Publications by authors named "William R Spreen"
Population pharmacokinetics of cabotegravir following intramuscular thigh injections in adults with and without HIV.
Antimicrob Agents Chemother
December 2024
Article Synopsis
- - Cabotegravir, used for HIV treatment and prevention via intramuscular injection, is being evaluated for thigh muscle as an alternative injection site compared to the traditional gluteal site, with a focus on its pharmacokinetics and demographic impacts.
- - In a study involving both HIV-negative and HIV-positive participants, researchers collected and analyzed cabotegravir concentration data from thigh and gluteal injections, finding significant differences in absorption rates based on sex and body mass index (BMI).
- - The analysis indicates that while thigh injections have a slower absorption rate and slightly lower bioavailability compared to gluteal injections, the results provide important insights for optimizing dosing strategies and future research on cabotegravir use.
Article Synopsis
- * This method improves patient satisfaction by reducing concerns about stigma, adherence anxiety, and the daily reminder of their status, as it's administered by healthcare professionals.
- * The review provides practical guidance on starting the treatment, handling missed doses, and transitioning to other medications, with case scenarios to illustrate real-life situations faced by clinicians.
Pharmacokinetics and tolerability of cabotegravir and rilpivirine long-acting intramuscular injections to the (lateral thigh) muscles of healthy adult participants.
Antimicrob Agents Chemother
January 2024
Article Synopsis
- Cabotegravir + rilpivirine is the first long-acting HIV treatment approved for intramuscular administration, typically in the gluteal area, but the lateral thigh is being explored as an alternative injection site.
- A study assessed the safety and pharmacokinetics of this treatment in healthy adults after they received initial oral doses followed by thigh injections, with evaluations continuing for 52 weeks post-injection.
- Results showed that thigh injections had similar tolerability and effectiveness compared to gluteal injections, with the most common side effects being mild pain and swelling at the injection site.
Efficacy, safety, and tolerability of switching to long-acting cabotegravir plus rilpivirine versus continuing fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with HIV, 12-month results (SOLAR): a randomised, open-label, phase 3b, non-inferiority trial.
Lancet HIV
September 2023
Article Synopsis
- Cabotegravir plus rilpivirine is the only approved long-acting treatment for HIV-1, administered every 2 months, and the SOLAR study compares its effectiveness to daily oral therapy with bictegravir, emtricitabine, and tenofovir alafenamide.
- This phase 3b study involved 687 participants across 118 centers in 14 countries and aimed to assess if the long-acting regimen could maintain HIV virological suppression similarly to the daily regimen.
- The study found that 67% of participants switched to long-acting therapy, demonstrating significant interest in alternatives to daily medications for maintaining HIV suppression.
Article Synopsis
- Expanded analysis of predictors of confirmed virologic failure (CVF) in 1651 participants taking cabotegravir + rilpivirine long-acting (CAB + RPV LA) included data beyond 48 weeks and considered various demographic and viral factors.
- Results showed that 1.4% of participants experienced CVF, with risks increasing for those with mutations associated with rilpivirine resistance, specific HIV subtypes, and higher body mass index.
- The study concluded that having two or more of these baseline factors has a significant impact on the risk of CVF, indicating the importance of these factors in effectively managing treatment with CAB + RPV LA.
Long-Acting Cabotegravir and Rilpivirine Dosed Every 2 Months in Adults With Human Immunodeficiency Virus 1 Type 1 Infection: 152-Week Results From ATLAS-2M, a Randomized, Open-Label, Phase 3b, Noninferiority Study.
Clin Infect Dis
May 2023
Article Synopsis
- The ATLAS-2M study evaluated the effectiveness and safety of cabotegravir (CAB) + rilpivirine (RPV) for maintaining HIV-1 suppression, comparing two dosing schedules: every 8 weeks (Q8W) and every 4 weeks (Q4W).
- Results showed that both dosing regimens were effective, with 87% of participants maintaining low HIV-1 levels after 152 weeks, and Q8W dosing was confirmed to be noninferior to Q4W.
- The study found that safety profiles were similar for both groups, with no new safety concerns, confirming CAB + RPV as a long-term treatment option for HIV-1 suppression.
Article Synopsis
- Limited data on the effects of cabotegravir + rilpivirine (CAB + RPV) in pregnant women living with HIV showed 25 pregnancies after exposure, with diverse outcomes including 10 live births.
- The study involved women who had taken CAB + RPV and then transitioned to other antiretroviral medications when they became pregnant, with ongoing monitoring of drug levels post-exposure.
- Results indicated that drug concentrations during pregnancy were comparable to those in non-pregnant women, but there was one reported case of congenital anomaly among the live births, prompting further investigation into pregnancy safety and outcomes.
Perspectives of people living with HIV-1 on implementation of long-acting cabotegravir plus rilpivirine in US healthcare settings: results from the CUSTOMIZE hybrid III implementation-effectiveness study.
J Int AIDS Soc
September 2022
Article Synopsis
- The CUSTOMIZE study evaluated the effectiveness of monthly long-acting injections of cabotegravir and rilpivirine for people living with HIV-1 across diverse clinics in the US.
- After 12 months, the majority of participants maintained suppressed viral loads and reported high levels of acceptability for the treatment, with scores increasing from baseline.
- Most participants preferred the long-acting injections over daily oral medications, and many felt that the COVID-19 pandemic did not significantly interfere with their treatment.
Perspectives of healthcare providers on implementation of long-acting cabotegravir plus rilpivirine in US healthcare settings from a Hybrid III Implementation-effectiveness study (CUSTOMIZE).
J Int AIDS Soc
September 2022
Article Synopsis
- CUSTOMIZE was a 12-month study that evaluated a new injectable HIV treatment regimen (cabotegravir + rilpivirine) across various US healthcare settings to understand its implementation outcomes.
- Conducted at eight different types of clinics, the study gathered data through surveys and interviews from healthcare staff to assess the treatment's acceptability, appropriateness, and feasibility.
- Results showed high satisfaction among staff regarding the treatment's implementation, with notable improvements in concerns about patient attendance at appointments over time, though issues like injection pain remained consistent.
Article Synopsis
- The study aimed to analyze the pharmacokinetics of cabotegravir, focusing on how different factors (both intrinsic and extrinsic) affect the drug's variability in the body using data from various clinical trials.
- Researchers utilized advanced statistical tools like NONMEM and R to evaluate a large dataset of plasma concentrations from HIV-1-infected and uninfected subjects, testing different dosing methods and identifying trends related to demographics and health metrics.
- The findings suggest a population pharmacokinetic model that can guide dosing strategies without necessitating adjustments based on individual factors like race or age, highlighting certain influences from smoking and body metrics on drug absorption and clearance.
Background: Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women.
View Article and Find Full Text PDFBackground: In the LATTE study, daily oral cabotegravir + rilpivirine demonstrated higher rates of efficacy than efavirenz + 2 nucleoside reverse-transcriptase inhibitors (NRTIs) through Week 96 in antiretroviral therapy (ART)-naive adults with human immunodeficiency virus (HIV)-1. We present the results from 6 years of continued treatment with oral cabotegravir + rilpivirine.
Methods: LATTE was a phase IIb, randomized, multicenter, partially blinded, dose-ranging study in ART-naive adults with HIV-1.
Long-acting (LA) cabotegravir demonstrated superior efficacy versus daily oral standard-of-care for HIV-1 preexposure prophylaxis. This phase 1 study assessed safety, tolerability, pharmacokinetics, and acceptability of cabotegravir in 47 HIV-negative adult Chinese men at low risk of acquiring HIV-1. Participants received once-daily oral cabotegravir 30 mg for 4 weeks and, after a 1-week washout, five 600-mg (3-mL) intramuscular cabotegravir LA injections at weeks 5, 9, 17, 25, and 33.
View Article and Find Full Text PDFInitiation of long-acting cabotegravir plus rilpivirine as direct-to-injection or with an oral lead-in in adults with HIV-1 infection: week 124 results of the open-label phase 3 FLAIR study.
Lancet HIV
November 2021
Article Synopsis
- - A phase 3 study called FLAIR evaluated the effectiveness of switching HIV-1 suppressed participants from daily oral medication to long-acting intramuscular injections of cabotegravir plus rilpivirine over 124 weeks.
- - Participants were randomly assigned to either continue with their standard oral therapy or switch to the long-acting regimen, with the option to choose a four-week oral lead-in before the first injection.
- - Key outcomes measured included viral load levels, confirmed treatment failures, and overall safety, with results showing the non-inferiority of the new long-acting treatment compared to standard therapy.
Objectives: Long-acting formulations of cabotegravir (CAB) and rilpivirine (RPV) have demonstrated efficacy in Phase 3 studies. POLAR (NCT03639311) assessed antiviral activity and safety of CAB+RPV long-acting administered every 2 months (Q2M) in adults living with HIV-1 who previously received daily oral CAB+RPV in LATTE (NCT01641809).
Design: A Phase 2b, multicenter, open-label, rollover study.
Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study.
Lancet HIV
November 2021
Background: Long-acting cabotegravir and rilpivirine administered monthly or every 2 months might address the challenges associated with daily oral antiretroviral therapy. The ATLAS-2M week 48 results showed non-inferiority of long-acting cabotegravir and rilpivirine administered every 8 weeks compared with that of every 4 weeks. In this study, we report the efficacy, safety, and tolerability results from the week 96 analysis.
View Article and Find Full Text PDFEfficacy, Safety, and Durability of Long-Acting Cabotegravir and Rilpivirine in Adults With Human Immunodeficiency Virus Type 1 Infection: 5-Year Results From the LATTE-2 Study.
Open Forum Infect Dis
September 2021
Background: In the Long-Acting Antiretroviral Treatment Enabling Trial 2 (LATTE-2) phase 2b study, long-acting (LA) injectable cabotegravir + rilpivirine dosed every 8 weeks (Q8W) or every 4 weeks (Q4W) demonstrated comparable efficacy with daily oral antiretroviral therapy (ART) through 96 weeks in ART-naive adults with human immunodeficiency virus type 1 (HIV-1). Here we report efficacy, tolerability, and safety of cabotegravir + rilpivirine LA over approximately 5 years.
Methods: After 20 weeks of oral cabotegravir + abacavir/lamivudine, participants were randomized to cabotegravir + rilpivirine LA Q8W or Q4W or continue oral ART through the 96-week maintenance period.
Objective: We had previously shown that long-acting cabotegravir (CAB-LA) injections fully protected macaques from vaginal simian HIV (SHIV) infection. Here, we reassessed CAB-LA efficacy in the presence of depot medroxyprogesterone acetate and multiple sexually transmitted infections (STIs) that are known to increase HIV susceptibility in women.
Design: Two macaque models of increasing vaginal STI severity were used for efficacy assessment.
Background: ATLAS (NCT02951052), a phase 3, multicenter, open-label study, demonstrated that switching to injectable cabotegravir (CAB) with rilpivirine (RPV) long-acting dosed every 4 weeks was noninferior at week (W) 48 to continuing three-drug daily oral current antiretroviral therapy (CAR). Results from the W 96 analysis are presented.
Methods And Design: Participants completing W 52 of ATLAS were given the option to withdraw, transition to ATLAS-2M (NCT03299049), or enter an Extension Phase to continue long-acting therapy (Long-acting arm) or switch from CAR to long-acting therapy (Switch arm).
Background: Advances in HIV-1 therapeutics have led to the development of a range of daily oral treatment regimens, which share similar high efficacy rates. Consequently, more emphasis is being placed upon the individual's experience of treatment and impact on quality of life. The first long-acting injectable antiretroviral therapy for HIV-1 (long-acting cabotegravir + rilpivirine [CAB + RPV LA]) may address challenges associated with oral treatment for HIV-1, such as stigma, pill burden/fatigue, drug-food interactions, and adherence.
View Article and Find Full Text PDFArticle Synopsis
- There is a growing need for less frequent and more convenient HIV treatment options to alleviate issues like stigma and the burden of daily medication.
- The phase 3 ATLAS and FLAIR studies demonstrated that long-acting cabotegravir and rilpivirine, given every 4 weeks, is as effective as standard daily oral therapy in maintaining viral suppression in HIV-1 patients over 48 weeks.
- The FLAIR study reveals ongoing data and effectiveness of switching to long-acting treatments in virologically suppressed adults over a longer period of 96 weeks.
Objective: Efficacy and safety of long-acting cabotegravir (CAB) and rilpivirine (RPV) dosed intramuscularly every 4 or 8 weeks has been demonstrated in three Phase 3 trials. Here, factors associated with virologic failure at Week 48 were evaluated post hoc.
Design And Methods: Data from 1039 adults naive to long-acting CAB+RPV were pooled in a multivariable analysis to examine the influence of baseline viral and participant factors, dosing regimen and drug concentrations on confirmed virologic failure (CVF) occurrence using a logistic regression model.
Article Synopsis
- - The ATLAS and FLAIR studies tested a long-acting injectable treatment (cabotegravir + rilpivirine) for HIV-1 against current daily oral regimens in adults with suppressed viral loads.
- - After 48 weeks, the injectable treatment showed similar effectiveness in keeping HIV-1 levels low compared to the daily regimen, with noninferiority criteria met and only a small percentage experiencing treatment failure.
- - While injection site reactions were common, overall safety profiles were comparable, indicating that monthly injections could be a viable option for managing HIV-1.
Background: Cabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure.
Objectives: To investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokinetics (PK) and safety of oral cabotegravir (30 mg/day) and intramuscular cabotegravir LA (400 mg every 4 weeks or 600 mg every 8 weeks).
Background: Simplified regimens for the treatment of human immunodeficiency virus type 1 (HIV-1) infection may increase patient satisfaction and facilitate adherence.
Methods: In this phase 3, open-label, multicenter, noninferiority trial involving patients who had had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy, we randomly assigned participants (1:1) to either continue their oral therapy or switch to monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and long-acting rilpivirine, a nonnucleoside reverse-transcriptase inhibitor. The primary end point was the percentage of participants with an HIV-1 RNA level of 50 copies per milliliter or higher at week 48, determined with the use of the Food and Drug Administration snapshot algorithm.