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

Landovitz, Raphael J.; Li, Sue; Eron, Joseph J.; Grinsztejn, Beatriz; Dawood, Halima; Liu, Albert Y.; Magnus, Manya; Hosseinipour, Mina C.; Panchia, Ravindre; Cottle, Leslie; Chau, Gordon; Richardson, Paul; Marzinke, Mark A.; Eshleman, Susan H.; Kofron, Ryan; Adeyeye, Adeola; Burns, David; Rinehart, Alex; Margolis, David; Cohen, Myron S.; McCauley, Marybeth; Hendrix, Craig W.

doi:10.1016/s2352-3018(20)30106-5

Cited by 112 publications

(113 citation statements)

References 20 publications

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“… 43 A prespecified analysis focused on the pharmacokinetic tail phase after the last IM dose. 44 At 52–60 weeks after the last injection, 23% of men versus 63% of women still had detectable cabotegravir concentrations; at 76 weeks, these rates were 13% of men versus 42% of women. The mean time from last dose to undetectability was much longer for women than for men (67.3 vs. 43.7 weeks).…”

Section: Challenges With Long-acting Therapymentioning

confidence: 95%

The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data?

Scarsi

Swindells

2021

J Int Assoc Provid AIDS Care

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As with other chronic conditions, adherence to daily medications remains a challenge for many individuals living with HIV due to structural, behavioral, and social barriers. Unfortunately, high levels of adherence to antiretroviral therapy are required to maintain virologic suppression. Alternative approaches are being explored to decrease the burden of daily pill administration, including long-acting injectable, oral, and implantable products. Phase 3 data support the efficacy of nanoformulated injectable cabotegravir and rilpivirine for HIV treatment in patients with undetectable viremia, but we have yet to learn how this strategy may benefit those with medication adherence challenges. Despite this, the affected community and HIV providers are very interested in exploring the role of long-acting therapies to address some types of barriers to medication adherence. This review summarizes available information about the potential for long-acting therapy to improve adherence for some patients and outlines associated opportunities and challenges with the implementation of long-acting therapy for the treatment and prevention of HIV.

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Section: Challenges With Long-acting Therapymentioning

confidence: 95%

The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data?

Scarsi

Swindells

2021

J Int Assoc Provid AIDS Care

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“…Of note, the Canadian and US product information for Cabenuva (long-acting cabotegravir/rilpivirine) advises using a longer needle when administering the product to patients with a body mass index (BMI) > 30 kg/m 2 , to ensure intramuscular delivery as opposed to subcutaneous delivery [ 13 , 14 ]. The ECLAIR2 and HPTN 077 trials used a needle of 2 inches for participants with a BMI > 30 kg/m 2 and a needle of 1.5 inches for participants with a BMI < 30 kg/m 2 [ 15 , 16 ]; the ECLAIR2 trial noted changes in pharmacokinetic parameters associated with high BMI and/or longer needle length. Maximal concentration ( C max ) and the area under the curve (AUC) were higher in participants with a BMI below the median, while the concentration at the end of the dosing interval ( C trough ) was lower [ 16 ], although phase III trials have shown that lower C trough does not persist through week 48 [ 17 ].…”

Section: Intramuscular Administration Of Drugsmentioning

confidence: 99%

“…Maximal concentration ( C max ) and the area under the curve (AUC) were higher in participants with a BMI below the median, while the concentration at the end of the dosing interval ( C trough ) was lower [ 16 ], although phase III trials have shown that lower C trough does not persist through week 48 [ 17 ]. There are also gender differences in adipose layer thickness, which may result in different pharmacokinetics between men and women, as reported for both intramuscular cabotegravir and rilpivirine [ 15 , 18 ]. Other factors affecting the absorption and bioavailability of intramuscular injections include exercise and local blood flow (with greater drug absorption in the case of increased blood flow in the muscle) [ 11 ].…”

Section: Intramuscular Administration Of Drugsmentioning

confidence: 99%

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Pharmacokinetics and Drug–Drug Interactions of Long-Acting Intramuscular Cabotegravir and Rilpivirine

et al. 2021

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Combined antiretroviral treatments have significantly improved the morbidity and mortality related to HIV infection, thus transforming HIV infection into a chronic disease; however, the efficacy of antiretroviral treatments is highly dependent on the ability of infected individuals to adhere to life-long drug combination therapies. A major milestone in HIV treatment is the marketing of the long-acting intramuscular antiretroviral drugs cabotegravir and rilpivirine, allowing for infrequent drug administration, with the potential to improve adherence to therapy and treatment satisfaction. Intramuscular administration of cabotegravir and rilpivirine leads to differences in pharmacokinetics and drug-drug interaction (DDI) profiles compared with oral administration. A notable difference is the long elimination half-life with intramuscular administration, which reaches 5.6-11.5 weeks for cabotegravir and 13-28 weeks for rilpivirine, compared with 41 and 45 h, respectively, with their oral administration. Cabotegravir and rilpivirine have a low potential to cause DDIs, however these drugs can be victims of DDIs. Cabotegravir is mainly metabolized by UGT1A1, and rilpivirine is mainly metabolized by CYP3A4, therefore these agents are susceptible to DDIs with inhibitors, and particularly inducers of drug-metabolizing enzymes. Intramuscular administration of cabotegravir and rilpivirine has the advantage of eliminating DDIs occurring at the gastrointestinal level, however interactions can still occur at the hepatic level. This review provides insight on the intramuscular administration of drugs and summarizes the pharmacology of long-acting cabotegravir and rilpivirine. Particular emphasis is placed on DDI profiles after oral and intramuscular administration of these antiretroviral drugs.

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“…Cabotegravir in advanced stages of clinical trials, look promising for its use as long acting injectable with monthly or bimonthly administration for pre-exposure prophylaxis use and treatment of HIV infection. It has shown better safety profile and high acceptability in low risk uninfected participants in on-going clinical trial HPTN 077 [52]. Though there is possibility of cross resistance with already approved INSTIs through Q148 pathway, it still provides better alternative.…”

Section: Main Bodymentioning

confidence: 99%

The urgent need for more potent antiretroviral therapy in low-income countries to achieve UNAIDS 90-90-90 and complete eradication of AIDS by 2030

Ndashimye

Arts

2019

Infect Dis Poverty

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Background Over 90% of Human Immunodeficiency Virus (HIV) infected individuals will be on treatment by 2020 under UNAIDS 90–90-90 global targets. Under World Health Organisation (WHO) “Treat All” approach, this number will be approximately 36.4 million people with over 98% in low-income countries (LICs). Main body Pretreatment drug resistance (PDR) largely driven by frequently use of non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz and nevirapine, has been increasing with roll-out of combined antiretroviral therapy (cART) with 29% annual increase in some LICs countries. PDR has exceeded 10% in most LICs which warrants change of first line regimen to more robust classes under WHO recommendations. If no change in regimens is enforced in LICs, it’s estimated that over 16% of total deaths, 9% of new infections, and 8% of total cART costs will be contributed by HIV drug resistance by 2030. Less than optimal adherence, and adverse side effects associated with currently available drug regimens, all pose a great threat to achievement of 90% viral suppression and elimination of AIDS as a public health threat by 2030. This calls for urgent introduction of policies that advocate for voluntary and compulsory drug licensing of new more potent drugs which should also emphasize universal access of these drugs to all individuals worldwide. Conclusions The achievement of United Nations Programme on HIV and AIDS 2020 and 2030 targets in LICs depends on access to active cART with higher genetic barrier to drug resistance, better safety, and tolerability profiles. It’s also imperative to strengthen quality service delivery in terms of retention of patients to treatment, support for adherence to cART, patient follow up and adequate drug stocks to help achieve a free AIDS generation. Electronic supplementary material The online version of this article (10.1186/s40249-019-0573-1) contains supplementary material, which is available to authorized users.

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

Cited by 112 publications

References 20 publications

The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data?

The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data?

Pharmacokinetics and Drug–Drug Interactions of Long-Acting Intramuscular Cabotegravir and Rilpivirine

The urgent need for more potent antiretroviral therapy in low-income countries to achieve UNAIDS 90-90-90 and complete eradication of AIDS by 2030

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