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More than 80% of people with human immunodeficiency virus (HIV) in low- and middle-income countries (LMICs) take first-line tenofovir-disoproxil/lamivudine (or emtricitabine)/dolutegravir (TLD). Due to hard-fought activism, TLD now costs <$45 per person per year in more than 100 LMICs under Voluntary License. With final dolutegravir (DTG) patents expiring by 2029, generic TLD will soon be available globally. Here, we identify seven critical benchmarks that underpin TLDs' success which novel antiretroviral therapy (ART) should now meet, and an eighth benchmark for which novel ART should aim. These benchmarks are superior efficacy; high genetic barrier to resistance; safety in hepatitis B coinfection; favourable drug interaction profiles; HIV2 efficacy; safety in pregnancy, long-acting formulation availability and affordable pricing. We compare the generic TLD availability timeline with development timelines for two case-study novel ART combinations: islatravir/doravirine and cabotegravir/rilpivirine. We demonstrate that currently these regimens and trial programs will not meet key benchmarks required to compete with TLD. [ABSTRACT FROM AUTHOR]

Introduction: HIV is a global disease affecting millions of people. While treatments have improved over the past decades, treatment failure remains a significant issue for treatment experienced patients. Doravirine/islatravir is a new dual-therapy regimen with a promising resistance profile and reductions in central nervous system effects. Recent trials have shown non-inferiority compared to current standards of care. However, current research suggests that CD4 counts decrease in an islatravir-dose dependent manner, but more data is needed to determine the full extent of this effect at lower doses. Areas covered: Doravirine/islatravir is a therapeutic combination for the treatment of HIV which is currently in Phase 3 trials. This article reviews key studies regarding the safety and efficacy of the combination. Expert opinion: When approved, doravirine/islatravir should be considered for patients who have previously failed treatment due to viral resistance. It expands the selection of two-drug single-pill therapies and introduces a novel mechanism of action to the market. However, more data is needed regarding the effects of islatravir on CD4 counts. ISL doses as low as 0.25 mg proved non-inferior to current treatments. Therefore, evaluation of the long-term efficacy and safety of DOR/ISL should focus on reduced doses of ISL and minimizing CD4 reduction. [ABSTRACT FROM AUTHOR]

Rationale Methods Results Conclusions Doravirine (DOR) is an attractive new option both for ART‐naïve people with HIV (PWH) and those with suppressed HIV‐RNA who seek treatment simplification. We used real‐world data to examine the pattern of use of DOR‐containing regimens in these settings.All PWH enrolled in the Icona cohort after January 2020 who initiated a three‐drug regimen (3‐DR) with DOR or an integrase inhibitor (INSTI)‐based regimen as first antiretroviral therapy (ART) or when switching ART, with HIV‐RNA ≤50 copies/mL, were included. We used univariate and multivariable logistic regression models to identify demographic factors, immuno‐virological and laboratory markers associated with the prescription of 3‐DR DOR instead of INSTI‐based regimens.A total of 5803 PWH were included; 1958 were in the first regimen (80 DOR, 1,878 INSTI) and 3854 (387 DOR, 3,458 INSTI) were ART‐experienced virologically suppressed. In the first line, 3‐DR DOR was more frequently started in people who inject drugs, and its use was also associated with higher body mass index, higher low‐density lipoprotein levels, and less advanced HIV disease compared with PWH initiating an INSTI‐based regimen. In the switch setting, older age, Italian origin, higher estimated glomerular filtration rate and aspartate aminotransferase levels were all strongly associated with 3‐DR DOR use, as well as higher a CD4/CD8 ratio (only vs. 3‐DR INSTI), while the association with lipid abnormalities was attenuated.Our analysis shows that among PWH in care in Italy, those with less advanced HIV disease but with other fragilities and potential risk factors for comorbidities are more likely to use DOR‐ than INSTI‐based regimens, regardless of prior treatment history. [ABSTRACT FROM AUTHOR]

BackgroundIMPAACT 2014 study is a phase I/II, multicenter, open-label, nonrandomized study of doravirine (DOR) co-formulated with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) as fixed-dose combination (DOR FDC) in adolescents with HIV-1. We report the efficacy, safety, and tolerability of DOR FDC through 96 weeks.MethodsParticipants were adolescents aged 12 to

The Aim of this study is to assess the cardiovascular safety of doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF). We analyzed data from 37 virologically suppressed people living with HIV starting DOR/3TC/TDF, collecting viro-immunological and metabolic parameters as well as the 10-year risk of cardiovascular disease (10Y-CD) using both the Framingham risk score and D:A:D score.After 48 weeks, we observed a significant reduction in 10Y-CD both via the Framingham score (−0.7, p =.021) and the D:A:D score (−0.41, p =.012). After 96 weeks, we registered a significant reduction in 10Y-CD calculated via the D:A:D score (−0.98, p =.009). Regarding serum lipid markers, after 48 weeks we observed a significant reduction in total cholesterol (−17 mg/dL, p <.001), triglycerides (−21 mg/dL, p =.015), and LDL cholesterol (−8 mg/dL, p =.022). After 96 weeks, we registered a significant reduction in total cholesterol (−19 mg/dL, p <.001). DOR/3TC/TDF has shown a favorable metabolic profile, with a significant reduction in 10Y-CD, independently from the use of lipid-lowering drugs. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusions Treatment‐related weight gain and metabolic complications with antiretroviral integrase‐based regimens, especially among Black women, suggest the need for alternative options.We conducted a 48‐week, open‐label, single‐arm, single‐centre, phase IIIb switch study to evaluate the tolerability, safety and efficacy of switching from stable efavirenz‐ or dolutegravir‐based antiretroviral therapy to doravirine/lamivudine/tenofovir disoproxil fumarate in Black women.The 101 participants enrolled (median age 35 years; interquartile range 31–40) were on efavirenz (n = 46; mean duration on therapy 1.7 years) or dolutegravir‐based (n = 55; mean duration 1.5 years) antiretrovirals at screening. Retention at 48 weeks was 92/101 participants, and viral suppression was >90% throughout the study, with a single case of doravirine resistance (106 M, V108I and H221Y mutations). The mean weight percentage change at week 48 was 4.7% (95% confidence interval [CI] 3.0–6.5; p < 0.001), and the adjusted mean change was 2.7 kg (95% CI 1.50–3.98; p < 0.001); for efavirenz, the percentage change was 5.0% (95% CI 2.9–7.1; p < 0.001), and the adjusted weight gain was 3.5 kg (95% CI 1.93–5.13); for dolutegravir, the percentage change was 4.5% (95% CI 1.8–7.3; p < 0.001), and the adjusted weight gain was 2.1 kg (95% CI 0.26–3.90). Statistically significant decreases in lipid panel percent mean to week 48 included: total cholesterol −8.4% (95% CI −11.3 to −5.5; p < 0.001), triglycerides −10.4% (95% CI −16.4 to −4.4; p < 0.001) and high‐density lipoprotein −14.8% (95% CI −18.5 to −11.2%; p < 0.001), with minor differences when disaggregating the mean percent change in lipids between previous efavirenz/dolutegravir regimens. Adverse events due to doravirine were few and mild.Our findings suggest that a switch to doravirine from efavirenz or dolutegravir is safe and effective in Black women, with significant improvement in lipid profiles, but does not arrest progressive weight gain. [ABSTRACT FROM AUTHOR]

Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with efficacy against some NNRTI-resistant mutants. Although DOR resistance mutations are established for HIV-1 subtype B, it is less clear for non-B subtypes. This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication-defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others did not significantly impact DOR susceptibility. We observed an agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y188L caused high-level resistance, in agreement with the predictions. These mutations are frequently observed in patients failing efavirenz- or nevirapine-based first-line regimens. However, they are also observed in those failing a protease inhibitor-based second-line regimen, as we have observed in our database. Genotypic drug resistance testing is therefore vital prior to the initiation of DOR-based treatment for those previously exposed to efavirenz or nevirapine. [ABSTRACT FROM AUTHOR]

Doravarine (DOR) is an antiviral drug with a marketed authorization for the management of occupational blood and body fluid exposure. The currently existing packaging, consisting of multiple unit bottles comprising 30 tablets, is not fully appropriate for daily nominative dispensing at the hospital. This study aims at assessing the impact of the change in packaging on the key attributes of the drug: assay, impurity profile, and dissolution. As the first step, which is not fully depicted in the literature, the main potential impurities that could appear during storage (i.e., degradation products (DPs) of DOR) were characterized using a forced degradation protocol followed by an LC-MS/MS analysis. These results paved the way for in silico toxicological assessment and targeted degradation product profiling. Based on this study, the assessment of the implication of repackaging on the formation of DOR's degradation products should be a primary focus. [ABSTRACT FROM AUTHOR]

Integrase strand transfer inhibitors (INSTI) are associated with neuropsychiatric adverse events (NPAEs). The aim of this study was to evaluate improvements in NPAEs after switching an INSTI-based regimen to darunavir/cobicistat (DRV/c) or doravirine (DOR). Methods: A prospective cohort study was conducted to evaluate the reversibility of NPAEs via the Patient Health Questionnaire (PHQ-9), the Insomnia Severity Index (ISI), and the Hospital Anxiety and Depression Scale (HADS-A and D) in patients who started antiretroviral therapy with dolutegravir (DTG) or bictegravir (BIC). These patients were switched to DRV/c or DOR. Scales were compared at the moment of the switch and 12 weeks later. Results: We included 1153 treatment-naïve men, 676 (58.7%) with BIC and 477 (41.3%) with DTG. A total of 32 (2.7%) experienced NPAEs that led to discontinuation. Insomnia was found in 20 patients; depression via PHQ-9 in 21 patients, via HADS-D in 5 patients, and anxiety via HADS-A in 12 patients. All of them were evaluated by a psychiatrist at the moment of the symptoms; 7 (21.8%) started psychotropic drugs. After 12 weeks of follow-up, PHQ-9, ISI, HADS-A, and HADS-D decreased, with a p-value ≤ 0.05. Conclusions: NPAEs seem to improve after switching to a DRV/c- or DOR-based regimen after the first 4 and 12 weeks. [ABSTRACT FROM AUTHOR]

Background Weight gain has been well-described with integrase strand transfer inhibitors (INSTIs) and tenofovir alafenamide (TAF). Doravirine (DOR) has been identified as a relatively “weight-neutral” drug; however, there is little data describing its effect on weight change in routine clinical practice. Methods We conducted a retrospective chart review of weight change among people with HIV changing from an INSTI- to a non-INSTI regimen with DOR. Results At the time of ART switch, among 49 people with HIV, the mean age was 47 years, 24% were female, and 75% had HIV-1 viral load

BackgroundWe studied the pharmacokinetics (PK) and safety of 100-mg doravirine and doravirine/lamivudine/tenofovir disoproxil fumarate fixed-dose combination (100/300/300 mg DOR FDC) treatment in adolescents with HIV-1.MethodsAdolescents ages 12 to younger than 18 years were enrolled in 2 sequential cohorts. Cohort 1 evaluated intensive PK and short-term safety of 100-mg single-dose doravirine in adolescents ≥35 kg. Cohort 2 participants either initiated treatment with DOR FDC (antiretroviral (ARV)-naïve) or switched to DOR FDC from a previous ARV regimen (virologically suppressed). The first 10 Cohort 2 participants had intensive PK evaluations, and safety, sparse PK, and HIV RNA were assessed through week 24.ResultsFifty-five adolescents, median age 15.0 years and baseline weight 51.5 kg, were enrolled. Nine participants completed Cohort 1 PK assessments (8 of the 9 participants weighed ≥45 kg) and 45 initiated study drug in Cohort 2. The doravirine geometric mean (GM) AUC 0-∞ was 34.8 μM∙hour, and the GM C 24 was 514 nM after a single dose, with a predicted steady-state GM C 24,ss,pred of 690 nM. Cohort 2 enrolled adolescents weighing ≥45 kg. Plasma concentrations of doravirine, tenofovir, and lamivudine achieved by Cohort 2 participants were similar to those reported in adults. No drug-related serious or grade 3 or 4 adverse events occurred. Forty-two of 45 participants (93.3%; 95% CI: [81.7, 98.6]) achieved or maintained HIV-1 RNA

Background Limited data are available regarding the susceptibility of the reverse transcriptase V106 polymorphism to doravirine. Methods Doravirine susceptibility was measured in site-directed mutants (SDMs) containing V106I, V106A, V106M, and Y188L mutations in subtype B (NL4-3, HXB2) and CRF02_AG background and in recombinant viruses with RT harboring V106I alone derived from 50 people with HIV. Results HIV-1 B subtype was detected in 1523 of 2705 cases. Prevalence of V106I was 3.2% in B and 2.5% in non-B subtypes, and was higher in subtype F (8.1%) and D (14.3%). Fold-changes (FC) in susceptibility for SDMs were below doravirine biological cutoff (3.0) for V106I, but not for V106A, V106M, and Y188L. Clinically derived viruses tested included 22 B (median FC, 1.2; interquartile range [IQR], 0.9–1.6) and 28 non-B subtypes (median FC, 1.8; IQR, 0.9–3.0). Nine (18%) viruses showed FC values equal or higher than the doravirine biological FC cutoff. Conclusions The prevalence of the HIV-1 RT V106I polymorphism in MeditRes HIV consortium remains low, but significantly more prevalent in subtypes D and F. V106I minimally decreased the susceptibility to doravirine in SDMs and most clinical isolates. Reduced susceptibility seems to occur at increased frequency in subtype F1; however, the clinical impact remains to be investigated. Clinical Trials Registration NCT04894357. [ABSTRACT FROM AUTHOR]

Objective s : The availability of doravirine (DOR) allowed clinicians to prescribe a dolutegravir (DTG)‐based two‐drug regimen (2DR) in individuals not eligible to receive lamivudine (3TC) or rilpivirine (RPV). The aims of this study were to describe the durability of DTG + DOR compared with DTG/3TC and DTG/RPV and the rate of virological failure and target not‐detected maintenance over time. Methods: This retrospective, monocentric analysis included all subjects who started a DTG‐based 2DR from 2018 to 2022 as a simplification. Descriptive statistics and non‐parametric tests to describe and compare the groups were applied. Kaplan–Meier probability curves and Cox regression models for regimens durability were used. Results: The study enrolled 710 individuals: 499 treated with DTG/3TC, 140 with DTG/RPV, and 71 with DTG + DOR. A 2DR with DOR was prescribed to older subjects who had a longer infection, greater exposure to different antiretroviral regimens, a higher proportion of resistance‐associated mutations, and a worse immune‐virologic status. Over a cumulative follow‐up of 68 152 weeks, 42 discontinuations were registered (5.9%). DTG + DOR had a risk of treatment interruption of 7.8% at 48 weeks and 9.8% at 96 weeks, significantly higher than the other 2DRs. In the multivariate Cox model, DTG + DOR and DTG/RPV were significantly associated with discontinuation. The maintenance of target not detected during follow‐up was similar among groups. The rate of virological failure was higher for DTG + DOR through different event definitions. Conclusions: DTG + DOR durability was high over a long follow‐up albeit lower than for other 2DRs. This combination might be an effective option in people with HIV that has proven difficult to treat. [ABSTRACT FROM AUTHOR]

Aims: The pharmacokinetics of doravirine has been studied in clinical trials but not in real‐world settings. Our study aims to characterize and identify factors influencing doravirine (a CYP3A4 substrate) pharmacokinetics in real‐world people with HIV (PWH). Methods: A total of 174 doravirine concentrations measured in 146 PWH followed up in the therapeutic drug monitoring (TDM) program at the University Hospital of Lausanne (Switzerland) between 2019 and 2023 were included in the analysis. Demographic data, clinical information and comedications were recorded during the routine SHCS visits (every 3–6 months). Population pharmacokinetic analysis and Monte Carlo simulations to investigate the clinical significance of the covariates retained in the final model were performed using NONMEM. Results: A one‐compartment model with first‐order absorption and linear elimination best described doravirine pharmacokinetics. Potent CYP3A4 inhibitors and, to a lesser extent age, were the only tested covariates to significantly impact doravirine clearance (CL). Potent CYP3A4 inhibitors reduced CL by 50%, and a 30% decrease in CL was observed in an 80‐year‐old compared with a 55‐year‐old PWH. The effect of potent CYP3A4 inhibitors was prominent, explaining 59% of between‐subject variability in CL. Model‐based simulations predicted 2.8‐fold and 1.6‐fold increases in median steady‐state trough and maximum doravirine concentrations, respectively, when a potent CYP3A4 inhibitor was co‐administered. Conclusions: Our findings show that potent CYP3A4 inhibitors and age influence doravirine pharmacokinetics. However, given the good tolerability of doravirine, dosing adjustment of doravirine is probably not mandatory in those situations. TDM remains useful essentially in specific clinical situations, such as hepatic impairment, suspected nonadherence or pregnancy. [ABSTRACT FROM AUTHOR]

Background Islatravir is a new antiretroviral drug that inhibits the reverse transcriptase (RT) of HIV-1 through multiple mechanisms. It is proposed to be used in combination with doravirine, a new NNRTI. M184V/I mutations have been shown to reduce the in vitro antiviral activity of islatravir, but their effect when pre-selected during ART has not been investigated. Methods HIV-1 rt sequences were obtained from four individuals of the Garrahan HIV cohort prior to, or during virological failure to ART. HIV-1 infectious molecular clones were constructed on an NL4-3 backbone, and infectious viruses were produced by transfection of 293T cells. Fold-changes in IC50 were calculated for each mutant versus the NL4-3 WT. HIV-1 phenotypic drug resistance was tested in vitro against NRTIs and NNRTIs. Results In all the cases, M184I/V, either alone or in the presence of other mutations, was associated with reduced susceptibility to islatravir, abacavir and lamivudine. Viruses carrying M184V/I showed variable levels of resistance to islatravir (4.8 to 33.8-fold). The greatest reduction in susceptibility was observed for viruses carrying the mutations M184V + V106I (33.8-fold resistance) or M184V + I142V (25.2-fold resistance). For NNRTIs, the presence of V106I alone did not affect susceptibility to doravirine or etravirine, but showed a modest reduction in susceptibility to efavirenz (6-fold). Susceptibility to doravirine was slightly reduced only for one of the mutants carrying V106I in combination with Y181C and M184V. Conclusions Mutations and polymorphisms selected in vivo together with M184V/I depend on the viral genetic context and on ART history, and could affect the efficacy of islatravir once available for use in the clinic. [ABSTRACT FROM AUTHOR]

Background: Weight gain has been well-described with integrase strand transfer inhibitors (INSTIs) and tenofovir alafenamide (TAF). Doravirine (DOR) has been identified as a relatively "weight-neutral" drug; however, there is little data describing its effect on weight change in routine clinical practice. Methods: We conducted a retrospective chart review of weight change among people with HIV changing from an INSTI- to a non-INSTI regimen with DOR. Results: At the time of ART switch, among 49 people with HIV, the mean age was 47 years, 24% were female, and 75% had HIV-1 viral load <200 copies/mL. Most (55%) people with HIV were taking bictegravir/TAF/emtricitabine prior to the switch. Although 84% switched due to concerns about weight gain, only 16% had a weight gain of ≥10% in the year preceding, and 49% had no substantial change in weight. 86% switched to DOR/lamivudine/tenofovir disoproxil fumarate. A weight decrease (−2.6% [95% CI: −5.1, −0.1%, p =.041] was seen over the year following the ART switch. Weight change prior to switch was greatest in the year 2021 compared to 2019, 2020, and 2022. Conclusions: Overall, modest changes in weight were seen following ART switch from INSTI-based regimen to a DOR-based, non-INSTI regimen. Further investigations with larger people with HIV cohorts will be helpful to guide clinical practice, while the impact of the COVID-19 pandemic on weight change should also be considered. [ABSTRACT FROM AUTHOR]

Abstract HIV post- exposure prophylaxis (PEP) is a prevention tool for individuals with a recent potential exposure to HIV. Doravirine has been available since 2019 in combination with tenofovir disoproxil fumarate and lamivudine and has not been evaluated as a PEP. DOR/3TC/TDF is our department’s most commonly prescribed PEP treatment since 2021. This study evaluates the completion rate of the DOR/3TC/TDF as compared to EVG/c/FTC/TAF for PEP, which was the regimen prescribed until 2020 in our hospital. This retrospective observational study was conducted between January 2020 and September 2021. The subjects included consecutively were adults who consulted for an HIV sexual exposure accident and for whom DOR/3TC/TDF in 2021 or EVG/c/FTC/TAF in 2020 was prescribed. The outcomes were the completion rate to the end of treatment (28 days), the seroconversion rate, and the description of side effects. During the study period, 311 people were included: 140 treated with DOR/3TC/TDF and 171 treated with EVGc/FTC/TAF. Considering subjects with a follow-up visit, the completion rate was 96.8% (90/93) in the DOR/3TC/TDF group, and 94.6% (123/130) in the EVG/c/FTC/TAF group (p-value: 0.53). The number of people lost to follow-up was nearly equivalent in both groups: 27.1% (38/140) in the DOR/3TC/TDF group and 23.4% (40/171) in the EVG/c/FTC/TAF group (p-value: 0.45). A side effect was described for 38% (36/94) in the DOR/3TC/TDF group, and 29.7% (38/128) in the EVG/c/FTC/TAF group. No cases of seroconversion were observed. DOR/3TC/TDF appears to have a similar safety profile to EVG/c/FTC/TAF. Due to its lower cost, it seems to be a treatment option for consideration in the context of HIV-exposure accidents.

A novel and economical reverse phase high performance liquid chromatography (RP-HPLC) method has been developed to reliably and precisely quantify the amount of Doravirine in both bulk and solid dose forms. The separation procedure was performed with a Dionex C18 column with dimensions of 250 x 4.6mm and a particle size of 5μ. The experiment used the isocratic method, using a mobile phase composed of a combination of Ortho phosphoric acid pH-6.0 buffer and methanol in a ratio of 60:40 (v/v). The mobile phase was introduced into the column by means of a pump, with a flow rate of 1.0 mL min-1. The eluent from the column was identified using a UV detector configured to operate at a wavelength of 316 nm. The experiment lasted for a total of 6 minutes, during which the column was maintained at the surrounding temperature. The measured retention period for Doravirine was found to be 2.20 minutes. The standard curves demonstrated linearity within the concentration range of 10-50 μg/ml, with a good coefficient of determination (R2 = 0.9997). The trial yielded a range of percentage recoveries, ranging from 102% to 98%. Furthermore, the RSD was calculated to be 0.3693%. The quantified percentage composition of a commercially accessible Doravirine formulation was found to be 100.30%. The technique was validated following the guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The proposed RP-HPLC technology has undergone validation via research, demonstrating its attributes of simplicity, specificity, speed, dependability, and consistency. Hence, the methodology proposed in this research may be used for the routine examination of Doravirine in both its concentrated and solid forms, particularly for the goal of ensuring quality control. [ABSTRACT FROM AUTHOR]

Background: Currently available antiretroviral 2-drug regimen (2DR) fixed dose combinations may not be suitable for specific situations including the presence of resistance associated mutations (RAM) or drug − drug interactions (DDI). The data on the use of the non-nucleoside reverse transcriptase inhibitor doravirine (DOR) and the integrase inhibitor dolutegravir (DTG) as an alternative 2DR remain scarce. Methods: People living with HIV with DOR + DTG as a 2DR are being followed in a prospective observational study. Results: This analysis describes 85 participants with a median age of 57 years. Median CD4-nadir was 173/µl and a majority (66%) had a history of HIV-associated or AIDS-defining conditions. Antiretroviral history was mostly extensive, and documentation of RAM was frequent. The main reasons for choosing DOR + DTG were DDI (29%), tolerability (25%), and cardiovascular risk reduction (21%). Plasma viral load at switch was < 50 copies/ml in all but 3 instances, median CD4 count was 600/µl. DOR + DTG was later changed to another regimen in 10 participants after a median of 265 days, the other 75 participants have remained on DOR + DTG for a median of 947 days. Conclusion: DOR + DTG as a 2DR proved to be a durable treatment option even in extensively pretreated individuals. [ABSTRACT FROM AUTHOR]

The objective of the present research is to develop a reliable, sensitive, and robust stability-indicating RP-HPLC method to quantify doravirine along with its impurities (IMP-A, IMP-B). The separation was accomplished on a Inertsil ODS C18 (250 × 4.6 mm, 5 μm) column at 216 nm using 0.1% orthophosphoric acid and acetonitrile at a flow rate of 1 mL/min eluted with a retention time of IMP-A, IMP-B, and doravirine of 2.52 min, 3.96 min, and 8.74 min respectively. The optimized method was validated in terms of accuracy, precision, linearity, specificity, system suitability, and robustness as per International Council for Harmonization guidelines. The optimized method showed linearity within the concentration range 10–200 μg/mL, 0.7–14 μg/mL, and 0.5–10 μg/mL for doravirine, IMP-A, and IMP-B respectively. The method was found to be precise at %RSD < 2 and accurate with percentage recovery for doravirine, IMP-A, and IMP-B of 100.46%, 100.2%, and 99.2% respectively. The optimized method proved to be sensitive, robust, and specific. This optimized method can be routinely employed in quality control laboratories for the quantification of doravirine along with its impurities. [ABSTRACT FROM AUTHOR]

Abstract Background Doravirine (DOR) is a newly approved antiretroviral belonging to the class of non-nucleoside reverse transcriptase inhibitors (NNRTI), well tolerated and leading to an improved lipid profile in antiretroviral experienced people living with HIV (PLWH). We aimed at evaluating if the lipid-lowering effect is linked to the drug class, using real-life data from the SCOLTA cohort. Methods We compared the lipid profile modifications in experienced PLWH switching to a DOR-based regimen from rilpivirine or another NNRTI-based regimen or from an integrase strand transferase (INSTI)-based regimen. T0 and T1 were defined as the baseline and 6-month follow-up respectively. Data were collected at baseline and prospectively every six months and changes from baseline were compared using a multivariable linear model. Results In 107 PLWH, enrolled in the SCOLTA DOR cohort, with undetectable HIV-RNA at baseline, 32.7% switched from RPV-based regimens (DOR1), 29.9% from other NNRTI-including regimens (DOR2) and 37.4% switched from INSTI-including regimens (DOR3). At T1, TC significantly decreased in DOR2 (-15 mg/dL) and DOR3 (-23 mg/dL), and significantly more in DOR3 than in DOR1 (-6 mg/dL) (p = 0.016). HDL-C declined in DOR2 (-2 mg/dL) whereas it increased in DOR1 (+ 3 mg/dL) (p = 0.042) and remained stable in DOR3. LDL-C significantly decreased from baseline in DOR2 (-12 mg/dL) and DOR3 (-22 mg/dL) and was different between DOR1 (-8 mg/dL) and DOR3 (p = 0.022). TC/HDL ratio showed a significant decline in the DOR3 group (-0.45), although similar to DOR1 (-0.23, p = 0.315) and DOR2 (-0.19, p = 0.254). Triglycerides did not noticeably change. ALT significantly decreased in PLWH with a baseline level > 40 UI/mL. Conclusions PLWH on doravirine treatment showed different trends in blood lipids according to their previous regimen. In PLWH switching from RPV, minimal modifications were seen, whereas in those switching from other NNRTIs and from INSTI-including regimens, we observed an overall improvement in lipid profile, seemingly independent of the “statin effect” of TDF.

Abstract Background Doravirine has a unique resistance profile but how this profile might increase its usefulness beyond first-line therapy in persons with susceptible viruses has not been well studied. We sought to determine scenarios in which doravirine would retain activity against isolates from ART-naïve persons with transmitted drug resistance (TDR) and to identify gaps in available doravirine susceptibility data. Methods We analyzed published in vitro doravirine susceptibility data and applied the results to 42,535 RT sequences from ART-naïve persons published between 2017 and 2021. NNRTI drug resistance mutations (DRMs) were defined as those with a Stanford HIV Drug Resistance Database doravirine penalty score either alone or in combination with other mutations. Results V106A, Y188L, F227C/L, M230L, and Y318F were associated with the greatest reductions in doravirine susceptibility. However, several NNRTI DRMs and DRM combinations lacking these canonical resistance mutations had > tenfold reduced susceptibility including G190E, one isolate with G190S, three isolates with L100I + K103N, one isolate with K103N + P225H, and isolates with L100I + K103N + V108I and K101E + Y181C + G190A. Of the 42,535 ART-naïve sequences, 3,374 (7.9%) contained a NNRTI DRM of which 2,788 (82.6%) contained 1 DRM (n = 33 distinct mutations), 426 (12.6%) contained 2 DRMs (79 distinct pairs of mutations), and 143 (4.2%) contained ≥ 3 DRMs (86 distinct mutation patterns). Among the 2,788 sequences with one DRM, 112 (4.0%) were associated with ≥ 3.0-fold reduced doravirine susceptibility while 2,625 (94.2%) were associated with

HIV post- exposure prophylaxis (PEP) is a prevention tool for individuals with a recent potential exposure to HIV. Doravirine has been available since 2019 in combination with tenofovir disoproxil fumarate and lamivudine and has not been evaluated as a PEP. DOR/3TC/TDF is our department's most commonly prescribed PEP treatment since 2021. This study evaluates the completion rate of the DOR/3TC/TDF as compared to EVG/c/FTC/TAF for PEP, which was the regimen prescribed until 2020 in our hospital. This retrospective observational study was conducted between January 2020 and September 2021. The subjects included consecutively were adults who consulted for an HIV sexual exposure accident and for whom DOR/3TC/TDF in 2021 or EVG/c/FTC/TAF in 2020 was prescribed. The outcomes were the completion rate to the end of treatment (28 days), the seroconversion rate, and the description of side effects. During the study period, 311 people were included: 140 treated with DOR/3TC/TDF and 171 treated with EVGc/FTC/TAF. Considering subjects with a follow-up visit, the completion rate was 96.8% (90/93) in the DOR/3TC/TDF group, and 94.6% (123/130) in the EVG/c/FTC/TAF group (p-value: 0.53). The number of people lost to follow-up was nearly equivalent in both groups: 27.1% (38/140) in the DOR/3TC/TDF group and 23.4% (40/171) in the EVG/c/FTC/TAF group (p-value: 0.45). A side effect was described for 38% (36/94) in the DOR/3TC/TDF group, and 29.7% (38/128) in the EVG/c/FTC/TAF group. No cases of seroconversion were observed. DOR/3TC/TDF appears to have a similar safety profile to EVG/c/FTC/TAF. Due to its lower cost, it seems to be a treatment option for consideration in the context of HIV-exposure accidents. [ABSTRACT FROM AUTHOR]

Background New regimens may provide better tolerability, convenience, and safety for nonoccupational human immunodeficiency virus (HIV) postexposure prophylaxis (PEP). For this reason, we evaluated the single-tablet regimen of doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) for 28 days. Methods This was a prospective, open-label, single-arm trial including individuals with potential HIV-1 exposure within 72 hours. The primary endpoint was noncompletion of PEP at day 28. Secondary endpoints were adverse effects, adherence, and rate of seroconversion. We performed follow-up at day 7, week 4, and week 12. Results Between September 2019 and March 2022, the study enrolled 399 individuals. Median age was 30 (interquartile range [IQR], 27–36) years, and 91% (n = 364) were male. The mode of exposure was sex between men in 84% (n = 331) of cases; risk assessment for HIV-1 transmission was considered as "high" in 97% (n = 385) of the participants. Median time from exposure to consultation was 24 (IQR, 13–40) hours. Noncompletion of PEP was 29% (n = 114) (95% confidence interval [CI], 24%–33%) and 20% (n = 72) (95% CI, 16%–25%) per modified intention-to-treat. Main reasons for noncompletion were loss to follow-up (n = 104 [91%]) and intolerance (n = 8 [7%]). Older age was associated with a lower risk of premature discontinuation (OR, 0.94; P <.001). One hundred twenty-three (31%) participants reported adverse events, mostly mild and self-limited (82%); discontinuation occurred in 8 cases (2%). Adherence to PEP in the assessed users was 96%. There were no HIV seroconversions. Conclusions DOR/3TC/TDF is a well-tolerated option for nonoccupational PEP. Clinical Trials Registration. NCT04233372. [ABSTRACT FROM AUTHOR]

In the past, one of the most widely used non-nucleoside reverse transcriptase inhibitors (NNRTI) in first-line antiretroviral therapy (ART) of HIV infection was efavirenz (EFV), which is already used as a cost-effective treatment in developing countries due to its efficacy, tolerability, and availability. However, EFV also demonstrates several adverse effects, like hepatotoxicity, altered lipid profile, neuropsychological symptoms, and behavioral effects in children after in utero exposure. In 2018, another NNRTI, doravirine (DOR), was approved due to its similar efficacy but better safety profile. Preclinical safety studies demonstrated that DOR is not genotoxic and exhibits no developmental toxicity or effects on fertility in rats. Zebrafish (Danio rerio) embryos have been widely accepted as a vertebrate model for pharmacological and developmental studies. We used zebrafish embryos as an in vivo model to investigate the developmental toxicity of DOR compared to EFV. After exposure of the embryos to the drugs from the gastrula stage up to different developmental stages (30 embryos for each arm, in three independent experiments), we assessed their survival, morphology, hatching rate, apoptosis in the developing head, locomotion behavior, vasculature development, and neutral lipid distribution. Overall, DOR showed a better safety profile than EFV in our model. Therapeutic and supra-therapeutic doses of DOR induced very low mortality [survival rates: 92, 90, 88, 88, and 81% at 1, 5, 10, 25, and 50 μM, respectively, at 24 h post fecundation (hpf), and 88, 85, 88, 89, and 75% at the same doses, respectively, at 48 hpf] and mild morphological alterations compared to EFV exposure also in the sub-therapeutic ranges (survival rates: 80, 77, 69, 63, and 44% at 1, 5, 10, 25, and 50 μM, respectively, at 24 hpf and 72, 70, 63, 52, and 0% at the same doses, respectively, at 48 hpf). Further, DOR only slightly affected the hatching rate at supra-therapeutic doses (97, 98, 96, 87, and 83% at 1, 5, 10, 25, and 50 μM, respectively, at 72 hpf), while EFV already strongly reduced hatching at sub-therapeutic doses (83, 49, 11, 0, and 0% at 1, 5, 10, 25, and 50 μM, respectively, at the same time endpoint). Both DOR at therapeutic doses and most severely EFV at sub-therapeutic doses enhanced apoptosis in the developing head during crucial phases of embryo neurodevelopment and perturbed the locomotor behavior. Furthermore, EFV strongly affected angiogenesis and disturbed neutral lipid homeostasis even at sub-therapeutic doses compared to DOR at therapeutic concentrations. Our findings in zebrafish embryos add further data confirming the higher safety of DOR with respect to EFV regarding embryo development, neurogenesis, angiogenesis, and lipid metabolism. Further studies are needed to explore the molecular mechanisms underlying the better pharmacological safety profile of DOR, and further human studies are required to confirm these results in the zebrafish animal model. [ABSTRACT FROM AUTHOR]

Doravirine (DOR) is a newly approved non-nucleoside reverse transcriptase inhibitor (NNRTI). We aimed to investigate, in a real-life setting, how switching to a DOR-based regimen rather than a rilpivirine (RPV)-based regimen impacted metabolic and hepatic safety. The analysis included 551 antiretroviral treatment (ART)-experienced people living with HIV (PLWH), starting RPV-based or DOR-based regimens with viral load < 200 copies/mL, baseline (T0), and at least one control visit (6-month visit, T1). We enrolled 295 PLWH in the RPV and 256 in the DOR cohort. At T1, total cholesterol (TC), low-density lipoprotein-C (LDL-C), and triglycerides significantly decreased in both DOR and RPV cohorts, while high-density lipoprotein-C (HDL-C) only decreased in RPV-treated people. Consistently, the TC/HDL-C ratio declined more markedly in the DOR (−0.36, p < 0.0001) than in the RPV cohort (−0.08, p = 0.25) (comparison p = 0.39). Similar trends were observed when excluding the PLWH on lipid-lowering treatment from the analysis. People with normal alanine aminotransferase (ALT) levels showed a slight ALT increase in both cohorts, and those with baseline ALT > 40 IU/L experienced a significant decline (−14 IU/L, p = 0.008) only in the DOR cohort. Lipid profile improved in both cohorts, and there was a significant reduction in ALT in PLWH with higher-than-normal baseline levels on DOR-based ART. [ABSTRACT FROM AUTHOR]

ABSTRACT: Objectives: There are limited data on the prevalence of doravirine (DOR)-associated drug resistance mutations in people with HIV (PWH) in Botswana. This cross-sectional, retrospective study aimed to explore the prevalence of DOR-associated resistance mutations among ART-naïve and -experienced PWH in Botswana enrolled in the population-based Botswana Combination Prevention Project (BCPP). Methods: A total of 6078 HIV-1C pol sequences were analysed for DOR-associated resistance mutations using the Stanford HIV drug resistance database, and their levels were predicted according to the Stanford DRM penalty scores and resistance interpretation. Virologic failure was defined as HIV-1 RNA load (VL) >400 copies/mL. Results: Among 6078 PWH, 5999 (99%) had known ART status, and 4529/5999 (79%) were on ART at time of sampling. The suppression rate among ART-experienced was 4517/4729 (96%). The overall prevalence of any DOR-associated resistance mutations was 181/1473 (12.3% [95% confidence interval {CI}: 10.7–14.1]); by ART status: 42/212 (19.8% [95% CI: 14.7–25.4]) among ART-failing individuals (VL ≥400 copies/mL) and 139/1261 (11.0% [95% CI: 9.3–12.9]) among ART-naïve individuals (P < 0.01). Intermediate DOR-associated resistance mutations were observed in 106/1261 (7.8% [95% CI: 6.9–10.1]) in ART-naïve individuals and 29/212 (13.7% [95% CI: 9.4–8.5]) among ART-experienced participants (P < 0.01). High-level DOR-associated resistance mutations were observed in 33/1261 (2.6% [95% CI: 1.8–3.7]) among ART-naïve and 13/212 (6.1% [95% CI: 3.6–10.8]) among ART-failing PWH (P < 0.01). PWH failing ART with at least one EFV/NVP-associated resistance mutation had high prevalence 13/67 (19.4%) of high-level DOR-associated resistance mutations. Conclusion: DOR-associated mutations were rare (11.0%) among ART-naive PWH but present in 62.7% of Botswana individuals who failed NNRTI-based ART with at least one EFV/NVP-associated resistance mutation. Testing for HIV drug resistance should underpin the use of DOR in PWH who have taken first-generation NNRTIs.

The pharmacokinetics of doravirine (DOR) have not been clarified in patients undergoing hemodialysis (HD). In this study, we evaluated the pharmacokinetics of DOR in four HIV-1-infected patients undergoing HD who were administered DOR. The participants were patients undergoing HD for end-stage renal disease and were administered DOR. DOR was administered once daily (one tablet of 100 mg), every evening. On days of HD treatment, DOR was administered after the end of the procedure. After administration of DOR for at least 1 week, the plasma DOR concentration was measured. The median plasma trough DOR concentration was 766.9 ng/mL (range: 509–1085 ng/mL). The median DOR clearance by HD, DOR elimination rate, half-life (T 1/2) of plasma DOR concentration during HD, and T 1/2 during the non-HD period were 85.04 mL/min, 73.12%, 7.71 h, and 13.76 h, respectively. The T 1/2 during the HD period was significantly shorter than the T 1/2 during the non-HD period (p = 0.0030). In this study, elimination of DOR by HD was confirmed. Viral suppression was maintained in all patients undergoing HD, and none had adverse events or safety problems. As DOR is eliminated by HD, monitoring its plasma concentration is considered necessary for clinical use. [ABSTRACT FROM AUTHOR]

Thanks to the modern ARV regimens and the fact that the morbidity and mortality of metabolic syndrome increases with age, clinicians are continuously researching effective and safe antiretroviral regimens with low impact on the lipid profile. Doravirine (DOR) is the latest non-nucleoside reverse-transcriptase inhibitor (NNRTI) that shows long-term safety and tolerability and a favorable lipid profile. The aim of this study is to assess the impact of DOR-based three-drug regimens on the lipid profile in clinical practice. We retrospectively analyzed a cohort of 38 treatment-experienced, virologically suppressed people living with HIV (PLWH) switching to this regimen, following the eligibility criteria. We carried out comparison analysis of immunological and metabolic parameters between baseline and 48 weeks of follow up. In our cohort of treatment-experienced, virologically suppressed PLWH, three-drug regimens with DOR showed good efficacy and a positive profile on lipid metabolism at 48 weeks of follow up. [ABSTRACT FROM AUTHOR]

Background: Doravirine (DOR) is a newly approved antiretroviral belonging to the class of non-nucleoside reverse transcriptase inhibitors (NNRTI), well tolerated and leading to an improved lipid profile in antiretroviral experienced people living with HIV (PLWH). We aimed at evaluating if the lipid-lowering effect is linked to the drug class, using real-life data from the SCOLTA cohort. Methods: We compared the lipid profile modifications in experienced PLWH switching to a DOR-based regimen from rilpivirine or another NNRTI-based regimen or from an integrase strand transferase (INSTI)-based regimen. T0 and T1 were defined as the baseline and 6-month follow-up respectively. Data were collected at baseline and prospectively every six months and changes from baseline were compared using a multivariable linear model. Results: In 107 PLWH, enrolled in the SCOLTA DOR cohort, with undetectable HIV-RNA at baseline, 32.7% switched from RPV-based regimens (DOR1), 29.9% from other NNRTI-including regimens (DOR2) and 37.4% switched from INSTI-including regimens (DOR3). At T1, TC significantly decreased in DOR2 (-15 mg/dL) and DOR3 (-23 mg/dL), and significantly more in DOR3 than in DOR1 (-6 mg/dL) (p = 0.016). HDL-C declined in DOR2 (-2 mg/dL) whereas it increased in DOR1 (+ 3 mg/dL) (p = 0.042) and remained stable in DOR3. LDL-C significantly decreased from baseline in DOR2 (-12 mg/dL) and DOR3 (-22 mg/dL) and was different between DOR1 (-8 mg/dL) and DOR3 (p = 0.022). TC/HDL ratio showed a significant decline in the DOR3 group (-0.45), although similar to DOR1 (-0.23, p = 0.315) and DOR2 (-0.19, p = 0.254). Triglycerides did not noticeably change. ALT significantly decreased in PLWH with a baseline level > 40 UI/mL. Conclusions: PLWH on doravirine treatment showed different trends in blood lipids according to their previous regimen. In PLWH switching from RPV, minimal modifications were seen, whereas in those switching from other NNRTIs and from INSTI-including regimens, we observed an overall improvement in lipid profile, seemingly independent of the "statin effect" of TDF. [ABSTRACT FROM AUTHOR]

Hung-Chin Tsai,1– 5 I-Tzu Chen,1 Hui-Min Chang,6– 8 Susan Shin-Jung Lee,1,2 Yao-Shen Chen1,2 1Division of Infectious Diseases, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; 2Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 3Department of Parasitology, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan; 5Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan; 6Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; 7Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 8Department of Pharmacy and Graduate Institute of Pharmaceutical Technology, Tajen University, Pingtung, TaiwanCorrespondence: Hung-Chin Tsai, Division of Infectious Diseases, Department of Medicine Kaohsiung Veterans General Hospital, #386 Ta-Chung 1st Road, Kaohsiung, 813, Taiwan, Tel +886 7 3422121 ext. 2029, Fax +886 7 346 8292, Email hctsai1011@yahoo.com.tw; tsaihungchin@gmail.comPurpose: This study aimed to investigate the prevalence of resistance to a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based single-tablet regimen (STR) in Taiwanese patients and clarify the clinical implications of using doravirine in patients who fail NNRTI treatment.Patients and Methods: Taiwanese patients infected with HIV-1 who failed NNRTI-based STR treatment were enrolled in this retrospective cohort study from 2015 to 2020. Mutations associated with drug resistance were identified using the 2019 International Antiviral Society-USA list of drug-resistant mutations in HIV, and drug susceptibility was assessed according to the Stanford HIV Drug Resistance Database version 9. Median values of continuous variables were compared between two groups using the Mann–Whitney U-test, and categorical variables were compared using the chi-square test or Fisher’s exact test.Results: A total of 107 patients were included, of whom 29 were treatment failure to the initial STRs, and 78 failed treatment after switching to an STR. Seventy-four patients failed treatment with TDF/FTC/EFV (Atripla), 30 with TDF/FTC/RPV (Complera) and 3 with TAF/FTC/RPV (Odefsey). The prevalence rates of resistance to nucleoside reverse transcriptase inhibitors (NRTIs), NNRTIs, protease inhibitors (PIs) and integrase strand transfer inhibitors (INSTIs) were 76%, 86%, 3% and 2%, respectively. Among the 29 patients failure to the initial STRs, 62% developed doravirine resistance, compared to 64% of the 78 the patients who failed treatment after switching to an STR. There were no significant differences in the prevalence of specific NNRTI or doravirine resistance-associated mutations between these two groups. The patients with K65R mutations were more likely to have NNRTI resistance (p = 0.037) and doravirine resistance (p < 0.001).Conclusion: Our findings showed a high rate of doravirine cross-resistance in patients with NNRTI-based STR treatment failure. Doravirine should be used cautiously as a salvage regimen in patients who fail NNRTI treatment.Keywords: HIV, doravirine, drug resistance, single-tablet regimen, virological failure

Background: Doravirine has a unique resistance profile but how this profile might increase its usefulness beyond first-line therapy in persons with susceptible viruses has not been well studied. We sought to determine scenarios in which doravirine would retain activity against isolates from ART-naïve persons with transmitted drug resistance (TDR) and to identify gaps in available doravirine susceptibility data. Methods: We analyzed published in vitro doravirine susceptibility data and applied the results to 42,535 RT sequences from ART-naïve persons published between 2017 and 2021. NNRTI drug resistance mutations (DRMs) were defined as those with a Stanford HIV Drug Resistance Database doravirine penalty score either alone or in combination with other mutations. Results: V106A, Y188L, F227C/L, M230L, and Y318F were associated with the greatest reductions in doravirine susceptibility. However, several NNRTI DRMs and DRM combinations lacking these canonical resistance mutations had > tenfold reduced susceptibility including G190E, one isolate with G190S, three isolates with L100I + K103N, one isolate with K103N + P225H, and isolates with L100I + K103N + V108I and K101E + Y181C + G190A. Of the 42,535 ART-naïve sequences, 3,374 (7.9%) contained a NNRTI DRM of which 2,788 (82.6%) contained 1 DRM (n = 33 distinct mutations), 426 (12.6%) contained 2 DRMs (79 distinct pairs of mutations), and 143 (4.2%) contained ≥ 3 DRMs (86 distinct mutation patterns). Among the 2,788 sequences with one DRM, 112 (4.0%) were associated with ≥ 3.0-fold reduced doravirine susceptibility while 2,625 (94.2%) were associated with < 3.0-fold reduced susceptibility. Data were not available for individual NNRTI DRMs in 51 sequences (1.8%). Among the 426 sequences with two NNRTI DRMs, 180 (42.3%) were associated with ≥ 3.0 fold reduced doravirine susceptibility while just 32 (7.5%) had < 3.0 fold reduced susceptibility. Data were not available for 214 (50.2%) sequences containing two NNRTI DRMs. Conclusions: First-line therapy containing doravirine plus two NRTIs is expected to be effective in treating most persons with TDR as more than 80% of TDR sequences had a single NNRTI DRM and as more than 90% with a single DRM were expected to be susceptible to doravirine. However, caution is required for the use of doravirine in persons with more than one NNRTI DRM even if none of the DRMs are canonical doravirine-resistance mutations. [ABSTRACT FROM AUTHOR]

Doravirine (DOR) is a novel antiretroviral agent with a favorable resistance profile and high tolerability. However, evidence is limited on DOR among elderly people living with HIV (PLWH) and whether it might modulate chronic inflammation. We aimed to investigate the efficacy, safety, and tolerability of DOR as a switching strategy among elderly PLWH and its impact on chronic inflammation in a real-life setting. We recruited a cohort of ART-experienced PLWH undergoing a therapeutic switch to a DOR-based regimen under virologic control (defined as HIV-RNA <200 copies/mL), regardless of the previous ART regimen. The primary objective was the evaluation of the rate of virologic control at 48 weeks post-switch. Secondary objectives included analyzing immune and metabolic outcomes. Plasmatic hs-CRP, IL-6, and D-dimer levels were measured as chronic inflammation markers. Overall, 150 PLWH were screened, and 147 were enrolled into the study. A total of 134 PLWH completed the follow-up. The rate of virological control was 96.1% (122/134; CIs : 91.0%-98.7%) in the per-protocol analysis. After 48 weeks from the switch, we recorded significant reductions in serum fasting glycemia ( P 0.019), triglycerides ( P 0.024), and total cholesterol/HDL ratio ( P 0.017); no clinically significant differences were detected in the body weight and BMI, as long as in immune, hepatic, and renal profiles. A significant reduction in IL-6 ( P 0.019) and hs-CRP ( P 0.019) was observed. DOR is an effective and safe treatment choice for elderly PLWH. The intriguing modulatory effect of DOR-based regimens on chronic systemic inflammation deserves further investigation.

Doravirine (DOR) concentrations and HIV-1 RNA were evaluated in genital fluids from adults with HIV on stable therapy who switched to DOR + FTC/TAF. High protein-unbound DOR concentrations were observed in both seminal plasma and cervicovaginal fluid. DOR + FTC/TAF maintained viral suppression in genital fluids in all but 1 participant. [ABSTRACT FROM AUTHOR]

The main objective of proposed method is to develop, validate & to perform the forced degradation studies for the simultaneous quantification of lamivudine, doravirine and tenofovir in active pharmaceutical ingredient (API) and formulation using reverse phase ultra-performance liquid chromatography (RP-UPLC). The estimation was performed using HSS C18 (100mm×2.1mm, 1.8µ) column with acetonitrile and 0.1% ortho phosphoric acid (OPA) (35:65) as mobile phase ran in isocratic mode at rate of flow 0.3 mL/minute. The column temperature maintained at 30°C and detection wavelength used was 260nm. The developed method validated as per ICH guidelines. Method obeyed Beer's law in the range of concentration of 37.5 µg/mL-225 µg/mL, 37.5 µg/mL-225 µg/mL and 12.5 µg/mL-75 µg/mL for lamivudine, tenofovir and doravirine respectively. The method is stable when exposed to different stressed conditions with less degradation. For regular analysis of estimate of lamivudine, tenofovir, and doravirine in tablet formulation, this UPLC method can be employed. [ABSTRACT FROM AUTHOR]

In Russia, before 2022, the list of vital and essential drugs for HIV-infected patients previously untreated with antiretroviral drugs included the fixed-dose combination rilpivirine/tenofovir disoproxil fumarate/emtricitabine (RPV/TDF/FTC) but not doravirine/tenofovir disoproxil fumarate/lamivudine (DOR/TDF/3TC). An indirect comparison of the efficacy of DOR/TDF/3TC and RPV/TDF/FTC defined by virologic suppression (HIV-1 RNA of <50 copies/mL at week 48) was made. The per-patient drug costs over 1 year were compared in a cost-minimization analysis. A budget impact analysis considered the costs to the healthcare system of including DOR/TDF/3TC as a treatment option for eligible patients in Russia over a 3-year time horizon. The indirect treatment comparison of DOR/TDF/3TC and RPV/TDF/FTC in treatment-naïve patients with baseline HIV-1 RNA 100,000 copies/ml or less showed no statistically significant difference (RR 0.914, 95% CI 0.833–1.003). In the cost-minimization analysis, the per-patient cost of one year of treatment with RPV/TDF/FTC and DOR/TDF/3TC was, respectively, ₽320,975 and ₽151,192, for a saving of ₽169,783. In the budget impact analysis, the adoption of DOR/TDF/3TC into clinical practice is expected to reduce drug costs by ₽333 million (23.8%) in year 3. Fixed-dose combination DOR/TDF/3TC is equally effective and cost-saving compared to RPV/TDF/FTC from Russian vital and essential drugs list perspective. [ABSTRACT FROM AUTHOR]

Abstract Background To establish a simple, sensitive, accurate, precise, efficient, economical RP-UPLC method for simultaneous estimation of Doravirine, Lamivudine and Tenofovir disoproxil fumarate in bulk and their combined pharmaceutical formulations. Optimization of Chromatographic separation was achieved on analytical column HSS C18 (100 × 2.1 mm, 1.8 μ) maintained at temperature 30 °C and mobile phase consisting of 0.01 N Potassium dihydrogen orthophosphate buffer (pH-4.8) and acetonitrile in the ratio 60:40 v/v and at a flow rate 0.3 mL/min in isocratic mode. The injection volume was set as 1 µl detection wavelength is 260 nm. The proposed method validation was done as per International Council on Harmonization Q2 (R1) guidelines. Results Doravirine, Lamivudine and Tenofovir disoproxil fumarate were eluted at retention times of 1.2, 1.5, and 1.8 min respectively. The proposed method was identified an excellent linearity over concentration range of 12.5–75.0 µg/mL for Doravirine and 37.5–225.0 µg/mL for Lamivudine and 37.5–225.0 µg/mL for Tenofovir disoproxil fumarate. The percentage relative standard deviation for intra-day and inter-day precision of the present method was less than 2% for Doravirine, Lamivudine and Tenofovir disoproxil fumarate. Accuracy of the present method was evaluated by recovery studies which were in the range of 99.62–99.88% for Doravirine and 98.78–99.44% for Lamivudine and 99.67–100.52% for Tenofovir disoproxil fumarate. The limit of detection and limit of quantification were found to be 0.249 µg/mL and 0.756 µg/mL for Doravirine and 0.24 µg/mL and 0.727 µg/mL for Lamivudine and 0.797 µg/mL and 2.966 µg/mL for Tenofovir disoproxil fumarate. Forced degradation studies were carried out under various stress conditions like acid, base, peroxide, thermal, photo and neutral conditions. Conclusions The present method makes sure about no degraded impurity peak interference at the retention time of analyte peak hence can be applied for quality control investigation of Doravirine, Lamivudine and Tenofovir disoproxil fumarate in bulk and pharmaceutical formulations.

Supplemental Digital Content is Available in the Text. Background: Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for treatment and prevention of HIV-1. We present efficacy and safety data for islatravir and doravirine (DOR) through 96 weeks of the phase 2b trial (NCT03272347). Methods: In this randomized, double-blind, dose-ranging trial, participants initially received islatravir (0.25, 0.75, or 2.25 mg) with doravirine (100 mg) and lamivudine (3TC, 300 mg) or a fixed-dose combination of doravirine, 3TC, and tenofovir disoproxil fumarate (DOR/3TC/TDF) daily. Beginning at week 24, participants receiving islatravir stopped 3TC if HIV-1 RNA from the prior visit was <50 copies per milliliter and continued taking the assigned islatravir dose (still blinded) with doravirine. All islatravir groups transitioned to open-label use of 0.75 mg between weeks 60 and 84. Efficacy end points at week 96 included the proportion of participants maintaining HIV-1 RNA of <50 copies per milliliter (FDA Snapshot). Safety was assessed by adverse event (AE) reporting. Results: One hundred twenty-one treatment-naive participants received the study drugs and were included in the analyses. Through week 96, HIV-1 RNA<50 copies per milliliter was maintained in 86.2% (25/29), 90.0% (27/30), and 67.7% (21/31) of participants in the 0.25-, 0.75-, and 2.25-mg islatravir groups, respectively, 81.1% (73/90) of the combined islatravir group, and 80.6% (25/31) of the DOR/3TC/TDF group. One participant in the 2.25-mg islatravir group had Protocol-Defined Virologic Failure after week 48. Drug-related AE rates were higher for DOR/3TC/TDF participants (22.6%) compared with islatravir (combined 7.8%). Two participants (2.2%) receiving islatravir with doravirine and one (3.2%) receiving DOR/3TC/TDF discontinued because of an AE. Conclusions: Treatment regimens containing islatravir and doravirine maintained viral suppression through week 96 and were well tolerated regardless of dose. [ABSTRACT FROM AUTHOR]

We determined total and unbound concentrations of doravirine (DOR) in cerebrospinal fluid and blood plasma. Total and unbound DOR concentrations in cerebrospinal fluid exceeded the half-maximal effective concentration against wild-type virus (5.1 ng/mL) in all patients, suggesting that DOR may contribute to inhibit viral replication in this compartment. [ABSTRACT FROM AUTHOR]

Introduction: Extensive use of antiretroviral therapy has remarkably improved the survival rates of people living with HIV. Doravirine (DOR) is a newly-approved antiretroviral belonging to the class of non-nucleoside reverse transcriptase inhibitors. Here, we compared the efficacy and safety of DOR + tenofovir dipivoxil fumarate (TDF)+Lamivudine (3TC)/Emtritabine (FTC) with traditional triple therapies in treatment-naïve HIV-1-positive adults. Methods: Randomized controlled trials involving treatment-naïve HIV-1-positive adults that met inclusion criteria were systematically retrieved and data on the following outcomes extracted: virological suppression, adverse events, severe adverse events, and drug-related adverse events. A Bayesian network meta-analysis was then performed on the data. Results: This study included a total of 39 randomized controlled trials involving 26 antiretroviral therapies and 21,110 HIV1-positive patients. At week 48, relative to the other 25 regimens included in the network of virological suppression, DOR + TDF+3TC/FTC exhibited superiority to some efavirenz, nevirapine, atazanavir, or lopinavir-based regimens, including efavirenz + abacavir+3TC [Odd Ratio (OR) = 0.52, 95% confidence interval (CrI) = 0.35–0.77]. At week 48, the performance of DOR + TDF+3TC/FTC was relatively similar to all other analyzed regimens in terms of adverse events. The DOR + TDF+3TC/FTC regimen performed better in terms of severe adverse events and drug-related adverse events. Conclusion: The network meta-analysis showed that DOR + TDF+3TC/FTC has good efficacy and safety at 48 weeks. Systematic Review Registration: Open Science Framework, https://osf.io/6ybp7. [ABSTRACT FROM AUTHOR]

Alexander E Rock,1 Jeremy Lerner,2 Melissa E Badowski1 1University of Illinois, College of Pharmacy, Department of Pharmacy Practice, Section of Infectious Diseases Pharmacotherapy, Chicago, IL 60612, USA; 2University of Illinois, College of Pharmacy, Department of Pharmacy Practice, Chicago, IL 60612, USACorrespondence: Melissa E BadowskiUniversity of Illinois, College of Pharmacy, Department of Pharmacy Practice, Section of Infectious Diseases Pharmacotherapy, 833 S. Wood, Room164, MC886, Chicago, IL 60612, USAEmail Badowski@uic.eduAbstract: The utility of doravirine in the management of HIV-1 infection is approved for use in patients who are antiretroviral-naïve as well as patients who have achieved stable virologic suppression and are interested in replacing their current antiretroviral therapy. The role of doravirine continues to evolve as data emerges on the potential for new combination therapy with the investigational agent, islatravir, as well as a potential strategy to minimize post-marketing safety concerns with recommended first-line agents, such as integrase inhibitors. The goal of this review is to assess recent and emerging data on the non-nucleoside reverse transcriptase inhibitor, doravirine.Keywords: doravirine, HIV-1, antiretroviral therapy, non-nucleoside reverse transcriptase inhibitor

Introduction: Extensive use of antiretroviral therapy has remarkably improved the survival rates of people living with HIV. Doravirine (DOR) is a newly-approved antiretroviral belonging to the class of non-nucleoside reverse transcriptase inhibitors. Here, we compared the efficacy and safety of DOR + tenofovir dipivoxil fumarate (TDF)+Lamivudine (3TC)/Emtritabine (FTC) with traditional triple therapies in treatment-naïve HIV-1-positive adults.Methods: Randomized controlled trials involving treatment-naïve HIV-1-positive adults that met inclusion criteria were systematically retrieved and data on the following outcomes extracted: virological suppression, adverse events, severe adverse events, and drug-related adverse events. A Bayesian network meta-analysis was then performed on the data.Results: This study included a total of 39 randomized controlled trials involving 26 antiretroviral therapies and 21,110 HIV1-positive patients. At week 48, relative to the other 25 regimens included in the network of virological suppression, DOR + TDF+3TC/FTC exhibited superiority to some efavirenz, nevirapine, atazanavir, or lopinavir-based regimens, including efavirenz + abacavir+3TC [Odd Ratio (OR) = 0.52, 95% confidence interval (CrI) = 0.35–0.77]. At week 48, the performance of DOR + TDF+3TC/FTC was relatively similar to all other analyzed regimens in terms of adverse events. The DOR + TDF+3TC/FTC regimen performed better in terms of severe adverse events and drug-related adverse events.Conclusion: The network meta-analysis showed that DOR + TDF+3TC/FTC has good efficacy and safety at 48 weeks.Systematic Review Registration: Open Science Framework, https://osf.io/6ybp7.

As part of a combined antiretroviral regimen, doravirine is safe and effective at suppressing viral replication in both treatment-naive and treatment-experienced adults living with human immunodeficiency virus (HIV)-1 who have no history of drug resistance against doravirine. In virologically suppressed individuals switching to a combination of doravirine, lamivudine, and tenofovir disoproxil fumarate, no resistance was found after 48 weeks. In treatment-naive individuals, rare cases (

Aim of this study is to assess the impact of doravirine (DOR)-based regimens on cardiovascular risk in treatment-experienced people living with HIV (PLWHIV). We retrospectively analyzed a cohort of 40 treatment-experienced PLWHIV switching to a DOR-based three-drug regimen, evaluating 10-year risk of manifesting clinical cardiovascular diseases (CD) through the Framingham Risk Score at baseline, 12, and 24 weeks of follow-up. At baseline, median predicted 10-year risk of cardiovascular disease (10Y-CD) was 8.0% (interquartile range 4.0–13.0). After 12 weeks, we observed a significant reduction in 10Y-CD (mean decrease −2.21, p = .012); similarly, we observed a nonsignificant reduction at week 24 (p = .336). Regarding metabolic parameters, after 24 weeks we observed a significant reduction in total cholesterol (median change −8.8 mg/dL, p = .018), low-density lipoprotein cholesterol (median −9.5 mg/dL, p = .007), and triglycerides (median −19.8 mg/dL, p < .001). Our results show a favorable metabolic impact of DOR-based regimens along with a promising reduction in 10-year risk of cardiovascular disease. [ABSTRACT FROM AUTHOR]