RESUMO
BACKGROUND: As a result of effective combination antiretroviral therapy (cART) and advanced supportive healthcare, a growing number of human immunodeficiency virus (HIV)-infected children survive into adulthood. The period of transition to adult care is often associated with impaired adherence to treatment and discontinuity of care. We aimed to evaluate virological and social outcomes of HIV-infected adolescents and young adults (AYAs) before and after transition, and explore which factors are associated with virological failure. METHODS: We included 59 HIV-infected AYAs from the Netherlands who had entered into pediatric care and transitioned from pediatric to adult healthcare. We used HIV RNA load and cART data from the Dutch Stichting HIV Monitoring database (1996-2014), and collected social and treatment data from patients' medical records from all Dutch pediatric HIV treatment centers and 14 Dutch adult treatment centers involved. We evaluated risk factors for virological failure (VF) in a logistic regression model adjusted for repeated measurements. RESULTS: HIV VF occurred frequently during the study period (14%-36%). During the transition period (from 18 to 19 years of age) there was a significant increase in VF compared with the reference group of children aged 12-13 years (odds ratio, 4.26 [95% confidence interval, 1.12-16.28]; P = .03). Characteristics significantly associated with VF were low educational attainment and lack of autonomy regarding medication adherence at transition. CONCLUSIONS: HIV-infected AYAs are vulnerable to VF, especially during the transition period. Identification of HIV-infected adolescents at high risk for VF might help to improve treatment success in this group.
Assuntos
Infecções por HIV/epidemiologia , Transição para Assistência do Adulto , Adolescente , Fatores Etários , Terapia Antirretroviral de Alta Atividade , Criança , Pré-Escolar , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Infecções por HIV/virologia , Humanos , Perda de Seguimento , Masculino , Países Baixos/epidemiologia , Razão de Chances , Fatores de Risco , Fatores Socioeconômicos , Falha de Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: Whether zidovudine (AZT)-associated lipoatrophy occurrence differs by concomitant exposure to protease (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) remains unclear. Baseline body composition data from a randomized trial in subjects stable on first-line AZT-based therapy were used to explore this issue. METHODS: In this substudy of the PREPARE trial, centrally read baseline whole-body dual energy x-ray aborptiometry (DXA) and single-slice abdominal CT scans were analyzed with respect to duration and type of prior AZT/lamivudine (3TC) combination antiretroviral therapy (cART), including by multivariate linear regression adjusted for age, gender, ethnicity, body mass index (BMI), and nadir CD4. RESULTS: DXA and CT, from 134 and 136 patients, respectively [87% male; 82% Caucasian; mean (SD) age, 45.6 years (10); BMI, 24.3 kg/m² (3.2)], were analyzed. Prior AZT/3TC cART exposure was 5.5 (2.2) years. Seventy-eight and 27 patients had concomitantly and exclusively used NNRTIs and PIs, respectively. AZT/3TC cART, AZT/3TC/NNRTI, and AZT/3TC/PI, respectively, were associated with the presence of a mean (95% CI) of 247 g (-438 to -56; P = .012), 267 g (-467 to -66; P = .010), and 216 g (-430 to -1.7; P = .048) less baseline limb fat per additional year of prior exposure. Although abdominal subcutaneous (SAT) adipose tissue was likewise less with longer AZT/3TC cART, this was only significant for AZT/3TC/ NNRTI but not AZT/3TC/PI. Visceral adipose tissue (VAT) amount was not clearly associated to prior treatment. Increased age and male gender were independently associated with lower limb fat and SAT, but more VAT. CONCLUSIONS: Longer exposure to AZT/3TC, regardless of whether in combination with PI or NNRTI, as well as increased age and male gender are independently associated with lower limb fat mass.
Assuntos
Infecções por HIV/tratamento farmacológico , Lamivudina/efeitos adversos , Lamivudina/uso terapêutico , Gordura Subcutânea/efeitos dos fármacos , Zidovudina/efeitos adversos , Zidovudina/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Composição Corporal/efeitos dos fármacos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/complicações , Humanos , Lamivudina/administração & dosagem , Masculino , Zidovudina/administração & dosagemRESUMO
OBJECTIVES: The aim of the study was to compare the effects on lipids, body composition and renal function of once-daily ritonavir-boosted saquinavir (SQV/r) or atazanavir (ATV/r) in combination with tenofovir/emtricitabine (TDF/FTC) over 48 weeks. METHODS: An investigator-initiated, randomized, open-label, multinational trial comparing SQV/r 2000/100 mg and ATV/r 300/100 mg once daily, both in combination with TDF/FTC, in 123 treatment-naïve HIV-1-infected adults was carried out. The primary endpoint was to demonstrate noninferiority of SQV/r compared with ATV/r with respect to the change in fasting cholesterol after 24 weeks. Secondary outcome measures were changes in metabolic abnormalities, body composition, renal function, and virological and immunological efficacy over 48 weeks. Patients who had used at least one dose of trial drug were included in the analysis. RESULTS: Data for 118 patients were analysed (57 patients on SQV/r and 61 on ATV/r). At week 24, changes in lipids were modest, without increases in triglycerides, including a significant rise in high-density lipoprotein (HDL) cholesterol and a nonsignificant decrease in the total:HDL cholesterol ratio in both arms with no significant difference between arms. Lipid changes at week 48 were similar to the changes observed up to week 24, with no significant change in the homeostasis model assessment (HOMA) index. Adipose tissue increased regardless of the regimen, particularly in the peripheral compartment and to a lesser extent in the central abdominal compartment, with an increase in adipose tissue reaching statistical significance in the ATV/r arm. A slight decline in the estimated glomerular filtration rate (eGFR) was observed in both arms during the first 24 weeks, with no progression thereafter. The immunological and virological responses were similar over the 48 weeks. CONCLUSIONS: Combined with TDF/FTC, both SQV/r 2000/100 mg and ATV/r 300/100 mg had comparable modest effects on lipids, had little effect on glucose metabolism, conserved adipose tissue, and similarly reduced eGFR. The virological efficacy was similar.
Assuntos
Adenina/análogos & derivados , Desoxicitidina/análogos & derivados , Dislipidemias/etiologia , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Oligopeptídeos/farmacocinética , Organofosfonatos/farmacocinética , Piridinas/farmacocinética , Saquinavir/farmacocinética , Adenina/administração & dosagem , Adenina/farmacocinética , Adulto , Sulfato de Atazanavir , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Esquema de Medicação , Dislipidemias/induzido quimicamente , Dislipidemias/metabolismo , Emtricitabina , Feminino , Taxa de Filtração Glomerular , Infecções por HIV/tratamento farmacológico , Humanos , Nefropatias , Masculino , Oligopeptídeos/administração & dosagem , Organofosfonatos/administração & dosagem , Piridinas/administração & dosagem , Saquinavir/administração & dosagem , Tenofovir , Resultado do TratamentoRESUMO
Loss of gut mucosal integrity and an aberrant gut microbiota are proposed mechanisms contributing to chronic inflammation and increased morbidity and mortality during antiretroviral-treated HIV disease. Sexual practice has recently been uncovered as a major source of microbiota variation, potentially confounding prior observations of gut microbiota alterations among persons with HIV (PWH). To overcome this and other confounding factors, we examine a well-powered subset of AGEhIV Cohort participants comprising antiretroviral-treated PWH and seronegative controls matched for age, body-mass index, sex, and sexual practice. We report significant gut microbiota differences in PWH regardless of sex and sexual practice including Gammaproteobacteria enrichment, Lachnospiraceae and Ruminococcaceae depletion, and decreased alpha diversity. Men who have sex with men (MSM) exhibit a distinct microbiota signature characterized by Prevotella enrichment and increased alpha diversity, which is linked with receptive anal intercourse in both males and females. Finally, the HIV-associated microbiota signature correlates with inflammatory markers including suPAR, nadir CD4 count, and prevalence of age-associated noncommunicable comorbidities.
Assuntos
Disbiose/complicações , Trato Gastrointestinal/patologia , Infecções por HIV/complicações , Doenças não Transmissíveis , Comportamento Sexual , Biodiversidade , Estudos de Casos e Controles , Comorbidade , Microbioma Gastrointestinal , Homossexualidade Masculina , Humanos , Inflamação/patologia , Modelos Lineares , Modelos Logísticos , MasculinoRESUMO
Since the registration of maraviroc (MVC) as an antiretroviral agent in 2008, only studies with a follow-up time of <5 years have been published. Therefore, little is known about its long-term safety and efficacy in clinical practice. In this cohort study, data on long-term follow-up of MVC treatment in routine practice were analysed. A retrospective cohort study was conducted at University Medical Centre Utrecht with a follow-up period up to almost 10 years. The efficacy and tolerability of MVC-containing antiretroviral therapy (ART) was analysed in human immunodeficiency virus type 1 (HIV-1)-infected patients. The cohort consisted of 111 HIV patients who were treated for a median of 11.0 years (IQR 4.0-15.0 years) and with a median of 4 (IQR 2-6) previous ART regimens. The median time of MVC use was 49 months (IQR 21-82 months). Mean CD4+ T-cell counts continued to increase up to 9 years following initiation of MVC. Patients with a detectable viral load (≥50 copies/mL HIV-RNA) at the start of MVC-containing ART reached high proportions of viral suppression. Only three patients (2.7%) experienced treatment failure despite optimal therapy. Nine patients (8.1%) discontinued MVC owing to intolerance of their ART regimen. Severe laboratory abnormalities were deemed to be unrelated to MVC use. During the 487 person-years of follow-up, 18 patients (16.2%) died. MVC use in this heavily pre-treated cohort was generally well tolerated during long-term follow-up. Furthermore, use of MVC resulted in a good immunological and virological response in clinical practice.
Assuntos
Inibidores da Fusão de HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Maraviroc/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Linfócito CD4 , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Seguimentos , Inibidores da Fusão de HIV/efeitos adversos , Hospitais Universitários , Humanos , Masculino , Maraviroc/efeitos adversos , Pessoa de Meia-Idade , Países Baixos , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
BACKGROUND: HIV-associated cognitive deficiency in perinatally HIV-infected (PHIV) children has been studied in Western countries in a population of which an increasing proportion has been internationally adopted. Studies often lack an appropriate internationally adopted HIV-uninfected control group, potentially confounding the relationship between HIV and cognitive functioning. This study aims to further elucidate the association between treated HIV infection and cognitive development by addressing the background of international adoption. METHODS: We cross-sectionally studied the impact of HIV on cognition by comparing PHIV children and HIV- uninfected controls, matched for age-, sex-, ethnicity-, socioeconomic status (SES)- and adoption status. We used a standardized neuropsychological test battery to measure intelligence (IQ), and the cognitive domains of processing speed, working memory, executive function, learning ability and visual-motor function and compared outcomes using lineair regression models, adjusted for IQ. We determined cognitive profiles and cognitive impairment by using multivariate normative comparison (MNC) and explored associations with HIV disease- and treatment-related factors. RESULTS: We enrolled fourteen PHIV children (mean age 10.45 years [1.73 SD], 93% adopted from sub-Saharan Africa at a median age of 3.3 years [IQR 2.1-4.2]) and fifteen HIV- uninfected controls. Groups did not clinically nor statistically differ in age, sex, ethnicity, SES, region of birth, adoption status and age at adoption. PHIV scored consistently lower on all cognitive domains and MNC outcomes. Compared to controls, PHIV children had a significant lower IQ (mean 81 [SD 11] versus mean 97 [SD 15], p = 0.005), and a poorer cognitive profile by MNC (Hotelling's T2 mean -4.36 [SD 5.6] versus mean 0.16 [SD 4.5], p = 0.021), not associated with HIV disease- and treatment-related factors. Two PHIV (14%) and one control (7%) were classified as cognitively impaired (p = 0.598). CONCLUSIONS: Findings indicate treated HIV-infection to be independently associated with lower IQ and poorer cognitive profiles in PHIV children, irrespective of a background of international adoption.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Cognição , Infecções por HIV/fisiopatologia , Deficiência Intelectual/etiologia , Adoção , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Feminino , Infecções por HIV/congênito , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Testes de Inteligência , Internacionalidade , Masculino , Estudos ProspectivosRESUMO
Optimal adherence is essential for successful antiretroviral therapy. We analyzed the relation between minimum plasma drug concentration (Cmin) and total drug exposure over 24 hr (AUC24) with virologic failure for therapy-adherent patients in the nevirapine (NVP) and efavirenz (EFV) groups of the double nonnucleoside study (2NN), which compared the efficacy of NVP and/or EFV together with stavudine and lamivudine. The objective was to find cutoff values of the Cmin and AUC24 below which the risk of virologic failure increased. The relation between Cmin and AUC24 with virologic failure (never a plasma viral load [pVL] < 50 copies/ml or a rebound to two consecutive pVL > 50 copies/ml) was analyzed with proportional hazard analyses. Data were censored at end of study or change of allocated treatment. The risk of virologic failure with NVP (n = 511) started to increase at a Cmin < 3.1 mg/L (hazard ratio [HR], 1.33; 95% confidence interval [CI], 0.89-1.97), but there was no cutoff value below which a statistically significant increased risk occurred. Neither was such a cutoff point identified for the AUC24. The risk of virologic failure with EFV (n = 312) was significantly increased at a Cmin < 1.1 mg/L (HR, 1.95; 95% CI, 1.08-3.54) and an AUC24 < 40 mg x hr x L1 (HR, 1.95; 95% CI, 1.07-3.54). Both cutoff values represent the median values for adherent patients. These associations were driven by patients from Thailand. Adjusting for geographical region made the association between Cmin and AUC24 with virologic failure statistically nonsignificant. The sensitivity of the Cmin values was too low (29% for NVP, 64% for EFV) to be an adequate predictor for virologic failure. We conclude that identifying the Cmin value for the sole purpose of predicting virologic failure in patients who report to be adherent to NVP or EFV is questionable because of the absence of a concentration-response relation (NVP) or the low sensitivity for such a cutoff value (NVP and EFV).
Assuntos
Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Nevirapina/farmacocinética , Nevirapina/uso terapêutico , Oxazinas/farmacocinética , Oxazinas/uso terapêutico , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Alcinos , Fármacos Anti-HIV/sangue , Área Sob a Curva , Benzoxazinas , Ciclopropanos , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Lamivudina/sangue , Lamivudina/farmacocinética , Lamivudina/uso terapêutico , Masculino , Nevirapina/sangue , Oxazinas/sangue , Cooperação do Paciente , Modelos de Riscos Proporcionais , Estudos Prospectivos , RNA Viral/sangue , Curva ROC , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores da Transcriptase Reversa/sangue , Estavudina/sangue , Estavudina/farmacocinética , Estavudina/uso terapêuticoRESUMO
BACKGROUND: The 2NN Study was a randomised comparison of the non-nucleoside reverse-transcriptase inhibitors (NNRTI) nevirapine and efavirenz. METHODS: In this multicentre, open-label, randomised trial, 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily, nevirapine 200 mg twice daily, efavirenz 600 mg once daily, or nevirapine (400 mg) and efavirenz (800 mg) once daily, plus stavudine and lamivudine, for 48 weeks. The primary endpoint was the proportion of patients with treatment failure (less than 1 log(10) decline in plasma HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards, disease progression [new Centers for Disease Control and Prevention grade C event or death], or change of allocated treatment). Analyses were by intention to treat. FINDINGS: Treatment failure occurred in 96 (43.6%) of 220 patients assigned nevirapine once daily, 169 (43.7%) of 387 assigned nevirapine twice daily, 151 (37.8%) of 400 assigned efavirenz, and 111 (53.1%) of 209 assigned nevirapine plus efavirenz. The difference between nevirapine twice daily and efavirenz was 5.9% (95% CI -0.9 to 12.8). There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 (p=0.193) or the increases in CD4-positive cells (p=0.800). Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events, and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz. Of 25 observed deaths, two were attributed to nevirapine. INTERPRETATION: Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy, so triple-drug regimens with either NNRTI are valid for first-line treatment. There are, however, differences in safety profiles. Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1 , Nevirapina/administração & dosagem , Oxazinas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Alcinos , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas , Ciclopropanos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Masculino , Nevirapina/efeitos adversos , Oxazinas/efeitos adversos , RNA Viral/sangue , Inibidores da Transcriptase Reversa/efeitos adversos , Falha de TratamentoRESUMO
Occult hepatitis B virus (HBV) infection is diagnosed when HBc antibodies and HBV-DNA are detectable in serum while hepatitis B surface antigen (HBsAg) is not. The clinical relevance of this phenomenon in HIV-1 patients starting highly active antiretroviral therapy (HAART) is unknown. We followed 93 therapy naive HIV-1-infected adults who were anti-HBc positive, HBsAg and HBeAg negative, during first year of HAART. At baseline, HBV-DNA was quantified, and HBV genotype was determined in the HBV-DNA-positive patients by sequencing a part of the HBV genome. Four of 93 patients (4%) were HBV DNA positive at baseline. All four patients tested negative for HBV-DNA after 1 year. They all received lamivudine as part of their HAART. They had no clinically significant liver enzyme elevations (LEE) during the first year of HAART. Two of the patients had a genotype A, one genotype E, and in the fourth patient sequencing was not possible. In one patient we found significant mutations in the a determinant region of HBsAg, at positions 142 and 144. In our population of therapy-naive HIV-1-infected adults who were anti-HBc positive, we found occult HBV infection in 4% of the patients. We did not find an increased risk for LEE in our population of patients after the start of HAART. Our results illustrate that occult HBV infection is more a diagnostic than a clinical problem. It may be caused by very low levels of HBV replication, concurrent presence of HBsAg and anti-HBs, or mutations in the HBsAg a determinant.
Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Hepatite B/complicações , Adulto , Substituição de Aminoácidos , DNA Viral/sangue , DNA Viral/classificação , DNA Viral/genética , Feminino , Genótipo , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/genética , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Humanos , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sequência de DNARESUMO
BACKGROUND: Changes in body fat distribution are an adverse effect of therapy with HIV protease inhibitors (PI). It has been suggested that nucleoside analogue reverse transcriptase inhibitors (NRTI) may also contribute to this so-called lipodystrophy syndrome, but the relative contribution of the two drug classes is unclear as they are usually administered concomitantly. METHOD: The occurrence of lipodystrophy, as reported by physicians using no standardized criteria, was followed in patients randomly assigned to treatment with either a PI alone or a PI combined with an NRTI. The patients were part of a multicenter, open-label, randomized comparison of ritonavir (RTV)/saquinavir (SQV) with or without the addition of stavudine (d4T) in HIV-1-infected patients without prior PI and d4T experience (the Prometheus study). RESULTS: Lipodystrophy was reported in 29 of 175 (17%) patients during 96 weeks of follow up. Overall, it was reported significantly more frequently in patients who were randomized to RTV/SQV/d4T (22/88; 25%), than in patients randomized to RTV/SQV alone (7/87; 8%) (P = 0.003). When the analysis was limited to patients without any prior antiretroviral experience, lipodystrophy likewise was significantly more frequent in patients randomized to RTV/SQV/d4T (12/50; 24%) than in those randomized to RTV/SQV (2/44; 5%) (P = 0.008). CONCLUSION: This randomized clinical trial, in spite of not having been blinded, supports a contributory role of NRTI in the development of antiretroviral therapy-associated lipodystrophy. The low incidence of lipodystrophy in patients with no or limited NRTI exposure supports further evaluation of NRTI-sparing regimens as alternatives to current antiretroviral regimens.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , HIV-1 , Lipodistrofia/induzido quimicamente , Inibidores da Transcriptase Reversa/efeitos adversos , Ritonavir/uso terapêutico , Saquinavir/uso terapêutico , Estavudina/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Quimioterapia Combinada , Seguimentos , Infecções por HIV/complicações , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , RNA Viral/sangue , RNA Viral/efeitos dos fármacos , Inibidores da Transcriptase Reversa/uso terapêutico , Fatores de Risco , Estavudina/uso terapêutico , Fatores de TempoRESUMO
OBJECTIVES: To determine the effect of adjuvant prednisolone use on the development of abacavir (ABC)- and nevirapine (NVP)-associated hypersensitivity reactions (HSR). METHODS: Randomized open-label study in antiretroviral-naive adult HIV-1 infected patients using a factorial design in which NVP and/or hydroxyurea (HU) and/or prednisolone are added to a regimen of ABC, zidovudine and lamivudine. Prednisolone (40 mg once daily) was added for the first 2 weeks of treatment. As it was difficult to distinguish ABC-associated HSR from NVP-associated HSR, these events were treated as a composite endpoint. The odds ratio (OR) of developing HSR for prednisolone-use was calculated with and without stratification by NVP and/or HU. Logistic regression was performed to identify risk factors for developing HSR. RESULTS: Of the 229 patients 115 were randomized to prednisolone and 114 to no-prednisolone; 19 (17%) and 11 (10%) patients, respectively, developed HSR. The expected prevention of HSR by prednisolone use was not observed. In fact use of prednisolone showed an increased risk for HSR although this did not reach statistical significance [OR, 1.82; 95% confidence interval (CI), 0.82-4.03]. There was a higher incidence of HSR in the NVP group than in the non-NVP group (20% versus 6%; P = 0.002). An additional risk factor identified in a multivariate logistic model was a high baseline CD4 cell count (OR, 1.26 per 100 x 10(6) cells/l increase; 95% CI, 1.06-1.51). CONCLUSIONS: The simultaneous start of ABC and NVP in first-line antiretroviral regimens should be avoided because of a high (20%) incidence of HSR. Short-term therapy with prednisolone did not prevent HSR in patients using ABC with or without NVP.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Didesoxinucleosídeos/efeitos adversos , Hipersensibilidade a Drogas/prevenção & controle , Infecções por HIV/tratamento farmacológico , Nevirapina/efeitos adversos , Prednisolona/uso terapêutico , Adulto , Fármacos Anti-HIV/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Didesoxinucleosídeos/uso terapêutico , Feminino , HIV-1 , Humanos , Masculino , Pessoa de Meia-Idade , Nevirapina/uso terapêutico , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêuticoRESUMO
OBJECTIVE: To investigate the risk of hepatotoxicity after initiation of protease inhibitor-containing highly active antiretroviral therapy (HAART) for HIV-1 infected patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) co-infection. DESIGN: Retrospective study with 394 HIV-1-infected patients initiating HAART at a single university clinic. METHODS: Liver enzyme elevation (LEE) was defined as alanine aminotransferase or aspartate aminotransferase at least five times the upper limit of normal and an absolute increase of > 100 U/l. Relative risks for time to LEE were estimated using Cox proportional hazards models. RESULTS: Of 394 patients 7% were hepatitis B surface antigen (HBsAg)-positive and 14% were anti-HCV-positive. Patients with chronic hepatitis had a higher risk for LEE compared with patients without co-infection: 37% versus 12% respectively. After adjustment for higher baseline transaminases, the presence of HBsAg or anti-HCV remained associated with an increased risk of LEE - relative risk 2.78 (95% confidence interval, 1.50-5.16) and 2.46 (95% confidence interval, 1.43-4.24) respectively. In patients with LEE, transaminases declined whether HAART was continued or modified. Of patients with chronic HBV infection 38% lost HBeAg or developed anti-HBe after initiation of HAART, and one seroconverted from HBsAg-positive to anti-HBs-positive. However, there was no clear relationship with LEE. CONCLUSIONS: HIV-1-infected patients co-infected with HBV or HCV were at considerably higher risk of developing LEE when HAART was initiated compared with patients without co-infection, but it is usually not necessary to modify antiretroviral therapy.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/efeitos adversos , Adulto , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Quimioterapia Combinada , Feminino , HIV-1 , Hepatite B Crônica/complicações , Hepatite C/complicações , Humanos , Testes de Função Hepática , MasculinoRESUMO
OBJECTIVE: To investigate the relationship between exposure to antiretroviral drugs and the initial decline of plasma HIV-1 RNA. DESIGN: Open-label study in antiretroviral-naive HIV-1 infected patients using a quadruple drug regimen [nelfinavir (NFV), saquinavir (SQV), stavudine, and lamivudine]. METHODS: The elimination rate constant (k) for HIV-1 clearance was calculated during the first 2 weeks of treatment in 29 patients. Exposure to NFV and SQV was quantified on each study visit. Observed NFV and SQV concentrations were related to those expected in a reference population and a concentration ratio was calculated. The median concentration ratios for NFV and SQV, the baseline CD4+ lymphocyte count and baseline log10 HIV-1 RNA were correlated with k. RESULTS: A significant positive correlation was observed between k and the median NFV (P = 0.001) or SQV concentration ratio (P = 0.016) in univariate analysis. In multivariate analyses, the median NFV concentration ratio remained significantly correlated with k. CONCLUSIONS: The variation in the rate of decline of plasma HIV-1 RNA between patients after the initiation of a quadruple drug regimen could be explained by differences in exposure to NFV or SQV. Determination of k could be used to optimise further antiretroviral drug therapy and may be a first tool to assess antiretroviral activities of new or increasing doses of drugs administered in combination regimens. Furthermore, our data suggest that exposure to antiretroviral drugs should be incorporated in mathematical models to describe HIV-1 dynamics in more detail.
Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , HIV-1 , Nelfinavir/farmacocinética , Saquinavir/farmacocinética , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Quimioterapia Combinada , Infecções por HIV/imunologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/uso terapêutico , HIV-1/genética , Humanos , Nelfinavir/sangue , Nelfinavir/uso terapêutico , RNA Viral/sangue , Saquinavir/sangue , Saquinavir/uso terapêuticoRESUMO
OBJECTIVE: To investigate and to compare the steady-state plasma pharmacokinetics of nevirapine in a dosing regimen of 400 mg once daily versus 200 mg twice daily in HIV-1-infected individuals. DESIGN: Open-label, randomized, cross-over study. METHODS: Twenty HIV-1-infected individuals who already used nevirapine as part of their antiretroviral regimen were randomized to continue their current regimen (200 mg twice daily) or to switch to the alternate regimen (400 mg once daily). The steady-state plasma pharmacokinetics of nevirapine were assessed after 2 weeks during a 24-h period. Subsequently, patients were switched to the alternate regimen and the pharmacokinetics of nevirapine were assessed again after 2 weeks. Non-compartmental methods were used to calculate the area under the plasma concentration versus time curve (AUC[24h]), and the maximal (Cmax) and minimal plasma concentration (Cmin), the time to Cmax (t(max)), the plasma elimination half-life (t1/2), the apparent oral clearance (Cl/F) and the apparent volume of distribution (V/F). Differences in these pharmacokinetic parameters for the two dosing regimens were tested using ANOVA. RESULTS: The exposure to nevirapine, as measured by the AUC[24h], was not significantly different between the 400 mg once daily and 200 mg twice daily dosing regimen (P = 0.60). Furthermore, the values for t(max), t1/2 Cl/F and V/F were not significantly different between the two dosing regimens (P > or = 0.08). However, Cmax and Cmin were higher and lower, respectively, when nevirapine was used in the once daily regimen as compared with the twice daily regimen. The median values for Cmax and Cmin as measured for the once daily and twice daily regimens were 6.69 and 5.74 microg/ml, respectively (P = 0.03), and 2.88 and 3.73 microg/ml, respectively (P < 0.01). CONCLUSION: These data show that the daily exposure to nevirapine, as measured by the plasma AUC[24h], is not different between a 400 mg once daily and a 200 mg twice daily dosing regimen. However, Cmax and Cmin are higher and lower, respectively, for the once daily regimen as compared with the twice daily regimen. The clinical implications of these differences remain to be established.
Assuntos
Infecções por HIV/tratamento farmacológico , HIV-1 , Nevirapina/administração & dosagem , Nevirapina/farmacocinética , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Estudos Cross-Over , Esquema de Medicação , Quimioterapia Combinada , Feminino , Infecções por HIV/metabolismo , Humanos , Masculino , Equivalência TerapêuticaRESUMO
BACKGROUND: Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. OBJECTIVES: In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. METHODS: Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and naïve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). RESULTS: Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naïve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the naïve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of naïve CD4+ T cells at baseline resulted in modest long-term naïve T-cell recovery. CONCLUSIONS: Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Naïve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported for immune recovery in adults after chemotherapy and bone marrow transplantation.
Assuntos
Envelhecimento/imunologia , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/imunologia , HIV-1/imunologia , Inibidores da Transcriptase Reversa/uso terapêutico , Adulto , Didanosina/uso terapêutico , Seguimentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Memória Imunológica , Pessoa de Meia-Idade , Nevirapina/uso terapêutico , Fatores de Tempo , Zidovudina/uso terapêuticoRESUMO
OBJECTIVE: To assess the tolerability, virological, immunological and clinical effects of nevirapine in the setting of a compassionate use programme in pretreated HIV-infected individuals. DESIGN: Retrospective observational cohort-study in 13 HIV-outpatient clinics in The Netherlands. MAIN OUTCOME MEASURES: plasma HIV-1 RNA levels; CD4 cell counts; incidence of new AIDS-defining diseases; multivariate analysis of predictors for virological success; incidence of skin rashes. RESULTS: 187 HIV-infected individuals treated with nevirapine in the Nevirapine Named Patient Programme in The Netherlands were included. After 48 weeks, 38% of patients had an HIV-1 RNA level below 1,000 copies/ml. In multivariate regression analysis, prior treatment with three or less nucleoside analogue reverse transcriptase inhibitors, and a higher baseline CD4 cell count was predictive of virological success. The median CD4 cell count remained stable over the 48 weeks. Eleven patients experienced a new AIDS-defining event. The total incidence of rash (including rash not leading to discontinuation of nevirapine) was 13.9 and 6.4% of the patients discontinued nevirapine because of rash. None of the 28 patients with undetectable HIV-1 RNA levels at baseline developed a rash. CONCLUSIONS: We conclude that nevirapine when used as part of salvage therapy, is safe and most likely to give sustained suppression of HIV-1 in patients that have been less extensively pretreated. CD4 cell counts remained stable despite the low rate of virological success, this also occurred in patients not concurrently using protease inhibitors (PIs). The incidence of nevirapine-related rash in PI-pretreated patients and especially in patients with undetectable HIV-1 RNA levels at the start of nevirapine treatment, is considerably lower than previously reported for antiretroviral-naive patients.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Nevirapina/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Terapia de Salvação , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Quimioterapia Combinada , Feminino , Infecções por HIV/virologia , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Estudos RetrospectivosAssuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Herpesvirus Humano 8/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Sarcoma de Kaposi/tratamento farmacológico , Adulto , Células Cultivadas , Efeito Citopatogênico Viral , Humanos , Masculino , Carga Viral , Zalcitabina/uso terapêutico , Zidovudina/uso terapêuticoAssuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Contagem de Linfócito CD4 , Esquema de Medicação , Infecções por HIV/imunologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/genética , Humanos , Lamivudina/uso terapêutico , Nelfinavir/uso terapêutico , RNA Viral/sangue , Inibidores da Transcriptase Reversa/uso terapêutico , Saquinavir/uso terapêutico , Estavudina/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Carga ViralAssuntos
Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Lamivudina/administração & dosagem , Nelfinavir/administração & dosagem , Saquinavir/administração & dosagem , Estavudina/administração & dosagem , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Masculino , Projetos Piloto , Resultado do Tratamento , Carga ViralRESUMO
OBJECTIVES: Optimal plasma concentrations of antiretroviral drugs are required during pregnancy to treat maternal HIV infection and prevent mother-to-child transmission. We investigated the effect of pregnancy on nevirapine (NVP) plasma concentrations. METHODS: We included all HIV-1-infected women for whom NVP plasma concentrations were available as part of routine patient care at two university hospitals. Plasma NVP concentrations were compared for pregnant (n=45) and non-pregnant (n=152) women. Univariate and multivariate linear regression analyses were used to identify and adjust for other confounding factors associated with NVP plasma concentrations. For pregnant women who had a plasma NVP concentration available both during and outside pregnancy, a paired analysis was performed. RESULTS: Steady-state NVP plasma concentrations were lower in pregnant women: 5.2 mg/L (interquartile range 3.9-6.8) vs. 5.8 mg/L (4.3-7.7) (P=0.08). After adjusting for confounders, both pregnancy (regression coefficient=-0.90 mg/L, P=0.046) and African descent (regression coefficient=+1.13 mg/L, P=0.005) influenced NVP concentrations significantly. The paired analysis showed mean concentrations of 4.8 mg/L during pregnancy and 5.8 mg/L outside pregnancy (paired t-test, P=0.073). CONCLUSIONS: Pregnancy has a moderate but significant lowering effect on NVP plasma concentrations. Being of African descent compensates for the lowering effect of pregnancy on NVP concentrations.