Long-acting prescriptions and therapy for HIV-1 from market launch to the present in Germany (May 2021 to December 2023).

Background: In Europe, the combination of cabotegravir (CAB) with rilpivirine (RPV) has been approved as a dual injection long-acting (LA) therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections in adults since December 2020. Studies have shown that between 36 and 61% of people living with HIV (PLWHIV) prefer LA therapy. However, there are no real-world data on the number of people receiving LA therapy, in Germany or internationally. The aim of this study was to assess the current situation and trends in usage of LA therapy for the treatment of HIV-1 in Germany. Methods: Based on pharmacy prescription data derived from Insight Health, the monthly number of prescriptions for oral CAB, CAB-LA, and RPV-LA over the entire period of availability in Germany was analyzed and evaluated (May 2021 to December 2023). The number of 1st and 2nd initiation injections and subsequent maintenance injections was calculated on the basis of the prescriptions for oral CAB initiation. Results: The bimonthly schedule resulted in two growing cohorts from September 2021 with an estimated 14,523 CAB-LA prescriptions over the entire period. Accordingly, in December 2023, there were approximately 1,364 PLWHIV receiving LA therapy, of whom 1,318 were receiving maintenance therapy. Only treatments with bimonthly regimens were carried out. Accounting for people not covered by statutory health insurance (~13%), a total of ~1,600 PLWHIV were receiving LA therapy in Germany in December 2023. The average rounded annual cost of therapy in 2023 was €11,940 (maintenance therapy with initiation) and €10,950 (maintenance therapy without initiation). Conclusion: To our knowledge, this is the first study of real-world use and number of people receiving LA therapy. A strength of our study is the nearly complete coverage of people with statutory health insurance in Germany. The predicted demand for LA therapy does not match the actual number of people receiving LA therapy. Although the number of PLWHIV receiving LA therapy increased steadily, they accounted for just under 2% of the estimated total number of people receiving HIV therapy in Germany in 2023, almost 2 years after the market launch. No significant increase in prescriptions is expected; on the contrary, the trend is leveling off and is unlikely to change drastically in the near future. Hence, the need for this mode of therapy in Germany appears to be limited. Follow-up studies at regular intervals on the further course would be useful and are recommended, as well as investigations into the possible reasons for the slow uptake to inform public health experts and possibly broaden treatment options.

Negative impact of a health insurer-mandated de-simplification from a single-tablet regimen to a two-tablet regimen.

OBJECTIVES: Antiretroviral therapy (ART) accounts for a considerable proportion of HIV care expenses. In June 2021, a Dutch healthcare insurer implemented a mandatory policy to de-simplify branded RPV/TDF/FTC (Eviplera) into a two-tablet regimen containing rilpivirine (Edurant) and generic TDF/FTC as part of cost-saving measures. The objectives of this study were to evaluate the acceptance of this policy, the trends in ART dispensation, and cost developments. DESIGN: A retrospective database study. METHODS: In this study, medication dispensation data were obtained from the Dutch Foundation for Pharmaceutical Statistics (SFK). This database covers 98% of all medication dispensations from Dutch pharmacies including people with HIV who receive ART. We received pseudonymized data exclusively from individuals insured by the insurer for the years 2020-2022. Costs were calculated using Dutch drug prices for each year. RESULTS: In June 2021, 128 people with HIV were on branded RPV/TDF/FTC. Following the policy implementation, 59 (46%) had switched to RPV + generic TDF/FTC, but after 1.5 years, only 17 of 128 individuals (13%) used the proposed two-tablet regimen. The other 111/128 used RPV/TDF/FTC with prescriptions for 'medical necessity' ( n  = 29), switched to RPV/TAF/FTC ( n  = 51), or other ART ( n  = 31). Despite expectations of cost-savings, costs increased from €72 988 in May 2021 to €75 649 in May 2022. CONCLUSION: A mandatory switch from an STR to a TTR in people with HIV proved unsuccessful, marked by low acceptance, and increased costs after 1 year. This underscores the necessity of incorporating patient and prescriber involvement in changing medication policies.

In Silico Pharmacokinetics Evaluation of Forgiveness for Doravirine and Rilpivirine.

BACKGROUND: This study aimed to evaluate the concentrations of rilpivirine (RLP) and doravirine (DOR) after 3 days-off using simulations from population pharmacokinetics models. METHODS: The authors conducted a series of 500 sets of 10,000 Monte Carlo simulations to examine the steady-state conditions for 2 common dosage levels: 25 mg/d for RLP and 100 mg/d for DOR. These simulations were conducted under 2 scenarios: 1 without drug cessation and another after a 3-day break. The validity of the implementation was established through a comparison of median trough concentrations (C24h) with previously reported data. Subsequently, the proportion of simulated patients with C24h and C72h after 3 days-off (C72h/3do) that exceeded the inhibitory concentration 50 (IC50), 5.2 mcg/L for DOR and 20.5 mcg/L for RLP respectively, was calculated. The inhibitory quotient (IQ) was also computed, which was 6 times IC50 for DOR and 4.5 times IC50 for RLP. Finally, nomograms were constructed to estimate the probability of having C72h/3do > IC50 or > IQ for different ranges of C24h. RESULTS: Simulated C24h median ± SD for RLP were 61.8 ± 0.4 mcg/L and for DOR 397 ± 0 mcg/L. For RLP, 99.3 ± 0.1% exceeded IC50 at C24h, 16.4 ± 0.4% at C72h/3do, and none surpassed the IQ threshold. In contrast, DOR had 100% ± 0% above IC50 at C24h, 93.6 ± 0.2% at C72h/3do, and 58.6 ± 0.5% exceeded the IQ. CONCLUSIONS: These findings suggest that treatment with DOR may offer a more forgiving therapeutic profile than RLP, given the larger proportion of patients achieving effective drug exposure with DOR. However, it is important to acknowledge a significant limitation of this study, namely, the assumption that drug concentration is a perfect surrogate for drug effectiveness.

Study protocol: the ILANA study - exploring optimal implementation strategies for long-acting antiretroviral therapy to ensure equity in clinical care and policy for women, racially minoritised people and older people living with HIV in the UK - a qualitative multiphase longitudinal study design.

INTRODUCTION: Cabotegravir and rilpivirine (CAB+RPV long-acting (LA)) is recommended as a treatment for HIV-1 allowing people living with HIV to receive 2 monthly injectable treatment, rather than daily pills. Providing injectable therapy in a system designed to provide and manage study participants on oral treatments poses logistical challenges namely how resources are used to accommodate patient preference within constrained health economies with capacity limitations. In this pragmatic multicentre study, we aim to understand the implementation of CAB-RPV-LA administration in two settings via mixed methods to explore perspectives of participants and the clinical team delivering CAB+RPV LA. METHODS AND ANALYSIS: Women, racially minoritised people and older people are chronically under-represented in HIV clinical trials so the ILANA trial has set recruitment caps to ensure recruitment of 50% women, 50% ethnically diverse people and 30% over 50 years of age to include a more representative study population. Using a mixed-methods approach, the primary objective is to identify and evaluate the critical implementation strategies for CAB+RPV LA in both hospital and community settings. Secondary objectives include evaluating feasibility and acceptability of CAB+RPV LA administration at UK clinics and community settings from the perspective of HIV care providers, nurses and representatives at community sites, evaluating barriers to implementation, the utility of implementation strategies and adherence. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Health Research Authority Research Ethics Committee (REC reference: 22/PR/0318). The dissemination strategy has been formulated with the SHARE Collaborative Community Advisory Board to maximise the impact of this work on clinical care and policy. This strategy draws on and leverages existing resources within the participating organisations, such as their academic infrastructure, professional relationships and community networks. The strategy will leverage the Public Engagement Team and press office to support dissemination of findings. TRIAL REGISTRATION NUMBER: NCT05294159.

Cost-Effectiveness of Juluca for Human Immunodeficiency Virus Infection Treatment in Virologically Suppressed Adults in Taiwan.

OBJECTIVES: Although the efficacy of traditional 3-drug regimens for the treatment of HIV is well established, tolerability and toxicity concerns remain. New 2-drug regimens such as Juluca (dolutegravir [DTG]/rilpivirine [RPV]) offer noninferior efficacy versus 3-drug regimens (SWORD-1 and SWORD-2 studies), while reducing cumulative drug exposure and potentially long-term toxicities and drug-drug interactions. Here, we assess the cost-effectiveness of DTG/RPV for the treatment of HIV-1 for virologically suppressed adults in Taiwan. METHODS: A hybrid decision tree and Markov cohort state transition model was used to evaluate the expected economic costs and clinical outcomes associated with DTG/RPV and comparators. Model health states were defined by viral load and CD4 cell count. Efficacy and safety data were informed from SWORD-1 and SWORD-2 studies and the literature. The risk of long-term toxicities (cardiovascular disease, bone fractures, and chronic kidney disease) were included. Current branded drug acquisition prices were included, and healthcare costs informed by a bespoke costing study using National Health Insurance Research Database data. Incremental cost-effectiveness ratios were calculated and compared with a willingness-to-pay threshold of 2 times Taiwan's gross domestic product (NT$1 550 000). RESULTS: DTG/RPV was found to be a cost-saving regimen compared to 3 comparators (rilpivirine [RPV]/emtricitabine [FTC]/tenofovir disoproxil fumarate [TDF], dolutegravir [DTG]/abacavir [ABC]/lamivudine [3TC], and elvitegravir [EVG]/cobicistat [c]/emtricitabine [FTC]/tenofovir alafenamide [TAF]) and fell in the southwest quadrant of the cost-effectiveness plane where it is generating significant savings with a small decrement in lifetime quality-adjusted life-years (-0.005). It was, however, more expensive than efavirenz [EFV]/emtricitabine [FTC]/ tenofovir disoproxil fumarate [TDF]. CONCLUSIONS: DTG/RPV is cost-saving compared to RPV/FTC/TDF, DTG/ABC/3TC, and EVG/c/FTC/TAF, and provides comparable efficacy with reduced cumulative drug exposure.

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).

Cost-effectiveness of the long-acting regimen cabotegravir plus rilpivirine for the treatment of HIV-1 and its potential impact on adherence and viral transmission: A modelling study.

INTRODUCTION: Combination antiretroviral therapy (cART) improves outcomes for people living with HIV (PLWH) but requires adherence to daily dosing. Suboptimal adherence results in reduced treatment effectiveness, increased costs, and greater risk of resistance and onwards transmission. Treatment with long-acting (LA), injection-based ART administered by healthcare professionals (directly observed therapy (DOT)) eliminates the need for adherence to daily dosing and may improve clinical outcomes. This study reports the cost-effectiveness of the cabotegravir plus rilpivirine LA regimen (CAB+RPV LA) and models the potential impact of LA DOT therapies. METHODS: Parameterisation was performed using pooled data from recent CAB+RPV LA Phase III trials. The analysis was conducted using a cohort-level hybrid decision-tree and state-transition model, with states defined by viral load and CD4 cell count. The efficacy of oral cART was adjusted to reflect adherence to daily regimens from published data. A Canadian health service perspective was adopted. RESULTS: CAB+RPV LA is predicted to be the dominant intervention when compared to oral cART, generating, per 1,000 patients treated, lifetime cost-savings of $1.5 million, QALY and life-year gains of 107 and 138 respectively with three new HIV cases averted. CONCLUSIONS: Economic evaluations of LA DOTs need to account for the impact of adherence and HIV transmission. This study adds to the existing literature by incorporating transmission and using clinical data from the first LA DOT regimen. Providing PLWH and healthcare providers with novel modes of ART administration, enhancing individualisation of treatment, may facilitate the achievement of UNAIDS 95-95-95 objectives.

Long-acting injectable HIV therapies: the next frontier: Republication.

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.

A Multiple Dose Phase 1 Assessment of Rilpivirine Long Acting in a Model of Preexposure Prophylaxis Against HIV.

The MWRI-01 study characterized the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of rilpivirine (RPV) long acting (LA) in a model of preexposure prophylaxis (PrEP). Prospective, open-label Phase 1 study. The safety and acceptability of three repeated doses of RPV LA were monitored. Blood, tissue (rectal, cervical, and vaginal), and biological fluids (vaginal and endocervical) were collected at baseline and at 1- to 2-month intervals throughout the study for PK and PD assessment. Eight women and four men received three intramuscular doses of 1,200 mg of RPV LA given 8 weeks apart. There were a total of 195 adverse events (AEs) reported, of which 138 (70.8%) were Grade 1 and 55 (28.2%) were Grade 2. The most common AE was injection site pain. Geometric mean (90% confidence interval) plasma RPV concentrations at 56 days after the first and third doses were 39 (33-45) ng/mL (female)/29 (17-40) ng/mL (male) and 59 (45-62) ng/mL (female)/40 (30-51) ng/mL (male), respectively. Exposure to RPV LA was associated with significant inhibition of HIV-1BaL viral replication in the ex vivo rectal explant model (p < .0001) that persisted for up to 4 months after the third dose of RPV LA. In contrast, no viral suppression was seen in cervicovaginal tissue. Multiple dose administration of RPV LA was safe and well tolerated, and was associated with prolonged suppression of viral replication in rectal explant tissue.

Alternative switching strategies based on regimens with a low genetic barrier: do clinicians have a choice nowadays?

Clinicians sometimes use switching strategies based on regimens such as RAL + ABC/3TC or RPV + ABC/3TC in order to resolve tolerability or safety issues associated with conventional recommended first-line strategies. Despite the low genetic barrier of these regimens, high safety and efficacy rates have been reported in retrospective studies.

Dolutegravir Plus Rilpivirine as a Switch Option in cART-Experienced Patients: 96-Week Data.

BACKGROUND: Data from clinical studies confirm the efficacy of switching to dolutegravir (DTG) plus rilpivirine (RPV) in selected patients. OBJECTIVE: The primary objective is to report the 96-week virological suppression in our cohort, assessing the durability of this strategy in complicated situations. The secondary objective is to describe the safety and metabolic profile. METHODS: All patients who had switched to DTG plus RPV between October 1, 2014, and September 30, 2015, were analyzed using a retrospective-prospective design, approved by ethics committees. Routine metabolic, immunological, and virological data were regularly sent to the coordinating center. Viral control was classified as HIV-1 RNA ≥50 copies/mL, 1 to 49 copies/mL, or undetectable (no virus detected [NVD]). RESULTS: We followed 145 patients for a median of 101 weeks. The median age was 52 years; 31.7% were women, and 9.6% non-Caucasian; 50.3% had failed at least 1 antiretroviral regimen; and 15% had ≥50 copies/mL at baseline. The reasons for switching were as follows: simplification (51.7%), toxicity (36.5%), drug-drug interactions (6.9%), persistent low-level viremia (3.0%), nonadherence (2.1%), and viral failure (1.4%). By week 96, seven patients dropped out. At week 96, none had ≥50 HIV-1 RNA copies/mL, 138 (95.2%) had <50 copies/mL, and 123 (84.8%) had NVD. The low- to high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio decreased significantly ( P = 0.04). Of the 287 baseline altered laboratory parameters, 32.7% normalized by week 96. Serum glucose and total- and LDL-cholesterol normalization were statistically significant. CONCLUSIONS: Switching to DTG plus RPV improved viral suppression and LDL-C/HDL-C ratio.

Effectiveness, Safety, and Costs of a Treatment Switch to Dolutegravir Plus Rilpivirine Dual Therapy in Treatment-Experienced HIV Patients.

BACKGROUND: Evidence about the use of dolutegravir (DTG) and rilpivirine (RPV) as an antiretroviral therapy (ART) in treatment-experienced patients is scarce. OBJECTIVE: To explore the effectiveness, safety, and costs of switching to a DTG plus RPV regimen in this population. METHODS: This observational, prospective study included all treatment-experienced patients who switched to DTG plus RPV between November 2014 and July 2016. Patients were excluded if resistance mutations to integrase inhibitors or RPV were found. The effectiveness endpoint was the proportion of patients who achieved virological suppression (viral load [VL] <50 copies/mL) at week 48 (W48). Safety (incidence of adverse events leading to discontinuation and laboratory abnormalities), adherence, and costs were analyzed. RESULTS: A total of 35 patients were included, and 91.4% were virologically suppressed at baseline. Patients were treated with ART for a median of 14 years (interquartile range = 7-20). At W48, 91.4% of patients were virologically suppressed (95% CI = 77.0-98.2). Two of the 3 patients not suppressed at baseline achieved undetectable VL at W48, and 2 patients discontinued DTG plus RPV (intolerance and a drug-drug interaction). None of the virologically suppressed patients at baseline showed virological rebound through W48. There were no significant changes in lipid, liver, and renal profiles. The proportion of patients with an ART adherence >90% increased from 65.6% to 93.8% ( P = 0.004). The annual per-patient ART costs dropped by €665 ( P = 0.265). CONCLUSIONS: Switching to DTG plus RPV seems to be an effective and safe strategy. Significant improvements in patients' adherence and costs were achieved.

Switching to a rilpivirine/emtricitabine/tenofovir single-tablet regimen in RNA-suppressed patients infected with human immunodeficiency virus 1: Effectiveness, safety and costs at 96 weeks.

OBJECTIVES: This study evaluates the effectiveness, safety and costs of switching to a rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) regimen in treatment-experienced HIV-1-infected patients with sustained virological suppression. METHODS: Observational, prospective study. Study population included all treatment-experienced patients with sustained virological suppression who switched to RPV/FTC/TDF during 2013 in a tertiary hospital. Patients were followed until they completed 96 weeks of treatment. The effectiveness end-point was defined as the proportion of patients who maintained virological suppression at week 96 by intention-to-treat analysis (discontinuation=failure). The safety of RPV/FTC/TDF (incidence of adverse events leading to discontinuation and laboratory abnormalities) and adherence to this regimen were evaluated, and the cost of switching was analysed. RESULTS: One-hundred forty-six patients were included. At week 96, 71.9% of patients remained virologically suppressed; 6.8% experienced virological failure. During follow-up, 25.3% of patients discontinued RPV/FTC/TDF (14.4% because of adverse events, mainly renal impairment). Throughout the 96 weeks, there were significant decreases in total cholesterol (TC) (14.0 mg/dL, P<.001), TC/HDL cholesterol ratio (0.4 mg/dL, P=.019) and triglycerides (42.0 mg/dL, P<.001). A slight decrease in glomerular filtration rate was observed (4.3 mL/min/1.73 m2 , P<.001). Switching to RPV/FTC/TDF improved adherence in the subgroup of patients whose previous treatment was based on a twice-daily schedule, although differences did not reach statistical significance. Switching to RPV/FTC/TDF reduced the annual per-patient antiretroviral cost by €1744 (P<.001). CONCLUSIONS: In virologically suppressed patients, the switch to a RPV/FTC/TDF regimen was associated with a mild but maintained improvement in lipid parameters and a significant reduction in costs. However, the relatively high rates of virological failure and treatment discontinuation because of adverse events make this combination a less favourable choice over other regimens currently available.

Long-acting rilpivirine as potential pre-exposure prophylaxis for HIV-1 prevention (the MWRI-01 study): an open-label, phase 1, compartmental, pharmacokinetic and pharmacodynamic assessment.

BACKGROUND: Long-acting injectable antiretroviral agents are being developed for HIV-1 prevention. The MWRI-01 study was done to characterise the safety, acceptability, and pharmacokinetic and pharmacodynamic profile of long-acting rilpivirine. METHODS: We did a phase 1 open-label study at the University of Pittsburgh. We enrolled healthy individuals (aged 18-45 years) who were seronegative for HIV-1. Participants were assigned alternately one intramuscular dose of either 1200 mg or 600 mg long-acting rilpivirine, beginning with the 1200 mg dose. We obtained plasma specimens, genital and rectal fluids, and tissue samples (rectal, cervical, and vaginal) before and after exposure to long-acting rilpivirine for assessment of pharmacokinetics and ex-vivo biopsy challenge with HIV-1. Our primary objective was to characterise product safety, and the analysis included all enrolled participants. This trial is registered with ClinicalTrials.gov, number NCT01656018. FINDINGS: 36 participants were enrolled into the study, of whom 24 were women and 12 men. 12 women and six men received each dose. 204 adverse events were reported among the 36 participants, of which 200 (98%) were grade 1-2. The most common adverse event was injection site reaction. All grade 3 and 4 adverse events were deemed not related to rilpivirine. Geometric mean (90% CI) concentrations in plasma of rilpivirine at day 28 post dose were 53 ng/mL (38-67) in women and 43 ng/mL (23-63) in men for the 1200 mg dose and 28 ng/mL (19-37) in women and 17 ng/mL (9-24) in men for the 600 mg dose. The tissue-to-plasma ratio for rilpivirine in rectal tissue was about two-fold higher than in vaginal and cervical tissue (1·10-1·53 vs 0·61-0·72 and 0·50-0·71, respectively). Exposure to long-acting rilpivirine suppressed viral replication significantly in rectal tissue (p<0·0001), and this suppression persisted for up to 4 months. By contrast, no viral suppression was seen in cervical or vaginal tissue. INTERPRETATION: Ongoing research will characterise longer term safety and acceptability of multiple injections and help ascertain whether long-acting rilpivirine should advance to assessment of efficacy in preventing HIV-1 infection. FUNDING: Bill & Melinda Gates Foundation.

Switch from unboosted protease inhibitor to a single-tablet regimen containing rilpivirine improves cholesterol and triglycerides.

This study aimed to evaluate the efficacy, tolerability and potential savings of combined antiretroviral therapy (cART) simplification from an unboosted protease inhibitor (PI) regimen with atazanavir or fosamprenavir to a single-tablet regimen (STR) based on rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) among HIV-1-infected patients with HIV-1 RNA <50 copies/mL. This was a retrospective, multicentre, open-label, 12-week trial. Plasma HIV-1-RNA levels, CD4+ cell counts, cholesterol, triglycerides, bilirubin, glycaemia, creatinine and physical examination were performed at baseline and at scheduled follow-up. All patient costs were calculated and were estimated for 52 weeks of therapy. Fifty-one patients were enrolled [28 male (54.9%)]. At baseline, 30 patients (58.8%) were treated with FTC/TDF, 20 (39.2%) with abacavir/lamivudine and 1 (2.0%) with lamivudine/zidovudine. Thirty-three patients (64.7%) received atazanavir. All patients maintained HIV-RNA <50 copies/mL; the median CD4+ cell count remained stable. Mean triglycerides decreased from 124 mg/dL (range, 39-625) at enrolment to 108.7 mg/dL (range, 39-561) at study end (P = 0.25). At baseline, mean cholesterol was 172.8 ± 38.1 mg/dL and decreased to 161.9 ± 38.6 mg/dL (P = 0.038); likewise, median total bilirubin decreased from 1.07 mg/dL (range, 0.2-4.7) to 0.6 mg/dL (range, 0.13-3.1) (P <0.001). cART-related annual cost reduction with a STR was €3155.47 per patient (-24%). Non-cART patient management expenses were €402.68 vs. €299.10 for atazanavir or fosamprenavir and STR regimens, respectively. Switching to RPV/FTC/TDF from an unboosted PI in virologically suppressed HIV-infected patients is safe and is associated with a reduction in triglycerides, cholesterol and cART-related costs.

Cost-effectiveness of Injectable Preexposure Prophylaxis for HIV Prevention in South Africa.

BACKGROUND: Long-acting injectable antiretrovirals such as rilpivirine (RPV) could promote adherence to preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) prevention. However, the cost-effectiveness of injectable PrEP is unclear. METHODS: We constructed a dynamic model of the heterosexual HIV epidemic in KwaZulu-Natal, South Africa, and analyzed scenarios of RPV PrEP scale-up for combination HIV prevention in comparison with a reference scenario without PrEP. We estimated new HIV infections, life-years and costs, and incremental cost-effectiveness ratios (ICERs), over 10-year and lifetime horizons, assuming a societal perspective. RESULTS: Compared with no PrEP, unprioritized scale-up of RVP PrEP covering 2.5%-15% of adults prevented up to 9% of new infections over 10 years. HIV prevention doubled (17%) when the same coverage was prioritized to 20- to 29-year-old women, costing $10 880-$19 213 per infection prevented. Prioritization of PrEP to 80% of individuals at highest behavioral risk achieved comparable prevention (4%-8%) at <1% overall coverage, costing $298-$1242 per infection prevented. Over lifetime, PrEP scale-up among 20- to 29-year-old women was very cost-effective (<$1600 per life-year gained), dominating unprioritized PrEP, while risk prioritization was cost-saving. PrEP's 10-year impact decreased by almost 50% with increases in ICERs (up to 4.2-fold) in conservative base-case analysis. Sensitivity analysis identified PrEP's costs, efficacy, and reliability of delivery as the principal drivers of uncertainty in PrEP's cost-effectiveness, and PrEP remained cost-effective under the assumption of universal access to second-line antiretroviral therapy. CONCLUSIONS: Compared with no PrEP, prioritized scale-up of RPV PrEP in KwaZulu-Natal could be very cost-effective or cost-saving, but suboptimal PrEP would erode benefits and increase costs.

Initiation of rilpivirine, tenofovir and emtricitabine (RPV/TDF/FTC) regimen in 363 patients with virological vigilance assessment in 'real life'.

OBJECTIVES: To study the single-tablet regimen (STR) combination rilpivirine/tenofovir/emtricitabine (RPV/TDF/FTC) as soon as it became available. We describe a 14 month follow-up in a real clinical setting with a focus on resistance to RPV/TDF/FTC and polymorphisms associated with these drugs. METHODS: We estimated drug resistance at STR baseline by combining all available resistance tests, resulting in a cumulative virtual genotype. Physicians were advised of current or archived resistance mutations for the three drugs. Virological response was analysed according to resistance genotype at baseline. RESULTS: Three hundred and sixty-three patients received RPV/TDF/FTC; 79% had received previous treatment and RPV/TDF/FTC was the result of a switch of one drug to rilpivirine in two-thirds of cases. The cumulative genotype showed 4% of rilpivirine resistance mutations at baseline and 16% of polymorphisms concerning non-nucleoside reverse transcriptase inhibitors (NNRTIs). With a median duration of STR of 8 months, 78% of patients with these polymorphisms were virologically suppressed compared with 96% with wild-type genotypes. Five genotypes were determined during the follow-up, revealing three rilpivirine resistance-associated mutations: E138Q/Y181I, M230L and K101P (potentially with a K101Q intermediate). CONCLUSIONS: This observational study reflects routine clinical practice and the relevance of virological advice. It also confirms the efficacy of this STR (RPV/TDF/FTC) for naive and virologically suppressed pretreated patients with a low prevalence of virological failure and resistance if the cumulative baseline genotype is free of resistance to NNRTIs and/or polymorphisms associated with NNRTIs.

Single-tablet regimens in HIV: does it really make a difference?

OBJECTIVES: Review of the available data on the currently available single-tablet regimens (STRs), from the analysis of efficacy and safety to the key points of value in terms of adherence, quality of life and pharmacoeconomic evaluation. METHODS: For this narrative review, literature searches have been performed in PubMed, IndexRevMed and Cochrane, using the search terms HIV, single-tablet, one-pill, single dose, fixed-dose, and STR. These have been reviewed and complemented with the most recent publications of interest. RESULTS: Fixed-dose combinations are a significant advance in antiretroviral treatment simplification, contributing to an increase in compliance with complex chronic therapies, thus improving patients' quality of life. Reducing the number of pills and daily doses is associated with higher adherence and better quality of life. As a fixed-dose combination tablet given once daily, EFV/FTC/TDF was the first available STR combining efficacy, tolerability and convenience, with the simplest dosing schedule and smallest numbers of pills of any ART combination therapy. The RPV/FTC/TDF is a next-generation NNRTI-based STR, a once daily complete ART regimen for the treatment of HIV-1 infection. Recently the combination of EVG/COBI/FTC/TDF was also approved by the European Commission, and is the first integrase inhibitor-based STR. Receiving antiretroviral therapy as once daily STR is associated with both clinical and economic benefits, which confirms previous research. CONCLUSIONS: The associated benefits of STRs provide a valid strategy for the treatment of HIV-infected patients.

Cost-effectiveness of efavirenz vs rilpivirine in HIV patients initiating first-line combination antiretroviral therapy.

OBJECTIVE: In US treatment guidelines, efavirenz (EFV) is the preferred non-nucleoside reverse transcriptase inhibitor (NNRTI) for first-line HIV treatment. In the ECHO and THRIVE trials comparing EFV with another NNRTI, rilpivirine (RPV), both medications had similar virologic suppression rates at 96-weeks; however, RPV had higher rates of virologic failure and drug resistance and lower rates of discontinuation due to adverse events. This study compared the cost-effectiveness of EFV to RPV in first-line HIV treatment in the US. METHODS: A Markov model with 14 health states was constructed to estimate 10-year costs and clinical outcomes from a US payer perspective for antiretroviral naïve HIV patients initiating EFV or RPV. First-line efficacy data came from 96-week results of the ECHO and THRIVE trials, which compared EFV and RPV, both in combination with two nucleos(t)ide reverse transcriptase inhibitors. Other clinical inputs, mortality rates, and costs (2011 US$) came from published sources. Subsequent therapy lines (second, third, non-suppressive) were based on US treatment guidelines and common to both treatment arms. Robustness of study results was assessed in sensitivity analyses varying model inputs by ±25%. Potential limitations of the model center on the ability of any model to capture the clinical complexity of HIV treatment. RESULTS: In the base case, 10-year costs were lower for EFV compared to RPV ($214,031 vs $222,090). Life expectancy (8.44 years) and years without AIDS (8.40 years) were equal; years in virologic suppression were similar (EFV = 7.87 years, RPV = 7.86 years). EFV had modest cost savings compared to RPV in terms of incremental cost-effectiveness per life-year gained, life-year gained in viral suppression, and life-year gained without AIDS. In sensitivity analyses, EFV remained cost-saving compared to RPV in over 90% of scenarios, demonstrating the robustness of study results. CONCLUSIONS: EFV was predicted to be modestly cost-saving compared with RPV over 10 years in US patients initiating first-line HIV treatment. Sensitivity analyses suggest that results may hold across multiple settings.

Rilpivirine: a second-generation nonnucleoside reverse transcriptase inhibitor.

PURPOSE: The pharmacology, pharmacokinetics, drug interactions, clinical efficacy, adverse effects, dosage and administration, and place in therapy of rilpivirine are reviewed. SUMMARY: Rilpivirine is a human immunodeficiency virus type 1 (HIV-1)-specific nonnucleoside reverse transcriptase inhibitor (NNRTI) indicated for use in combination with other antiretroviral agents in adult patients not previously treated with antiretroviral therapy. Rilpivirine is primarily metabolized by the cytochrome P-450 (CYP)3A isoenzyme system. Therefore, providers should be cautious when administering drugs that are inhibitors or inducers of this pathway. Coadministration with CYP 3A inhibitors may lead to increased concentrations of rilpivirine, thereby increasing the risk of adverse effects. Coadministration with inducers of CYP3A isoenzymes or drugs that increase gastric pH may lead to decreased concentrations of rilpivirine, thus promoting virological failure or resistance to rilpivirine. Two Phase III, randomized, double-blind, double-dummy, active-controlled trials compared rilpivirine with efavirenz in HIV-infected adults not previously treated with an antiretroviral. The investigators concluded that rilpivirine, when combined with two nucleoside or nucleotide reverse transcriptase inhibitors, was noninferior to efavirenz for reaching the endpoint of confirmed virological response (HIV-1 RNA level of <50 copies/mL) in adults with HIV infection not previously treated with antiretroviral therapy. The most commonly reported adverse effects included depression, insomnia, headache, and rash. Rilpivirine is administered as a single 25-mg tablet given once daily in combination with other antiretroviral drugs in order to optimize efficacy and reduce resistance. CONCLUSION: Rilpivirine is a viable NNRTI for HIV-infected patients who have not previously received antiretroviral therapy.