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PloS One 2024The introduction of antiretroviral therapy (ART) has successfully changed the clinical course of people with HIV, leading to a significant decline in the incidence of...
The introduction of antiretroviral therapy (ART) has successfully changed the clinical course of people with HIV, leading to a significant decline in the incidence of HIV-related neurocognitive disorders. Integrase strand transferase inhibitors (INSTI) are recommended and preferred first-line ART for the treatment of HIV-1 infection in ART-naïve subjects. This type of therapy regimen is expected to have higher CNS penetration, which may bring more cognitive stability or even make significant cognitive improvement in people with HIV. The study aimed to follow up on neurocognitive performance in HIV subjects on two types of INSTI therapy regimens at two-time points, one year apart. The study sample consisted of 61 ART naïve male participants, of which 32 were prescribed raltegravir (RAL) and 29 dolutegravir (DTG). There was no significant difference between subsamples according to the main sociodemographic (age, education level) and clinical characteristics (duration of therapy, nadir CD4 cells level, CD4 cells count, CD8 cells, CD4/CD8 ratio). For neurocognitive assessment, six measures were used: general cognitive ability (MoCA test), verbal fluency (total sum score for phonemic and category fluency), verbal working memory (digit span forward), cognitive capacity (digit span backwards), sustained attention (Color Trail Test 1), and divided attention (Color Trail Test 2). In both therapy groups (RAL and DTG), there was no significant decrease in neurocognitive achievement on all used measures over a one-year follow-up in both therapy groups. A statistically significant interactive effect of time and type of therapy was found on the measure of divided attention-DTG group showed slight improvement, whereas RAL group showed slight decrease in performance. During the one-year follow-up of persons on INSTI-based regimen, no significant changes in cognitive achievement were recorded, which suggests that the existing therapy can have a potentially positive effect on the maintenance of neurocognitive achievement.
Topics: Humans; Male; HIV Infections; Adult; Follow-Up Studies; Cognition; Raltegravir Potassium; HIV Integrase Inhibitors; Middle Aged; Pyridones; Piperazines; Heterocyclic Compounds, 3-Ring; Oxazines; Neuropsychological Tests; HIV-1
PubMed: 38923982
DOI: 10.1371/journal.pone.0306278 -
The Lancet. HIV Jun 2024Due to the low number of individuals with HIV-2, no randomised trials of HIV-2 treatment have ever been done. We hypothesised that a non-comparative study describing the... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of three antiretroviral therapy regimens for treatment-naive African adults living with HIV-2 (FIT-2): a pilot, phase 2, non-comparative, open-label, randomised controlled trial.
BACKGROUND
Due to the low number of individuals with HIV-2, no randomised trials of HIV-2 treatment have ever been done. We hypothesised that a non-comparative study describing the outcomes of several antiretroviral therapy (ART) regimens in parallel groups would improve understanding of how differences between HIV-1 and HIV-2 might lead to different therapeutic approaches.
METHODS
This pilot, phase 2, non-comparative, open-label, randomised controlled trial was done in Burkina Faso, Côte d'Ivoire, Senegal, and Togo. Adults with HIV-2 who were ART naive with CD4 counts of 200 cells per μL or greater were randomly assigned 1:1:1 to one of three treatment groups. A computer-generated sequentially numbered block randomisation list stratified by country was used for online allocation to the next available treatment group. In all groups, tenofovir disoproxil fumarate (henceforth tenofovir) was dosed at 245 mg once daily with either emtricitabine at 200 mg once daily or lamivudine at 300 mg once daily. The triple nucleoside reverse transcriptase inhibitor (NRTI) group received zidovudine at 250 mg twice daily. The ritonavir-boosted lopinavir group received lopinavir at 400 mg twice daily boosted with ritonavir at 100 mg twice daily. The raltegravir group received raltegravir at 400 mg twice daily. The primary outcome was the rate of treatment success at week 96, defined as an absence of serious morbidity event during follow-up, plasma HIV-2 RNA less than 50 copies per mL at week 96, and a substantial increase in CD4 cells between baseline and week 96. This trial is registered at ClinicalTrials.gov, NCT02150993, and is closed to new participants.
FINDINGS
Between Jan 26, 2016, and June 29, 2017, 210 participants were randomly assigned to treatment groups. Five participants died during the 96 weeks of follow-up (triple NRTI group, n=2; ritonavir-boosted lopinavir group, n=2; and raltegravir group, n=1), eight had a serious morbidity event (triple NRTI group, n=4; ritonavir-boosted lopinavir group, n=3; and raltegravir group, n=1), 17 had plasma HIV-2 RNA of 50 copies per mL or greater at least once (triple NRTI group, n=11; ritonavir-boosted lopinavir group, n=4; and raltegravir group, n=2), 32 (all in the triple NRTI group) switched to another ART regimen, and 18 permanently discontinued ART (triple NRTI group, n=5; ritonavir-boosted lopinavir group, n=7; and raltegravir group, n=6). The Data Safety Monitoring Board recommended premature termination of the triple NRTI regimen for safety reasons. The overall treatment success rate was 57% (95% CI 47-66) in the ritonavir-boosted lopinavir group and 59% (49-68) in the raltegravir group.
INTERPRETATION
The raltegravir and ritonavir-boosted lopinavir regimens were efficient and safe in adults with HIV-2. Both regimens could be compared in future phase 3 trials. The results of this pilot study suggest a trend towards better virological and immunological efficacy in the raltegravir-based regimen.
FUNDING
ANRS MIE.
Topics: Humans; HIV Infections; Adult; Male; Female; HIV-2; Tenofovir; Pilot Projects; CD4 Lymphocyte Count; Emtricitabine; Anti-HIV Agents; Treatment Outcome; Ritonavir; Lopinavir; Raltegravir Potassium; Lamivudine; Viral Load; Antiretroviral Therapy, Highly Active; Middle Aged; Zidovudine; Drug Therapy, Combination; HIV-1
PubMed: 38740027
DOI: 10.1016/S2352-3018(24)00085-7 -
Science Advances Mar 2024People living with human immunodeficiency virus (HIV) receiving integrase strand transfer inhibitors (INSTIs) have been reported to experience virological failure in the...
People living with human immunodeficiency virus (HIV) receiving integrase strand transfer inhibitors (INSTIs) have been reported to experience virological failure in the absence of resistance mutations in integrase. To elucidate INSTI resistance mechanisms, we propagated HIV-1 in the presence of escalating concentrations of the INSTI dolutegravir. HIV-1 became resistant to dolutegravir by sequentially acquiring mutations in the envelope glycoprotein (Env) and the nucleocapsid protein. The selected Env mutations enhance the ability of the virus to spread via cell-cell transfer, thereby increasing the multiplicity of infection (MOI). While the selected Env mutations confer broad resistance to multiple classes of antiretrovirals, the fold resistance is ~2 logs higher for INSTIs than for other classes of drugs. We demonstrate that INSTIs are more readily overwhelmed by high MOI than other classes of antiretrovirals. Our findings advance the understanding of how HIV-1 can evolve resistance to antiretrovirals, including the potent INSTIs, in the absence of drug-target gene mutations.
Topics: Humans; Raltegravir Potassium; HIV Integrase Inhibitors; HIV-1; HIV Integrase; Mutation
PubMed: 38427738
DOI: 10.1126/sciadv.adn0042 -
International Journal of Molecular... Feb 2024Rosmarinic acid (RA) is a phenolic compound with antiviral properties, often encountered in dietary supplements and herbal drugs. Data on the pharmacokinetics of RA are...
Rosmarinic acid (RA) is a phenolic compound with antiviral properties, often encountered in dietary supplements and herbal drugs. Data on the pharmacokinetics of RA are lacking in cases of the chronic use of supplements containing this compound, and only limited data on the metabolism and distribution of RA are available. The aim of the study was to investigate the plasma levels of RA after 12 weeks of use and determine potential interactions of RA and selected antiretroviral drugs. Patients infected with human immunodeficiency virus took a supplement containing RA for 12 weeks, after which the RA concentrations in the plasma samples were analyzed. A detailed in silico analysis was conducted in order to elucidate the potential interactions between RA and the drugs efavirenz, darunavir and raltegravir. It was found that RA can be detected in patients' plasma samples, mainly in the form of sulphoglucuronide. The potential interactions are suggested on the level of liver metabolizing enzymes and efflux P-glycoprotein, with RA competing with antiretroviral drugs as a substrate in metabolism and distribution systems. The present study suggests that the simultaneous use of RA and antiretroviral therapy (containing efavirenz, darunavir or raltegravir) may affect the plasma levels of RA after prolonged supplementation.
Topics: Humans; Raltegravir Potassium; Darunavir; Rosmarinic Acid; HIV Infections; Anti-Retroviral Agents; Anti-HIV Agents; Alkynes; Cyclopropanes; Benzoxazines
PubMed: 38396908
DOI: 10.3390/ijms25042230 -
ACS Infectious Diseases Mar 2024HIV-1 integrase (IN) is an important molecular target for the development of anti-AIDS drugs. A recently FDA-approved second-generation integrase strand transfer...
HIV-1 integrase (IN) is an important molecular target for the development of anti-AIDS drugs. A recently FDA-approved second-generation integrase strand transfer inhibitor (INSTI) cabotegravir (CAB, 2021) is being marketed for use in long-duration antiviral formulations. However, missed doses during extended therapy can potentially result in persistent low levels of CAB that could select for resistant mutant forms of IN, leading to virological failure. We report a series of -substituted bicyclic carbamoyl pyridones (BiCAPs) that are simplified analogs of CAB. Several of these potently inhibit wild-type HIV-1 in single-round infection assays in cultured cells and retain high inhibitory potencies against a panel of viral constructs carrying resistant mutant forms of IN. Our lead compound, , proved to be more potent than CAB against the therapeutically important resistant double mutants E138K/Q148K (>12-fold relative to CAB) and G140S/Q148R (>36-fold relative to CAB). A significant number of the BiCAPs also potently inhibit the drug-resistant IN mutant R263K, which has proven to be problematic for the FDA-approved second-generation INSTIs.
Topics: Raltegravir Potassium; HIV Integrase Inhibitors; Pyridones; HIV Integrase
PubMed: 38346249
DOI: 10.1021/acsinfecdis.3c00525 -
Medicine Oct 2023Raltegravir and other third-line drugs have shown promise in improving outcomes in treatment-experienced patients. However, the efficacy and tolerability of these agents...
Raltegravir and other third-line drugs have shown promise in improving outcomes in treatment-experienced patients. However, the efficacy and tolerability of these agents vary. This study assessed real-life virologic success, long-term survival, and adverse events in patients receiving raltegravir or other third-line drugs as salvage regimens. This retrospective cohort study included adults who experienced treatment failure (human immunodeficiency syndrome-1 RNA plasma viral load >1000 copies/mL) and subsequently initiated raltegravir or other third-line drugs (darunavir/ritonavir, maraviroc, or etravirine). Propensity score matching methods were employed to account for differences at the time of switching from failing antiretroviral therapy regimens. The matched subset was analyzed using the Kaplan-Meier method and Generalized Wilcoxon tests to evaluate the probability of achieving virologic suppression (plasma viral load <50 copies/mL). Mortality rates, toxicity, treatment interruption, virologic failure, and loss to follow-up were determined using Poisson regression. One hundred and sixty-eight patients initiating salvage regimens were included, with 123 receiving raltegravir and 45 other third-line drugs. Propensity score matching resulted in a subset of 90 patients, 45 in each group. During the follow-up period, there were no significant differences observed between the groups in terms of virologic suppression (77.8% vs 82.2%, P = .73), mortality rates (4.04 vs 6.18 persons per 100 person-years [p-y]; P = .67), drug toxicity (0.00 vs 2.06 persons per 100 p-y; P = .49), treatment interruption (8.07 vs 0.00 persons per 100 p-y; P = .06), virologic failure (2.02 vs 4.12 persons per 100 p-y; P = .61), and loss of follow-up (6.05 vs 4.12 persons per 100 p-y; P = .70). Our findings indicate comparable survival and virological success rates between raltegravir and other drugs used in salvage regimens. Similar rates of drug toxicity, treatment interruption, virologic failure, and loss of follow-up were also observed. These results suggest that raltegravir may be a viable option for salvage therapy, demonstrating outcomes comparable to other third-line drugs in real life.
Topics: Adult; Humans; Raltegravir Potassium; Anti-HIV Agents; Retrospective Studies; Salvage Therapy; Darunavir; HIV Infections; Drug-Related Side Effects and Adverse Reactions; Viral Load; Treatment Outcome
PubMed: 37800823
DOI: 10.1097/MD.0000000000035407 -
European Journal of Drug Metabolism and... Jul 2023People living with HIV may present co-morbidities requiring the initiation and subsequently the discontinuation of medications with inducing properties. The time to...
BACKGROUND
People living with HIV may present co-morbidities requiring the initiation and subsequently the discontinuation of medications with inducing properties. The time to reach maximal enzyme induction and to return to baseline enzyme levels has not been thoroughly characterized.
OBJECTIVE
The aim of this study was to evaluate the onset and disappearance of dolutegravir [uridine diphosphate glucuronosyltransferase (UGT) 1A1 and cytochrome P450 (CYP) 3A4 substrate] and raltegravir (UGT1A1 substrate) induction with strong and moderate inducers using physiologically based pharmacokinetic (PBPK) modeling.
METHODS
The predictive performance of the PBPK model to simulate dolutegravir and raltegravir pharmacokinetics and to reproduce the strength of induction was verified using clinical drug-drug interaction studies (steady-state induction) and switch studies (residual induction). The model was considered verified when the predictions were within 2-fold of the observed data. One hundred virtual individuals (50% female) were generated to simulate the unstudied scenarios. The results were used to calculate the fold-change in CYP3A4 and UGT1A1 enzyme levels upon initiation and discontinuation of strong (rifampicin) or moderate (efavirenz or rifabutin) inducers.
RESULTS
The time for reaching maximal induction and subsequent disappearance of CYP3A4 induction was 14 days for rifampicin and efavirenz but 7 days for rifabutin. The distinct timelines for the moderate inducers relate to their different half-lives and plasma concentrations. The induction and de-induction processes were more rapid for UGT1A1.
CONCLUSIONS
Our simulations support the common practice of maintaining the adjusted dosage of a drug for another 2 weeks after stopping an inducer. Furthermore, our simulations suggest that an inducer should be administered for at least 14 days before conducting interaction studies to reach maximal induction.
Topics: Humans; Female; Male; Rifampin; Cytochrome P-450 CYP3A; Raltegravir Potassium; Drug Interactions; Glucuronosyltransferase; Rifabutin
PubMed: 37278880
DOI: 10.1007/s13318-023-00833-9 -
The New Microbiologica May 2023Management of heavily treatment experienced (HTE) people with HIV remains a challenge. Tailored antiretroviral therapy (ART) is needed in this fragile population who...
Management of heavily treatment experienced (HTE) people with HIV remains a challenge. Tailored antiretroviral therapy (ART) is needed in this fragile population who almost invariably harbor viral quasispecies with resistance-associated mutations (RAMs). The reference method for HIV genotypic resistance testing (GRT) has long been Sanger sequencing (SS), but next-generation sequencing (NGS), following recent progress in workflow and cost-effectiveness, is replacing SS because of higher sensitivity. From the PRESTIGIO Registry, we present a case of a 59-year-old HTE woman who failed darunavir/ritonavir plus raltegravir at low-viremia levels due mainly to high pill burden and poor adherence. NGS-GRT was performed on HIV-RNA at failure and the results were compared to all past SS-GRT data available (historical genotype). In this case, NGS-GRT did not detect any minority drug-resistant variants. After discussing several therapeutic options, the treatment was changed to dolutegravir 50 mg twice daily plus doravirine 100 mg once a day, based on clinical history, adherence issues, and pill burden, as well as the historical SS-GRT and the latest NGS-GRT results. At six months follow-up visit, the patient had HIV-RNA below 30 copies/ml and CD4+ T cell count increased from 673 cells/ mm3 to 688 cells/ mm3. Close follow-up of this patient is ongoing.
Topics: Humans; Raltegravir Potassium; Darunavir; Ritonavir; HIV-1; Anti-HIV Agents; HIV Infections; HIV Seropositivity; RNA; Viral Load; Drug Resistance, Viral; Treatment Outcome
PubMed: 37247247
DOI: No ID Found -
Archivos Argentinos de Pediatria Feb 2024Antiretroviral (ARV) drug resistance is a public health issue. Resistance has also been observed in the case of integrase strand transfer inhibitors (INSTIs) used in...
Antiretroviral (ARV) drug resistance is a public health issue. Resistance has also been observed in the case of integrase strand transfer inhibitors (INSTIs) used in pediatrics. The objective of this article is to describe 3 cases of INSTI resistance. These are the cases of 3 children with vertically-transmitted human immunodeficiency virus (HIV). They were started on ARVs as infants and preschoolers, with poor treatment adherence, and had different management plans due to associated comorbidities and virological failure due to resistance. In the 3 cases, resistance developed rapidly as a result of virological failure and INSTI involvement. Treatment adherence should be monitored so that any increase in viremia can be detected early. Virological failure in a patient treated with raltegravir forces to a rapid change in ARV therapy because its continued use may favor new mutations and resistance to second-generation INSTIs.
Topics: Humans; Child; HIV Integrase Inhibitors; Uruguay; HIV-1; Raltegravir Potassium; HIV Infections; Anti-HIV Agents; Mutation
PubMed: 37216306
DOI: 10.5546/aap.2023-02992.eng -
The Pediatric Infectious Disease Journal Jul 2023Zimbabwe introduced raltegravir (RAL) granules at 14 facilities providing point-of-care HIV birth testing, aiming to initiate all newborns with HIV on a RAL-based...
Zimbabwe introduced raltegravir (RAL) granules at 14 facilities providing point-of-care HIV birth testing, aiming to initiate all newborns with HIV on a RAL-based regimen. From June 2020 to July 2021, we tested 3172 of the 6989 (45%) newborns exposed to HIV; we diagnosed 59(2%) with HIV infection, of whom 27 (46%) initiated RAL. The SARS-CoV-2 coronavirus disease pandemic exacerbated supply chain and trained provider shortages, contributing to low birth testing, RAL uptake and 6-month viral load testing.
Topics: Humans; Infant, Newborn; Female; Pregnancy; Raltegravir Potassium; HIV Infections; Pandemics; Zimbabwe; COVID-19; SARS-CoV-2; Viral Load; Anti-HIV Agents
PubMed: 37000925
DOI: 10.1097/INF.0000000000003906