Brief Report: Efficacy and Safety of Oral Islatravir Once Daily in Combination With Doravirine Through 96 Weeks for Treatment-Naive Adults With HIV-1 Infection Receiving Initial Treatment With Islatravir, Doravirine, and Lamivudine.

BACKGROUND: Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for treatment and prevention of HIV-1. We present efficacy and safety data for islatravir and doravirine (DOR) through 96 weeks of the phase 2b trial (NCT03272347). METHODS: In this randomized, double-blind, dose-ranging trial, participants initially received islatravir (0.25, 0.75, or 2.25 mg) with doravirine (100 mg) and lamivudine (3TC, 300 mg) or a fixed-dose combination of doravirine, 3TC, and tenofovir disoproxil fumarate (DOR/3TC/TDF) daily. Beginning at week 24, participants receiving islatravir stopped 3TC if HIV-1 RNA from the prior visit was <50 copies per milliliter and continued taking the assigned islatravir dose (still blinded) with doravirine. All islatravir groups transitioned to open-label use of 0.75 mg between weeks 60 and 84. Efficacy end points at week 96 included the proportion of participants maintaining HIV-1 RNA of <50 copies per milliliter (FDA Snapshot). Safety was assessed by adverse event (AE) reporting. RESULTS: One hundred twenty-one treatment-naive participants received the study drugs and were included in the analyses. Through week 96, HIV-1 RNA<50 copies per milliliter was maintained in 86.2% (25/29), 90.0% (27/30), and 67.7% (21/31) of participants in the 0.25-, 0.75-, and 2.25-mg islatravir groups, respectively, 81.1% (73/90) of the combined islatravir group, and 80.6% (25/31) of the DOR/3TC/TDF group. One participant in the 2.25-mg islatravir group had Protocol-Defined Virologic Failure after week 48. Drug-related AE rates were higher for DOR/3TC/TDF participants (22.6%) compared with islatravir (combined 7.8%). Two participants (2.2%) receiving islatravir with doravirine and one (3.2%) receiving DOR/3TC/TDF discontinued because of an AE. CONCLUSIONS: Treatment regimens containing islatravir and doravirine maintained viral suppression through week 96 and were well tolerated regardless of dose.

Islatravir in combination with doravirine for treatment-naive adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine: a phase 2b, randomised, double-blind, dose-ranging trial.

BACKGROUND: Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1 infection. We aimed to assess the efficacy and safety of islatravir-based regimens for the treatment of HIV-1. METHODS: We did a phase 2b, randomised, double-blind, comparator-controlled, dose-ranging trial at 24 clinics or hospitals in four countries (Chile, France, the UK, and the USA). Treatment-naive adults (≥18 years) with plasma HIV-1 RNA concentrations of at least 1000 copies per mL, CD4 T-cell counts of at least 200 cells per mL, and a calculated creatinine clearance of at least 50 mL/min (all within 60 days before study treatment) were eligible for inclusion. Participants were randomly assigned (1:1:1:1) with a block size of four via an interactive voice and web response system to receive oral treatment with one of three doses of islatravir (0·25 mg, 0·75 mg, or 2·25 mg) plus doravirine (100 mg) and lamivudine (300 mg) or to doravirine (100 mg) plus lamivudine (300 mg) plus tenofovir disoproxil fumarate (TDF; 300 mg) once daily with placebo (part 1). Treatment groups were stratified according to screening HIV-1 RNA concentration (≤100 000 copies per mL or >100 000 copies per mL). After at least 24 weeks of treatment, participants taking islatravir who achieved an HIV-1 RNA concentration lower than 50 copies per mL switched to a two-drug regimen of islatravir and doravirine (part 2). All participants and study investigators were masked to treatment in part 1; in part 2, the islatravir dose was masked to all participants and investigators, but the other drugs were given open label. The primary efficacy outcomes were the proportions of participants with an HIV-1 RNA concentration lower than 50 copies per mL at weeks 24 and 48 (US Food and Drug Administration snapshot approach). The primary safety outcomes were the number of participants experiencing adverse events and the number of participants discontinuing study drug owing to adverse events. All participants who received at least one dose of any study drug were included in the analyses. This trial is ongoing, but closed to enrolment of new participants; herein, we report study findings through 48 weeks of treatment. This trial is registered with ClinicalTrials.gov, NCT03272347. FINDINGS: Between Nov 27, 2017, and April 25, 2019, 121 participants (mean age 31 years [SD 10·9], 112 [93%] male, 92 [76%] white, 27 [22%] with HIV-1 RNA concentration >100 000 copies per mL) were randomly assigned: 29 to the 0·25 mg, 30 to the 0·75 mg, and 31 to the 2·25 mg islatravir groups, and 31 to the doravirine, lamivudine, and TDF group. At week 24, 26 (90%) of 29 participants in the 0·25 mg islatravir group, 30 (100%) of 30 in the 0·75 mg islatravir group, and 27 (87%) of 31 in the 2·25 mg islatravir group achieved HIV-1 RNA concentrations lower than 50 copies per mL compared with 27 (87%) of 31 in the doravirine plus lamivudine plus TDF group (difference 2·8%, 95% CI -14·9 to 20·4, for the 0·25 mg islatravir group; 12·9%, -1·6 to 27·5, for the 0·75 mg islatravir group; and 0·3%, -17·9 to 18·5, for the 2·25 mg islatravir group). At week 48, these data were 26 (90%) of 29 in the 0·25 mg islatravir group, 27 (90%) of 30 in the 0·75 mg islatravir group, and 24 (77%) of 31 in the 2·25 mg islatravir group compared with 26 (84%) of 31 in the doravirine plus lamivudine plus TDF group (difference 6·1%, 95% CI -12·4 to 24·4, for the 0·25 mg islatravir group; 6·2%, -12·2 to 24·6, for the 0·75 mg islatravir group; and -6·1%, -27·1 to 14·8, for the 2·75 mg islatravir group). 66 (73%) of participants in the islatravir groups combined and 24 (77%) of those in the doravirine plus lamivudine plus TDF group reported at least one adverse event. Two participants in the 2·25 mg islatravir group and one participant in the doravirine plus lamivudine plus TDF group discontinued owing to an adverse event. No deaths were reported up to week 48. INTERPRETATION: Treatment regimens containing islatravir and doravirine showed antiviral efficacy and were well tolerated regardless of dose. Doravirine in combination with islatravir has the potential to be a potent two-drug regimen that warrants further clinical development. FUNDING: Merck, Sharp, & Dohme Corp, a subsidiary of Merck & Co., Inc.

Utilidad clínica de la IgIV en enfermedades autoinmunes e inflamatorias / Clinical utility of the IgIV in autoinmune and inflamatory diseases

Las inmunoglobulinas (Igs) son un grupo de glicoproteínas que se hallan presentes en el plasma y líquidos intersticiales, constituyen los anticuerpos (Acs) que el organismo elabora ante la entrada de un antígeno (Ag) y que tienen la capacidad de unirse específicamente al mismo. Son producidas y secretadas en gran cantidad por las células plasmáticas resultantes de la activación y diferenciación de los linfocitos B, pudiendo encontrarse en forma soluble o unida a la membrana de los linfocitos B, constituyendo el receptor de la célula B específica para el antígeno (BCR). Las Igs en el hombre son de cinco clases diferentes: IgG, IgM, IgA, IgD e IgE. En la figura 1 se observa la estructura básica que posee una molécula de Ac. Está constituída por cuatro cadenas polipépticas: dos cadenas pesadas (H) y dos cadenas livianas (L). Ambas cadenas, tanto pesadas como livianas son idénticas, se hallan unidas por puentes disulfuro, y se dividen en dos regiones: una llamada "variable" (VL) y otra la región "constante" (CL). Las cadenas livianas, menores o ligeras pueden ser de dos tipos: Kappa y Lambda, comunes a todas las Igs. En el humano el 65 por ciento de los Acs poseen Kappa y el 35 por ciento Lambda. Las cadenas pesadas son esencialmente de cinco tipos diferentes, y definen la clase o isotipo de ac: (IgM), (IgD); (IgG), (IgE) y (IgA). El sitio de combinación del Ac con el Ag está determinado en forma conjunta por la estructura espacial de las regiones de las cadenas livianas y pesadas. Por lo tanto, una molécula de Ac, como la mostrada en la figura 1, posee dos sitios de unión, es decir es bivalente. La digestión enzimática de los Acs por papaína genera los fragmentos llamdos Fab (cada uno con su sitio de combinación) y un fragmento llamado Fc, asimismo la digestión por la pepsina permite generar un fragmento llamado F(ab)2 y el Fc. La variabilidad en las regiones V, no es uniforme, sino que existen sectores de hipervariabilidad, que determinan la complementariedad con la superficie tridimensional del Ag. Estos sitios se denominan idiotipo, que comportan como verdaderos Ags, contra los cuales se pueden producir Acs anti-idiotípicos, (éste sería un mecanismo de regulación inmune normal). La función primaria de los Acs es la de unirse al Ag, en algunos casos esta unión tiene consecuencias directas, como por ejemplo, neutralización de toxinas bacteriana o inhibición de la penetración del virus en las células

Utilidad clínica del laboratorio inmunológico / Clinical useful of the immunological laboratory

The clinical utility of the laboratory of inmunology in the diagnosis, evolution and prognosis of the different inmunological, reumathological and allergical diseases are analized