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BMJ Paediatrics Open Jul 2022In 2020, Zimbabwe adopted the WHO's recommendation to use raltegravir (RAL) granule-based regimens for treatment of neonates identified with HIV at the time of birth...
BACKGROUND
In 2020, Zimbabwe adopted the WHO's recommendation to use raltegravir (RAL) granule-based regimens for treatment of neonates identified with HIV at the time of birth testing. This study explores the acceptability of RAL granules by caregivers and healthcare workers (HCWs).
METHODS
Interviews were conducted with 15 caregivers and 12 HCWs from 8 health facilities in Zimbabwe participating in the introductory pilot of RAL granules treatment for newborns. Eligible caregivers included those who had administered RAL to their infant and attended either 8th or 28th day of life appointments. Caregivers of neonates recently initiated on RAL were selected through convenience sampling. Eligible HCWs who provided RAL preparation, administration instructions and support to caregivers of neonates on RAL for at least 3 months were recruited from the same facilities as the caregivers. Interview transcripts were coded and thematically analysed.
RESULTS
Caregivers reported that their babies looked healthier after RAL initiation, with improved skin appearance and weight gain. Some caregivers wanted their child to remain on RAL beyond 28 days instead of switching regimens, as recommended by national guidelines. HCWs observed that RAL granules improved health outcomes compared with other regimens. HCWs reported challenges with caregivers understanding dosing instructions, measuring with a syringe, swirling and not shaking the medicine, discarding unused medication and following the changes in the dosing schedule and amount when RAL was initiated a few days after birth. HCWs stated that adequate counselling and repeat demonstrations were crucial to ensure that caregivers clearly understood RAL dosing and administration instructions. HCWs requested more standardised training targeting nurses with guidance on handling missed doses and clarification on mixing RAL granules with water and not breastmilk.
CONCLUSION
While feedback from caregivers and HCWs on RAL implementation was positive, barriers were also noted. Adequate training and sufficient instruction and support for caregivers would help to ensure that RAL granules are prepared, dosed and administered correctly.
Topics: Caregivers; Counseling; HIV Infections; Health Personnel; Humans; Infant; Infant, Newborn; Raltegravir Potassium
PubMed: 36053612
DOI: 10.1136/bmjpo-2022-001474 -
The New England Journal of Medicine Sep 2022Data on the effectiveness and safety of dolutegravir-based antiretroviral therapy (ART) for human immunodeficiency virus type 1 (HIV-1) infection in pregnancy as... (Comparative Study)
Comparative Study
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.).
Topics: Adult; Anti-HIV Agents; Atazanavir Sulfate; Cobicistat; Cohort Studies; Darunavir; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Infant, Newborn; Oxazines; Piperazines; Pregnancy; Premature Birth; Pyridones; Quinolones; Raltegravir Potassium; Rilpivirine; Ritonavir; United States
PubMed: 36053505
DOI: 10.1056/NEJMoa2200600 -
Journal of Acquired Immune Deficiency... Dec 2022Integrase inhibitors have been associated with excess gestational weight gain that may lead to adverse pregnancy outcomes (APOs). This post hoc analysis of NICHD P1081... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Integrase inhibitors have been associated with excess gestational weight gain that may lead to adverse pregnancy outcomes (APOs). This post hoc analysis of NICHD P1081 compared antepartum changes in weight and body mass index (BMI) in pregnant women initiating raltegravir- or efavirenz-based combined antiretroviral therapy (cART) and examined associations between rates of weight gain and APOs.
SETTING
NICHD P1081 enrolled antiretroviral-naive pregnant women living with HIV in the second and third trimester in Brazil, Tanzania, South Africa, Thailand, Argentina, and the United States.
METHODS
Two hundred eighty-one women enrolled between 20 and 31 gestational weeks were randomized to raltegravir- or efavirenz-based cART and followed for ≥4 weeks. A low rate of weight gain was defined as <0.18 kg/wk and high as >0.59 kg/wk. We compared weight gain and BMI increase between treatment arms using Kruskal-Wallis tests. Logistic regression was used to investigate the association between weight gain and APOs.
RESULTS
Raltegravir-based cART was associated with significantly higher antepartum weight gain (median 0.36 kg/wk versus 0.29 kg/wk, P = 0.01) and BMI increase (median 0.14 kg/m 2 /wk versus 0.11 kg/m 2 /wk, P = 0.01) compared with efavirenz-based treatment. Women on raltegravir had less low weight gain (18% versus 36%) and more high weight gain (21% versus 12%) ( P = 0.001). Women with low weight gain were more likely than those with normal weight gain to have small for gestational age infants or a composite of APOs.
CONCLUSIONS
A raltegravir-based antiretroviral regimen was associated with significantly higher antepartum rate of weight gain and BMI increase compared with efavirenz-based treatment in antiretroviral-naive pregnant women.
Topics: Female; Pregnancy; Humans; United States; Raltegravir Potassium; National Institute of Child Health and Human Development (U.S.); HIV Infections; Integrase Inhibitors; Weight Gain
PubMed: 36049477
DOI: 10.1097/QAI.0000000000003081 -
Journal of the International AIDS... Jun 2022ACTG A5288 was a strategy trial conducted in diverse populations from multiple continents of people living with HIV (PLWH) failing second-line protease inhibitor...
Third-line antiretroviral therapy, including raltegravir (RAL), darunavir (DRV/r) and/or etravirine (ETR), is well tolerated and achieves durable virologic suppression over 144 weeks in resource-limited settings: ACTG A5288 strategy trial.
INTRODUCTION
ACTG A5288 was a strategy trial conducted in diverse populations from multiple continents of people living with HIV (PLWH) failing second-line protease inhibitor (PI)-based antiretroviral therapy (ART) from 10 low- and middle-income countries (LMICs). Participants resistant to lopinavir (LPV) and/or multiple nucleotide reverse transcriptase inhibitors started on third-line regimens that included raltegravir (RAL), darunavir/ritonavir (DRV/r) and/or etravirine (ETR) according to their resistance profiles. At 48 weeks, 87% of these participants achieved HIV-1 RNA ≤200 copies/ml. We report here long-term outcomes over 144 weeks.
METHODS
Study participants were enrolled from 2013 to 2015, prior to the availability of dolutegravir in LMICs. "Extended Follow-up" of the study started after the last participant enrolled had reached 48 weeks and included participants still on antiretroviral (ARV) regimens containing RAL, DRV/r and/or ETR at that time. RAL, DRV/r and ETR were provided for an additional 96 weeks (giving total follow-up of ≥144 weeks), with HIV-1 RNA measured at 48 and 96 weeks and CD4 count at 96 weeks after entry into Extended Follow-up. Proportion of participants with HIV-1 RNA ≤200 copies/ml was estimated every 24 weeks, using imputation if necessary to handle the different measurement schedule in Extended Follow-up; mean CD4 count changes were estimated using loess regression.
RESULTS AND DISCUSSION
Of 257 participants (38% females), at study entry, median CD4 count was 179 cells/mm , and HIV-1 RNA was 4.6 log copies/ml. Median follow-up was 168 weeks (IQR: 156-204); 15 (6%) participants were lost to follow-up and 9 (4%) died. 27/246 (11%), 26/246 (11%) and 13/92 (14%) of participants who started RAL, DRV/r and ETR, respectively, discontinued these drugs; only three due to adverse events. 87%, 86%, 83% and 80% of the participants had HIV-1 RNA ≤200 copies/ml at weeks 48, 96, 144 and 168 (95% CI at week 168: 74-85%), respectively. Mean increase from study entry in CD4 count at week 168 was 265 cells/mm (95% CI 247-283).
CONCLUSIONS
Third-line regimens comprising of RAL, DRV/r and/or ETR were very well tolerated and had high rates of durable virologic suppression among PLWH in LMICs who were failing on second-line PI-based ART prior to the availability of dolutegravir.
Topics: Anti-HIV Agents; Anti-Retroviral Agents; Darunavir; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Nitriles; Pyrimidines; RNA; Raltegravir Potassium; Ritonavir; Viral Load
PubMed: 36039892
DOI: 10.1002/jia2.25905 -
Drug Discoveries & Therapeutics Sep 2022This study was aimed at assessing the adherence and incorrect drug intake associated with changes in the dosing schedule of raltegravir, the first integrase strand...
This study was aimed at assessing the adherence and incorrect drug intake associated with changes in the dosing schedule of raltegravir, the first integrase strand transfer inhibitor, from 400 mg twice a day (BID) to 600 mg × 2 tablets once a day (QD) in human immunodeficiency virus (HIV)-infected patients. Medication adherence over 1 month was evaluated in 25 male patients using the 100-mm visual analog scale (VAS) at the 3-day recall pill count and during pharmacist counseling after the first post-change visit. VAS scores before and after the raltegravir formulation change were compared. Medication adherence increased from 96 ± 4.3 mm (BID) to 100 ± 0.3 mm (QD) (P < 0.05). The patients exhibited improved medication adherence; however, three patients incorrectly took the drug when the formulation changed. This discovery can be used to facilitate the treatment of HIV-infected patients to increase treatment suitability and safety.
Topics: Drug Administration Schedule; HIV Infections; Humans; Integrases; Male; Medication Adherence; Medication Errors; Raltegravir Potassium; Tablets
PubMed: 36002310
DOI: 10.5582/ddt.2022.01054 -
The Journal of Antimicrobial... Sep 2022In prior studies, HIV-1 BF recombinants with subtype F integrases failed to develop resistance to raltegravir through the Q148H mutational pathway. We aimed to determine...
HIV-1 subtype F integrase polymorphisms external to the catalytic core domain contribute to severe loss of replication capacity in context of the integrase inhibitor resistance mutation Q148H.
BACKGROUND
In prior studies, HIV-1 BF recombinants with subtype F integrases failed to develop resistance to raltegravir through the Q148H mutational pathway. We aimed to determine the role of subtype-specific polymorphisms in integrase on drug susceptibility, viral replication and integration.
METHODS
Integrase sequences were retrieved from the Los Alamos Database or obtained from the Garrahan HIV cohort. HIV-1 infectious molecular clones with or without Q148H (+ G140S) resistance mutations were constructed using integrases of subtype B (NL4-3) or F1(BF) ARMA159 and URTR23. Integrase chimeras were generated by reciprocal exchanges of a 200 bp fragment spanning amino acids 85-150 of the catalytic core domain (CCD) of NL4-3-Q148H and either ARMA159-Q148H or URTR23-Q148H. Viral infections were quantified by p24 ELISA and Alu-gag integration PCR assay.
RESULTS
At least 18 different polymorphisms distinguish subtype B from F1(BF) recombinant integrases. In phenotypic experiments, p24 at Day 15 post-infection was high (105-106 pg/mL) for WT and NL4-3-Q148H; by contrast, it was low (102-104 pg/mL) for both F1(BF)-Q148H + G140S viruses, and undetectable for the Q148H mutants. Compared with WT viruses, integrated DNA was reduced by 5-fold for NL4-3-Q148H (P = 0.05), 9-fold for URTR23-Q148H (P = 0.01) and 16000-fold for ARMA159-Q148H (P = 0.01). Reciprocal exchange between B and F1(BF) of an integrase CCD region failed to rescue the replicative defect of F1(BF) integrase mutants.
CONCLUSIONS
The functional impairment of Q148H in the context of subtype F integrases from BF recombinants explains the lack of selection of this pathway in vivo. Non-B polymorphisms external to the integrase CCD may influence the pathway to integrase strand transfer inhibitor resistance.
Topics: Amino Acids; Catalytic Domain; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Humans; Mutation; Pyrrolidinones; Raltegravir Potassium
PubMed: 35897124
DOI: 10.1093/jac/dkac238 -
The Lancet. HIV Jun 2022Over the past decade, antiretroviral therapy (ART) regimens that include integrase strand inhibitors (INSTIs) have become the most commonly used for people with HIV...
BACKGROUND
Over the past decade, antiretroviral therapy (ART) regimens that include integrase strand inhibitors (INSTIs) have become the most commonly used for people with HIV starting ART. Although trials and observational studies have compared virological failure on INSTI-based with other regimens, few data are available on mortality in people with HIV treated with INSTIs in routine care. Therefore, we compared all-cause mortality between different INSTI-based and non-INSTI-based regimens in adults with HIV starting ART from 2013 to 2018.
METHODS
This cohort study used data on people with HIV in Europe and North America from the Antiretroviral Therapy Cohort Collaboration (ART-CC) and UK Collaborative HIV Cohort (UK CHIC). We studied the most common third antiretroviral drugs (additional to nucleoside reverse transcriptase inhibitor) used from 2013 to 2018: rilpivirine, darunavir, raltegravir, elvitegravir, dolutegravir, efavirenz, and others. Adjusted hazard ratios (aHRs; adjusted for clinical and demographic characteristics, comorbid conditions, and other drugs in the regimen) for mortality were estimated using Cox models stratified by ART start year and cohort, with multiple imputation of missing data.
FINDINGS
62 500 ART-naive people with HIV starting ART (12 422 [19·9%] women; median age 38 [IQR 30-48]) were included in the study. 1243 (2·0%) died during 188 952 person-years of follow-up (median 3·0 years [IQR 1·6-4·4]). There was little evidence that mortality rates differed between regimens with dolutegravir, elvitegravir, rilpivirine, darunavir, or efavirenz as the third drug. However, mortality was higher for raltegravir compared with dolutegravir (aHR 1·49, 95% CI 1·15-1·94), elvitegravir (1·86, 1·43-2·42), rilpivirine (1·99, 1·49-2·66), darunavir (1·62, 1·33-1·98), and efavirenz (2·12, 1·60-2·81) regimens. Results were similar for analyses making different assumptions about missing data and consistent across the time periods 2013-15 and 2016-18. Rates of virological suppression were higher for dolutegravir than other third drugs.
INTERPRETATION
This large study of patients starting ART since the introduction of INSTIs found little evidence that mortality rates differed between most first-line ART regimens; however, raltegravir-based regimens were associated with higher mortality. Although unmeasured confounding cannot be excluded as an explanation for our findings, virological benefits of first-line INSTIs-based ART might not translate to differences in mortality.
FUNDING
US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council.
Topics: Adult; Anti-HIV Agents; Cohort Studies; Darunavir; Europe; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; North America; Raltegravir Potassium; Rilpivirine
PubMed: 35659335
DOI: 10.1016/S2352-3018(22)00046-7 -
Acta Medica Portuguesa Jul 2022Although raltegravir has been available since 2007, data are lacking on the Portuguese population living with HIV who initiated this antiretroviral therapy. Hence, this...
INTRODUCTION
Although raltegravir has been available since 2007, data are lacking on the Portuguese population living with HIV who initiated this antiretroviral therapy. Hence, this study aimed to characterize the patients who initiated raltegravir-based regimens between January 2015 and December 2017, on sociodemographics, clinical features, and treatment satisfaction.
MATERIAL AND METHODS
Observational, retrospective, multicentre study conducted at 11 reference sites. Sociodemographic and clinical data were collected retrospectively from hospital medical records. For participants continuing raltegravir at study inclusion, the HIV Treatment Satisfaction Questionnaire was administered to assess satisfaction with raltegravir-based therapy. Descriptive statistics were performed. Treatment-naïve and treatment-experienced subgroups were compared for demographic and clinical variables.
RESULTS
A total of 302 patients were included; mostly men (69.5%) with a mean age of 49 years old. Approximately half of the patients had at least one non-AIDS-related comorbidity at baseline (53.3%), such as hypercholesterolemia, arterial hypertension, diabetes mellitus, and depression. Moreover, 52.3% were treatment-experienced patients with up to two treatments prior to raltegravir. Across the study time points, there was a reduction in the viral load and improvement in CD4 counts in both the treatment-naïve and treatment-experienced subgroups. Continuing users of raltegravir reported high treatment satisfaction (55.4 ± 7.2 points).
CONCLUSION
Raltegravir-based regimens seem like a valid therapeutic option in heterogeneous populations of HIV-infected patients, in patients with previous ART experience and as part of first-line therapeutic options alongside with the latest generation of drugs from its class.
Topics: Male; Humans; Middle Aged; Female; Raltegravir Potassium; Retrospective Studies; Portugal; Viral Load; HIV Infections
PubMed: 35333155
DOI: 10.20344/amp.16785 -
Journal of Neuroimmune Pharmacology :... Jun 2023Women with HIV(WWH) are more likely to discontinue/change antiretroviral therapy(ART) due to side effects including neuropsychiatric symptoms. Efavirenz and integrase...
Women with HIV(WWH) are more likely to discontinue/change antiretroviral therapy(ART) due to side effects including neuropsychiatric symptoms. Efavirenz and integrase strand transfer inhibitors(INSTIs) are particularly concerning. We focused on these ART agents and neuropsychiatric symptoms in previously developed subgroups of WWH that differed on key sociodemographic factors as well as longitudinal behavioral and clinical profiles. WWH from the Women's Interagency HIV Study were included if they had ART data available, completed the Perceived Stress Scale-10 and PTSD Checklist-Civilian. Questionnaires were completed biannually beginning in 2008 through 2016. To examine ART-symptom associations, constrained continuation ratio model via penalized maximum likelihood were fit within 5 subgroups of WWH. Data from 1882 WWH contributed a total of 4598 observations. 353 women were previously defined as primarily having well-controlled HIV with vascular comorbidities, 463 with legacy effects(CD4 nadir < 250cells/mL), 274 aged ≤ 45 with hepatitis, 453 between 35-55 years, and 339 with poorly-controlled HIV/substance users. INSTIs, but not efavirenz, were associated with symptoms among key subgroups of WWH. Among those with HIV legacy effects, dolutegravir and elvitegravir were associated with greater stress/anxiety and avoidance symptoms(P's < 0.01); dolutegravir was also associated with greater re-experiencing symptoms(P = 0.005). Elvitegravir related to greater re-experiencing and hyperarousal among women with well-controlled HIV with vascular comorbidities(P's < 0.022). Raltegravir was associated with less hyperarousal, but only among women aged ≤ 45 years(P = 0.001). The adverse neuropsychiatric effects of INSTIs do not appear to be consistent across all WWH. Key characteristics (e.g., age, hepatitis positivity) may need consideration to fully weight the risk-benefit ratio of dolutegravir and elvitegravir in WWH.
Topics: Humans; Female; HIV Integrase Inhibitors; Raltegravir Potassium; Anti-HIV Agents; HIV Infections; Oxazines; Benzoxazines
PubMed: 35178611
DOI: 10.1007/s11481-021-10042-3 -
Journal of Global Antimicrobial... Jun 2022We aimed to investigate the incidence of low-level viremia (LLV) and its impact on virologic failure (VF) in people living with HIV (PLWH) on stable antiretroviral...
OBJECTIVES
We aimed to investigate the incidence of low-level viremia (LLV) and its impact on virologic failure (VF) in people living with HIV (PLWH) on stable antiretroviral therapy (ART) who switched to co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide (EVG/c/FTC/TAF).
METHODS
PLWH aged 18 years or older who had received ART with plasma HIV RNA load (PVL) <50 copies/mL for 6 months or longer and switched to EVG/c/FTC/TAF between March and October 2018 were retrospectively included. The incidence of LLV (defined as PVL of 50-999 copies/mL) and VF (PVL ≥1000 copies/mL) was calculated and represented by Kaplan-Meier plots. The generalised estimating equation model was constructed to identify factors associated with LLV and VF. Resistance-associated mutations were determined using population sequencing.
RESULTS
A total of 1078 PLWH were included. The incidence rates of LLV and VF after the switch to EVG/c/FTC/TAF were 3.5 and 0.8 events per 100 person-years of follow-up, respectively, whereas the respective cumulative incidence of LLV and VF reached 11.7% and 2.9% within 3 years of follow-up. LLV was associated with any LLV episode before or after the switch and prior exposure to integrase strand transfer inhibitor-based ART. VF was associated with any LLV before or after the switch and prior exposure to raltegravir, but not the level or frequency of LLV.
CONCLUSION
The risks of LLV and VF were low in PLWH who had achieved virologic suppression and switched to EVG/c/FTC/TAF, and the presence of LLV and prior exposure to raltegravir increased the risk of VF.
Topics: Anti-HIV Agents; Emtricitabine; HIV Infections; HIV-1; Humans; Incidence; Quinolones; Raltegravir Potassium; Retrospective Studies; Viremia
PubMed: 35172201
DOI: 10.1016/j.jgar.2022.02.007