GENDER DIFFERENCES in METABOLIC PROFILE and CARDIOVASCULAR RISK AMONG BRAZILIAN HIV-INFECTED PATIENTS ON HAART: RAPID II STUDY

Universidade Federal de São Paulo, São Paulo, BrazilInst Infectol Emilio Ribas, São Paulo, BrazilHosp & Maternidade Celso Pierro, Campinas, SP, BrazilUniv Fed Bahia, Salvador, BA, BrazilBristol Myers Squibb Co, São Paulo, BrazilBristol Myers Squibb Co, Plainsboro, NJ USAHosp Correia Picanco, Recife, PE, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc

In-vivo selection of the mutation F121Y in a patient failing raltegravir containing salvage regimen

AbstractRaltegravir is an integrase inhibitor (INI) licensed for clinical use and other INI are in advanced stage of development. Different resistance mutations in HIV integrase from patients using these antiretroviral drugs have been described and G148H/R/K, N155H and less frequently Y143C/H/R are considered major resistant mutations to raltegravir. Both Stanford Database and Geno2Pheno list F121Y as conferring intermediate resistance “in vitro” both to raltegravir and elvitegravir. We report for the first time the “in vivo” selection F121Y and evolution to Y143R in a 31years old male clade B HIV-1 infected patient failing a raltegravir-containing salvage regimen. Plasma samples nine months prior to raltegravir (RAL-Naïve) and at weeks 32, 40 and 88 after RAL-containing regimen were analyzed. Antiretroviral susceptibility was evaluated at Stanford and Geno2Pheno from sequences obtained with RT-PCR. After a Viral load at week 12 below 50 copies/mL, viremia raised at week 20 to 4.5log10. The emergence of F121Y was observed at week 32 and 40, alongside with L74I, T97A, Q137H and V151I. At week 88 F121Y was no longer detected, L74I and T97A were maintained and Y143R emerged. F121Y might be an alternative pathway to Y143R. Changing of RAL-containing regimen upon the identification of F121Y might avoid the evolution of raltegravir resistance

Evaluation of subclinical atheromatous disease in HIV/AIDS patients: assessment of pulse wave velocity (PWV) and carotid intimamedia thickness (IMT)

A terapia anti-retroviral altamente potente (HAART), determinou uma melhora significativa do prognóstico dos pacientes vivendo com HIV/aids. Contudo, a presença de toxicidades agudas e crônicas, incluindo risco aumentado de doenças cardiovasculares, acarretou novas implicações para a qualidade e expectativa de vida destes pacientes. O objetivo deste estudo foi determinar o risco cardiovascular de pacientes HIV/aids tratados e nãotratados com esquema HAART. De 02/2008 a 07/2009 foram incluídos 118 indivíduos entre 18 e 70 anos, procedentes do Instituto de Infectologia Emílio Ribas e do Hospital Universitário da USP, além de voluntários saudáveis. Os indivíduos foram distribuídos em 4 grupos: (1) pacientes com infecção pelo HIV em uso de HAART; (2) pacientes com infecção pelo HIV sem tratamento (naïve); (3) pacientes diabéticos não insulino-dependentes (DM); (4) controle. Foram avaliados em todos os participantes: parâmetros bioquímicos, teste de tolerância oral à glicose, PCR ultra-sensível, microalbuminúria, sorologias para hepatite B e hepatite C, ECG, EMI, VOP, escore de risco de Framingham (ERF) e presença de síndrome metabólica (SM). Os pacientes DM tinham idade mais avançada (51,7 ± 9,7 anos) e 75, 8% eram do sexo feminino. Os dados foram ajustados para a idade (média ± erro-padrão). A relação cintura-quadril foi maior no grupo HAART que no controle (0,94 ± 0,01 vs. 0,88 ± 0,01, p< 0,0001); a pressão arterial sistólica média aferida no dia da visita foi maior no grupo HAART comparado ao grupo naive e controle (124,7 ± 2,3 vs. 118,1 ± 2,4 vs. 119,8 ± 2,2 mmHg, respectivamente; p= 0,001 e p= 0,005), e a pressão arterial diastólica média foi maior no grupo HAART que no naive (78,2 ± 1,8 vs. 75,9 ± 1,9 mmHg, respectivamente; p= 0,03); os níveis séricos de triglicérides estavam mais elevados no grupo HAART comparado aos grupos naive e controle (233,7 ± 193,4 vs. 137,3 ± 108,6 vs. 147,2 ± 87,3 mg/dL, respectivamente; p= 0,03 e p=0,04); microalbuminúria foi maior no grupo HAART que nos grupos naive e DM (86,2 ± 27,3 vs. 49,8 ± 30,5 vs. 30,8 ± 30,6 mg/dL, respectivamente; p= 0,01 e p= 0,009). A EMI da carótida direita foi maior no grupo naive comparado aos grupos HAART e controle (0,55 ± 0,02 vs. 0,52 ± 0,02 vs. 0,52 ± 0,02 mm, respectivamente; p< 0,0001), enquanto a EMI da carótida esquerda foi maior no grupo HAART comparado aos grupos naive e DM (0,64 ± 0,04 vs. 0,53 ± 0,04 vs. 0,52 ± 0,04, respectivamente; p< 0,0001). Houve diferença significativa em relação à VOP entre os grupos HAART e controle (9,7 ± 1,8 vs 8,7 ± 0,03 m/seg, p = 0,03). SM foi mais freqüente no grupo HAART que nos grupos naive e controle (41,4% vs. 25,0% vs. 28,1%, p= 0,0001). O ERF evidenciou risco alto em 27,6% dos pacientes do grupo HAART, o que foi significativo em relação aos grupos naive e controle (p=0,003). O nadir de CD4 foi menor nos pacientes do grupo HAART comparado ao grupo naive (208 ± 191 vs. 449 ± 176 células/L, p< 0,0001). A carga viral atual foi maior no grupo naive que no grupo HAART (13.633 ± 25.314 vs. 76 ± 61 cópias/ml, p= 0,005). Este estudo demonstra que pacientes com infecção pelo HIV em uso de HAART apresentam maior risco cardiovascular em relação aos pacientes não-tratados, evidenciado pela presença de maior freqüência de SM, maior ERF, maior rigidez arterial e presença de aterosclerose prematura mensurada pelo EMI da carótida esquerda. Isto ocorreu mesmo na ausência de viremia detectável, o que significa que devemos ter atenção para o risco de aterosclerose subclinica no seguimento de pacientes HIV/aids sob adequado tratamento antiretroviral, inclusive com eficaz controle imunológico e virológico.The highly active antiretroviral therapy (HAART), led to a significant improvement in the prognosis of patients living with HIV/AIDS. However, the presence of acute and chronic toxicities, including increased risk of cardiovascular disease, yielded further implications for the quality and life expectancy of these patients. The aim of this study was to determine the cardiovascular risk of HIV/AIDS patients treated and untreated with HAART. From february/2008 to july/2009 we enrolled 118 subjects between 18 and 70 years, attending at the Institute of Infectious Diseases Emilio Ribas and the University Hospital from USP, as well as healthy volunteers. The subjects were divided into 4 groups: (1) patients with HIV-infection on HAART; (2) patients with untreated HIV-infection (ART-naive); (3) diabetic patients not insulin-dependent (DM); (4) controls. Were evaluated in all participants: biochemical parameters, oral glucose tolerance test, high-sensitivity Creactive protein, microalbuminuria, serologies for hepatitis B and hepatitis C, ECG, carotid IMT, PWV, Framingham risk score (FRE) and the presence of metabolic syndrome (MS). The DM patients were older (51.7 ± 9.7 years) and 75.8% were female. The data were adjusted for age (mean ± standard error). The waist-to-hip ratio was higher in the HAART-treated patients than in the controls (0.94 ± 0.01 vs. 0.88 ± 0.01, p< 0.0001), the mean systolic blood pressure measured on the day of the visit was higher in the HAARTtreated patients compared to the ART-naive and controls (124.7 ± 2.3 vs. 118.1 ± 2.4 vs. 119.8 ± 2.2 mmHg, respectively, p= 0.001 and p= 0.005), and the mean diastolic blood pressure was higher in the HAART-treated patients than in the ART-naive (78.2 ± 1.8 vs. 75.9 ± 1.9 mmHg, respectively, p= 0.03); serum triglycerides were higher in the HAART-treated patients compared to the ART-naive subjects and controls (233.7 ± 193.4 vs. 137.3 ± 108.6 vs. 147.2 ± 87.3 mg/dL, respectively, p= 0.03 and p= 0.04); microalbuminuria was higher in the HAART-treated patients than in the ARTnaive and DM (86.2 ± 27.3 vs. 49.8 ± 30.5 vs. 30.8 ± 30.6 mg/dL, respectively, p=0.01 and p=0.009). The right carotid IMT was increased in the ART-naive compared to HAART-treated patients and controls (0.55 ± 0.02 vs. 0.52 ± 0.02 vs. 0.52 ± 0.02 mm, respectively, p< 0.0001), while the left carotid IMT was increased in the HAART-treated patients compared to the ART-naive and DM (0.64 ± 0.04 vs. 0.53 ± 0.04 vs. 0.52 ± 0.04, respectively, p< 0.0001). There was significant difference in PWV between the HAART-treated patients and controls (9.7 ± 1.8 vs. 8.7 ± 0.03 m/s, p= 0.03). MS was more prevalent in the HAART-treated patients than in the ART-naive and controls (41.4% vs. 25.0% vs. 28.1%, p= 0.0001). The FRE showed high risk in 27.6% of HAART-treated patients, which was significant compared to ART-naive and controls (p= 0.003). The nadir CD4 count was lower in HAART-treated patients compared to the ART-naive (208 ± 191 vs. 449 ± 176 cells/L, p<0.0001). Current viral load was higher in the ART-naive than in the HAART-treated patients (13,633 ± 25,314 vs. 76 ± 61 copies/ml, p= 0.005). This study shows that patients with HIV infection receiving HAART have a higher cardiovascular risk compared to untreated patients, as evidenced by the presence of a higher frequency of MS, higher ERF, increased arterial stiffness and the presence of early atherosclerosis measured by left carotid IMT. These abnormalities occurred even in the absence of detectable viremia, which means that physicians must pay attention to the risk of subclinical atherosclerosis as a result of HIV-infected patients under appropriate antiretroviral treatment, including effective virological and immunological control

Alterations in renal function in HIV/AIDS patients treated with therapeutic regimens including indinavir

Complicações renais e urológicas incluindo nefrolitíase, cristalúria, cólica renal e lombalgia, são eventos adversos bem conhecidos do indinavir (IDV), um inibidor de protease (IP) largamente utilizado no tratamento de pacientes infectados com o vírus da imunodeficiência humana (HIV). Prévios estudos em ratos demonstraram que o IDV, um potente IP capaz de provocar uma sustentada supressão da carga viral do HIV, induz vasoconstricção renal, diminui a filtração glomerular (RFG) e reduz a excreção urinária de nitrito (NO2-), sugerindo que a vasoconstricção causada pelo IDV deve ser mediada pelo óxido nítrico (NO). Os objetivos deste estudo foram investigar a ocorrência de insuficiência renal (clearance de creatinina < 80ml/min) em pacientes com infecção pelo HIV tratados com terapia anti-retroviral altamente potente incluindo o inibidor de protease IDV, e mensurar a excreção urinária de nitrato (NO3-) nestes pacientes, comparando-os com outro grupo de pacientes tratados com efavirenz (EFV), um inibidor de transcriptase reversa não-análogo de nucleosídeo (NNRTI). No período compreendido entre março de 2000 e outubro de 2003, estudamos 36 pacientes infectados pelo HIV que estavam em terapia com IDV na dose de 800 mg de 8/8 horas por pelo menos 12 meses. Os pacientes foram avaliados para uma variedade de parâmetros clínicos e laboratoriais: idade, peso, tempo de infecção, tempo de uso de IDV, uso de sulfametoxazol-trimetoprim (SMX-TMP) ou sulfadiazina, exames bioquímicos (colesterol total, triglicérides, magnésio, sódio, potássio e creatinina), exame do sedimento urinário, clearance de creatinina, osmolaridade urinária, volume urinário de 24 h, fração de excreção de sódio (FENa), fração de excreção de potássio (FEK) e fração de excreção de água (FEH2O). NO3 urinário foi mensurado em 18 pacientes recebendo terapia anti-retroviral com IDV e 8 pacientes recebendo terapia com EFV. Leucocitúria ocorreu em 78.8% dos pacientes tratados com IDV. Clearance de creatinina diminuído foi observado em 21 pacientes e foi associado com menor peso e uso de derivados de sulfa. Nestes pacientes com diminuição da função renal, também detectamos menor osmolaridade urinária e uma FEH2O mais alta. A excreção urinária de NO3- foi significativamente menor nos pacientes tratados com IDV (908 ± 181) quando comparados aos pacientes do grupo EFV (2247 ± 648, p<0.01). Nossos resultados mostram que insuficiência renal ocorreu em 58% dos pacientes tratados com IDV e foi associada com menor peso corpóreo e uso de derivados de sulfa. A menor excreção urinária de NO3- e as alterações na osmolaridade e FEH2O sugerem que o IDV diminui a produção de óxido nítrico e causa dano tubular, respectivamente. Sugerimos então que os pacientes em uso de IDV sejam monitorados routineiramente para função renal através do clearance de creatinina.Renal and urological complications including nephrolithiasis, crystalluria, renal colic and flank pain are significant side effects of the HIV protease inhibitor indinavir (IDV), and IDV has been widely used in the treatment of human immunodeficiency virus (HIV) infection. Previous studies in rats demonstrated that IDV, a potent protease inhibitor that causes profound and sustained supression of HIV replication, also induces renal vasoconstriction, decreases glomerular filtration rate (GFR) and reduces urinary excretion of nitrite (NO2-), suggesting that IDV-vasoconstriction may be mediated by nitric oxide (NO). The objectives of this study were to investigate the occurrence of renal failure (creatinine clearance <80ml/min) in human HIV patients treated with highy active antiretroviral therapy (HAART), including IDV, and to measure urinary excretion of nitrate (NO3-) in those patients, comparing it with that of another group of patients treated with the non-nucleoside reverse-transcriptase inhibitor efavirenz (EFV). From March 2000 through October 2003, we evaluated 36 patients infected with HIV who was receiving IDV 800 mg q8h for at least 12 months. The patients were assessed for a variety of clinical and laboratory parameters including age, body weight, duration of infection, time of IDV treatment, trimethoprim/sulfamethoxazole (TMP/SMX) or sulfadiazine use, biochemistry (total cholesterol, triglycerides, magnesium, sodium, potassium and creatinine), urinalysis, creatinine clearance, urine osmolality, 24-hour urine volume, fractional excretion of sodium (FENa), potassium (FEK) and water (FEH2O). Urinary NO3 was measured in 18 IDV-treated patients and compared with that of 8 EFV-treated patients. Leukocyturia occurred in 78.8% of the IDV-treated patients. Reduced creatinine clearance was observed in 21 patients and was associated with lower body weight and sulfa-derivated use. In these renal failure patients, we also detected a lower osmolality and a higher FEH2O. Excretion of NO3- was significantly lower in IDV-treated patients (908 ± 181) than in EFV-treated patients (2247 ± 648, p<0.01). Our data show that renal failure occurred in 58% of IDV-treated patients and was associated with lower body weight and sulfa administration. The lower NO3- excretion suggests that this drug decreases nitric oxide production, and the alterations in osmolality and FEH2O indicate that it also causes tubular damage. Based on our findings, we suggest that the renal function of patients under IDV treatment should be closely monitored with creatinine clearance

Primary Antiretroviral Drug Resistance among HIV Type 1-Infected Individuals in Brazil

Infection with drug-resistant human immunodeficiency virus type 1 (HIV-1) has been documented in all countries that have surveyed for it and may result in an unfavorable response to therapy. the prevalence and characteristics of individuals with transmitted resistance to antiretroviral drugs have been scarcely described in Brazil. We performed antiretroviral resistance testing prior to initiation of therapy in 400 subjects enrolled from 20 centers in 13 Brazilian cities between March and September 2007. Genotyping was conducted using PCR-amplified HIV pol products by automated sequencing, and genotype interpretation was done according to the IAS-USA consensus. of 400 eligible participants, 387 (95.8%) were successfully tested. Seven percent of antiretroviral-naive patients carried viruses with one or more major mutation associated with drug resistance. the prevalence of these mutations was 1.0% for protease inhibitors, 4.4% for nonnucleoside reverse transcriptase inhibitors, and 1.3% for nucleoside reverse transcriptase inhibitors. the frequency of multidrug resistance among the resistant strains was 13.6%. Among subjects infected with drug-resistant virus, the majority were infected with subtype B viruses (91%). Subjects from the city of São Paulo had higher transmitted resistance mutations compared to the rest of the country. Reporting a partner taking antiretroviral medications was associated with a higher chance of harboring HIV variants with major drug resistance mutations [odds ratio = 2.57 (95% confidence interval, 1.07-6.16); p = 0.014].Resistance testing in drug-naive individuals identified 7% of subjects with mutations associated with reduced susceptibility to antiretroviral drugs. Continued surveillance of drug-resistant HIV-1 in Brazil is warranted when guidelines for HIV prophylaxis and treatment are updated. Resistance testing among drug-naive patients prior to treatment initiation should be considered, mainly directed at subjects whose partners are already on antiretroviral therapy.Laboratorio Pfizer do BrasilUniv Fed Rio Grande do Sul, Hosp Clin, Porto Alegre, RS, BrazilHosp Univ Prof Edgard Santos, Salvador, BA, BrazilPontificia Univ Catolica, Hosp & Maternidade Celso Pierro, Campinas, SP, BrazilHosp Heliopolis, São Paulo, BrazilInst Infectol Emilio Ribas, São Paulo, BrazilProjeto Praca Onze, Rio de Janeiro, BrazilCRT AIDS, São Paulo, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilUniv Estadual Campinas, Campinas, SP, BrazilUniv Fed Rio de Janeiro, Rio de Janeiro, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc