RÉSUMÉ
Integrase strand transfer inhibitors (INSTI) are associated with neuropsychiatric adverse events (NPAEs). The aim of this study was to evaluate improvements in NPAEs after switching an INSTI-based regimen to darunavir/cobicistat (DRV/c) or doravirine (DOR). Methods: A prospective cohort study was conducted to evaluate the reversibility of NPAEs via the Patient Health Questionnaire (PHQ-9), the Insomnia Severity Index (ISI), and the Hospital Anxiety and Depression Scale (HADS-A and D) in patients who started antiretroviral therapy with dolutegravir (DTG) or bictegravir (BIC). These patients were switched to DRV/c or DOR. Scales were compared at the moment of the switch and 12 weeks later. Results: We included 1153 treatment-naïve men, 676 (58.7%) with BIC and 477 (41.3%) with DTG. A total of 32 (2.7%) experienced NPAEs that led to discontinuation. Insomnia was found in 20 patients; depression via PHQ-9 in 21 patients, via HADS-D in 5 patients, and anxiety via HADS-A in 12 patients. All of them were evaluated by a psychiatrist at the moment of the symptoms; 7 (21.8%) started psychotropic drugs. After 12 weeks of follow-up, PHQ-9, ISI, HADS-A, and HADS-D decreased, with a p-value ≤ 0.05. Conclusions: NPAEs seem to improve after switching to a DRV/c- or DOR-based regimen after the first 4 and 12 weeks.
Sujet(s)
Cobicistat , Darunavir , Infections à VIH , Pyridones , Humains , Mâle , Darunavir/effets indésirables , Darunavir/usage thérapeutique , Darunavir/administration et posologie , Infections à VIH/traitement médicamenteux , Adulte d'âge moyen , Études prospectives , Adulte , Cobicistat/effets indésirables , Cobicistat/usage thérapeutique , Cobicistat/administration et posologie , Pyridones/effets indésirables , Inhibiteurs de l'intégrase du VIH/effets indésirables , Inhibiteurs de l'intégrase du VIH/usage thérapeutique , Inhibiteurs de l'intégrase du VIH/administration et posologie , Composés hétérocycliques 3 noyaux/effets indésirables , Composés hétérocycliques 3 noyaux/usage thérapeutique , Composés hétérocycliques 3 noyaux/administration et posologie , Troubles de l'endormissement et du maintien du sommeil/induit chimiquement , Substitution de médicament/effets indésirables , Agents antiVIH/effets indésirables , Agents antiVIH/usage thérapeutique , Pipérazines/effets indésirables , TriazolesRÉSUMÉ
Real-life data on doravirine (DOR) in different drug combinations are limited. We evaluated the effectiveness of DOR plus two nucleos(t)ide reverse transcriptase inhibitors (NRTI), mainly abacavir/lamivudine, and dual therapies in people with HIV (PWH), mostly virologically suppressed. Ambispective observational study that enrolled adults PWH who initiated a DOR-based regimen from September 2020 to February 2022 at a referral center in Spain. Participants were grouped as follows: A, received DOR plus two NRTI; B, dual therapy (DT) with DOR plus dolutegravir (DTG) or darunavir/cobicistat (DRVc); C, DOR plus ≥two antiretroviral drugs. The primary endpoints were treatment effectiveness at week 48 by intention-to-treat (ITT) and per-protocol analysis (OT). A cohort of 187 participants, 91% virologically suppressed, were analyzed after a median follow-up of 112 weeks (80-136). Group A received DOR plus abacavir/lamivudine (ABV/3TC) (n = 109) or tenofovir/emtricitabine (TFV/3TC) (n = 45). At week 48, the effectiveness of DOR plus ABV/3TC by ITT was 90.8% (CI95, 88.0-93.6), better than with TFV/FTC [73.3% (66.7-79.9); P = 0.003]. Only one virologic failure was observed. Mild adverse effects were the cause of treatment discontinuation in 7.8%, followed by switching to a single-tablet regimen. In group B, the effectiveness by ITT was 92.9% (CI95, 88.0-97.8) at week 48. No adverse effects or virologic failure were registered in this group. DOR plus two NRTI or DT have long-term effectiveness and safety as a switching option for PWH, mostly virologically suppressed. The DOR plus ABV/3TC combination has shown even better effectiveness than TFV/FTC.IMPORTANCEDOR-based regimens have shown long-term effectiveness and safety in PWH, mostly virologically suppressed. The combination of DOR plus ABV/3TC has shown even better safety and effectiveness than TFV/FTC. DOR plus two NRTI offers cost benefits compared to other regimens.
Sujet(s)
Agents antiVIH , Infections à VIH , Lamivudine , Pyridones , Triazoles , Humains , Infections à VIH/traitement médicamenteux , Infections à VIH/virologie , Femelle , Pyridones/effets indésirables , Mâle , Adulte , Adulte d'âge moyen , Lamivudine/usage thérapeutique , Lamivudine/effets indésirables , Lamivudine/administration et posologie , Agents antiVIH/usage thérapeutique , Agents antiVIH/effets indésirables , Agents antiVIH/administration et posologie , Triazoles/usage thérapeutique , Triazoles/effets indésirables , Triazoles/administration et posologie , Didéoxynucléosides/usage thérapeutique , Didéoxynucléosides/effets indésirables , Didéoxynucléosides/administration et posologie , Association médicamenteuse , Composés hétérocycliques 3 noyaux/usage thérapeutique , Composés hétérocycliques 3 noyaux/effets indésirables , Composés hétérocycliques 3 noyaux/administration et posologie , Oxazines/usage thérapeutique , Inhibiteurs de la transcriptase inverse/usage thérapeutique , Inhibiteurs de la transcriptase inverse/effets indésirables , Espagne , Résultat thérapeutique , Cobicistat/usage thérapeutique , Cobicistat/effets indésirables , Cobicistat/administration et posologie , Darunavir/usage thérapeutique , Darunavir/effets indésirables , Pipérazines/effets indésirables , Charge virale/effets des médicaments et des substances chimiques , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/génétique , Cyclopropanes , Didéoxyadénosine/analogues et dérivésSujet(s)
Cobicistat , Dexaméthasone , Manie , Humains , Femelle , Dexaméthasone/administration et posologie , Dexaméthasone/effets indésirables , Adulte d'âge moyen , Manie/induit chimiquement , Cobicistat/administration et posologie , Cobicistat/effets indésirables , Association de médicaments , Trouble bipolaire/traitement médicamenteux , Trouble bipolaire/induit chimiquement , Glucocorticoïdes/administration et posologie , Glucocorticoïdes/effets indésirables , Interactions médicamenteusesRÉSUMÉ
Lactic acidosis is a rare but serious side effect in individuals receiving nucleoside reverse transcriptase inhibitors. An underweight woman with HIV was admitted to our hospital because of nausea and diffuse myalgia. Her antiretroviral regimen had been changed to tenofovir disoproxil fumarate (TDF)/emtricitabine and darunavir/cobicistat 3 months prior, after which her renal function had gradually declined. After admission, she was diagnosed with lactic acidosis, and a liver biopsy suggested mitochondrial damage. Her plasma tenofovir levels were elevated at the onset of lactic acidosis. We hypothesise that the patient's low body weight, combined with the addition of cobicistat, induced renal dysfunction and led to elevated plasma tenofovir concentrations, resulting in mitochondrial damage and lactic acidosis. Careful monitoring of renal function and lactic acidosis is required during use of TDF-containing regimens for underweight HIV patients, particularly when combined with cobicistat.
Sujet(s)
Acidose lactique , Agents antiVIH , Infections à VIH , Femelle , Humains , Acidose lactique/induit chimiquement , Acidose lactique/traitement médicamenteux , Adénine/effets indésirables , Agents antiVIH/effets indésirables , Cobicistat/effets indésirables , Association médicamenteuse , Infections à VIH/complications , Infections à VIH/traitement médicamenteux , Ténofovir/effets indésirables , Maigreur/induit chimiquement , Maigreur/traitement médicamenteux , Résultat thérapeutique , Adulte d'âge moyenRÉSUMÉ
INTRODUCTION: Darunavir (DRV)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir alafenamide (TAF) is the only protease inhibitor-based single-tablet regimen (STR) approved for the treatment of HIV infection of adults and pediatric patients weighing at least 40 kg. DRV/COBI/FTC/TAF has demonstrated to be an effective regimen, to have a high genetic barrier to resistance, and to be well tolerated. AREAS COVERED: The authors summarize the chemistry and pharmacology of DRV, COBI, FTC, and TAF and discuss trials conducted on antiretroviral therapy (ART)-naïve and -experienced people living with HIV designed to evaluate safety, tolerability, and efficacy of the STR. This work also reports studies comparing DRV/COBI/FTC/TAF with competitive agents in real-world settings. EXPERT OPINION: Despite the availability of newer antiretroviral drugs and strategies in the management of HIV infection, including long-acting therapies, DRV/COBI/FTC/TAF is still considered an alternative regimen for the treatment of ART-naïve adults. DRV/COBI/FTC/TAF is an effective, well-tolerated, and safe antiretroviral regimen and represents a valid option for people who need to switch therapy due to tolerability issues, such as the onset of neuropsychiatric effects related to integrase strand transfer inhibitors, or virological failure.
Sujet(s)
Agents antiVIH , Infections à VIH , VIH-1 (Virus de l'Immunodéficience Humaine de type 1) , Humains , Adulte , Enfant , Infections à VIH/traitement médicamenteux , Emtricitabine/effets indésirables , Ténofovir , Agents antiVIH/effets indésirables , Darunavir/effets indésirables , Cobicistat/effets indésirables , Adénine , Association médicamenteuse , Comprimés/usage thérapeutiqueRÉSUMÉ
OBJECTIVE: To compare lipid profile changes and cardiovascular events among HIV naïve and experienced patients from a real-world cohort treated with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate or dolutegravir/abacavir/lamivudine. METHOD: A retrospective cohort study in HIV naïve and experienced people at a reference hospital in Spain was done. During the follow-up (March 2015-June 2019), patients were treated with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate or dolutegravir/abacavir/lamivudine. Epidemiological, clinical and immunovirological variables were recorded. A statistical analysis of the lipid profile at baseline, 48 and 120 weeks after initiating the study therapy, cardiovascular events (myocardial infarction, heart failure, cerebrovascular accident, deep venous thrombosis, myocardiopathy, non-ST- segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction) and cardiovascular risks factors was performed. Data were analysed in naïve and experienced patients from each of the study treatments. The data was obtained from the medical history. The statistical analysis was performed with SPSS v.24 software. RESULTS: A total of 266 and 191 patients receiving treatment with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate and dolutegravir/abacavir/lamivudine were included in the study, respectively. After 120 weeks of treatment, a worsening of the lipid profile was found in the elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate group, both in naïve and experienced patients, whereas not so conspicuously observed in the dolutegravir/abacavir/lamivudine group. Statistically significant differences between both groups were found in experienced patients favoring dolutegravir/abacavir/lamivudine; in total cholesterol (204.1 ± 38.2 vs. 187.3 ± 29.4, p < 0.001) and LDL-C (126.1 ± 31.9 vs. 113.5 ± 28.5, p = 0.001) at week 48, and in total cholesterol (201.1 ± 33.4 vs. 188.7 ± 33.9, p = 0.013) and HDL-C (54.2 ± 15.6 vs. 48.3 ± 14.3, p = 0.01) at week 120. No significant differences in cardiovascular events were found, neither in naïve nor in experienced patients. CONCLUSIONS: The lipid profile among elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate group worsened throughout the follow-up, both in naïve and experienced patients, not so remarkable in the dolutegravir/abacavir/lamivudine group. Both regimens were well tolerated, with similar rates of cardiovascular events.
Sujet(s)
Agents antiVIH , Infections à VIH , Infarctus du myocarde , Humains , Lamivudine , Emtricitabine/effets indésirables , Études rétrospectives , Adénine , Infections à VIH/traitement médicamenteux , Agents antiVIH/usage thérapeutique , Cobicistat/effets indésirables , Lipides/usage thérapeutique , Cholestérol/usage thérapeutique , Infarctus du myocarde/induit chimiquement , Infarctus du myocarde/traitement médicamenteux , Fumarates/usage thérapeutiqueRÉSUMÉ
OBJECTIVE: To compare lipid profile changes and cardiovascular events among HIV naïve and experienced patients from a real-world cohort treated with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate or dolutegravir/abacavir/lamivudine. METHOD: A retrospective cohort study in HIV naïve and experienced people at a reference hospital in Spain was done. During the follow-up (March 2015-June 2019), patients were treated with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate or dolutegravir/abacavir/lamivudine. Epidemiological, clinical, and immunovirological variables were recorded. A statistical analysis of the lipid profile at baseline, 48, and 120â¯weeks after initiating the study therapy, cardiovascular events (myocardial infarction, heart failure, cerebrovascular accident, deep venous thrombosis, myocardiopathy, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction), and cardiovascular risks factors was performed. Data were analysed in naïve and experienced patients from each of the study treatments. The data were obtained from the medical history. The statistical analysis was performed with SPSS v. 24 software. RESULTS: A total of 266 and 191 patients receiving treatment with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate and dolutegravir/abacavir/lamivudine were included in the study, respectively. After 120â¯weeks of treatment, a worsening of the lipid profile was found in the elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate group, both in naïve and experienced patients, whereas not so conspicuously observed in the dolutegravir/abacavir/lamivudine group. Statistically significant differences between both groups were found in experienced patients favouring dolutegravir/abacavir/lamivudine; in total cholesterol (204.1±38.2 vs. 187.3±29.4, Pâ¯<â¯.001) and LDL-C (126.1±31.9 vs. 113.5±28.5, Pâ¯=â¯.001) at week 48, and in total cholesterol (201.1±33.4 vs. 188.7±33.9, Pâ¯=â¯.013) and HDL-C (54.2±15.6 vs. 48.3±14.3, Pâ¯=â¯.01) at week 120. No significant differences in cardiovascular events were found, neither in naïve nor in experienced patients. CONCLUSIONS: The lipid profile among elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate group worsened throughout the follow-up, both in naïve and experienced patients, not so remarkable in the dolutegravir/abacavir/lamivudine group. Both regimens were well tolerated, with similar rates of cardiovascular events.
Sujet(s)
Agents antiVIH , Infections à VIH , Infarctus du myocarde , Humains , Lamivudine , Emtricitabine/effets indésirables , Études rétrospectives , Adénine , Infections à VIH/traitement médicamenteux , Agents antiVIH/usage thérapeutique , Cobicistat/effets indésirables , Lipides/usage thérapeutique , Cholestérol/usage thérapeutique , Infarctus du myocarde/induit chimiquement , Infarctus du myocarde/traitement médicamenteux , Fumarates/usage thérapeutiqueRÉSUMÉ
BACKGROUND: Solid-organ transplantation due to end-stage organ disease is increasingly performed in people living with HIV. Despite improved transplant outcomes, management of these patients remains challenging due to higher risk for allograft rejection, infection and drug-drug interactions (DDIs). Complex regimens for multi-drug resistant HIV-viruses may cause DDIs particularly if the regimen contains drugs such as ritonavir or cobicistat. CASE PRESENTATION: Here we report on a case of an HIV-infected renal transplant recipient on long-term immunosuppressive therapy with mycophenolate mofetil and tacrolimus dosed at 0.5 mg every 11 days due to the co-administration of a darunavir/ritonavir containing antiretroviral regimen. In the presented case the pharmacokinetic booster was switched from ritonavir to cobicistat for treatment simplification. A close monitoring of tacrolimus drug levels was performed in order to prevent possible sub- or supratherapeutic tacrolimus trough levels. A progressive decrease in tacrolimus concentrations was observed after switch requiring shortening of tacrolimus dosing interval. This observation was unexpected considering that cobicistat is devoid of inducing properties. CONCLUSIONS: This case highlights the fact that the pharmacokinetic boosters ritonavir and cobicistat are not fully interchangeable. Therapeutic drug monitoring of tacrolimus is warranted to maintain levels within the therapeutic range.
Sujet(s)
Agents antiVIH , Infections à VIH , Transplantation rénale , Humains , Cobicistat/usage thérapeutique , Cobicistat/effets indésirables , Ritonavir/usage thérapeutique , Tacrolimus/effets indésirables , Transplantation rénale/effets indésirables , Infections à VIH/traitement médicamenteux , Agents antiVIH/usage thérapeutique , Antirétroviraux/usage thérapeutiqueRÉSUMÉ
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.
Sujet(s)
Agents antiVIH , Infections à VIH , Inhibiteurs de l'intégrase du VIH , Humains , Infections à VIH/traitement médicamenteux , Infections à VIH/diagnostic , Raltégravir de potassium/effets indésirables , Inhibiteurs de l'intégrase/usage thérapeutique , Composés hétérocycliques 3 noyaux/effets indésirables , Pyridones/effets indésirables , Agents antiVIH/effets indésirables , Emtricitabine/usage thérapeutique , Cobicistat/effets indésirables , Inhibiteurs de l'intégrase du VIH/effets indésirablesRÉSUMÉ
OBJECTIVE: Our objective was to evaluate the prevalence of pre-existing neurological and/or psychiatric comorbidities (NPCs) and efficacy/safety outcomes for participants with versus without baseline NPCs in AMBER and EMERALD. METHODS: AMBER (treatment-naïve population) and EMERALD (virologically suppressed population) were phase III randomized studies of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg. The primary objective of this post hoc analysis was to assess virological response (HIV-1 RNA <50 copies/mL) at week 48 by intent-to-treat US Food and Drug Administration snapshot analysis comparing participants with and without baseline NPCs. RESULTS: Among participants in AMBER, 88/362 (24%) in the D/C/F/TAF arm and 99/363 (27%) in the control arm had baseline NPCs; in EMERALD, 294/763 (39%; D/C/F/TAF) and 166/378 (44%; control) participants had baseline NPCs. At baseline, psychiatric NPCs were more common than neurological NPCs in both studies; the most common of each type were depression and headache, respectively. High virological response rates were achieved with D/C/F/TAF across studies regardless of baseline NPCs at weeks 48 (range 86%-95%) and 96 (range 80%-91%). No participants in either study with a baseline NPC prematurely discontinued because of a study drug-related neurological or psychiatric adverse event. CONCLUSION: D/C/F/TAF may be a suitable treatment option for individuals with HIV-1 and NPCs.
Sujet(s)
Agents antiVIH , Infections à VIH , Humains , Agents antiVIH/usage thérapeutique , Cobicistat/effets indésirables , Darunavir/usage thérapeutique , Association médicamenteuse , Emtricitabine/usage thérapeutique , Infections à VIH/traitement médicamenteuxRÉSUMÉ
OBJECTIVES: We assessed the virologic efficacy of switching to co-formulated elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate (E/C/F/TDF) in patients with controlled HIV infection. METHODS: We conducted a retrospective multicenter observational cohort study including adult patients with controlled HIV-1 infection on any stable antiretroviral (ART) regimen, who switched to E/C/F/TDF. Success was measured by the proportion of patients with plasma viral load < 50 copies/ml at W48 using the FDA snapshot algorithm. We also assessed risk factors associated with virological failure (VF). RESULTS: 382 patients with HIV RNA < 50 copies/mL who switched to E/C/F/TDF were included in the study. Most patients (69.9%) were male, with median age 44 years (IQR 38-51), who had been on ART for a median of 7 years (IQR 4-13). Median CD4 count was 614/mm3 and 24.6% of the patients had a history of previous virological failure. The reasons for switching were simplification (67.0%) and tolerance issues (22.0%). At week 48, 314 (82.0% [95% CI 78.4-86.0]) patients had HIV RNA < 50 copies/mL, 13 (3.5% [95% CI 3.64-8.41]) experienced virological failure. Genotype at failure was available in 6/13 patients with detection of resistance-associated mutations to integrase inhibitors and NRTIs in 5/6 (83.3%) patients. We found no predictive factor associated with virological failure except for a borderline significance with the duration of viral suppression before the switch. Tolerability of E/C/F/TDF was good with 23/382 (6.0%) patients experiencing mild adverse reactions. CONCLUSION: In our cohort, switching well-suppressed patients to E/C/F/TDF resulted in few virologic failures and was well tolerated. However, resistance to integrase inhibitors emerged in patients with virological failure.
Sujet(s)
Agents antiVIH , Infections à VIH , Adulte , Humains , Mâle , Femelle , Infections à VIH/traitement médicamenteux , Ténofovir/usage thérapeutique , Ténofovir/effets indésirables , Emtricitabine/usage thérapeutique , Emtricitabine/effets indésirables , Cobicistat/usage thérapeutique , Cobicistat/effets indésirables , Agents antiVIH/effets indésirables , Inhibiteurs de l'intégrase/usage thérapeutique , Études de cohortes , ARNRÉSUMÉ
BACKGROUND: Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as compared with other ART regimens commonly used in the United States and Europe, particularly when initiated before conception, are limited. METHODS: We conducted a study involving pregnancies in persons with HIV-1 infection in the Pediatric HIV/AIDS Cohort Study whose initial ART in pregnancy included dolutegravir, atazanavir-ritonavir, darunavir-ritonavir, oral rilpivirine, raltegravir, or elvitegravir-cobicistat. Viral suppression at delivery and the risks of infants being born preterm, having low birth weight, and being small for gestational age were compared between each non-dolutegravir-based ART regimen and dolutegravir-based ART. Supplementary analyses that included participants in the Swiss Mother and Child HIV Cohort Study were conducted to improve the precision of our results. RESULTS: Of the pregnancies in the study, 120 were in participants who received dolutegravir, 464 in those who received atazanavir-ritonavir, 185 in those who received darunavir-ritonavir, 243 in those who received rilpivirine, 86 in those who received raltegravir, and 159 in those who received elvitegravir-cobicistat. The median age at conception was 29 years; 51% of the pregnancies were in participants who started ART before conception. Viral suppression was present at delivery in 96.7% of the pregnancies in participants who received dolutegravir; corresponding percentages were 84.0% for atazanavir-ritonavir, 89.2% for raltegravir, and 89.8% for elvitegravir-cobicistat (adjusted risk differences vs. dolutegravir, -13.0 percentage points [95% confidence interval {CI}, -17.0 to -6.1], -17.0 percentage points [95% CI, -27.0 to -2.4], and -7.0 percentage points [95% CI, -13.3 to -0.0], respectively). The observed risks of preterm birth were 13.6 to 17.6%. Adjusted risks of infants being born preterm, having low birth weight, or being small for gestational age did not differ substantially between non-dolutegravir-based ART and dolutegravir. Results of supplementary analyses were similar. CONCLUSIONS: Atazanavir-ritonavir and raltegravir were associated with less frequent viral suppression at delivery than dolutegravir. No clear differences in adverse birth outcomes were observed with dolutegravir-based ART as compared with non-dolutegravir-based ART, although samples were small. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).
Sujet(s)
Agents antiVIH , Infections à VIH , Inhibiteurs de protéase du VIH , VIH-1 (Virus de l'Immunodéficience Humaine de type 1) , Composés hétérocycliques 3 noyaux , Oxazines , Pipérazines , Naissance prématurée , Pyridones , Adulte , Agents antiVIH/effets indésirables , Agents antiVIH/usage thérapeutique , Sulfate d'atazanavir/effets indésirables , Sulfate d'atazanavir/usage thérapeutique , Cobicistat/effets indésirables , Cobicistat/usage thérapeutique , Études de cohortes , Darunavir/effets indésirables , Darunavir/usage thérapeutique , Femelle , Infections à VIH/traitement médicamenteux , Inhibiteurs de protéase du VIH/effets indésirables , Inhibiteurs de protéase du VIH/usage thérapeutique , Composés hétérocycliques 3 noyaux/effets indésirables , Composés hétérocycliques 3 noyaux/usage thérapeutique , Humains , Nouveau-né , Oxazines/effets indésirables , Oxazines/usage thérapeutique , Pipérazines/effets indésirables , Pipérazines/usage thérapeutique , Grossesse , Naissance prématurée/induit chimiquement , Pyridones/effets indésirables , Pyridones/usage thérapeutique , Quinolinone/effets indésirables , Quinolinone/usage thérapeutique , Raltégravir de potassium/effets indésirables , Raltégravir de potassium/usage thérapeutique , Rilpivirine/effets indésirables , Rilpivirine/usage thérapeutique , Ritonavir/effets indésirables , Ritonavir/usage thérapeutique , États-UnisRÉSUMÉ
A 53-year-old man presented with rhabdomyolysis and acute kidney injury. The symptoms were presumably caused by a drug-drug interaction between an antiretroviral drug combination and atorvastatin. As a booster, cobicistat can also increase the toxicity of statins via inhibition of the enzyme cytochrome p450 3A4 (CYP3A4). After stopping atorvastatin and after intravenous fluid therapy, the symptoms regressed completely.
Sujet(s)
Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase , Rhabdomyolyse , Mâle , Humains , Adulte d'âge moyen , Atorvastatine/effets indésirables , Cobicistat/effets indésirables , Cytochrome P-450 CYP3A , Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase/effets indésirables , Rhabdomyolyse/induit chimiquement , Interactions médicamenteuses , Association médicamenteuseRÉSUMÉ
Gastrointestinal intolerance has been associated with ritonavir-boosted protease inhibitors. This post hoc analysis evaluated gastrointestinal adverse events of interest (AEOIs; diarrhea, nausea, abdominal discomfort, flatulence [MedDRAv21]) through Wk96 among patients enrolled in the phase 3 AMBER (treatment-naïve) and EMERALD (virologically suppressed) studies of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10â mg. 362 and 763 patients initiated D/C/F/TAF in AMBER and EMERALD, respectively. All D/C/F/TAF-related gastrointestinal AEOIs were grade 1/2 in severity; none were serious. Across studies, incidence of D/C/F/TAF-related diarrhea and nausea were each ≤5% in Wk1 (≤1% post-Wk2); prevalence of each decreased to <5% post-Wk2. In each study, there was 1 case of D/C/F/TAF-related abdominal discomfort during Wk1 and none thereafter. Incidence of D/C/F/TAF-related flatulence was <1% throughout. Median duration of D/C/F/TAF-related gastrointestinal AEOIs was 16.5 (AMBER) and 8.5 (EMERALD) days. In conclusion, in treatment-naïve and virologically suppressed patients, incidences and prevalences of D/C/F/TAF-related gastrointestinal AEOIs were low and tended to present early.
Sujet(s)
Agents antiVIH , Infections à VIH , VIH-1 (Virus de l'Immunodéficience Humaine de type 1) , Alanine , Agents antiVIH/effets indésirables , Cobicistat/effets indésirables , Darunavir/effets indésirables , Diarrhée/induit chimiquement , Diarrhée/épidémiologie , Emtricitabine/effets indésirables , Météorisme/induit chimiquement , Météorisme/traitement médicamenteux , Infections à VIH/traitement médicamenteux , Humains , Incidence , Nausée/induit chimiquement , Nausée/traitement médicamenteux , Ténofovir/analogues et dérivésRÉSUMÉ
To evaluate the reasons for changing to monotherapy with protease inhibitors, together with the proportion and reasons for the interruption to treatment, in patients who have been treated at some point with cobicistat-boosted darunavir (DRV/c). Outpatients in a tertiary hospital. Observational retrospective study to evaluate monotherapy with DRV/c (800 mg/150 mg) in adult patients with human immunodeficiency virus infection, from December 2014 to July 2022. Demographic variables, viral load, cluster of differentiation 4 lymphocyte lymphocyte count, and antiretroviral therapy were assessed. 42 patients were included. 36% of the patients were undergoing monotherapy at the time of the analysis. The main reason for discontinuation was poor adherence. At time of analysis, 80% of the patients in monotherapy had an undetectable viral load. Antiretroviral therapy recommendations advise against exposing the patient to functional monotherapy with a single drug due to the high risk of virological failure and the onset of resistance to a single drug. Following the analysis of the results, DRV/c in monotherapy is not an effective strategy in the medium and long term due to factors such as lack of adherence or virological failure, although it can be maintained in specific circumstances. Therefore, patients undergoing monotherapy require close monitoring.
Sujet(s)
Agents antiVIH , Infections à VIH , Inhibiteurs de protéase du VIH , VIH-1 (Virus de l'Immunodéficience Humaine de type 1) , Adulte , Humains , Darunavir/usage thérapeutique , Darunavir/effets indésirables , Inhibiteurs de protéase du VIH/usage thérapeutique , Inhibiteurs de protéase du VIH/effets indésirables , Études rétrospectives , Ritonavir/usage thérapeutique , Cobicistat/usage thérapeutique , Cobicistat/effets indésirables , Infections à VIH/traitement médicamenteux , Charge viraleRÉSUMÉ
Ergotism is an uncommon condition that affects patients with exposure to ergot alkaloids causing ischemia of extremities. We report the case of lower extremities ischemia caused by ergot toxicity in a human immunodeficiency virus (HIV) positive individual due to the interaction between ergot alkaloid and Cobicistat. In addition, we present a brief review of medical, and pharmacological aspects of this condition. To our knowledge, this is the second reported case describing this interaction.
Sujet(s)
Agonistes des récepteurs alpha-1 adrénergiques/effets indésirables , Agents antiVIH/effets indésirables , Cobicistat/effets indésirables , Ergotamine/effets indésirables , Ergotisme/diagnostic , Infections à VIH/traitement médicamenteux , Ischémie/induit chimiquement , Membre inférieur/vascularisation , Interactions médicamenteuses , Ergotisme/étiologie , Infections à VIH/complications , Humains , Mâle , Migraines/traitement médicamenteux , Jeune adulteRÉSUMÉ
BACKGROUND: There are significant drug-drug interactions between human immunodeficiency virus antiretroviral therapy and intranasal steroids, leading to high serum concentrations of iatrogenic steroids and subsequently Cushing's syndrome. METHOD: All articles in the literature on cases of intranasal steroid and antiretroviral therapy interactions were reviewed. Full-length manuscripts were analysed and the relevant data were extracted. RESULTS: A literature search and further cross-referencing yielded a total of seven reports on drug-drug interactions of intranasal corticosteroids and human immunodeficiency virus protease inhibitors, published between 1999 and 2019. CONCLUSION: The use of potent steroids metabolised via CYP3A4, such as fluticasone and budesonide, are not recommended for patients taking ritonavir or cobicistat. Mometasone should be used cautiously with ritonavir because of pharmacokinetic similarities to fluticasone. There was a delayed onset of symptoms in many cases, most likely due to the relatively lower systemic bioavailability of intranasal fluticasone.
Sujet(s)
Hormones corticosurrénaliennes/effets indésirables , Syndrome de Cushing/induit chimiquement , Infections à VIH/traitement médicamenteux , Inhibiteurs de protéase du VIH/effets indésirables , VIH (Virus de l'Immunodéficience Humaine) , Administration par voie nasale , Hormones corticosurrénaliennes/administration et posologie , Adulte , Cobicistat/administration et posologie , Cobicistat/effets indésirables , Interactions médicamenteuses , Fluticasone/administration et posologie , Fluticasone/effets indésirables , Inhibiteurs de protéase du VIH/administration et posologie , Humains , Mâle , Ritonavir/administration et posologie , Ritonavir/effets indésirablesRÉSUMÉ
The single-tablet regimen darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg has undergone phase III studies AMBER (NCT02431247) and EMERALD (NCT02269917) in HIV-infected patients. An existing population pharmacokinetic (PopPK) model for cobicistat-boosted darunavir (DRV) was updated to describe DRV PK in AMBER and EMERALD. For TAF, a PopPK model was developed using richly sampled phase I/II data and updated with sparsely sampled AMBER data. Individual exposure metrics for DRV and TAF in patients receiving D/C/F/TAF were derived (AMBER, n=356; EMERALD, n=750). The DRV PopPK model is a two-compartment model with sequential zero-order, first-order input. TAF PK is described by a one-compartment model with dual parallel input for absorption (slow and fast pathway). DRV covariates were α1-acid-glycoprotein and body weight. TAF covariates were lean body weight and α1-acid-glycoprotein. DRV and TAF PK were unaffected by age, race, or gender. Estimated DRV mean (SD) C0h and AUC24h, respectively, were 1899 (759) ng/mL and 87,909 (20,232) ng*h/mL in AMBER; 1813 (859) ng/mL and 85,972 (22,413) ng*h/mL in EMERALD. Estimated TAF mean (SD) AUC24h was 132 (41) ng*h/mL. These PK parameters were in line with historical data. No apparent relationships of DRV or TAF exposure with efficacy (virologic response) or safety (metabolic, cardiac, liver, gastrointestinal, skin, bone, renal, pancreas, lipid events) parameters were seen. Additionally, our findings demonstrate that in patients with low plasma concentrations, there is no risk of decreased virologic response or virologic rebound. This supports the use of a once-daily, single-tablet regimen of D/C/F/TAF 800/150/200/10 mg for the treatment of HIV-1-infected subjects.
Sujet(s)
Alanine/pharmacocinétique , Agents antiVIH/pharmacocinétique , Cobicistat/pharmacocinétique , Darunavir/pharmacocinétique , Emtricitabine/pharmacocinétique , Infections à VIH/traitement médicamenteux , Ténofovir/analogues et dérivés , Adulte , Sujet âgé , Alanine/administration et posologie , Alanine/effets indésirables , Agents antiVIH/administration et posologie , Agents antiVIH/effets indésirables , Variation intra-population , Cobicistat/administration et posologie , Cobicistat/effets indésirables , Darunavir/administration et posologie , Darunavir/effets indésirables , Association médicamenteuse , Emtricitabine/administration et posologie , Emtricitabine/effets indésirables , Femelle , Infections à VIH/sang , Infections à VIH/diagnostic , Infections à VIH/virologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/isolement et purification , Humains , Mâle , Adulte d'âge moyen , Comprimés , Ténofovir/administration et posologie , Ténofovir/effets indésirables , Ténofovir/pharmacocinétique , Résultat thérapeutique , Charge virale/effets des médicaments et des substances chimiques , Jeune adulteRÉSUMÉ
The aim of this study was to evaluate both positive outcomes, including reduction of respiratory support aid and duration of hospital stay, and negative ones, including mortality and a composite of invasive mechanical ventilation or death, in patients with coronavirus disease 2019 (COVID-19) pneumonia treated with or without oral darunavir/cobicistat (DRV/c, 800/150 mg/day) used in different treatment durations. The secondary objective was to evaluate the percentage of patients treated with DRV/c who were exposed to potentially severe drug-drug interactions (DDIs) and died during hospitalization. This observational retrospective study was conducted in consecutive patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy. Kaplan-Meier survival curves and Cox proportional hazards regression were used to compare patients receiving standard of care with or without DRV/c. Adjustment for key confounders was applied. Two hundred seventy-three patients (115 on DRV/c) were included, 75.8% males, mean age was 64.6 (±13.2) years. Clinical improvement was similar between the groups, depicted by respiratory aid switch (p > .05). The same was observed for duration of hospital stay [13.2 (±8.9) for DRV/c vs. 13.4 (±7.2) days for no-DRV/c, p = .9]. Patients on DRV/c had higher rates of mortality (25.2% vs. 10.1%, p < .0001. The rate of composite outcome of mechanical ventilation and death was higher in the DRV/c group (37.4% vs. 25.3%, p = .03). Multiple serious DDI associated with DRV/c were observed in the 19 patients who died. DRV/c should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials.
Sujet(s)
Agents antiVIH/usage thérapeutique , Traitements médicamenteux de la COVID-19 , Cobicistat/usage thérapeutique , Darunavir/usage thérapeutique , Adulte , Agents antiVIH/effets indésirables , COVID-19/mortalité , COVID-19/virologie , Cobicistat/effets indésirables , Darunavir/effets indésirables , Association médicamenteuse , Femelle , Humains , Mâle , Adulte d'âge moyen , Études rétrospectives , SARS-CoV-2/isolement et purificationRÉSUMÉ
Substantial anatomical and physiological changes occur during pregnancy and labor, which impact on drug absorption, distribution, metabolism, and elimination. Reduced maternal concentrations may have a clinically important impact on the efficacy of anti-infectives for mother, fetus, and neonate, with potential dosing implications. However, there is a paucity of pregnancy-specific data examining this. Existing data on the pharmacokinetics of anti-infectives in pregnancy are summarized and evaluated, with emphasis on agents that are used in treatment of HIV, tuberculosis, malaria, and common bacterial infections. Limitations and challenges in achieving ideal study designs in pregnant populations are highlighted, and key quality considerations for the generation of the highest quality evidence are outlined. PubMed was searched for each chosen anti-infective. Pharmacokinetic studies which either compared pharmacokinetics from pregnant women against nonpregnant controls, or which assessed concentrations against a known minimum inhibitory concentration were included. Two independent reviewers extracted data from each study and appraised them using the 24-point ClinPK Checklist. The main finding was that there is a lack of published data for anti-infectives in pregnancy, despite their clinical importance. Of the studies identified, only those investigating cobicistat-boosted antiretroviral regimens firmly concluded that these should not be used in pregnancy. Most studies concluded either that further research was needed, or that there were significant pharmacokinetic differences between pregnant and nonpregnant participants which had uncertain clinical significance. Challenges in applying existing quality grading systems to these studies were noted, suggesting a development of a refined system for appraisal of pharmacokinetic studies in "special populations" may be warranted.