Impact of switching to injectables cabotegravir and rilpivirine on sleep disturbances in a cohort of people living with HIV.

BACKGROUND: Recently, injectable cabotegravir/rilpivirine (ICAB/RPV) became available for HIV treatment. However, there are no real-life data on the impact of switching to ICAB/RPV on sleep disturbances (SD). Therefore, we aimed at assessing and investigating this aspect in our cohort. METHODS: A SD multidimensional assessment (Epworth Sleepiness scale, Insomnia severity Index, Berlin Questionnaire, and Pittsburg Sleep Quality Index, PSQI) was performed to all people who consented before starting ICAB/RPV and 12 wk after the switch. Demographics, life-style habits, laboratory, and clinical data were collected from medical health records. RESULTS: To June 2023, 46 people were included, 76.1% males, with a median age of 48.5 (IQR: 41-57), 50% had multimorbidity, 13% was on polypharmacy. Median age with HIV and CD4 + T cell count nadir were 10 (5-19.5) years and 360 (205-500) cell/mm3, respectively. The reason to start a long-acting strategy was person's choice in all cases. Baseline antiretroviral regimens were mostly: tenofovir alafenamide/emtricitabine/rilpivirine (39.1%) and dolutegravir/lamivudine (32.6%). No significant changes were observed in any of the scores for each questionnaire, but for a worsening PSQI. 37% people reported a subjectively improved sleep quality, even if statistically significant changes were not observed in almost all the sleep parameters. CONCLUSIONS: To the best of our knowledge, this is the first study exploring impact of switching to ICAB/RPV on SD. Despite integrase inhibitor have been associated with SD, we did not observed a negative impact on sleep quality after the switch to ICAB/RPV. More studies and with larger number of people are necessary to confirm our results.

Long-Acting Injectable ART in Practice: A Mixed Methods Implementation Study Assessing the Feasibility of Using LAI ART in High Risk Populations and At Alternative Low Barrier Care Sites.

Long-acting injectable (LAI) antiretroviral therapy (ART) has the potential to change the lives of people living with HIV (PLWH). To ensure equitable access to new treatment modalities, we examined the feasibility and acceptability of administering Cabotegravir Rilpivirine Long Acting (CAB/RPV LA) to individuals who experience challenging social determinants of health (SDoH) and struggle with adherence to traditional oral ART. Quantitative and qualitative data were used to assess feasibility of utilizing ART at alternative clinic. Data were collected on individuals eligible to receive CAB/RPV LA at an alternative street-based clinic and on individuals receiving CAB/RPV LA at a traditional HIV clinic. After 6 months, participants were interviewed about their experience. Providers involved in the implementation were also interviewed about their experiences. Only one participant (out of 5) who received CAB/RPV LA at the alternative clinic received consistent treatment, whereas 17 out of 18 participants receiving CAB/RPV LA at the traditional clinic site were adherent. Participants and providers believed that LAI had potential for making treatment adherence easier, but identified several barriers, including discrepancies between patients' desires and their lifestyles, impact of LAI on interactions with the medical system, risk of resistance accompanying sub-optimal adherence, and need for a very high level of resources. While LAI has major potential benefits for high-risk patients, these benefits must be balanced with the complexities of implementation. Despite challenges that impacted study outcomes, improving treatment outcomes for PLWH requires addressing SDoH and substance use.

Development of a physiologically-based pharmacokinetic model to simulate the pharmacokinetics of intramuscular antiretroviral drugs.

There is growing interest in the use of long-acting (LA) injectable drugs to improve treatment adherence. However, their long elimination half-life complicates the conduct of clinical trials. Physiologically-based pharmacokinetic (PBPK) modeling is a mathematical tool that allows to simulate unknown clinical scenarios for LA formulations. Thus, this work aimed to develop and verify a mechanistic intramuscular PBPK model. The framework describing the release of a LA drug from the depot was developed by including both the physiology of the injection site and the physicochemical properties of the drug. The framework was coded in Matlab® 2020a and implemented in our existing PBPK model for the verification step using clinical data for LA cabotegravir, rilpivirine, and paliperidone. The model was considered verified when the simulations were within twofold of observed data. Furthermore, a local sensitivity analysis was conducted to assess the impact of various factors relevant for the drug release from the depot on pharmacokinetics. The PBPK model was successfully verified since all predictions were within twofold of observed clinical data. Peak concentration, area under the concentration-time curve, and trough concentration were sensitive to media viscosity, drug solubility, drug density, and diffusion layer thickness. Additionally, inflammation was shown to impact the drug release from the depot. The developed framework correctly described the release and the drug disposition of LA formulations upon intramuscular administration. It can be implemented in PBPK models to address pharmacological questions related to the use of LA formulations.

Rilpivirine and cabotegravir trough concentrations in people with HIV on long-term treatment with long-acting injectable antiretrovirals.

OBJECTIVE: Large inter-individual variability in the pharmacokinetics of rilpivirine and cabotegravir has been reported in the first weeks after starting long-acting injectable (LAI) therapy. Here, we assessed the distribution of rilpivirine and cabotegravir trough concentrations in people with HIV (PWH) on long-term LAI treatment. METHODS: Adult PWH treated with LAI for at least 32 weeks with an assessment of drug plasma trough concentrations were considered. The proportion of rilpivirine and cabotegravir plasma trough concentrations below four-times the protein-adjusted concentrations required for 90% inhibition of viral replication (4×PA-IC90) was estimated. RESULTS: Sixty-seven PWH were identified. LAI treatment duration was 216 ±â€Š80 weeks (range 32-320 weeks). Cabotegravir concentrations were associated with lower inter-individual variability compared with rilpivirine (45% versus 84%; P < 0.05). No differences were found in rilpivirine (160 ±â€Š118 versus 189 ±â€Š81 ng/mL; P = 0.430) and cabotegravir (1758 ±â€Š807 versus 1969 ±â€Š802 ng/mL; P = 0.416) trough concentrations in males (n = 55) versus females (n = 12). A non-significant trend for lower cabotegravir concentrations was found in PWH with a body mass index >30 kg/m2 (n = 9) versus non-obese participants (1916 ±â€Š905 versus 1606 ±â€Š576 ng/mL; P = 0.131). Three out of the 67 PWH had at least one drug concentration <4×PA-IC90: 100% of PWH had undetectable HIV viral load. CONCLUSIONS: At steady state, optimal systemic exposure of cabotegravir and rilpivirine was found in most PWH; cabotegravir trough concentrations were associated with lower inter-individual variability compared with rilpivirine. The study was not powered to assess the contribution of sex and/or body weight on LAI exposure due to the small number of females and obese PWH included.

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.

The potential role of long-acting injectable cabotegravir-rilpivirine in the treatment of HIV in sub-Saharan Africa: a modelling analysis.

BACKGROUND: The use of a combination of the integrase inhibitor, cabotegravir, and the non-nucleoside reverse transcriptase inhibitor, rilpivirine, in a long-acting injectable form is being considered as an antiretroviral treatment option for people with HIV in sub-Saharan Africa. We aimed to model the effects of injectable cabotegravir-rilpivirine to help to inform its potential effectiveness and cost-effectiveness under different possible policies for its introduction. METHODS: We used an existing individual-based model of HIV to predict the effects of introducing monthly injections of cabotegravir-rilpivirine for people with HIV in low-income settings in sub-Saharan Africa. We evaluated policies in the context of 1000 setting scenarios that reflected characteristics of HIV epidemics and programmes in sub-Saharan Africa. We compared three policies for introduction of injectable cabotegravir-rilpivirine with continued use of dolutegravir-based oral regimens for: all individuals on antiretroviral therapy (ART); individuals with a recently measured viral load of more than 1000 copies per mL (signifying poor adherence to oral drugs, and often associated with drug resistance); and individuals with a recently measured viral load of less than 1000 copies per mL (a group with a lower prevalence of pre-existing drug resistance). We also did cost-effectiveness analysis, taking a health system perspective over a 10 year period, with 3% discounting of disability-adjusted life-years (DALYs) and costs. A cost-effectiveness threshold of US$500 per DALY averted was used to establish if a policy was cost-effective. FINDINGS: In our model, all policies involving the introduction of injectable cabotegravir-rilpivirine were predicted to lead to an increased proportion of people with HIV on ART, increased viral load suppression, and decreased AIDS-related mortality, with lesser benefits in people with a recently measured viral load of less than 1000 copies per mL. Its introduction is also predicted to lead to increases in resistance to integrase inhibitors and non-nucleoside reverse transcriptase inhibitors if introduced in all people with HIV on ART or in those with a recently measured viral load of less than 1000 copies per mL, but to a lesser extent if introduced in people with more than 1000 copies per mL due to concentration of its use in people less adherent to oral therapy. Consistent with the effect on AIDS-related mortality, all approaches to the introduction of injectable cabotegravir-rilpivirine are predicted to avert DALYs. Assuming a cost of $120 per person per year, use of this regimen in people with a recently measured viral load of more than 1000 copies per mL was borderline cost-effective (median cost per DALY averted across setting scenarios $404). The other approaches considered for its use are unlikely to be cost-effective unless the cost per year of injectable cabotegravir-rilpivirine is considerably reduced. INTERPRETATION: Our modelling suggests that injectable cabotegravir-rilpivirine offers potential benefits; however, to be a cost-effective option, its introduction might need to be carefully targeted to individuals with HIV who might otherwise have suboptimal adherence to ART. As data accumulate from trials and implementation studies, such findings can be incorporated into the model to better inform on the full consequences of policy alternatives. FUNDING: Bill & Melinda Gates Foundation, including through the HIV Modelling Consortium (OPP1191655).

Factors associated with interest in a long-acting HIV regimen: perspectives of people living with HIV and healthcare providers in four European countries.

OBJECTIVES: A novel long-acting regimen (LAR) of cabotegravir and rilpivirine for HIV treatment requires dosing every 2 months instead of daily. We assessed what proportion of people living with HIV and physicians would be interested in trying and offering LAR respectively and why. METHODS: 688 people living with HIV on treatment, and 120 HIV physicians completed web-based surveys in Germany, Italy, the UK and France during 2019. Balanced description of a hypothetical LAR regarding efficacy, administration and possible side effects were provided. The hypothetical long-acting injections were assumed to be cost-neutral to current daily oral antiretrovirals. Interest of people living with HIV in trying ('very'/'highly') and physicians' willingness to offer ('definitely'/'probably') this LAR in different situations, with perceived benefits/concerns was measured. RESULTS: Of people living with HIV, 65.8% were interested in trying LAR. The majority (~80%-90%) of those with unmet needs felt LAR would help, including those with strong medical needs (malabsorption and interfering gastrointestinal conditions), suboptimal adherence, confidentiality/privacy concerns and emotional burden of daily dosing. Of physicians, percentage willing to offer LAR varied situationally: strong medical need (dysphagia, 93.3%; malabsorption, 91.6%; interfering gastrointestinal issues, 90.0%; central nervous system disorders, 87.5%); suboptimal adherence (84.2%); confidentiality/privacy concerns (hiding medications, 86.6%) and convenience/lifestyle (84.2%). People living with HIV liked LAR for not having to carry pills when travelling (56.3%); physicians liked the increased patient contact (54.2%). Furthermore, 50.0% of people living with HIV perceived LAR would minimise transmission risk and improve their sexual health. The most disliked attribute was scheduling appointments (37.2%) and resource constraints (57.5%) for people living with HIV and physicians, respectively. Physicians estimated 25.7% of their patients would actually switch. CONCLUSION: Providers and people living with HIV viewed the described LAR as addressing several unmet needs. Alternative treatment routes and especially LAR may improve adherence and quality of life.

An evaluation of cabotegravir for HIV treatment and prevention.

Introduction: Oral pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) represent the cornerstones of HIV infection prevention and treatment. However, despite their high efficacy, the need to take daily oral pill(s) negatively impacts long-term patient adherence. In some cases, it can also be associated with drug-drug interactions and adverse gastrointestinal effects, as well as being a constant reminder to individuals of their HIV status. The availability of long-acting non-orally administered antiretroviral drugs could, therefore, be extremely useful. Cabotegravir (CAB) is a second-generation integrase strand transfer inhibitor, characterized by a relatively high genetic barrier and good antiretroviral potency, which is administrable as a long-acting injectable suspension (LAI CAB).Areas covered: The authors present and discuss the efficacy and available safety data of LAI CAB, either when co-administered with rilpivirine (RPV; LAI CAB + RPV) for the treatment of HIV infection, or when used as single agent for PrEP.Expert opinion: Cabotegravir has the potential to play a primary role in the treatment and prevention of HIV infection. The future availability of LAI CAB + RPV and LAI CAB may mark the beginning of an era of LAI ART and PrEP, respectively.

Long-acting injectable HIV therapies: the next frontier.

PURPOSE OF REVIEW: There has been significant development of long-acting injectable therapy for the management of HIV in recent years that has the potential to revolutionise HIV care as we know it. This review summarises the data and outlines the potential challenges in the field of long-acting antiretroviral therapy (ART). RECENT FINDINGS: In recent years, monthly and two monthly long-acting injectable ART in the form of cabotegravir and rilpivirine has shown safety and efficacy in large-scale phase 3 randomised control trials. Also, agents with novel mechanisms of action, such as Lenacapavir, have been tested in early-phase studies and are currently being tested in phase 2-3 clinical trials; if successful, this may allow six-monthly dosing schedules. SUMMARY: However, despite evidence that suggests that these therapies are efficacious and acceptable to patients, the challenge of integrating these agents into our current healthcare infrastructure and making these novel agents cost-effective and available to the populations most likely to benefit remains. The next frontier for long-acting therapy will be to introduce these agents in a real-world setting ensuring that the groups most in need of long-acting therapy are not left behind.

Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study.

BACKGROUND: Phase 3 clinical studies showed non-inferiority of long-acting intramuscular cabotegravir and rilpivirine dosed every 4 weeks to oral antiretroviral therapy. Important phase 2 results of every 8 weeks dosing, and supportive modelling, underpin further evaluation of every 8 weeks dosing in this trial, which has the potential to offer greater convenience. Our objective was to compare the week 48 antiviral efficacy of cabotegravir plus rilpivirine long-acting dosed every 8 weeks with that of every 4 weeks dosing. METHODS: ATLAS-2M is an ongoing, randomised, multicentre (13 countries; Australia, Argentina, Canada, France, Germany, Italy, Mexico, Russia, South Africa, South Korea, Spain, Sweden, and the USA), open-label, phase 3b, non-inferiority study of cabotegravir plus rilpivirine long-acting maintenance therapy administered intramuscularly every 8 weeks (cabotegravir 600 mg plus rilpivirine 900 mg) or every 4 weeks (cabotegravir 400 mg plus rilpivirine 600 mg) to treatment-experienced adults living with HIV-1. Eligible newly recruited individuals must have received an uninterrupted first or second oral standard-of-care regimen for at least 6 months without virological failure and be aged 18 years or older. Eligible participants from the ATLAS trial, from both the oral standard-of-care and long-acting groups, must have completed the 52-week comparative phase with an ATLAS-2M screening plasma HIV-1 RNA less than 50 copies per mL. Participants were randomly assigned 1:1 to receive cabotegravir plus rilpivirine long-acting every 8 weeks or every 4 weeks. The randomisation schedule was generated by means of the GlaxoSmithKline validated randomisation software RANDALL NG. The primary endpoint at week 48 was HIV-1 RNA ≥50 copies per mL (Snapshot, intention-to-treat exposed), with a non-inferiority margin of 4%. The trial is registered at ClinicalTrials.gov, NCT03299049 and is ongoing. FINDINGS: Screening occurred between Oct 27, 2017, and May 31, 2018. Of 1149 individuals screened, 1045 participants were randomised to the every 8 weeks (n=522) or every 4 weeks (n=523) groups; 37% (n=391) transitioned from every 4 weeks cabotegravir plus rilpivirine long-acting in ATLAS. Median participant age was 42 years (IQR 34-50); 27% (n=280) female at birth; 73% (n=763) white race. Cabotegravir plus rilpivirine long-acting every 8 weeks was non-inferior to dosing every 4 weeks (HIV-1 RNA ≥50 copies per mL; 2% vs 1%) with an adjusted treatment difference of 0·8 (95% CI -0·6-2·2). There were eight (2%, every 8 weeks group) and two (<1%, every 4 weeks group) confirmed virological failures (two sequential measures ≥200 copies per mL). For the every 8 weeks group, five (63%) of eight had archived non-nucleoside reverse transcriptase inhibitor resistance-associated mutations to rilpivirine at baseline. The safety profile was similar between dosing groups, with 844 (81%) of 1045 participants having adverse events (excluding injection site reactions); no treatment-related deaths occurred. INTERPRETATION: The efficacy and safety profiles of dosing every 8 weeks and dosing every 4 weeks were similar. These results support the use of cabotegravir plus rilpivirine long-acting administered every 2 months as a therapeutic option for people living with HIV-1. FUNDING: ViiV Healthcare and Janssen.

Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials.

BACKGROUND: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1. SETTING: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies. METHODS: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints. RESULTS: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm. CONCLUSION: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression.

Brief Report: Durable Suppression and Low Rate of Virologic Failure 3 Years After Switch to Dolutegravir + Rilpivirine 2-Drug Regimen: 148-Week Results From the SWORD-1 and SWORD-2 Randomized Clinical Trials.

BACKGROUND: The SWORD trials showed that in participants who achieved virologic suppression taking 3-drug or 4-drug regimens, switching to the 2-drug regimen dolutegravir plus rilpivirine was noninferior in maintaining HIV-1 RNA <50 copies/mL at the week 48 primary endpoint. We present pooled week 148 analysis results from both studies. SETTING: SWORD-1: 65 centers, 13 countries; SWORD-2: 60 centers, 11 countries. METHODS: SWORD-1 and SWORD-2 are identical, open-label, phase III studies. Participants with screening HIV-1 RNA <50 copies/mL for ≥6 months; no prior virologic failure; and no documented resistance-associated major protease inhibitor, integrase inhibitor, nucleoside reverse transcriptase inhibitor (NRTI), or non-NRTI mutations or integrase resistance-associated substitution R263K were randomly assigned 1:1 to switch to once-daily dolutegravir 50 mg plus rilpivirine 25 mg on day 1 (early-switch group) or to continue their current antiretroviral regimen and, if virologically suppressed at week 48, switch to dolutegravir plus rilpivirine at week 52 (late-switch group) until week 148. RESULTS: Using snapshot algorithm at week 148, 432 of 513 (84%) early-switch participants (148 weeks of exposure) and 428 of 477 (90%) late-switch participants (96 weeks of exposure) maintained HIV-1 RNA <50 copies/mL. Eleven participants (1%) on dolutegravir plus rilpivirine met the confirmed virologic withdrawal criterion through week 148 (early-switch group, n = 8; late-switch group, n = 3) with no integrase resistance identified. Non-NRTI resistance-associated mutations were identified in 6 participants (<1%). Drug-related adverse events (grades 2-4) were observed in 31 (6%) early-switch and 16 (3%) late-switch participants. Significant improvements in bone biomarkers were observed. Significant improvements were observed in renal biomarkers in participants taking tenofovir disoproxil fumarate pre-switch. CONCLUSION: Switching to the 2-drug regimen dolutegravir plus rilpivirine maintained virologic suppression for a high proportion of participants through 3 years, with low rates of virologic failure and a well-tolerated safety profile.

Cabotegravir and rilpivirine for the treatment of HIV.

Introduction: Antiretroviral treatment (ART) has led to improved control of HIV infection, giving the opportunity of exploring therapeutic alternatives as new long-acting (LA) regimens, that might improve the quality of life of people living with HIV (PLWH).Areas covered: This article overviews the pharmacokinetic and pharmacodynamic properties of LA cabotegravir and rilpivirine (CR), two nanoformulated drugs of intramuscular administration and focuses on assessing its role on the treatment of HIV infection.Expert opinion: In addition to the advantage of treatment simplification, which could be especially beneficial for population subgroups with significant HIV-related stigma, it also reduces the number of drugs, and probably, the risk of treatment-related toxicity. The similar efficacy when compared to oral triple therapies in clinical trials and the high satisfaction rates among both professionals and patients make LA CR a suitable alternative for the control of HIV infection in the modern era.

Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection.

BACKGROUND: Long-acting injectable regimens may simplify therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection. METHODS: We conducted a phase 3, randomized, open-label trial in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir-abacavir-lamivudine. Participants who had an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were randomly assigned (1:1) to continue the current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly injections of long-acting cabotegravir plus rilpivirine. The primary end point was the percentage of participants who had an HIV-1 RNA level of 50 copies per milliliter or higher at week 48 (Food and Drug Administration snapshot algorithm). RESULTS: At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 participants (2.1%) who received long-acting therapy and in 7 of 283 (2.5%) who received oral therapy (adjusted difference, -0.4 percentage points; 95% confidence interval [CI], -2.8 to 2.1), a result that met the criterion for noninferiority for the primary end point (margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% who received long-acting therapy and in 93.3% who received oral therapy (adjusted difference, 0.4 percentage points; 95% CI, -3.7 to 4.5), a result that met the criterion for noninferiority for this end point (margin, -10 percentage points). Of the participants who received long-acting therapy, 86% reported injection-site reactions (median duration, 3 days; mild or moderate severity, 99% of cases); 4 participants withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, who received long-acting therapy and in 4% and 1% who received oral therapy. Treatment satisfaction increased after participants switched to long-acting therapy; 91% preferred long-acting therapy at week 48. CONCLUSIONS: Therapy with long-acting cabotegravir plus rilpivirine was noninferior to oral therapy with dolutegravir-abacavir-lamivudine with regard to maintaining HIV-1 suppression. Injection-site reactions were common. (Funded by ViiV Healthcare and Janssen; FLAIR ClinicalTrials.gov number, NCT02938520.).

Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression.

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. RESULTS: Treatment was initiated in 308 participants per group. At week 48, HIV-1 RNA levels of 50 copies per milliliter or higher were found in 5 participants (1.6%) receiving long-acting therapy and in 3 (1.0%) receiving oral therapy (adjusted difference, 0.6 percentage points; 95% confidence interval [CI], -1.2 to 2.5), a result that met the criterion for noninferiority for the primary end point (noninferiority margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 92.5% of participants receiving long-acting therapy and in 95.5% of those receiving oral therapy (adjusted difference, -3.0 percentage points; 95% CI, -6.7 to 0.7), a result that met the criterion for noninferiority for this end point (noninferiority margin, -10 percentage points). Virologic failure was confirmed in 3 participants who received long-acting therapy and 4 participants who received oral therapy. Adverse events were more common in the long-acting-therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy and was mild or moderate in most cases; 1% withdrew because of this event. Serious adverse events were reported in no more than 5% of participants in each group. CONCLUSIONS: Monthly injections of long-acting cabotegravir and rilpivirine were noninferior to standard oral therapy for maintaining HIV-1 suppression. Injection-related adverse events were common but only infrequently led to medication withdrawal. (Funded by ViiV Healthcare and Janssen; ATLAS ClinicalTrials.gov number, NCT02951052.).

96-week results of a dual therapy with darunavir/ritonavir plus rilpivirine once a day vs triple therapy in patients with suppressed viraemia: virological success and non-HIV related morbidity evaluation.

Antiretroviral therapies have been tested with the goal of maintaining virological suppression with a particular attention in limiting drug-related toxicity. With this aim we designed the DUAL study: a randomized, open-label, multicenter, 96 weeks-long pilot exploratory study in virologically suppressed HIV-1+ patients with the aim of evaluating the immunovirological success and the impact on non-HIV related morbidity of switching to a dual therapy with darunavir-ritonavir (DRV/r) and rilpivirine (RPV). We recruited patients who received a PI/r-containing HAART for ≥6 months, HIV-RNA < 50 cp/mL for ≥3 months, eGFR > 60 mL/min/1,73m2, without DRV or RPV RAMs. We randomized patients in arm A: RPV + DRV/r QD or arm B: ongoing triple therapy. The primary endpoint has been defined as the percentage of patients with HIV-RNA < 50 cp/mL at week 48 (ITT). VACS index, Framingham CVD risk (FRS) and urinary RBP (uRBP) were calculated. We used Chi-square or Fisher statistics for categorical variables and Mann-Whitney U for continuous ones. Forty-one patients were enrolled (22 in arm A, 14 in arm B, plus 5 screening failures): 30 patients reached 96 weeks: 100% had HIV-RNA < 50 cp/mL in arm A versus 91.7% in arm B. Similar changes were observed in median CD4/mL between baseline and week 96 (+59 versus - 31, p: n.s.). Thirty-one in arm A and 23 in arm B adverse events took place, whereas only 1 was serious (arm A: turbinate hypertrophy, unrelated to HAART). Among the 6 discontinuations (3 in A, 3 in B), only 1 was related to adverse event (arm A: G3 depression, insomnia, weakness). VACS index, median FRS and median uRBP values did not vary from baseline to week 96. At 96-weeks all patients switched to a QD 2-drug regimen based on DRV/r + RPV maintained HIV-RNA suppression, but a single patient who showed a virological failure at week 4. CD4 counts increased overtime without significant differences between the two arms. The novel dual regimen was well tolerated with the same amount of discontinuation as the control arm. VACS index, FRS and uRBP did not differ between arms at week 96.

A literature review of the patent application publications on cabotegravir - an HIV integrase strand transfer inhibitor.

Introduction: Studies presented in the patent applications demonstrate that a new integrase strand transfer inhibitor cabotegravir might be used as long-acting antiretroviral formulation or delivery system that reduces dosing frequency and may therefore increase adherence and thus pre-exposure prophylaxis (PrEP) and treatment efficacy against HIV. As announced in 2019, the developer ViiV Healthcare seeks US and EU approval of long-acting, injectable HIV treatment.Area covered: This review covers all the patent applications published until October 2019 with cabotegravir in the examples or claim section of the patent application document. The patent applications cover drug substance synthesis, solid-state forms, therapeutic applications, in vitro and in vivo efficacy as well as the potential formulations of cabotegravir alone or in combination with other anti-HIV agents.Expert opinion: The results from multiple clinical studies suggest that cabotegravir can be used as PrEP agent and treatment agent against HIV. Multiple studies use cabotegravir in combination with other anti-HIV agents such as rilpivirine. Cabotegravir in combination with rilpivirine is an interesting therapeutic, due to the possibility of formulating long-acting formulation with dosing interval of every 4 weeks or less, thus reducing daily pill burden and improving patient's compliance.

Retrospective study on the outcome of two-drug regimens based on dolutegravir plus one reverse transcriptase inhibitor in virologically-suppressed HIV-infected patients.

This was a retrospective study on the efficacy and drug resistance mutations selected at virological failure (VF) in prospectively-followed HIV-infected patients switched to dolutegravir plus rilpivirine (DTG+RPV) or lamivudine (DTG+3TC) while virologically suppressed (HIV-RNA <50 copies/mL). VF was defined as HIV-RNA >50 copies/mL in two consecutive determinations or in a single determination if followed by treatment modification, or >1000 copies/mL in a single determination. Totally, 374 patients were analysed (307 switched to DTG+3TC and 67 to DTG+RPV); 220 had documented historical resistance. The median (IQR) time with HIV-RNA <50 copies/mL before switch was 4.52 (1.93-8.14) years. VF occurred in 17 patients after a median of 1.74 (0.90-2.46) years of follow-up in the 3TC group [incidence rate (95% CI) 3.34 (2.08-5.37) per 100-PYFU] and in 2 patients after a median of 1.78 (1.10-2.99) years of follow-up in the RPV group [incidence rate (95% CI) 1.57 (0.4-6.28) per 100-PYFU]. The 48-week estimated probabilities to maintain virological suppression during treatment with a two-drug regimen were 97.8% (95% CI 95.1-99.0%) vs. 98.3% (95% CI 88.6-99.8%) in the 3TC versus RPV group (P = 0.311). At switch, patients with VF had undetectable HIV-RNA since 0.71 (0.23-1.07) years versus 1.49 (0.64-2.2) years in those without VF (P = 0.001). In the 3TC group, VF was not associated with the presence of historical resistance to nucleoside analogues, and DTG-resistant variants were not selected at VF. One VF to DTG+RPV occurred because of historical resistance to RPV, accompanied by newly selected G140A and Q148R mutations. VF was infrequent with these regimens and was negatively associated with duration of viral undetectability. Drug resistance mutations selected at failure of these regimens were those expected in case of failure of any regimen including DTG, 3TC or RPV, but the impact of resistance to NRTIs on efficacy of DTG+3TC seems lower than expected.

Evaluating emtricitabine + rilpivirine + tenofovir alafenamide in combination for the treatment of HIV-infection.

Introduction: Antiretroviral therapy (ART) is recommended for all people who are living with HIV to suppress viral load and to stop the progression and transmission of HIV-1. Fixed-dose combinations of antiretrovirals largely reduce pill burden.Areas covered: The authors first provide an overview of the use of non-nucleoside reverse transcriptase inhibitor (NNRTI) based therapy in HIV care. They then summarize the properties of each drug in the fixed-dose combination of tenofovir alafenamide/emtricitabine/rilpivirine/(TAF/FTC/RPV). The efficacy and safety of each component and the combination as a whole are reviewed: FTC is non-inferior to lamivudine (3TC) at assessed dosages; TAF was non-inferior to tenofovir disoproxil fumarate (TDF); the viral efficacy of RPV is non-inferior with EFV at the assessed dosage; TAF/FTC/RPV is non-inferior in efficacy but shows less of a decline in bone mineral density and renal function compared to TDF/FTC/RPV. Finally, adverse effects and drug-drug interaction data with FTC/RPV/TAF are discussed.Expert opinion: TAF/FTC/RPV can be used as an initial regimen for people living with HIV whose HIV RNA <100,000 copies/ml and CD4 cell count > 200 cells/mm3 when INSTI-based regimens are not a treatment option. Future antiretroviral therapy development may focus on dual therapy-based regimens containing RPV, particularly as long-acting formulations.