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2.
Viruses ; 16(4)2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38675955

RESUMEN

Cardiovascular disease (CVD) is common in people with HIV (PWH), and has great impact in terms of morbidity and mortality. Several intertwined mechanisms are believed to play a role in determining the increased risk of CVD, including the effect of certain antiretrovirals; among these, the role of integrase strand-transfer inhibitors (INSTIs) is yet to be fully elucidated. We conducted a multicenter, observational study comprising 4984 PWH evaluating the antiretroviral therapy (ART)-related nature of CVD in real life settings, both in naïve vs. treatment-experienced people. A comparison was conducted between INSTIs vs. either protease inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs) considering demographic, baseline clinical characteristics, incidence of CVD in both 2-year and complete follow-up periods. Among 2357 PWH exposed to INSTIs, 24 people experienced CVD; the corresponding figure was 12 cases out of 2599 PWH exposed to other ART classes. At univariate and multivariate analysis, a tendency towards an increased risk of CVD was observed in the 2-year follow-up period in PWH exposed to INSTIs in the absence, however, of statistical significance. These findings leave open the hypothesis that INSTIs may play a role, albeit minimal, in determining an increased risk of CVD in PWH.


Asunto(s)
Enfermedades Cardiovasculares , Infecciones por VIH , Inhibidores de Integrasa VIH , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/complicaciones , Masculino , Femenino , Persona de Mediana Edad , Inhibidores de Integrasa VIH/uso terapéutico , Inhibidores de Integrasa VIH/efectos adversos , Adulto , Factores de Riesgo , Incidencia , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Inhibidores de la Transcriptasa Inversa/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/efectos adversos
3.
Lancet HIV ; 11(5): e321-e332, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38621392

RESUMEN

BACKGROUND: Integrase strand-transfer inhibitors (INSTIs) and tenofovir alafenamide have been associated with weight gain in several clinical trials and observational cohorts. However, whether weight gain associated with INSTIs and tenofovir alafenamide confers a higher risk of weight-related clinical events is unclear. We aimed to assess whether changes in BMI differentially increase hypertension or dyslipidaemia risk in people with HIV receiving INSTIs, tenofovir alafenamide, or both versus other contemporary regimens. METHODS: This multicentre, prospective observational study analysed prospective data from RESPOND, an international consortium of HIV cohorts for which recruitment began in 2017 and is still ongoing from HIV clinics and hospitals in 37 European countries and Australia. Participants were eligible if they were aged 18 years or older, receiving INSTI-containing antiretroviral therapy (ART) regimens or a contemporary non-INSTI, did not have hypertension or dyslipidaemia at baseline, and had baseline and at least two follow-up BMI, lipid, and blood pressure measurements. We excluded participants without baseline CD4 or HIV RNA results and those receiving non-ART medications associated with weight changes, including antipsychotics and mood stabilisers, corticosteroids, insulin, and insulin secretagogues. They were followed up from baseline until the earliest hypertension or dyslipidaemia event, their last visit, or Dec 31, 2021, whichever was earlier. The primary outcomes were incidence of hypertension and dyslipidaemia, for which we used multivariable Poisson regression adjusted for time-updated BMI to determine unadjusted and adjusted incidence rate ratios (IRRs) of hypertension and dyslipidaemia in people receiving INSTIs, tenofovir alafenamide, or both, and tested for interaction between time-updated ART regimen and BMI. FINDINGS: Of the 35 941 RESPOND participants, 9704 (7327 [75·5 %] male and 2377 [24·5%] female) were included in the hypertension analysis and 5231 (3796 [72·6%] male and 1435 [27·4%] female) were included in the dyslipidaemia analysis. In the univariable model, hypertension was more common in individuals receiving an INSTI with tenofovir alafenamide (IRR 1·70, 95% CI 1·54-1·88) or an INSTI without tenofovir alafenamide (1·41, 1·30-1·53) compared with those receiving neither INSTIs nor tenofovir alafenamide. Adjustment for time-updated BMI and confounders attenuated risk in participants receiving an INSTI with (IRR 1·48, 1·31-1·68) or without (1·25, 1·13-1·39) tenofovir alafenamide. Similarly, dyslipidaemia was more common in participants using tenofovir alafenamide with an INSTI (IRR 1·24, 1·10-1·40) and tenofovir alafenamide alone (1·22, 1·03-1·44) than in participants using neither INSTI nor tenofovir alafenamide. Adjustment for BMI and confounders attenuated the risk in participants receiving tenofovir alafenamide with an INSTI (adjusted IRR 1·21, 1·07-1·37), whereas the risk in those receiving tenofovir alafenamide alone became non-significant (1·15, 0·96-1·38). The associations between increasing BMI and risk of hypertension and dyslipidaemia did not differ between participants receiving different ART regimens (pinteraction=0·46 for hypertension; pinteraction=0·31 for dyslipidaemia). INTERPRETATION: Although residual confounding cannot be entirely excluded, the use of INSTIs was associated with incident hypertension, and the use of tenofovir alafenamide was associated with dyslipidaemia, with the latter association partly mediated by weight gain. These results reiterate the need for hypertension and dyslipidaemia screening in people with HIV. FUNDING: The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The Brighton HIV Cohort, The National Croatian HIV Cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort, The University of Cologne HIV Cohort, Merck Life Sciences, ViiV Healthcare, and Gilead Sciences.


Asunto(s)
Índice de Masa Corporal , Dislipidemias , Infecciones por VIH , Hipertensión , Tenofovir , Tenofovir/análogos & derivados , Humanos , Femenino , Masculino , Infecciones por VIH/tratamiento farmacológico , Tenofovir/efectos adversos , Tenofovir/uso terapéutico , Hipertensión/epidemiología , Hipertensión/inducido químicamente , Estudios Prospectivos , Dislipidemias/inducido químicamente , Dislipidemias/epidemiología , Persona de Mediana Edad , Adulto , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de Integrasa VIH/uso terapéutico , Alanina/efectos adversos , Australia/epidemiología , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Aumento de Peso/efectos de los fármacos , Europa (Continente)/epidemiología , Factores de Riesgo , Quimioterapia Combinada/efectos adversos
4.
BMC Infect Dis ; 24(1): 343, 2024 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-38515041

RESUMEN

BACKGROUND: Dolutegravir is an integrase strand transfer inhibitor that has been recommended for use in first-line antiretroviral regimens by the World Health Organisation and is currently being rolled out globally. There has been safety concerns with dolutegravir which has caused concern about its use in the general population. Dolutegravir first-line regimens have been used in South Africa since early 2020. Therefore, the aim of the present study was to assess the efficacy, safety, and tolerability of first-line dolutegravir-based antiretrovirals amongst adults living with HIV in Durban, South Africa. METHODS: This was a mixed-methods study, which comprised a cross-sectional survey and longitudinal retrospective follow-up of medical records. The study was conducted between October 2020 and January 2022. Data were described using descriptive and summary statistics. Bivariate logistic regression was applied to socio-demographic and clinical variables and crude odds ratios with a 95% confidence interval was calculated. Pearson chi-square tests, paired sample T-tests, and cross-tabulations were performed on selected variables. RESULTS: A total of 461 participants were enrolled in the study. There was a significant change in immunological outcomes (p < 0.001) after dolutegravir initiation. Furthermore, an assessment of laboratory parameters showed that there was a significant decrease in cholesterol (p < 0.001) and increase in creatinine (p < 0.001) levels. Increased weight was shown by 60.7% of the participants but was not associated with age, gender, CD4 counts, and previous antiretroviral usage. The study found that 43.6% of the participants experienced at least one side-effect. A total of 21.6% and 23.2% of the participants experienced neuropsychiatric and central nervous system side-effects, respectively. In the bivariate analyses, only gender was shown to be associated with side-effects, and only 1.7% of the participants discontinued the study due to side-effects. CONCLUSION: Our results suggest that dolutegravir is effective, safe, and well tolerated in the study population.


Asunto(s)
Infecciones por VIH , Inhibidores de Integrasa VIH , Oxazinas , Piperazinas , Piridonas , Adulto , Humanos , Infecciones por VIH/tratamiento farmacológico , Estudios de Cohortes , Estudios Retrospectivos , Sudáfrica , Estudios Transversales , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Antirretrovirales/uso terapéutico , Inhibidores de Integrasa VIH/efectos adversos
5.
Br J Clin Pharmacol ; 90(5): 1247-1257, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38332460

RESUMEN

AIMS: Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first-line dolutegravir-based antiretroviral therapy (ART). METHODS: We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, CD4 T-cell count, total body weight and co-trimoxazole use. RESULTS: We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 (SD 9.9) µmol.L-1. Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [ß] = 2.78 µmol.L-1 [95% confidence interval (CI) 0.54, 5.01]), TDF use (ß = 2.30 [0.53, 4.06]), male sex (ß = 5.20 [2.92, 7.48]), baseline serum creatinine (ß = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model (ß = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. CONCLUSIONS: Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.


Asunto(s)
Creatinina , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Piridonas , Humanos , Piridonas/farmacocinética , Oxazinas/farmacocinética , Oxazinas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Masculino , Creatinina/sangre , Femenino , Infecciones por VIH/tratamiento farmacológico , Adulto , Sudáfrica , Persona de Mediana Edad , Glucuronosiltransferasa/genética , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/efectos adversos , VIH-1/genética , VIH-1/efectos de los fármacos , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/uso terapéutico , Inhibidores de Integrasa VIH/efectos adversos , Tenofovir/farmacocinética , Tenofovir/uso terapéutico , Emtricitabina/uso terapéutico , Emtricitabina/farmacocinética , Polimorfismo de Nucleótido Simple
7.
Curr Opin HIV AIDS ; 19(1): 21-29, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-37934677

RESUMEN

PURPOSE OF REVIEW: The introduction of dolutegravir, an oral integrase inhibitor, within public health HIV programs has been a success, with excellent sustained viral load suppression, persistence, and safety. Initial concerns around integrase-inhibitors being implicated in safety concerns around immune reconstitution inflammatory syndromes (IRIS), neural tube defects, and weight gain, have been largely laid to rest, but new concerns about cardiovascular risk have arisen, including a link between hypertension and this antiretroviral class. RECENT FINDINGS: We review the pertinent studies here, and while we find both observational and randomized controlled study associations in some but not all studies, these are often confounded by associated weight gain and aging. In addition, definitions of hypertension, as well as measurement within the studies (such as cuff size), were not consistent within studies. SUMMARY: Careful analysis will be needed, as with the weight-gain signal, before assigning causation, especially as plausible physiological mechanisms for this rise in blood pressure are unclear.


Asunto(s)
Infecciones por VIH , Inhibidores de Integrasa VIH , Humanos , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/efectos adversos , Hipertensión/tratamiento farmacológico , Piridonas/efectos adversos , Aumento de Peso
8.
Lancet HIV ; 10(11): e723-e732, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37923486

RESUMEN

BACKGROUND: A recent observational study suggested that the risk of cardiovascular events could be higher among antiretroviral therapy (ART)-naive individuals with HIV who receive integrase strand-transfer inhibitor (INSTI)-based ART than among those who receive other ART regimens. We aimed to emulate target trials separately in ART-naive and ART-experienced individuals with HIV to examine the effect of using INSTI-based regimens versus other ART regimens on the 4-year risk of cardiovascular events. METHODS: We used routinely recorded clinical data from 12 cohorts that collected information on cardiovascular events, BMI, and blood pressure from two international consortia of cohorts of people with HIV from Europe and North America. For the target trial in individuals who had previously never used ART (ie, ART-naive), eligibility criteria were aged 18 years or older, a detectable HIV-RNA measurement while ART-naive (>50 copies per mL), and no history of a cardiovascular event or cancer. Eligibility criteria for the target trial in those with previous use of non-INSTI-based ART (ie, ART-experienced) were the same except that individuals had to have been on at least one non-INSTI-based ART regimen and be virally suppressed (≤50 copies per mL). We assessed eligibility for both trials for each person-month between January, 2013, and January, 2023, and assigned individuals to the treatment strategy that was compatible with their data. We estimated the standardised 4-year risks of cardiovascular events (myocardial infarction, stroke, or invasive cardiovascular procedure) via pooled logistic regression models adjusting for time and baseline covariates. In per-protocol analyses, we censored individuals if they deviated from their assigned treatment strategy for more than 2 months and weighted uncensored individuals by the inverse of their time-varying probability of remaining uncensored. The denominator of the weight was estimated via a pooled logistic model that included baseline and time-varying covariates. FINDINGS: The analysis in ART-naive individuals included 10 767 INSTI initiators and 8292 non-initiators of INSTI. There were 43 cardiovascular events in INSTI initiators (median follow-up of 29 months; IQR 15-45) and 52 in non-initiators (39 months; 18-47): standardised 4-year risks were 0·76% (95% CI 0·51 to 1·04) in INSTI initiators and 0·75% (0·54 to 0·98) in non-INSTI initiators; risk ratio 1·01 (0·57 to 1·57); risk difference 0·0089% (-0·43 to 0·36). The analysis in ART-experienced individuals included 7875 INSTI initiators and 373 965 non-initiators. There were 56 events in INSTI initiators (median follow-up 18 months; IQR 9-29) and 3103 events (808 unique) in non-INSTI initiators (26 months; 15-37) in non-initiators: standardised 4-year risks 1·41% (95% CI 0·88 to 2·03) in INSTI initiators and 1·48% (1·28 to 1·71) in non-initiators; risk ratio 0·95 (0·60 to 1·36); risk difference -0·068% (-0·60 to 0·52). INTERPRETATION: We estimated that INSTI use did not result in a clinically meaningful increase of cardiovascular events in ART-naive and ART-experienced individuals with HIV. FUNDING: National Institute of Allergy and Infectious Diseases and National Institute on Alcohol Abuse and Alcoholism.


Asunto(s)
Enfermedades Cardiovasculares , Infecciones por VIH , Inhibidores de Integrasa VIH , Adulto , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/efectos adversos , América del Norte , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Integrasas/uso terapéutico
9.
BMC Infect Dis ; 23(1): 744, 2023 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-37904127

RESUMEN

Dolutegravir (DTG), an integrase strand transfer inhibitor is currently the recommended first and second line anti-retroviral therapy (ART) anchor agent by the World Health Organization due to its favorable side effect profile, high efficacy and genetic barrier to resistance.Despite its very good side effect profile, there have been multiple case reports of ART experienced patients developing hyperglycemia within weeks to a few months after switching to DTG preceded by weight loss. At population level, however, DTG as well as other integrase inhibitors have been demonstrated to have a reduced risk of incident diabetes mellitus (T2DM) compared to other HIV drug classes.Following multiple similar reports of accelerated hyperglycemia in Uganda during the first pilot year of DTG use, the Uganda Ministry of Health recommended withholding dolutegravir in all patients who develop diabetes. Whether this recommendation should be applied to all patients with incident T2DM remains to be demonstrated.We present a clinical case of an HIV positive ART naïve man who was diagnosed with T2DM after 36 weeks on DTG. We describe changes in blood glucose, glycated hemoglobin, insulin resistance and pancreatic beta cell function before and after withholding DTG. We demonstrated that he was phenotypically different from the reported cases of accelerated hyperglycemia and he continued to have worsening insulin resistance despite withholding DTG. His blood glucose improved with dietary T2DM management. It is possible he had an inherent risk of developing T2DM independent of his exposure to DTG. This put in question whether DTG should universally be withheld in PLHIV with incident T2DM in Uganda.


Asunto(s)
Diabetes Mellitus Tipo 2 , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Infecciones por VIH , Inhibidores de Integrasa VIH , Hiperglucemia , Resistencia a la Insulina , Masculino , Humanos , Inhibidores de Integrasa VIH/efectos adversos , Glucemia , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Diabetes Mellitus Tipo 2/tratamiento farmacológico
10.
AIDS ; 37(14): 2259-2262, 2023 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-37877283

RESUMEN

We studied hepatic steatosis in people with HIV (PWH) who switched to an integrase inhibitor (INSTI)-based regimen. One hundred and fifty-four PWH were included. After 48 weeks, median (Q1-Q3) weight gain was 1.2 (-0.6 to 3.8) kg and median (Q1-Q3) controlled attenuation parameter (CAP) change was -4 (-33 to 27) dB/m. Weight gain was weakly correlated with CAP change [R2 95% confidence interval (CI) = 0.144 (-0.014 to 0.296); P = 0.074)]. Changes in hepatic steatosis after switching to INSTI-based regimens do not seem to parallel weight gain after 1 year.


Asunto(s)
Diagnóstico por Imagen de Elasticidad , Hígado Graso , Infecciones por VIH , Inhibidores de Integrasa VIH , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/efectos adversos , Aumento de Peso
11.
PLoS One ; 18(6): e0276473, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37307279

RESUMEN

BACKGROUND: Antiretroviral therapy (ART) decreases perinatal HIV transmission, but concerns exist regarding maternal and infant safety. We compared the incidence of congenital malformations and other adverse outcomes in pregnancies exposed to integrase inhibitor (INSTI) versus non-INSTI ART. SETTING: Single-site review of all pregnancies among women living with HIV between 2008 and 2018. METHODS: We used binomial family generalized estimating equations to model the relationship of congenital anomalies and pregnancy outcomes with exposure to INSTI or dolutegravir (DTG) versus non-INSTI ART. RESULTS: Among 257 pregnancies, 77 women received ≥1 INSTI (54 DTG, 14 elvitegravir, 15 raltegravir), 167 received non-INSTI, and 3 had missing data. Fifty congenital anomalies were identified in 36 infants. Infants with first-trimester DTG or any first-trimester INSTI exposure had higher odds of congenital anomalies than infants with first-trimester non-INSTI exposure (OR = 2.55; 95%CI = 1.07-6.10; OR = 2.61; 95%CI = 1.15-5.94, respectively). Infants with INSTI exposure after the second trimester had no increased odds of anomalies. Women with INSTI exposure had higher odds of preeclampsia (OR = 4.73; 95%CI = 1.70-13.19). Among women who received INSTI, grade ≥3 laboratory abnormalities were noted in 2.6% while receiving the INSTI and 3.9% while not receiving the INSTI, versus 16.2% in women who received non-INSTI. There was no association between INSTI exposure and other pregnancy outcomes. CONCLUSION: In our cohort, first-trimester INSTI exposure was associated with increased rates of congenital anomalies and use of INSTI during pregnancy was associated with preeclampsia. These findings underscore the need for continued monitoring of the safety of INSTI in pregnancy.


Asunto(s)
Anomalías Inducidas por Medicamentos , Inhibidores de Integrasa VIH , Exposición Materna , Lactante , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de Integrasa VIH/uso terapéutico , Exposición Materna/efectos adversos , Anomalías Inducidas por Medicamentos/epidemiología , Primer Trimestre del Embarazo , Preeclampsia/inducido químicamente , Antirretrovirales/efectos adversos , Estudios Retrospectivos , Estudios de Cohortes , Humanos , Masculino , Femenino , Embarazo , Recién Nacido
12.
Int J STD AIDS ; 34(12): 854-859, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37309139

RESUMEN

BACKGROUND: Research suggests that integrase strand transferase inhibitor use can lead to weight gain, and data from sub-Saharan countries are limited. This study investigated changes in weight in Namibians switched from tenofovir DF/emtricitabine/efavirenz (TEE) to tenofovir DF/lamivudine/dolutegravir (TLD). METHODS: Longitudinal, retrospective, and quantitative study from outpatient records of Namibians living with HIV/AIDS switched from efavirenz-to dolutegravir-based regimen at four clinics. A linear mixed effects model predicting weight 6 months prior to the switch, time of the switch, and at 6, 12-, and 18-months post-switch was run. A second analysis comparing change in weights between males and females was also run. RESULTS: 242 patients switched from TEE to TLD. Compared to patient weight at the time of the switch, weights were significantly higher at 6 (+0.9 kg, p = 0.004), 12 (+1.7 kg, p < 0.001), and 18 months (+1.4 kg, p < 0.001) post-switch. There was no significant weight change for males, but females had a significant weight gain at 12 (+1.58 kg, p = 0.012) and 18 months (+1.49 kg, p = 0.024) post switch. CONCLUSIONS: Females living with HIV in Namibia gain weight when switched from TEE to TLD. Clinical implications on the development of cardiometabolic complications is unclear and mechanisms by which the weight gain occurs are unknown.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Inhibidores de Integrasa VIH , Masculino , Femenino , Humanos , Infecciones por VIH/tratamiento farmacológico , Estudios Retrospectivos , Benzoxazinas/efectos adversos , Tenofovir/uso terapéutico , Lamivudine/uso terapéutico , Emtricitabina/uso terapéutico , Aumento de Peso , Inhibidores de Integrasa VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico
13.
J Antimicrob Chemother ; 78(8): 1944-1947, 2023 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-37311223

RESUMEN

OBJECTIVES: Concerns have been raised regarding neuropsychiatric adverse drug reactions of integrase inhibitors (INSTIs) in patients living with HIV. The aim of this study was to assess the risk of depression and suicidality reporting with INSTIs based on a global pharmacovigilance database. METHODS: Depression and suicidality cases in patients treated with INSTIs were identified within the WHO global database of individual case safety reports, VigiBase. Risk of depression and suicidality reporting with INSTIs compared with other ART was assessed using disproportionality analyses (case/non-case statistical approach). RESULTS: Of 19 991 410 reports over the study period, 124 184 reports concerned patients exposed to ART, including 22 661 patients exposed to an INSTI. Among patients treated with an INSTI, 547 cases of depression and 357 cases of suicidality were identified. Disproportionality analyses showed that depression [reporting OR (ROR) 3.6; 95% CI: 3.2-4.0] and suicidality (ROR 4.7; 95% CI: 4.1-5.4) were more reported with the use of INSTIs compared with other ART. Amongst INSTIs, depression reporting was significantly greater for bictegravir and dolutegravir, whereas suicidality reporting was significantly greater for dolutegravir only. CONCLUSIONS: Our findings suggest that depression and suicidality are adverse drug reactions of all INSTI agents, especially dolutegravir, which may occur within the first months of therapy.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Infecciones por VIH , Inhibidores de Integrasa VIH , Integrasa de VIH , Humanos , Inhibidores de Integrasa VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Depresión/epidemiología , Farmacovigilancia , Ideación Suicida , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Piridonas/farmacología
14.
N Engl J Med ; 388(25): 2349-2359, 2023 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-37342923

RESUMEN

BACKGROUND: Data to inform the switch from a ritonavir-boosted protease inhibitor (PI) to dolutegravir in patients living with human immunodeficiency virus (HIV) infection who do not have genotype information and who have viral suppression with second-line therapy containing a ritonavir-boosted PI have been limited. METHODS: In a prospective, multicenter, open-label trial conducted at four sites in Kenya, we randomly assigned, in a 1:1 ratio, previously treated patients without genotype information who had viral suppression while receiving treatment containing a ritonavir-boosted PI to either switch to dolutegravir or continue the current regimen. The primary end point was a plasma HIV type 1 RNA level of at least 50 copies per milliliter at week 48, assessed on the basis of the Food and Drug Administration snapshot algorithm. The noninferiority margin for the between-group difference in the percentage of participants who met the primary end point was 4 percentage points. Safety up to week 48 was assessed. RESULTS: A total of 795 participants were enrolled, with 398 assigned to switch to dolutegravir and 397 assigned to continue taking their ritonavir-boosted PI; 791 participants (397 in the dolutegravir group and 394 in the ritonavir-boosted PI group) were included in the intention-to-treat exposed population. At week 48, a total of 20 participants (5.0%) in the dolutegravir group and 20 (5.1%) in the ritonavir-boosted PI group met the primary end point (difference, -0.04 percentage points; 95% confidence interval, -3.1 to 3.0), a result that met the criterion for noninferiority. No mutations conferring resistance to dolutegravir or the ritonavir-boosted PI were detected at the time of treatment failure. The incidence of treatment-related grade 3 or 4 adverse events was similar in the dolutegravir group and the ritonavir-boosted PI group (5.7% and 6.9%, respectively). CONCLUSIONS: In previously treated patients with viral suppression for whom there were no data regarding the presence of drug-resistance mutations, dolutegravir treatment was noninferior to a regimen containing a ritonavir-boosted PI when the patients were switched from a ritonavir-boosted PI-based regimen. (Funded by ViiV Healthcare; 2SD ClinicalTrials.gov number, NCT04229290.).


Asunto(s)
Infecciones por VIH , Inhibidores de Integrasa VIH , VIH-1 , Humanos , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Quimioterapia Combinada , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , VIH-1/genética , Estudios Prospectivos , Piridonas/uso terapéutico , Ritonavir/efectos adversos , Ritonavir/uso terapéutico , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de Integrasa VIH/farmacología , Inhibidores de Integrasa VIH/uso terapéutico , Kenia
15.
Rev. esp. salud pública ; 97: e202306052, Jun. 2023. tab
Artículo en Español | IBECS | ID: ibc-222823

RESUMEN

FUNDAMENTOS: Los inhibidores de la integrasa se han posicionado recientemente en todas las Guías Clínicas de VIH como tratamiento antirretroviral de primera línea para el VIH. Sin embargo, dos de estos fármacos se han asociado también a efectos adversos a nivel del sistema nervioso central, concretamente con alteraciones del sueño. El objetivo del trabajo fue analizar la influencia de bictegravir y dolutegravir en la calidad del sueño en personas que viven con VIH (PVIH). MÉTODOS: Se realizó un estudio observacional y transversal entre los meses de diciembre de 2020 y enero de 2021 en las PVIH de las consultas de atención farmacéutica del hospital. Se recogieron variables demográficas y de adherencia. La calidad del sueño se midió mediante el Cuestionario de Pittsburgh o PSQI. Las PVIH se clasificaron en 2 grupos: el grupo estudio, constituido por participantes con bictegravir o dolutegravir en su tratamiento, y el grupo control, integrado por el resto de PVIH. Se analizó la influencia de las variables recogidas sobre el resultado del PSQI mediante la prueba de chi cuadrado/odds ratio para variables categóricas y el de t de Student o U de Mann Whitney para variables continuas. RESULTADOS: Se incluyeron 119 PVIH, de las cuales un 64% en el grupo estudio y un 67% en el grupo control sufrían trastornos del sueño según el PSQI (p=0,788). Tampoco hubo diferencias estadísticamente significativas cuando se compararon los diferentes componentes del sueño entre los dos grupos. CONCLUSIONES: Un elevado porcentaje de PVIH, independientemente de si el TAR incluye bictegravir o dolutegravir, tienen problemas relacionados con la calidad del sueño. No se encuentra correlación entre la calidad del sueño y el tratamiento con bictegravir o dolutegravir comparado con el resto de tratamientos.(AU)


BACKGROUND: HIV Clinical Guidelines have positioned integrase inhibitors recently as first-line treatment. However, two of these drugs have also been associated with adverse side effects on the central nervous system, especially with sleep disturbances. The objective was to analyse the influence of bictegravir and dolutegravir on the sleep quality in HIV patients. METHODS: An observational, cross-sectional study was carried out between December 2020 and January 2021 in HIV patients attended in a pharmacy care clinic. Demographic and adherence variables were collected. Sleep quality was measured using the Pittsburgh questionnaire or PSQI. We classified patients into two groups: patients with bictegravir or dolutegravir in their treatment (study group) and the rest (control group). The influence of the variables collected on the PSQI result was analysed using the Chi-Square test for categorical variables and the student t-test or Mann-Whitney U test for continuous variables. RESULTS: One hundred and nineteen patients were included. 64% in the study group and 67% in the control group suffered from sleep disorders according to the PSQI questionnaire (p=0.788). Neither were statistical differences found when the different components of sleep were analysed between the two groups. CONCLUSIONS: A high percentage of patients, regardless of whether their treatment includes bictegravir or dolutegravir, have problems with their sleep quality. We didn’t find a correlation between sleep quality and treatment with bictegravir or dolutegravir compared to the other treatments.(AU)


Asunto(s)
Humanos , Masculino , Femenino , Polisomnografía , Inhibidores de Integrasa VIH/efectos adversos , Trastornos del Inicio y del Mantenimiento del Sueño , VIH , Salud Pública , Trastornos del Sueño-Vigilia , Calidad de Vida , Estudios Transversales
16.
Clin Infect Dis ; 77(5): 729-737, 2023 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-37157869

RESUMEN

BACKGROUND: Integrase strand transfer inhibitors (INSTIs) have been associated with an increased risk for cardiovascular disease (CVD) events. We investigated the impact of starting INSTI-based antiretroviral therapy (ART) on CVD events among treatment-naïve people with human immunodeficiency virus using a target trial framework, which reduces the potential for confounding and selection bias. METHODS: We included Swiss HIV Cohort Study participants who were ART-naïve after May 2008, when INSTIs became available in Switzerland. Individuals were categorized according to their first ART regimen (INSTI vs other ART) and were followed from ART start until the first of CVD event (myocardial infarction, stroke, or invasive cardiovascular procedure), loss to follow-up, death, or last cohort visit. We calculated hazard ratios and risk differences using pooled logistic regression models with inverse probability of treatment and censoring weights. RESULTS: Of 5362 participants (median age 38 years, 21% women, 15% of African origin), 1837 (34.3%) started INSTI-based ART, and 3525 (65.7%) started other ART. Within 4.9 years (interquartile range, 2.4-7.4), 116 CVD events occurred. Starting INSTI-based ART was not associated with an increased risk for CVD events (adjusted hazard ratio, 0.80; 95% confidence interval [CI], .46-1.39). Adjusted risk differences between individuals who started INSTIs and those who started other ART were -0.17% (95% CI, -.37 to .19) after 1 year, -0.61% (-1.54 to 0.22) after 5 years, and -0.71% (-2.16 to 0.94) after 8 years. CONCLUSIONS: In this target trial emulation, we found no difference in short- or long-term risk for CVD events between treatment-naïve people with human immunodeficiency virus who started INSTI-based ART and those on other ART.


Asunto(s)
Fármacos Anti-VIH , Enfermedades Cardiovasculares , Infecciones por VIH , Inhibidores de Integrasa VIH , Adulto , Femenino , Humanos , Masculino , Fármacos Anti-VIH/efectos adversos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/tratamiento farmacológico , Estudios de Cohortes , VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/efectos adversos
17.
AIDS Res Hum Retroviruses ; 39(12): 644-651, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37140468

RESUMEN

Integrase strand-transfer inhibitors (INSTIs) are associated with weight gain in women living with HIV (WLH). Relationships between drug exposure, baseline obesity, and INSTI-associated weight gain remain unclear. Data from 2006 to 2016 were analyzed from virally suppressed WLH enrolled in the Women's Interagency HIV Study, who switched/added an INSTI to antiretroviral therapy: [raltegravir (RAL), dolutegravir (DTG), or elvitegravir (EVG)]. Percent body weight change was calculated from weights obtained a median 6 months pre-INSTI and 14 months post-INSTI initiation. Hair concentrations were measured with validated liquid chromatography-mass spectrometry (MS)/MS assays. Baseline (preswitch) weight status evaluated obese (body mass index, BMI, ≥30 kg/m2) versus nonobese (BMI <30 kg/m2). Mixed models examined the drug hair concentration*baseline obesity status interaction for each INSTI. There were 169 WLH included: 53 (31%) switched to RAL, 72 (43%) to DTG, and 44 (26%) to EVG. Women were median age 47-52 years, predominantly Non-Hispanic Black, median CD4 counts >500 cells/mm3, >75% with undetectable HIV-1 RNA. Over ∼1 year, women experienced median increases in body weight: 1.71% (-1.78, 5.00) with RAL; 2.40% (-2.82, 6.50) with EVG; and 2.48% (-3.60, 7.88) with DTG. Baseline obesity status modified the relationship between hair concentrations and percent weight change for DTG and RAL (p's < 0.05): higher DTG, yet lower RAL concentrations were associated with greater weight gain among nonobese women. Additional pharmacologic assessments are needed to understand the role of drug exposure in INSTI-associated weight gain.


Asunto(s)
Infecciones por VIH , Inhibidores de Integrasa VIH , Integrasa de VIH , VIH-1 , Humanos , Femenino , Persona de Mediana Edad , Raltegravir Potásico/uso terapéutico , Raltegravir Potásico/farmacología , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/efectos adversos , VIH-1/genética , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Oxazinas/uso terapéutico , Aumento de Peso , Obesidad/tratamiento farmacológico , Integrasa de VIH/genética
18.
Antivir Ther ; 28(2): 13596535231163703, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36896821

RESUMEN

BACKGROUND: Cohort studies suggest higher discontinuation rates with integrase strand transfer inhibitors (INSTIs) than are seen in clinical trials. We assessed discontinuations and adverse events (AEs) that were considered related to the initial INSTI in the first year following initiation among treatment-naïve people living with HIV (PLWH). METHODS: Newly diagnosed PLWH initiating raltegravir, elvitegravir/cobicistat, dolutegravir or bictegravir in combination with emtricitabine/tenofovir alafenamide or emtricitabine/tenofovir disoproxil fumarate between 10/2007 and 1/2020 at the Orlando Immunology Center were included. Unadjusted incidence rates (IRs) and incidence rate ratios (IRRs) were calculated for treatment-related discontinuations and AEs associated with the initial INSTI in the first year following initiation. RESULTS: Of 331 enrolled, 26 (8%) initiated raltegravir, 151 (46%) initiated elvitegravir/cobicistat, 74 (22%) initiated dolutegravir and 80 (24%) initiated bictegravir. Within the first year, treatment-related discontinuations occurred in 3 on elvitegravir/cobicistat (IR 0.02 per person-years (PPY)) and 5 on dolutegravir (IR 0.08 PPY); no treatment-related discontinuations occurred among those initiating raltegravir or bictegravir. Eleven treatment-related AEs occurred in 7 on raltegravir (IR 0.46 PPY), 100 treatment-related AEs occurred in 63 on elvitegravir/cobicistat (IR 0.72 PPY), 66 treatment-related AEs occurred in 37 on dolutegravir (IR 0.97 PPY) and 65 treatment-related AEs occurred in 34 on bictegravir (IR 0.88 PPY). Unadjusted IRRs did not reveal any significant difference between INSTIs in terms of early treatment-related discontinuations or AEs. CONCLUSIONS: In our cohort, treatment-related AEs occurred in 43% initiating INSTIs but were responsible for early discontinuation in only 2% with no treatment-related discontinuations observed among those initiating RAL or BIC.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Inhibidores de Integrasa VIH , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/diagnóstico , Raltegravir Potásico/efectos adversos , Inhibidores de Integrasa/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Piridonas/efectos adversos , Fármacos Anti-VIH/efectos adversos , Emtricitabina/uso terapéutico , Cobicistat/efectos adversos , Inhibidores de Integrasa VIH/efectos adversos
19.
AIDS Res Ther ; 20(1): 15, 2023 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-36915103

RESUMEN

BACKGROUND: Following reports of anti-retroviral therapy (ART) experienced Ugandan people living with HIV (PLHIV) presenting with diabetic ketoacidosis weeks to months following a switch to dolutegravir (DTG), the Uganda Ministry of Health recommended withholding DTG in both ART naïve and experienced PLHIV with diabetes mellitus (T2DM), as well as 3-monthly blood glucose monitoring for patients with T2DM risk factors. We sought to determine if the risk of T2DM is indeed heightened in nondiabetic ART naïve Ugandan PLHIV over the first 48 weeks on DTG. METHODS: Between January and October 2021, 243 PLHIV without T2DM were initiated on DTG based ART for 48 weeks. Two-hour oral glucose tolerance tests (2-h OGTT) were performed at baseline, 12, and 36 weeks; fasting blood glucose (FBG) was measured at 24 and 48 weeks. The primary outcome was the incidence of T2DM. Secondary outcomes included: incidence of pre-Diabetes Mellitus (pre-DM), median change in FBG from baseline to week 48 and 2-h blood glucose (2hBG) from baseline to week 36. Linear regression models were used to determine adjusted differences in FBG and 2hBG from baseline to weeks 48 and 36 respectively. RESULTS: The incidence of T2DM was 4 cases per 1000 PY (1/243) and pre-DM, 240 cases per 1000 person years (PY) (54/243). There was a significant increase in FBG from baseline to week 48 [median change from baseline (FBG): 3.6 mg/dl, interquartile range (IQR): - 3.6, 7.2, p-value (p) = 0.005] and significant reduction in 2hBG (2hBG: - 7.26 mg/dl, IQR: - 21.6, 14.4, p = 0.024) at week 36. A high CD4 count and increased waist circumference were associated with 2hBG increase at week 36. CONCLUSION: We demonstrated a low incidence of T2DM in Ugandan ART-naïve patients receiving DTG. We also demonstrated that longitudinal changes in BG were independent of conventional risk factors of T2DM in the first 48 weeks of therapy. Restricting the use of dolutegravir in Ugandan ART naïve patients perceived to be high risk for diabetes mellitus may be unwarranted.


Asunto(s)
Diabetes Mellitus Tipo 2 , Infecciones por VIH , Inhibidores de Integrasa VIH , Humanos , Glucemia , Automonitorización de la Glucosa Sanguínea , Diabetes Mellitus Tipo 2/inducido químicamente , Diabetes Mellitus Tipo 2/epidemiología , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Incidencia , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de Integrasa VIH/uso terapéutico
20.
AIDS Res Hum Retroviruses ; 39(6): 263-284, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36352827

RESUMEN

Integrase strand transfer inhibitors (INSTIs), including raltegravir (RAL), dolutegravir (DTG), elvitegravir (EVG), bictegravir (BIC), and cabotegravir (CAB), are increasingly used, given excellent data on their efficacy, effectiveness, and tolerability profile in adults, while data in children are accumulating. To review the most recent evidence on the efficacy, effectiveness, safety, and resistance of INSTIs in children, a quick narrative review of the available literature data was performed using the MEDLINE/PubMed and Scopus databases, including only English-language studies, published between 2009 and 2022. Six studies (259 children) on RAL use, 17 studies (3,448 children) on DTG, 2 studies (73 children) on EVG, and 1 study (102 children) on BIC were retrieved. Results on efficacy and effectiveness were close to those reported in adult studies, suggesting similarities between children and adult population. Resistance to RAL was detected in four studies, ranging between 5.0% to 35.3% of participants. In four studies resistance to DTG occurred in 12.4% to 22% of children. Adverse events to RAL have been uncommon reported. In studies on EVG, 8% to 74% of children developed uveitis, nausea, or abdominal pain. In DTG studies, the proportion of weight gain ranged from 10% to 87%, and neuropsychiatric effects ranged 1% to 16% of participants. One BIC study reported adverse events >10% of participants. The evidence supports high efficacy and low toxicity of INSTIs in pediatric and adolescent populations.


Asunto(s)
Infecciones por VIH , Inhibidores de Integrasa VIH , Integrasa de VIH , VIH-1 , Adulto , Niño , Humanos , Adolescente , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/efectos adversos , Raltegravir Potásico/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Oxazinas/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Farmacorresistencia Viral , Integrasas/farmacología , Integrasas/uso terapéutico
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