2002]

Objetivo: Estudiar la prevalencia del diagnóstico tardío (DT) de la infección por el virus de la inmunodeficiencia humana (VIH) y sus factores asociados. Métodos: Estudio transversal sobre los pacientes incluidos en la cohorte VACH cuya infección por el VIH hubiese sido diagnosticada entre 1997 y 2002. Consideramos DT los casos diagnosticados de sida concomitantemente o dentro del primer mes desde la primera serología positiva, o con recuento de CD4+ < 200/ml. Comparamos sus características epidemiológicas con las de los demás pacientes. Resultados: De 2.820 nuevos casos de infección por el VIH, 506 (18%) tuvieron DT. Éstos difirieron del resto en su menor edad media, mayor carga viral y en su distribución por sexos (mayor proporción de hombres), situación laboral, antecedentes penitenciarios y grupo de riesgo. La mediana de supervivencia durante el seguimiento fue menor en el grupo de DT. Conclusiones: El DT continúa siendo un problema preocupante por su magnitud y asociación con la mortalidad. Algunas características epidemiológicas proporcionan indicios para orientar futuros programas de información y prevención

Objective: To study the prevalence of delayed diagnosis of HIV infection and associated factors. Methods: A cross sectional study of patients included in the Spanish VACH cohort who had been diagnosed with HIV infection between 1997 and 2002 was performed. Delayed diagnosis was defined as patients diagnosed with HIV infection and AIDS simultaneously or within the first month after the first positive serologic test, or those with a first CD4+ cell count below 200/ml. The epidemiological characteristics of these patients were compared with those of the remaining patients Results: Of 2,820 new cases of HIV infection, delayed diagnosis was found in 506 (18%). These patients differed from the remaining patients in their lower mean age and higher HIV viral load, as well as in their distribution by sex (higher proportion of males), occupational status, history of incarceration in prison, and HIV-risk transmission group. The median survival during follow-up was significantly lower among AIDS patients with a delayed diagnosis. Conclusions: Delayed diagnosis remains a cause for concern in our environment, due to its magnitude and its association with mortality. Some epidemiological characteristics provide clues to guide future programs directed at increasing information and improving prevention

Interacciones que pueden comprometer la respuesta al tratamiento antirretroviral / Interactions that can compromise response to antiretroviral therapy

En este artículo se revisan las principales interacciones de los antirretrovirales con fármacos de otras familias que pueden comprometer la eficacia virológica. Tanto los inhibidores de la proteasa como los no nucleósidos presentan un elevado metabolismo hepático, por lo que los fármacos que actúan como inductores enzimáticos pueden reducir sus concentraciones plasmáticas. Los principales inductores son los antiepilépticos carbamacepina, fenitoína, fenobarbital; los antituberculosos rifampicina y rifabutina; los propios antirretrovirales nevirapina y efavirenz y algunos productos naturales, como la hierba de San Juan (Hypericum). Otro tipo de interacciones afecta a la absorción, y destaca la que se produce entre atazanavir y antiácidos, antihistamínicos H2 e inhibidores de la bomba de protones. La mayoría de estas interacciones se puede prevenir evitando la asociación o ajustando las dosis adecuadamente. Dada la elevada variabilidad interindividual, en algunos casos puede ser útil el seguimiento de las concentraciones plasmáticas

The present article reviews the main interactions of antiretroviral drugs with those from other families that can compromise virological efficacy. Both protease and non-nucleoside inhibitors are mainly metabolized in the liver and consequently drugs that act as enzyme inducers can reduce plasma levels of these antiretroviral agents. The main inducers are the antiepileptic drugs carbamazepine, phenytoin, and phenobarbital, the tuberculostatic agents, rifampicin and rifabutin, the antiretroviral agents nevirapine and efavirenz, and some natural products such as St. John's wort (Hypericum). Another type of interaction affects drug absorption. Notable among these is that produced between atazanavir and antacids H2-antihistamines and protein pump inhibitors. Most of these interactions can be prevented by avoiding the association or by adequately adjusting the dosage. Given that there is wide interindividual variability, monitoring plasma levels can be useful in some individuals