Low frequency of hypersensitivity reactions to abacavir in HIV infected patients in a referral center in Bahia, Brazil

Abstract Abacavir can cause a multi-systemic hypersensitivity reaction (HSR) in 5-8% of the patients, which is related to HLA-B*57-01 allele. In Brazil, the HLA-B*57-01 screening test became available only in March 2018, several years after abacavir was in use. In this retrospective study we reviewed medical charts of all patients receiving an abacavir-containing regimen to evaluate the frequency of HSR in patients followed at a referral center in Salvador, Brazil. A total of 192 patients who received abacavir were identified, most male (67.1%), black or racially mixed (77.8%), and having diagnosis of a previous AIDS defining conditions (83.7%). Only one patient developed HSR (incidence: 0.52%). The main reasons for abacavir-containing antiretroviral therapy discontinuation were virological failure (28%), adverse effects to other components of the regimen (25%), and simplification of therapy (16%). The low incidence of HSR to abacavir does not support the use of HLA-B*57-01 screening test, in Salvador, Brazil.

Epidemiological, clinical, and laboratory factors associated with chronic kidney disease in Mexican HIV-infected patients / Fatores epidemiológicos, clínicos e laboratoriais associados à doença renal crônica em pacientes mexicanos infectados pelo HIV

ABSTRACT Aim: To determine the prevalence of chronic kidney disease (CKD) and the epidemiological, clinical, and laboratory factors associated with CKD in Mexican HIV-infected patients. Methods: Cross-sectional study. We included 274 patients with HIV/AIDS. CKD was defined by the estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2 assessed by CKD-EPI) and albuminuria criteria from KDIGO guidelines. Clinical, epidemiological, and laboratory characteristics were compared between patients with and without CKD. The factors associated with CKD were assessed by logistic regression analysis. Results: The mean age was 41±11 years, and 72.3% of the patients were men. The global prevalence of CKD was 11.7% (n = 32); 7.2% (n = 20) were defined by eGFR criterion; 7.6% (n = 21), by the albuminuria criterion; and 3.2% (n = 9), by both CKD criteria. The most frequently observed stages of CKD were KDIGO G3A1 stage with 4.7% (n = 13), KDIGO G1A2 stage with 3.6% (n = 10) and KDIGO G3A2 stage with 1.7% (n = 5). The factors associated with CKD were use of abacavir/lamivudine (OR 3.2; 95% CI 1.1-8.9; p = 0.03), a CD4 lymphocyte count < 400 cells/µL (OR 2.6; 95% 1.03-6.4, p = 0.04), age (OR 1.1; 95% CI 1.04-1.2, p = 0.001) and albuminuria (OR 19.98; 95% CI: 5.5-72.2; p < 0.001). Conclusions: CKD was a frequent complication in HIV-infected patients. These findings confirm the importance of screening and the early detection of CKD, as well as the importance of identifying and treating traditional and non-traditional risk factors associated with CKD.

RESUMO Objetivo: Determinar a prevalência de doença renal crônica (DRC) e os fatores epidemiológicos, clínicos e laboratoriais associados à DRC em pacientes mexicanos infectados pelo HIV. Métodos: Estudo transversal. Incluímos 274 pacientes com HIV/AIDS. A DRC foi definida pela taxa de filtração glomerular estimada (TFGe < 60 mL/min/1,73 m2, avaliada pelo CKD-EPI) e pelos critérios de albuminúria das diretrizes do KDIGO. As características clínicas, epidemiológicas e laboratoriais foram comparadas entre pacientes com e sem DRC. Os fatores associados à DRC foram avaliados por análise de regressão logística. Resultados: A média da idade foi de 41 ± 11 anos e 72,3% dos pacientes eram homens. A prevalência global de DRC foi de 11,7% (n = 32); 7,2% (n = 20) foram definidos pelo critério TFGe; 7,6% (n = 21), pelo critério da albuminúria; e 3,2% (n = 9), pelos dois critérios para DRC. Os estágios mais frequentemente observados da DRC foram o estágio KDIGO G3A1 com 4,7% (n = 13); estágio KDIGO G1A2 com 3,6% (n = 10) e estágio KDIGO G3A2 com 1,7% (n = 5). Os fatores associados à DRC foram o uso de abacavir/lamivudina (OR 3,2; IC95% 1,1-8,9; p = 0,03), contagem de linfócitos CD4 < 400 células/µL (OR 2,6; 95% 1,03-6,4, p = 0,04), idade (OR 1,1; IC95% 1,04-1,2, p = 0,001) e albuminúria (OR 19,98; IC95%: 5,5-72,2; p < 0,001). Conclusões: A DRC foi uma complicação frequente em pacientes infectados pelo HIV. Esses achados confirmam a importância do rastreamento e da detecção precoce da DRC, bem como a importância de identificar e tratar os fatores de risco tradicionais e não tradicionais associados à DRC.

Zidovudine/Lamivudine vs. Abacavir/Lamivudine vs. Tenofovir/Emtricitabine in fixed-dose combinations as initial treatment for HIV patients: a systematic review and network meta-analysis / Zidovudina/Lamivudina vs Abacavir/Lamivudina vs Tenofovir/Emtricitabina en combinaciones de dosis fija como tratamiento inicial en pacientes con VIH: revisión sistemática y metanálisis en red

Abstract Introduction: Initial treatment of the HIV is based on the use of three drugs, two of which are nucleoside analog reverse-transcriptase inhibitors. There are three combinations of these drugs which have been approved by different guidelines, each with divergent results in terms of efficacy and safety. Objective: To compare the efficacy and safety of these three combinations. Methods: Systematic review and network meta-analysis of randomized clinical trials comparing fixed doses of Tenofovir Disoproxil Fumarate / Emtricitabine (TDF/FTC), Abacavir / Lamivudine (ABC/3TC) and Zidovudine / Lamivudine (ZDV/3TC). Results: Seven clinical trials met the eligibility criteria. The results suggested higher efficacy with TDF/FTC vs. ABC/3TC at 96 weeks and vs. ZDV/3TC at 48 weeks. However, there is clinical and statistical heterogeneity. Subgroup analysis were performed by third drug and by level of viral load prior to treatment, and found no differences in virological control. Network meta-analysis could only be carried out with TDF/FTC vs. ZDV/3TC, and the proportion of patients with virological response, with no differences at 48 weeks nor at 96 weeks. Direct comparisons showed an increased risk of bone marrow suppression of ZDV/3TC vs. TDF/FTC and of ABC/3TC hypersensitivity reactions vs. ZDV/3TC Conclusions: The results did not show differences in effectiveness among the interventions. However, due to the heterogeneity of the third drug and the follow-up time between the included studies, this result is not definitive. The results raise the need for further studies to help improve treatment recommendations in patients infected with HIV.

Resumen Introducción: El tratamiento inicial de la infección por VIH se basa en el uso de tres medicamentos, dos de ellos inhibidores de transcriptasa reversa análogos de nucleósido. Existen tres combinaciones de estos medicamentos aprobadas por diferentes guías, con resultados divergentes en cuanto a eficacia y seguridad. Objetivo: Comparar la eficacia y seguridad de las 3 combinaciones Métodos: Revisión sistemática y metanálisis en red de ensayos clínicos con asignación aleatoria comparando dosis fijas de Tenofovir Disoproxil Fumarato/Emtricitabina (TDF/FTC), Abacavir/Lamivudina (ABC/3TC) y Zidovudina/Lamivudina (ZDV/3TC). Resultados: Siete ensayos clínicos cumplieron los criterios de elegibilidad. Los resultados sugirieron mayor eficacia con TDF/FTC vs ABC/3TC a 96 semanas y vs. ZDV/3TC a 48 semanas. Sin embargo, existe heterogeneidad clínica y estadística. Se realizó análisis de subgrupos por tercer medicamento y por nivel de carga viral previa al tratamiento, sin encontrar diferencias en control virológico. Se pudo realizar metanálisis en red con TDF/FTC vs ZDV/3TC y proporción de pacientes con respuesta virológica, sin diferencias a las 48 semanas ni 96 semanas. Las comparaciones directas evidenciaron mayor riesgo de supresión de médula ósea de ZDV/3TC vs TDF/FTC y de reacciones de hipersensibilidad de ABC/3TC vs ZDV/3TC. Conclusión: Los resultados no demostraron diferencias en efectividad entre las intervenciones; sin embargo, debido a heterogeneidad en cuanto al tercer medicamento y el tiempo de seguimiento entre los estudios incluidos, dicho resultado no es definitivo. Los resultados plantean la necesidad de realizar nuevos estudios que ayuden a mejorar las recomendaciones de tratamiento en los pacientes infectados por el VIH.

Abacavir-induced liver toxicity

Abstract Abacavir-induced liver toxicity is a rare event almost exclusively occurring in HLA B*5701-positive patients. Herein, we report one case of abnormal liver function tests occurring in a young HLA B*5701-negative woman on a stable nevirapine-based regimen with no history of liver problems or alcohol abuse after switching to abacavir from tenofovir. We also investigated the reasons for abacavir discontinuation in a cohort of patients treated with abacavir-lamivudine-nevirapine.

HLA-B*5701 frequency in Chilean HIV-infected patients and in general population

It has been demonstrated that HLA-B*5701 screening reduces the risk for hypersensitivity reaction to abacavir in HIV-infected patients. Since B*5701 prevalence varies among different populations, it is important to determine the carrier frequency prior to its use for the screening of HIV-infected patients.The aim of this study was to determine HLA-B*5701 carrier frequency in Chilean general population and HIV-infected patients referred for B*5701 typing. For that purpose 300 blood bank donors and 492 abacavir-naïve HIV-infected patients from Chile were screened for B*5701 by a sequence specific primer PCR.We detected 14/300 (4.7 percent) B*57-positive individuals in the Chilean general population, 11 (3.7 percent) were B*5701 positive, and 3 (1 percent) had another subtype.All were heterozygous,thus a B*5701 allele frequency of 2 percent was determined.Eleven of 492 (2.2 percent) HIV-patients carried a B*5701 allele. The difference between these frequencies is probably due to slow progression of HIV infection in HLA-B*5701 carriers, thus less patients would require antiretroviral therapy and B*5701 typing. Considering the usefulness of B*5701 screening, its prevalence in the Chilean general population,and the availability of a validated method,we conclude that HLA-B*5701 typing in Chilean HIV-infected patients about to initiate abacavir treatment is strongly recommended.

Rapid identification of single nucleotide polymorphisms by fluorescence-based capillary electrophoresis

We describe the application of two different fluorescence-based techniques (ddNTP primer extension and single-strand conformation polymorphism (SSCP)) to the detection of single nucleotide polymorphisms (SNPs) by capillary electrophoresis. The ddNTP primer extension technique is based on the extension, in the presence of fluorescence-labeled dideoxy nucleotides (ddNTP, terminators), of an unlabeled oligonucleotide primer that binds to the complementary template immediately adjacent to the mutant nucleotide position. Given that there are no unlabeled dNTPs, a single ddNTP is added to its 3' end, resulting in a fluorescence-labeled primer extension product which is readily separated by capillary electrophoresis. On the other hand, the non-radioisotopic version of SSCP established in this study uses fluorescent dye to label the PCR products, which are also analyzed by capillary electrophoresis. These procedures were used to identify a well-defined SNP in exon 7 of the human p53 gene in DNA samples isolated from two human cell lines (CEM and THP-1 cells). The results revealed a heterozygous single-base transition (G to A) at nucleotide position 14071 in CEM cells, proving that both fluorescence-based ddNTP primer extension and SSCP are rapid, simple, robust, specific and with no ambiguity in interpretation for the detection of well-defined SNPs