We analyzed the effect of time to initiation of antiretroviral therapy (ART) after diagnosis on the probability of HIV-1 transmission events (HIV-TE) in naïve HIV-1-infected men having sex with men ...(MSM).
Mathematical model.
We used discrete event simulation modeling to estimate the probability of HIV-TE in the first 8 weeks after ART initiation; we varied ART initiation from D0 to D28 after simulated "diagnosis". The model inputs used sexual behavior parameters from the MSM population of the START trial, and transmission rates per-sex act and HIV-1 RNA from recent meta-analyses. HIV-1 RNA decay curves were modeled from the databases of Single (efavirenz EFV v dolutegravir DTG), Spring-2 (raltegravir RAL v DTG), and Flamingo (darunavir/ritonavir DRVr v DTG) trials.
We found that the number of HIV-TE per index patient in the first 8 weeks after ART initiation increased linearly for same-day ART to initiation on day 28. Small but statistically significant advantages of integrase strand transfer inhibitors (INSTI) over EFV and DRVr were found.
Rapid, if not same-day initiation of INSTI-based ART to newly diagnosed HIV-infected MSM has the potential for substantial public health benefits related to decreases in HIV-TE.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Long-acting injectable (LAI) antiretroviral therapy (ART) is a novel HIV treatment option for people with HIV. The first LAI ART regimen for HIV treatment received regulatory approval in the United ...States in January 2021. In February 2020, we collected qualitative data from 18 consumers and 23 clinical and non-clinical stakeholders to catalog anticipated individual-consumer, healthcare system, and structural levels barriers and facilitators to LAI ART implementation in Los Angeles County, California. Thematic analysis was guided by the CFIR implementation science model. CFIR constructs of intervention characteristics, individual characteristics, outer and inner setting, intervention characteristics, and implementation process emerged in analysis. Under intervention characteristics, anticipated facilitators included the relative advantage of LAI ART over pills for adherence and reduced treatment management burden and related anxiety; anticipated barriers included non-adherence to injection appointments, concerns of developing HIV resistance, discomfort with injection and cost. Anticipated facilitators based on individual characteristics included overall acceptability based on knowledge and positive beliefs about LAI ART. Participant noted several characteristics of the outer setting that could negatively impact implementation, such as medical mistrust, external policies, and LAI ART eligibility (i.e., to be virally suppressed prior to initiation). Participants were optimistic about the potential to decrease stigma but expressed that provider willingness for adoption could be hindered by challenges in organizational inner setting related to payment authorizations, increased staffing needs, medication procurement and storage, and provider and healthcare system readiness. Results from this pre-implementation study may inform rollout and scale-up of LAI ART in Los Angeles County.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Antiviral medication has emerged as an important tool in the prevention of HIV infection. In this randomized, controlled trial, an injectable long-acting agent, cabotegravir, was found to be superior ...to daily oral tenofovir disoproxil fumarate–emtricitabine in preventing incident HIV infection in cisgender men and transgender women who have sex with men.
Initiation of antiretroviral therapy (ART) for HIV infection using regimens that include integrase strand transfer inhibitors (INSTIs) is associated with a faster decline in HIV-1 RNA than what is ...observed with regimens that are anchored by other ART drug classes. We compared the impact of ART regimens that include dolutegravir (DTG), raltegravir (RAL), efavirenz (EFV), or darunavir/ritonavir (DRV/r), in treatment naïve men who have sex with men (MSM) on the probability of HIV-1 sexual transmission events (HIV-TE).
Mathematical model.
We used discrete event simulation modeling to estimate HIV-TE during the first 8 weeks after initiation of ART. HIV-1 RNA decay in men was modeled from the databases of three clinical trials: Single (DTG vs. EFV), Spring-2 (DTG vs. RAL) and Flamingo (DTG vs. DRV/r).
All regimens substantially reduced the number of HIV-TE compared to no treatment. DTG led to fewer HIV-TE than its comparator in each of the three trials: 22.72% fewer transmissions than EFV; 0.52% fewer transmissions than RAL; and 38.67% fewer transmissions than DRV/r. The number of patients needed to treat with DTG to prevent one transmission event instead of comparator was 48 vs EFV, 2,194 vs RAL, and 31 vs DRV/r.
Unsurprisingly, this mathematical model showed that all regimens reduced HIV-TE compared to no treatment. The results also suggest that that initial use of INSTIs, by virtue of their superior viral decay kinetics, have the potential to reduce HIV-1 horizontal transmission following initiation of ART in naïve MSM.
ClinicalTrials.gov NCT03183154.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PURPOSE OF REVIEWPreexposure prophylaxis for HIV prevention is highly effective when taken as prescribed. Adherence to required dosing regimens for protection may pose challenges. Long-acting agents ...for HIV prevention may have the potential to improve adherence via favorable pharmacokinetics supportive of infrequent dosing. This review focuses on the potential benefits and considerations for the study and use of 2 long-acting injectable agents, cabotegravir (GSK1265744LA, CAB LA) and rilpivirine (TMC278LA, RPV LA), for use as chemoprophylaxis for HIV prevention.
RECENT FINDINGSOral RPV is United States Food and Drug Administration approved for HIV treatment (in combination with other antiretrovirals). Both CAB LA and RPV LA are currently in phase 2a safety/tolerability/pharmacokinetic studies in anticipation and support of future efficacy evaluation. Both agents have favorable pharmacokinetics, and use is complicated by injection site reactions.
SUMMARYLong-acting injectable formulations, if safe and well tolerated, may improve pharmacokinetic coverage of exposures to HIV infection. Complexities around safety, tolerability, and starting/stopping protocols require careful consideration.
A global human immunodeficiency virus (HIV) epidemic persists despite data to support multiple effective and safe tools that prevent HIV transmission and acquisition. Human immunodeficiency virus ...preexposure prophylaxis (PrEP) for HIV-uninfected at-risk populations using tenofovir disoproxil fumarate emtricitabine is highly effective, safe, and recently endorsed by the US Preventive Services Task Force (USPSTF) as a grade A recommendation. In this Special Communication, we summarize current guidelines and expert recommendations in a call for wider adoption of PrEP prescribing activities by frontline primary care clinicians. Key components include the ideal contexts in which PrEP may be prescribed, eligibility criteria, clinical considerations and pitfalls, laboratory monitoring, prescription practices, situations that may warrant expert consultation, and future directions. Given the broad scope, access, and point-of-entry status of primary clinicians in health systems, generalists will need to be at the center of any successful effort to leverage the power of, and destigmatize PrEP to end the HIV epidemic.
PURPOSE OF REVIEWThis review highlights the development of long-acting injectable cabotegravir (CAB LA) for HIV preexposure prophylaxis (PrEP), with a focus on phase 2 studies and later development.
...RECENT FINDINGSEarly studies of CAB LA for HIV prevention offered promising pharmacokinetic data and paved the way for phase 2 studies, which have now been completed. On the basis of phase 2 data, dosing of CAB LA at 8-week intervals consistently delivers target trough concentrations in both men and women. Recent studies have shown no required dose adjustments for hepatic or renal disease and minimal drug--drug interactions. Additionally, injectable PrEP is desired by potential PrEP candidates. Still, gaps in knowledge remain with respect to implementation and delivery, the clinical significance of the pharmacologic tail, and dosing in key populations. Phase 3 trials are underway that are anticipated to inform some of these questions and provide efficacy and safety data to support regulatory submissions for CAB LA as a potential PrEP agent.
SUMMARYRecent studies have defined an appropriate CAB LA dosing interval and offered insight into its safety profile. Phase 3 studies will provide much-anticipated efficacy data. If efficacious, CAB LA may provide a desirable PrEP option for those who face challenges to daily pill adherence. A more complete understanding of how to best integrate LA PrEP into service delivery models will be critical for success.
Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration ...and as a long-acting injectable suspension (long-acting CAB CAB LA) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States.
HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population.
In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress.
ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Data on the use of antiretroviral drugs, including new drugs and formulations, for the treatment and prevention of HIV infection continue to guide optimal practices. OBJECTIVE: To ...evaluate new data and incorporate them into current recommendations for initiating HIV therapy, monitoring individuals starting on therapy, changing regimens, preventing HIV infection for those at risk, and special considerations for older people with HIV. EVIDENCE REVIEW: New evidence was collected since the previous International Antiviral (formerly AIDS) Society–USA recommendations in 2018, including data published or presented at peer-reviewed scientific conferences through August 22, 2020. A volunteer panel of 15 experts in HIV research and patient care considered these data and updated previous recommendations. FINDINGS: From 5316 citations about antiretroviral drugs identified, 549 were included to form the evidence basis for these recommendations. Antiretroviral therapy is recommended as soon as possible for all individuals with HIV who have detectable viremia. Most patients can start with a 3-drug regimen or now a 2-drug regimen, which includes an integrase strand transfer inhibitor. Effective options are available for patients who may be pregnant, those who have specific clinical conditions, such as kidney, liver, or cardiovascular disease, those who have opportunistic diseases, or those who have health care access issues. Recommended for the first time, a long-acting antiretroviral regimen injected once every 4 weeks for treatment or every 8 weeks pending approval by regulatory bodies and availability. For individuals at risk for HIV, preexposure prophylaxis with an oral regimen is recommended or, pending approval by regulatory bodies and availability, with a long-acting injection given every 8 weeks. Monitoring before and during therapy for effectiveness and safety is recommended. Switching therapy for virological failure is relatively rare at this time, and the recommendations for switching therapies for convenience and for other reasons are included. With the survival benefits provided by therapy, recommendations are made for older individuals with HIV. The current coronavirus disease 2019 pandemic poses particular challenges for HIV research, care, and efforts to end the HIV epidemic. CONCLUSION AND RELEVANCE: Advances in HIV prevention and management with antiretroviral drugs continue to improve clinical care and outcomes among individuals at risk for and with HIV.
IMPORTANCE: Recent advances in treatment and prevention of HIV warrant updated recommendations to guide optimal practice. OBJECTIVE: Based on a critical evaluation of new data, to provide clinicians ...with recommendations on use of antiretroviral drugs for the treatment and prevention of HIV, laboratory monitoring, care of people aging with HIV, substance use disorder and HIV, and new challenges in people with HIV, including COVID-19 and monkeypox virus infection. EVIDENCE REVIEW: A panel of volunteer expert physician scientists were appointed to update the 2020 consensus recommendations. Relevant evidence in the literature (PubMed and Embase searches, which initially yielded 7891 unique citations, of which 834 were considered relevant) and studies presented at peer-reviewed scientific conferences between January 2020 and October 2022 were considered. FINDINGS: Initiation of antiretroviral therapy (ART) is recommended as soon as possible after diagnosis of HIV. Barriers to care should be addressed, including ensuring access to ART and adherence support. Integrase strand transfer inhibitor–containing regimens remain the mainstay of initial therapy. For people who have achieved viral suppression with a daily oral regimen, long-acting injectable therapy with cabotegravir plus rilpivirine given as infrequently as every 2 months is now an option. Weight gain and metabolic complications have been linked to certain antiretroviral medications; novel strategies to ameliorate these complications are needed. Management of comorbidities throughout the life span is increasingly important, because people with HIV are living longer and confronting the health challenges of aging. In addition, management of substance use disorder in people with HIV requires an evidence-based, integrated approach. Options for preexposure prophylaxis include oral medications (tenofovir disoproxil fumarate or tenofovir alafenamide plus emtricitabine) and, for the first time, a long-acting injectable agent, cabotegravir. Recent global health emergencies, like the SARS-CoV-2 pandemic and monkeypox virus outbreak, continue to have a major effect on people with HIV and the delivery of services. To address these and other challenges, an equity-based approach is essential. CONCLUSIONS AND RELEVANCE: Advances in treatment and prevention of HIV continue to improve outcomes, but challenges and opportunities remain.
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