Review

Authors: Jean B Nachega, Kimberly K Scarsi, Monica Gandhi...

Intramuscular injection of long-acting cabotegravir and rilpivirine is a novel, long-acting antiretroviral therapy (ART) combination approved for use as a fully suppressive regimen for people living with HIV. Long-acting cabotegravir with rilpivirine ART has reduced required dosing frequency from once daily to once every month or every 2 months injections. This new era of long-acting ART, which includes other antiretrovirals and formulations in various stages of clinical development, holds tremendous promise to change the standard of HIV treatment. Although long-acting ART has high potential to be revolutionary in the landscape of HIV care, prevention, and treatment cascade, more data are needed to substantiate its efficacy and cost-effectiveness among patients at risk of non-adherence and across age groups, pregnancy, and post partum. Advocacy efforts and policy changes to optimise a sustained, high-quality, equitable reach of long-acting ART, especially in low-income and middle-income countries where most people living with HIV reside, are needed to realise the full benefits of long-acting ART.

Topics: Humans; Anti-HIV Agents; HIV Infections; Anti-Retroviral Agents; Rilpivirine; Injections, Intramuscular

PubMed: 37062293
DOI: 10.1016/S2352-3018(23)00051-6

Review

Authors: Guangdi Li, Yali Wang, Erik De Clercq...

HIV reverse transcriptase (RT) inhibitors are the important components of highly active antiretroviral therapies (HAARTs) for anti-HIV treatment and pre-exposure prophylaxis in clinical practice. Many RT inhibitors and their combination regimens have been approved in the past ten years, but a review on their drug discovery, pharmacology, and clinical efficacy is lacking. Here, we provide a comprehensive review of RT inhibitors (tenofovir alafenamide, rilpivirine, doravirine, dapivirine, azvudine and elsulfavirine) approved in the past decade, regarding their drug discovery, pharmacology, and clinical efficacy in randomized controlled trials. Novel RT inhibitors such as islatravir, MK-8504, MK-8507, MK8583, IQP-0528, and MIV-150 will be also highlighted. Future development may focus on the new generation of novel antiretroviral inhibitors with higher bioavailability, longer elimination half-life, more favorable side-effect profiles, fewer drug-drug interactions, and higher activities against circulating drug-resistant strains.

PubMed: 35847492
DOI: 10.1016/j.apsb.2021.11.009

Review

Authors: Charles Flexner, Andrew Owen, Marco Siccardi...

Long-acting and extended-release formulations represent one of the most important approaches to improving the treatment and prevention of chronic HIV infection. Long-acting small molecules and monoclonal antibodies have demonstrated potent anti-HIV activity in early- and late-stage clinical trials. Strategies to manage toxicity and falling drug concentrations after missed doses, as well as primary and secondary resistance to current drugs and monoclonal antibodies are important considerations. Long-acting injectable nanoformulations of the integrase inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitor rilpivirine were safe, well tolerated and efficacious in large randomised phase 3 studies. Regulatory approval for this two-drug combination for HIV maintenance therapy was granted in Canada in 2020 and is expected in the USA during 2021. 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (islatravir) is a novel nucleoside reverse transcriptase inhibitor in clinical development as a long-acting oral drug and as a long-acting subcutaneous polymer implant. GS-6207 is a novel HIV capsid inhibitor that is injected subcutaneously every 3 months. Broadly-neutralising monoclonal antibodies have potent antiviral activity in early human trials, however there is substantial baseline resistance and rapid development of resistance to these antibodies if used as monotherapy. Limitations of these antiretroviral approaches include management of toxicities and prevention of drug resistance when these drugs are discontinued and drug concentrations are slowly reduced over time. These approaches appear to be especially attractive for patients complaining of pill fatigue and for those experiencing HIV-associated stigma. As these formulations are shown to be safe, well tolerated and economical, they are likely to gain broader appeal.

Topics: Anti-HIV Agents; Canada; Delayed-Action Preparations; Deoxyadenosines; Drug Combinations; Drug Delivery Systems; HIV Antibodies; HIV Infections; HIV-1; Humans; Pyridones; Rilpivirine

PubMed: 33166693
DOI: 10.1016/j.ijantimicag.2020.106220

Authors: Amy G Cutrell, Jonathan M Schapiro, Carlo F Perno...

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. In a separate model, baseline factors statistically associated with CVF were further evaluated to understand CVF risk when present alone or in combination.

RESULTS

Overall, 1.25% (n = 13/1039) of participants experienced CVF. Proviral RPV resistance-associated mutations (RAMs), HIV-1 subtype A6/A1, higher BMI (associated with Week 8 CAB trough concentration) and lower Week 8 RPV trough concentrations were significantly associated (P < 0.05) with increased odds of CVF (all except RPV trough are knowable at baseline). Few participants (0.4%) with zero or one baseline factor had CVF. Only a combination of at least two baseline factors (observed in 3.4%; n = 35/1039) was associated with increased CVF risk (25.7%, n = 9/35).

CONCLUSION

CVF is an infrequent multifactorial event, with a rate of approximately 1% in the long-acting CAB+RPV arms across Phase 3 studies (FLAIR, ATLAS and ATLAS-2M) through Week 48. Presence of at least two of proviral RPV RAMs, HIV-1 subtype A6/A1 and/or BMI at least 30 kg/m2 was associated with increased CVF risk. These findings support the use of long-acting CAB+RPV in routine clinical practice.

Topics: Adult; Anti-HIV Agents; HIV Infections; HIV-1; Humans; Pyridones; Rilpivirine

PubMed: 33730748
DOI: 10.1097/QAD.0000000000002883

Observational Study

Authors: Monica Gandhi, Matthew Hickey, Elizabeth Imbert...

BACKGROUND

Intramuscular cabotegravir (CAB) and rilpivirine (RPV) is the only long-acting antiretroviral therapy (LA-ART) regimen approved for people with HIV (PWH). Long-acting ART holds promise for improving outcomes among populations with barriers to adherence but is only approved for PWH who have virologic suppression with use of oral ART before initiating injectables.

OBJECTIVE

To examine LA-ART in a population of PWH that includes those with viremia.

DESIGN

Observational cohort study.

SETTING

Urban academic safety-net HIV clinic.

PATIENTS

Publicly insured adults living with HIV with and without viral suppression, high rates of unstable housing, mental illness, and substance use.

INTERVENTION

Demonstration project of long-acting injectable CAB-RPV.

MEASUREMENTS

Descriptive statistics summarizing cohort outcomes to date, based on pharmacy team logs and electronic medical record data.

RESULTS

Between June 2021 and November 2022, 133 PWH at the Ward 86 HIV Clinic were started on LA-ART, 76 of whom had virologic suppression while using oral ART and 57 of whom had viremia. The median age was 46 years (IQR, 25 to 68 years); 117 (88%) were cisgender men, 83 (62%) had non-White race, 56 (42%) were experiencing unstable housing or homelessness, and 45 (34%) had substance use. Among those with virologic suppression, 100% (95% CI, 94% to 100%) maintained suppression. Among PWH with viremia, at a median of 33 days, 54 of 57 had viral suppression, 1 showed the expected 2-log reduction in HIV RNA level, and 2 experienced early virologic failure. Overall, 97.5% (CI, 89.1% to 99.8%) were projected to achieve virologic suppression by a median of 33 weeks. The current virologic failure rate of 1.5% in the cohort is similar to that across registrational clinical trials at 48 weeks.

LIMITATION

Single-site study.

CONCLUSION

This project demonstrates the ability of LA-ART to achieve virologic suppression among PWH, including those with viremia and challenges to adherence. Further data on the ability of LA-ART to achieve viral suppression in people with barriers to adherence are needed.

PRIMARY FUNDING SOURCE

National Institutes of Health, City and County of San Francisco, and Health Resources and Services Administration.

Topics: Adult; Male; Humans; Middle Aged; Anti-HIV Agents; Viremia; HIV Infections; Rilpivirine; Cohort Studies; Viral Load

PubMed: 37399555
DOI: 10.7326/M23-0788

Randomized Controlled Trial

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.

Authors: Edgar T Overton, Gary Richmond, Giuliano Rizzardini...

BACKGROUND

Cabotegravir (CAB) + rilpivirine (RPV) dosed intramuscularly monthly or every 2 months is a complete, long-acting (LA) regimen for the maintenance of HIV-1 virologic suppression. Here, we report the antiretroviral therapy as long acting suppression (ATLAS)-2M study week 152 results.

METHODS

ATLAS-2M is a phase 3b, randomized, multicenter study assessing the efficacy and safety of CAB+RPV LA every 8 weeks (Q8W) versus every 4 weeks (Q4W). Virologically suppressed (HIV-1 RNA <50 copies/mL) individuals were randomized to receive CAB+RPV LA Q8W or Q4W. Endpoints included the proportion of participants with plasma HIV-1 RNA ≥50 copies/mL and <50 copies/mL, incidence of confirmed virologic failure (CVF; 2 consecutive measurements ≥200 copies/mL), safety, and tolerability.

RESULTS

A total of 1045 participants received CAB+RPV LA (Q8W, n = 522; Q4W, n = 523). CAB+RPV LA Q8W demonstrated noninferior efficacy versus Q4W dosing, with 2.7% (n = 14) and 1.0% (n = 5) of participants having HIV-1 RNA ≥50 copies/mL, respectively, with adjusted treatment difference being 1.7% (95% CI: 0.1-3.3%), meeting the 4% noninferiority threshold. At week 152, 87% of participants maintained HIV-1 RNA <50 copies/mL (Q8W, 87% [n = 456]; Q4W, 86% [n = 449]). Overall, 12 (2.3%) participants in the Q8W arm and 2 (0.4%) in the Q4W arm had CVF. Eight and 10 participants with CVF had treatment-emergent, resistance-associated mutations to RPV and integrase inhibitors, respectively. Safety profiles were comparable, with no new safety signals observed since week 48.

CONCLUSIONS

These data demonstrate virologic suppression durability with CAB+RPV LA Q8W or Q4W for ∼3 years and confirm long-term efficacy, safety, and tolerability of CAB+RPV LA as a complete regimen to maintain HIV-1 virologic suppression.

Topics: Adult; Humans; Anti-HIV Agents; Anti-Retroviral Agents; HIV Infections; HIV Seropositivity; HIV-1; Rilpivirine; RNA, Viral; Viral Load

PubMed: 36660819
DOI: 10.1093/cid/ciad020

Review

Authors: Mariana Pereira, Nuno Vale

Rilpivirine is an antiretroviral drug used to treat AIDS worldwide. The drug is a non-nucleoside reverse transcriptase inhibitor that halts the cDNA elongation process and, thus, the capacity of the HIV-1 virus to replicate. With the new wave of drug repurposing in recent years, rilpivirine has been studied in this regard. This drug is useful in Zika virus treatment, with in vivo results indicating regression in neuronal effects often associated with this infection. Several cancer types have also been researched, from breast to leukemia and pancreatic cancer, and rilpivirine has proved to have inhibitory effects in various cell lines with low concentrations, causing cellular death, apoptosis, and cell cycle arrest. The pathways are not yet established, but some works have hypothesized and demonstrated that rilpivirine causes inhibition of Aurora A kinase and has effects on the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway and the vascular endothelial growth factors-receptors (VEGFs-VEGFRs) pathway, which are known to be altered in cancer and tumors and can be targeted for cancer treatment. Further testing and clinical trials are needed, but this review demonstrates the potential of rilpivirine's repurposing for cancer treatment.

Topics: Humans; Rilpivirine; Anti-Retroviral Agents; Reverse Transcriptase Inhibitors; HIV-1; Zika Virus; HIV Infections; Zika Virus Infection; Anti-HIV Agents

PubMed: 36769210
DOI: 10.3390/ijms24032890