Prevalence of Polypharmacy and Potential Drug-Drug Interactions Associated with Risk Factors in the Era of HIV Integrase Inhibitors: A Prospective Clinical Study.

People living with human immunodeficiency virus (PLWH), with the availability of modern antiretroviral drugs, have multiple comorbidities, which increase the risk of polypharmacy and potential drug-drug interactions (PDDIs). This is a particularly important issue for the aging population of PLWH. This study aims to review the prevalence and risk factors for PDDIs and polypharmacy in the era of HIV integrase inhibitors. A cross-sectional, two-center, prospective observational study was conducted on Turkish outpatients between October 2021 and April 2022. Polypharmacy was defined as the use of ≥5 non-HIV medications, excluding over-the-counter (OTC) drugs, and PDDIs were classified using the University of Liverpool HIV Drug Interaction Database (harmful/red flagged and potentially clinically relevant/amber flagged). The median age of the 502 PLWH included in the study was 42 ± 12.4 years and 86.1% were males. Most individuals (96.4%) were given integrase-based regimens (unboosted 68.7% and boosted 27.7%). In total, 30.7% of individuals were taking at least one OTC drug. The prevalence of polypharmacy was 6.8% (9.2% when OTC drugs were included). During the study period, the prevalence of PDDIs was 1.2% for red flag PDDIs and 16% for amber flag PDDIs. CD4+ T cell count >500 cells/mm3, number of comorbidities ≥3, comedication with drugs affecting blood and blood-forming organs, cardiovascular drugs, and vitamin/mineral supplements were associated with red flag or amber flag PDDIs. Drug interaction prevention is still important in HIV care. Individuals with multiple comorbidities should be closely monitored for non-HIV medications to prevent PDDIs.

Disparities in Dolutegravir Uptake Affecting Females of Reproductive Age With HIV in Low- and Middle-Income Countries After Initial Concerns About Teratogenicity : An Observational Study.

BACKGROUND: The transition to dolutegravir-containing antiretroviral therapy (ART) in low- and middle-income countries (LMICs) was complicated by an initial safety signal in May 2018 suggesting that exposure to dolutegravir at conception was possibly associated with infant neural tube defects. On the basis of additional evidence, in July 2019, the World Health Organization recommended dolutegravir for all adults and adolescents living with HIV. OBJECTIVE: To describe dolutegravir uptake and disparities by sex and age group in LMICs. DESIGN: Observational cohort study. SETTING: 87 sites that began using dolutegravir in 11 LMICs in the Asia-Pacific; Caribbean, Central and South America network for HIV epidemiology (CCASAnet); and sub-Saharan African regions of the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. PATIENTS: 134 672 patients aged 16 years or older who received HIV care from January 2017 through March 2020. MEASUREMENTS: Sex, age group, and dolutegravir uptake (that is, newly initiating ART with dolutegravir or switching to dolutegravir from another regimen). RESULTS: Differences in dolutegravir uptake among females of reproductive age (16 to 49 years) emerged after the safety signal. By the end of follow-up, the cumulative incidence of dolutegravir uptake among females 16 to 49 years old was 29.4% (95% CI, 29.0% to 29.7%) compared with 57.7% (CI, 57.2% to 58.3%) among males 16 to 49 years old. This disparity was greater in countries that began implementing dolutegravir before the safety signal and initially had highly restrictive policies versus countries with a later rollout. Dolutegravir uptake was similar among females and males aged 50 years or older. LIMITATION: Follow-up was limited to 6 to 8 months after international guidelines recommended expanding access to dolutegravir. CONCLUSION: Substantial disparities in dolutegravir uptake affecting females of reproductive age through early 2020 are documented. Although this disparity was anticipated because of country-level restrictions on access, the results highlight its extent and initial persistence. PRIMARY FUNDING SOURCE: National Institutes of Health.

A Health Literate Patient-focused Approach to the Redesign of the Raltegravir (ISENTRESS) Pediatric Kit and Instructions for Use.

BACKGROUND: Limited data exist regarding how medications for pediatric use can be developed to minimize medication errors. The integrase inhibitor raltegravir was developed for use in neonates (≥2 kg). Anticipating that neonatal administration would be performed primarily by mothers with varying degrees of health literacy, a health literate, patient-focused, iterative process was conducted to update/redesign the raltegravir granules for oral suspension pediatric kit and instructions for use (IFU) for neonatal use to be ready for regulatory submission. METHODS: Prototypes of an updated/redesigned raltegravir IFU were systematically assessed through multi-stage, iterative testing and evaluation involving untrained lay individuals with varying levels of health literacy, healthcare professionals and health literacy experts. RESULTS: This iterative process resulted in numerous refinements to the IFU and kit, including wording, layout, presentation, colored syringes and additional instructional steps. The revised raltegravir pediatric kit and IFU (to include neonatal dosing) were approved by the US Food and Drug Administration in 2017 and the European Union in 2018. No reported medication errors related to IFU utilization had been reported as of March 2021, reflecting >3 years of commercial use worldwide. CONCLUSIONS: This patient-focused process produced health literate instructions for preparing and administering an antiretroviral for neonatal use with complex dosing requirements. Testing demonstrated that lay users with a range of health literacy levels were able to accurately mix, measure and administer the product. This process demonstrates how a neonatal medication can be optimized for use through collaboration between the infectious disease expert community and a manufacturer.

Dolutegravir as First- or Second-Line Treatment for HIV-1 Infection in Children.

BACKGROUND: Children with human immunodeficiency virus type 1 (HIV-1) infection have limited options for effective antiretroviral treatment (ART). METHODS: We conducted an open-label, randomized, noninferiority trial comparing three-drug ART based on the HIV integrase inhibitor dolutegravir with standard care (non-dolutegravir-based ART) in children and adolescents starting first- or second-line ART. The primary end point was the proportion of participants with virologic or clinical treatment failure by 96 weeks, as estimated by the Kaplan-Meier method. Safety was assessed. RESULTS: From September 2016 through June 2018, a total of 707 children and adolescents who weighed at least 14 kg were randomly assigned to receive dolutegravir-based ART (350 participants) or standard care (357). The median age was 12.2 years (range, 2.9 to 18.0), the median weight was 30.7 kg (range, 14.0 to 85.0), and 49% of the participants were girls. By design, 311 participants (44%) started first-line ART (with 92% of those in the standard-care group receiving efavirenz-based ART), and 396 (56%) started second-line ART (with 98% of those in the standard-care group receiving boosted protease inhibitor-based ART). The median follow-up was 142 weeks. By 96 weeks, 47 participants in the dolutegravir group and 75 in the standard-care group had treatment failure (estimated probability, 0.14 vs. 0.22; difference, -0.08; 95% confidence interval, -0.14 to -0.03; P = 0.004). Treatment effects were similar with first- and second-line therapies (P = 0.16 for heterogeneity). A total of 35 participants in the dolutegravir group and 40 in the standard-care group had at least one serious adverse event (P = 0.53), and 73 and 86, respectively, had at least one adverse event of grade 3 or higher (P = 0.24). At least one ART-modifying adverse event occurred in 5 participants in the dolutegravir group and in 17 in the standard-care group (P = 0.01). CONCLUSIONS: In this trial involving children and adolescents with HIV-1 infection who were starting first- or second-line treatment, dolutegravir-based ART was superior to standard care. (Funded by ViiV Healthcare; ODYSSEY ClinicalTrials.gov number, NCT02259127; EUDRACT number, 2014-002632-14; and ISRCTN number, ISRCTN91737921.).

Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women.

BACKGROUND: Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection. METHODS: We conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection. RESULTS: The intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF-FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF-FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified. CONCLUSIONS: CAB-LA was superior to daily oral TDF-FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.).

Long-acting cabotegravir plus rilpivirine for treatment in adults with HIV-1 infection: 96-week results of the randomised, open-label, phase 3 FLAIR study.

BACKGROUND: There is a need for more convenient, less frequent treatment to help address challenges associated with daily oral HIV treatment in people living with HIV, including stigma, pill burden, drug-food interactions, and adherence. The phase 3 ATLAS and FLAIR studies showed non-inferiority of long-acting cabotegravir and rilpivirine dosed every 4 weeks compared with standard oral therapy for the maintenance of virological suppression in adults with HIV-1 over 48 weeks. We present the 96-week findings. METHODS: FLAIR is a randomised, phase 3, open-label, multicentre study done in 11 countries investigating whether switching to long-acting cabotegravir and rilpivirine is non-inferior to daily dolutegravir, abacavir, and lamivudine in virologically suppressed adults living with HIV-1. Antiretroviral therapy (ART)-naive participants received induction therapy with daily oral dolutegravir (50 mg), abacavir (600 mg), and lamivudine (300 mg) for 20 weeks. After 16 weeks, participants with less than 50 HIV-1 RNA copies per mL were randomly assigned (1:1) to continue the standard of care regimen (standard care group) or switch to receive daily oral cabotegravir 30 mg and rilpivirine 25 mg for at least 4 weeks followed by long-acting cabotegravir 400 mg and rilpivirine 600 mg, administered as two 2 mL intramuscular injections, every 4 weeks for at least 96 weeks (long-acting group). Randomisation was stratified by baseline (preinduction) HIV-1 RNA (<100 000 or ≥100 000 copies per mL) and sex at birth and used GlaxoSmithKline-verified randomisation software (RandAll NG, version 1.3.3) for treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or more assessed as per the US Food and Drug Administration (FDA) Snapshot algorithm at week 48, which has been reported previously. Here, we report the proportion of participants with 50 or more HIV-1 RNA copies per mL using the FDA Snapshot algorithm at week 96 (intention-to-treat population; non-inferiority margin 6%). The trial is registered with ClinicalTrials.gov, NCT02938520. FINDINGS: Between Oct 27, 2016, and March 24, 2017, 809 participants were screened. 631 (78%) participants entered the induction phase and 566 (70%) were randomly assigned to either the standard care group (283 [50%] participants) or the long-acting group (283 [50%]). Median age was 34 years (IQR 29 to 43), 62 (11%) were 50 years or older, 127 (22%) were women (sex at birth), and 419 (74%) were white. At week 96, nine (3%) participants in each arm had 50 or more HIV-1 RNA copies per mL, with an adjusted difference of 0·0 (95% CI -2·9 to 2·9), consistent with non-inferiority established at week 48. Across both treatment groups, adverse events leading to withdrawal were infrequent (14 [5%] participants in the long-acting group and four [1%] in the standard care group). Injection site reactions were the most common adverse event, reported by 245 (88%) participants in the long-acting group; their frequency decreased over time. Median injection site reaction duration was 3 days (IQR 2 to 4), and 3082 (99%) of 3100 reactions were grade 1 or 2. No deaths occurred during the maintenance phase. INTERPRETATION: The 96-week results reaffirm the 48-week results, showing long-acting cabotegravir and rilpivirine continued to be non-inferior compared with continuing a standard care regimen in adults with HIV-1 for the maintenance of viral suppression. These results support the durability of long-acting cabotegravir and rilpivirine, over an almost 2-year-long period, as a therapeutic option for virally suppressed adults with HIV-1. FUNDING: ViiV Healthcare and Janssen Research and Development.

Characterization of Human Immunodeficiency Virus (HIV) Infection in Cisgender Men and Transgender Women Who Have Sex With Men Receiving Injectable Cabotegravir for HIV Prevention: HPTN 083.

BACKGROUND: The HIV Prevention Trials Network (HPTN) 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was more effective than tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) in preventing human immunodeficiency virus (HIV) in cisgender men and transgender women who have sex with men. We characterized HIV infections that occurred in the blinded phase of HPTN 083. METHODS: Retrospective testing included HIV testing, viral load testing, quantification of study drugs, and HIV drug resistance testing. RESULTS: Fifty-eight infections were evaluated, including 51 incident infections (12 in CAB arm and 39 in TDF/FTC arm). In many cases (5 in CAB arm and 37 in TDF/FTC arm), infection was associated with low or unquantifiable study drug concentrations. In 4 cases, infection occurred with on-time CAB-LA injections and expected plasma CAB concentrations. CAB exposure was associated with prolonged viral suppression and delayed antibody expression. In some cases, delayed HIV diagnosis resulted in CAB provision to participants with undetected infection, delayed antiretroviral therapy, and emergence of drug resistance; most of these infections would have been detected earlier with viral load testing. CONCLUSIONS: Early detection of HIV infection and prompt antiretroviral therapy initiation could improve clinical outcomes in persons who become infected despite CAB-LA prophylaxis. Further studies are needed to elucidate the correlates of HIV protection in persons receiving CAB-LA.

ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing.

BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. METHODS: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. RESULTS: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9-18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. CONCLUSIONS: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. TRIAL REGISTRATION: NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014-002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.

Dolutegravir and pregnancy outcomes in women on antiretroviral therapy in Brazil: a retrospective national cohort study.

BACKGROUND: Dolutegravir has been widely available in Brazil since 2017. Following the signal that infants born to women with dolutegravir exposure at conception in Botswana had a higher risk of neural tube defects (NTDs), public health leaders initiated a national investigation to evaluate periconception dolutegravir exposure among all pregnant Brazilian women with HIV and its potential association with risk of NTDs, stillbirth, or miscarriage before 22 weeks (also called spontaneous abortion). METHODS: In this retrospective, observational, national, cohort study, we identified all women with pregnancies and possible dolutegravir exposure within 8 weeks of estimated date of conception between Jan 1, 2017, and May 31, 2018, and approximately 3:1 matched pregnant women exposed to efavirenz between Jan 1, 2015, and May 31, 2018, using the Brazilian antiretroviral therapy database. We did detailed chart reviews for identified women. The primary outcomes were NTD and a composite measure of NTD, stillbirth, or miscarriage. NTD incidences were calculated with 95% CI. The composite outcome was examined with logistic regression using propensity score matching weights to balance confounders. FINDINGS: Of 1427 included women, 382 were exposed to dolutegravir within 8 weeks of estimated date of conception. During pregnancy, 183 (48%) of 382 dolutegravir-exposed and 465 (44%) of 1045 efavirenz-exposed women received folic acid supplementation. There were 1452 birth outcomes. There were no NTDs in either dolutegravir-exposed (0, 95% CI 0-0·0010) or efavirenz-exposed groups (0, 95% CI 0-0·0036). There were 23 (6%) stillbirths or miscarriages in 384 dolutegravir-exposed fetuses and 28 (3%) in the 1068 efavirenz-exposed fetuses (p=0·0037). Logistic regression models did not consistently indicate an association between dolutegravir exposure and risk of stillbirths or miscarriages. After study closure, two confirmed NTD outcomes in fetuses with periconception dolutegravir exposure were reported to public health officials. An updated estimate of NTD incidence incorporating these cases and the estimated number of additional dolutegravir-exposed pregnancies between Jan 1, 2015 and Feb 28, 2019, is 0·0018 (95% CI 0·0005-0·0067). INTERPRETATION: Neither dolutegravir nor efavirenz exposure was associated with NTDs in our national cohort; incidence of NTDs is probably well under 1% in dolutegravir-exposed HIV-positive women but still slightly above HIV-uninfected women (0·06%) in Brazil. FUNDING: The Brazilian Ministry of Health and the United States' National Institutes of Health.

Starting or Switching to an Integrase Inhibitor-Based Regimen Affects PTSD Symptoms in Women with HIV.

As the use of Integrase inhibitor (INSTI)-class antiretroviral medications becomes more common to maintain long-term viral suppression, early reports suggest the potential for CNS side-effects when starting or switching to an INSTI-based regimen. In a population already at higher risk for developing mood and anxiety disorders, these drugs may have significant effects on PTSD scale symptom scores, particularly in women with HIV (WWH). A total of 551 participants were included after completing ≥ 1 WIHS study visits before and after starting/switching to an INSTI-based ART regimen. Of these, 14% were ART naïve, the remainder switched from primarily a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Using multivariable linear mixed effects models, we compared PTSD Civilian Checklist subscale scores before and after a "start/switch" to dolutegravir (DTG), raltegravir (RAL), or elvitegravir (EVG). Start/switch to EVG improved re-experiencing subscale symptoms (P's < 0.05). Switching to EVG improved symptoms of avoidance (P = 0.01). Starting RAL improved arousal subscale symptoms (P = 0.03); however, switching to RAL worsened re-experiencing subscale symptoms (P < 0.005). Starting DTG worsened avoidance subscale symptoms (P = 0.03), whereas switching to DTG did not change subscale or overall PTSD symptoms (P's > 0.08). In WWH, an EVG-based ART regimen is associated with improved PTSD symptoms, in both treatment naïve patients and those switching from other ART. While a RAL-based regimen was associated with better PTSD symptoms than in treatment naïve patients, switching onto a RAL-based regimen was associated with worse PTSD symptoms. DTG-based regimens either did not affect, or worsened symptoms, in both naïve and switch patients. Further studies are needed to determine mechanisms underlying differential effects of EVG, RAL and DTG on stress symptoms in WWH.

Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase.

Little is known about the impact of pretreatment drug resistance (PDR) on the efficacy of second generation integrase inhibitors. We sequenced pretreatment plasma specimens from the ADVANCE trial (NCT03122262). Our primary outcome was 96-week virologic success, defined as a sustained viral load <1000 copies/mL from 12 weeks onwards, <200 copies/mL from 24 weeks onwards, and <50 copies/mL after 48 weeks. Here we report how this outcome was impacted by PDR, defined by the World Health Organization (WHO) mutation list. Of 1053 trial participants, 874 (83%) have successful sequencing, including 289 (33%) randomized to EFV-based therapy and 585 (67%) randomized to DTG-based therapy. Fourteen percent (122/874) have ≥1 WHO-defined mutation, of which 98% (120/122) are NNRTI mutations. Rates of virologic suppression are lower in the total cohort among those with PDR 65% (73/112) compared to those without PDR (85% [605/713], P < 0.001), and for those on EFV-based treatment (60% [12/20] vs 86% [214/248], P = 0.002) and for those on DTG-based treatment (61/92 [66%] vs 84% [391/465] P < 0.001, P for interaction by regimen 0.49). Results are similar in multivariable models adjusted for clinical characteristics and adherence. NNRTI resistance prior to treatment is associated with long-term failure of integrase inhibitor-containing first-line regimens, and portends high rates of first-line failure in sub Saharan Africa.

Efectividad y seguridad de inhibidores de integrasa en la gestante con infección VIH en la Cohorte de embarazadas de la Comunidad de Madrid / Effectiveness and safety of integrase inhibitors in HIV-infected pregnant women followed up in the Madrid Cohort

INTRODUCCIÓN: El riesgo de transmisión vertical (TV) del VIH depende fundamentalmente de la edad gestacional de inicio del tratamiento antirretroviral y la carga viral materna al parto. Son crecientes las pautas con inhibidores de integrasa (INI) en embarazadas con situaciones de riesgo. Nuestro objetivo fue revisar la experiencia con INI en la Cohorte de Madrid de madres-niños. PACIENTES Y MÉTODOS: Estudio retrospectivo, multicéntrico, observacional, de gestantes con infección por VIH-1 expuestas a INI de 9 hospitales públicos durante 2000-2017. RESULTADOS: Hubo 67 gestantes (cohorte: 1.423) y 68 neonatos (el 17,6% prematuros, el 34,3% con profilaxis combinada). No hubo casos de TV. Veinte mujeres se diagnosticaron en la gestación actual. De 43 con tratamiento antirretroviral previo a gestación, el 65% recibía INI preconcepcional. El más empleado fue raltegravir (80,5%). Aumentó significativamente (p = 0,02) la proporción de madres con carga viral indetectable al parto. La tolerancia a INI fue adecuada. Hubo anomalías congénitas menores en el 11,7% de los niños. CONCLUSIONES: Los INI parecen seguros y eficaces como prevención de TV. Nuestros hallazgos refuerzan su utilidad como intensificación en gestantes que llegan al tercer trimestre con pauta no supresora

INTRODUCTION: The risk of HIV-1 mother-to-child transmission (MTCT) is associated mainly with gestational age at which antiretroviral therapy begins and the HIV-1 RNA plasma viral load at delivery. Regimens with integrase inhibitors (INI) are increasing in high-risk pregnant women. The objective was to review the experience with INI in a Madrid Cohort of mother-infant pairs. PATIENTS AND METHODS: Retrospective, multicentric, observational study, of HIV-infected pregnant women exposed to INI. Patients of 9 hospitals were included (2000-2017). RESULTS: Sixty-seven pregnant women exposed to INI (cohort: 1,423) and 68 children (17.6% premature babies, 34.3% with combined postexposure prophylaxis). There were no cases of MTCT. Of 24 women with no previous antiretroviral therapy, 20 were diagnosed in current pregnancy. Of 43 women with antiretroviral therapy before pregnancy, 65% received INI before conception. Raltegravir was the most used (80.5%). There was a statistically significant increase (p = 0,02) of mothers with undetectable viral load at delivery. INI were well tolerated. In 11.7% of exposed children minor congenital anomalies were detected. CONCLUSIONS: INI seem safe and effective in the prevention of MTCT. Our findings support their use as intensification regimens in pregnant women with high risk of MTCT

HIV-1 Integrase Inhibitors: A Comparative Review of Efficacy and Safety.

The newest class of antiretrovirals for all persons living with HIV are the integrase strand transfer inhibitors (INSTIs). Since 2007, five INSTIs have been introduced: raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. The INSTIs have favorable pharmacokinetic and pharmacodynamic properties, which contribute to both their effectiveness and their ease of use. With the exception of cabotegravir, each INSTI is US Food and Drug Administration approved for treatment-naïve individuals initiating antiretroviral therapy. All of the INSTIs, except raltegravir, are approved for antiretroviral treatment simplification for virologically suppressed patients without INSTI resistance. Data also support the use of dolutegravir and raltegravir in individuals with antiretroviral resistance as part of an optimized antiretroviral regimen. INSTIs are generally well tolerated by people living with HIV compared with older classes of antiretrovirals, but emerging data suggest that some INSTIs contribute to weight gain. Due to their efficacy, safety, and ease of use, HIV treatment guidelines recommend oral INSTIs as preferred components of antiretroviral therapy for individuals initiating therapy. The newest INSTI, cabotegravir, represents an alternative to oral administration of life-long antiretroviral therapy with the availability of a long-acting injectable formulation. This review summarizes the current use of INSTIs in adults living with HIV, highlighting the similarities and differences within the class related to pharmacodynamics, pharmacokinetics, safety, dosing, and administration that contribute to their role in modern antiretroviral therapy.

Survival among antiretroviral-experienced HIV-2 patients experiencing virologic failure with drug resistance mutations in Cote d'Ivoire West Africa.

INTRODUCTION: The long-term prognosis of HIV-2-infected patients receiving antiretroviral therapy (ART) is still challenging, due to the intrinsic resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) and the suboptimal response to some protease inhibitors (PI). The objective was to describe the 5-years outcomes among HIV-2 patients harboring drug-resistant viruses. METHODS: A clinic-based cohort of HIV-2-patients experiencing virologic failure, with at least one drug resistance mutation was followed from January 2012 to August 2017 in Côte d'Ivoire. Follow-up data included death, lost to follow-up (LTFU), immuno-virological responses. The Kaplan-Meier curve was used to estimate survival rates. RESULTS: A total of 31 HIV-2 patients with virologic failure and with at least one drug resistance mutation were included. Two-third of them were men, 28(90.3%) were on PI-based ART-regimen at enrolment and the median age was 50 years (IQR = 46-54). The median baseline CD4 count and viral load were 456 cells/mm3 and 3.7 log10 c/mL respectively, and the participants have been followed-up in median 57 months (IQR = 24-60). During this period, 21 (67.7%) patients switched at least one antiretroviral drug, including two (6.5%) and three (9.7%) who switched to a PI-based and an integrase inhibitor-based regimen respectively. A total of 10(32.3%) patients died and 4(12.9%) were LTFU. The 36 and 60-months survival rates were 68.5% and 64.9%, respectively. Among the 17 patients remaining in care, six(35.3%) had an undetectable viral load (<50 c/mL) and for the 11 others, the viral load ranged from 2.8 to 5.6 log10 c/mL. Twelve patients were receiving lopinavir at the time of first genotype, five(42%) had a genotypic susceptibility score (GSS) ≤1 and 4(33%) a GSS >2. CONCLUSIONS: The 36-months survival rate among ART-experienced HIV-2 patients with drug-resistant viruses is below 70%,lower than in HIV-1. There is urgent need to improve access to second-line ART for patients living with HIV-2 in West Africa.

Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial.

BACKGROUND: Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV. METHODS: We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial (NCT02259127) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (Ctrough) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses. FINDINGS: Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) Ctrough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM Ctrough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM Ctrough was 0·39 mg/L (48%), which was 54% lower than the GM Ctrough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM Ctrough was 0·46 mg/L (63%), which was 45% lower than the GM Ctrough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, Ctrough was close to the adult reference (with similar estimates on the two formulations in children in the 20 to <25 kg weight band), with total exposure (area under the concentration-time curve from 0 h to 24 h) in between reference values in adults dosed once and twice daily, where safety data are reassuring, although maximum concentrations were higher in children weighing 20 kg to less than 25 kg than in the twice-daily adult reference. Over a 24-week follow-up period in 47 children on 30 mg dispersible tablets or 50 mg film-coated tablets, none of the three reported adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) were considered related to dolutegravir. INTERPRETATION: Adult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg. FUNDING: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.

Tail-phase safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in HIV-uninfected adults: a secondary analysis of the HPTN 077 trial.

BACKGROUND: Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial. METHODS: HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18-65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t1/2app) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52-76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov, NCT02178800. FINDINGS: Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p<0·0001). At 52-60 weeks after final injection, nine (23%) of 40 male participants had detectable cabotegravir concentrations and at week 76, four (13%) of 30 male participants had detectable cabotegravir concentrations compared with 52 (63%) of 82 female participants and 27 (42%) of 64 female participants at the same timepoints. The median time from the last injection to the time when cabotegravir concentration decreased below the LLOQ was 43·7 weeks (IQR 31·1-66·6; range 20·4-152·5) for male participants and 67·3 weeks (29·1-89·6; 17·7-225·5) for female participants (p=0·0003). t1/2app was longer for female participants than male participants (geometric mean fold-change 1·33, 95% CI 1·06-1·68; p=0·014), and longer for participants with a high body-mass index (BMI) than those with a low BMI (1·31, 1·06-1·63; p=0·015). INTERPRETATION: The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials. FUNDING: National Institute of Allergy and Infectious Diseases.