abacavir and dolutegravir

There are more than 30 agents available for the treatment of HIV with guidelines shifting toward integrase strand transfer inhibitors (INSTIs) as part of first line therapy. The fixed dose combination of dolutegravir (DTG), abacavir (ABC), and lamivudine (3TC) is a convenient, well tolerated, and highly effective option for treating HIV infection and remains a first line therapy across several prominent guidelines.. In this drug evaluation, the authors provide a comprehensive overview of DTG/ABC/3TC for the treatment of HIV including the pharmacokinetics, pharmacodynamics, efficacy, safety, and tolerability. The authors also provide the reader with their expert perspectives on this particular treatment strategy.. While DTG/ABC/3TC remains a valuable HIV treatment option, newer combination regimens have entered the market. Bictegravir with tenofovir alafenamide and emtricitabine offers the benefit of same day initiation and efficacy in hepatitis B co-infection, while new two-drug regimens enhance the simplicity of HIV treatment. Continued study is required into the mechanisms and optimal management strategies for weight gain for many regimens, including DTG/ABC/3TC.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

Since the last revision of both European and American guidelines (EACS and DHHS), new data from clinical trials and cohort studies, as well as experience in clinical practice, have prompted significant changes to the list of recommended/preferred options for the treatment of HIV infected patients, highlighted the role of INSTI-based regimens. Dolutegravir (DTG) in combination with abacavir/lamivudine (ABC/3TC) is one of these preferred regimens in multiple clinical scenarios, including treatment-naive and treatment-experienced patients.. In this article we describe the coformulation of ABC/3TC/DTG in a fixed-dose combination (FDC) approved in September 2014 for the treatment of HIV infection. We focused our research on the efficacy and safety data resulting from phase 2 and 3 clinical study, particularly on the results of both SPRING (1 and 2) and SINGLE studies.. Triple combination therapy with ABC/3TC/DTG should be considered among the initial options for treatment-naive patients, being effective, well tolerated, with a high genetic barrier to resistance along with a convenient once-daily administration. In treatment-experienced patients the single-tablet regimen (STR) based on ABC/3TC/DTG could be used as simplification strategy in subjects with sustained viral suppression, as the high genetic barrier of DTG should ensure a safe switch from both NNRTI or PI based regimens.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; Tablets

Topics: Animals; Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Combinations; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

A fixed-dose, single-tablet regimen comprising the integrase strand transfer inhibitor (INSTI) dolutegravir and the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine (abacavir/dolutegravir/lamivudine; Triumeq®) is now available for the treatment of HIV-1 infection. In a randomized, double-blind, phase III trial in antiretroviral therapy (ART)-naive adults (SINGLE), once-daily dolutegravir plus abacavir/lamivudine had noninferior efficacy to once-daily efavirenz/tenofovir disoproxil fumarate (tenofovir DF)/emtricitabine with regard to establishing and sustaining virological suppression over 144 weeks, and subsequent superiority testing significantly favoured dolutegravir plus abacavir/lamivudine. This outcome was predominantly driven by more favourable rates of discontinuation due to adverse events versus the efavirenz/tenofovir DF/emtricitabine group. These data were generally supported by findings from other phase III trials in ART-naive adults receiving dolutegravir plus either abacavir/lamivudine or tenofovir DF/emtricitabine (SPRING-2 and FLAMINGO). Dolutegravir plus abacavir/lamivudine is generally well tolerated, with a tolerability profile that appears to be more favourable than efavirenz/tenofovir DF/emtricitabine. In the SINGLE trial, there were no major treatment-emergent INSTI or NRTI resistance-associated mutations in dolutegravir plus abacavir/lamivudine recipients with protocol-defined virological failure, indicating a high genetic barrier to resistance. Thus, triple combination therapy with abacavir, dolutegravir and lamivudine is an effective, generally well tolerated option for the management of HIV-1 infection, with the convenient once-daily fixed-dose tablet providing the first single-tablet regimen option without tenofovir DF.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Administration Schedule; Drug Combinations; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Lamivudine; Medication Adherence; Mutation; Oxazines; Piperazines; Practice Guidelines as Topic; Pyridones; Reverse Transcriptase Inhibitors; Tablets

With the introduction of the coformulated dolutegravir, abacavir and lamivudine , a new single tablet regimen (STR) is made available for the use in treatment-naive and treatment-experienced HIV-infected patients. This drug combination is the fourth STR that will be positioned next to the STRs with efavirenz, rilpivirine or elvitegravir as third agents, respectively.. The objective of this review is to provide an overview of the efficacy and safety of the combined dolutegravir/abacavir/lamivudine coformulation. The review will focus on dolutegravir and includes both published data as well as data presented at recent major international HIV/AIDS conferences.. The dolutegravir/abacavir/lamivudine regimen is highly effective in achieving sustained suppression of HIV-1 RNA plasma concentrations. The STR has a favorable safety profile and a low potential for drug interactions, which will contribute to a prominent role in therapy. As this STR contains abacavir as backbone component, the use requires patients to be HLA-B*5701 negative, with good hepatic function. Other first-line treatment combinations are preferred for patients with hepatitis B co-infection or with a high cardiovascular risk.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Administration Schedule; Drug Interactions; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; RNA, Viral; Tablets

Integration of the viral genome into the host cell chromatin is a central step in the replication cycle of HIV. Blocking the viral integrase (IN) enzyme therefore provides an attractive therapeutic strategy, as evidenced by the recent clinical approval of three IN strand transfer inhibitors. Dolutegravir is a therapy that is unique in its ability to evade HIV drug resistance in treatment-naïve patients.. This review starts by providing a brief summary of the history of HIV-1 IN inhibitors. The authors follow this with details of the discovery and preclinical and clinical developments of dolutegravir. Finally, the authors provide details of dolutegravir's post-launch including the launch of the combination pill of dolutegravir, abacavir and lamivudine in August 2014.. The launch of raltegravir, the first IN inhibitor from Merck & Co., has created new hopes for the patient. Indeed, pharmaceutical companies have not lost courage by attempting to address the major drawbacks of this first-in-class molecule. And while the drug elvitegravir has been inserted into a four-drug combination pill providing a once-daily dosing alternative, dolutegravir has demonstrated superiority in terms of its efficacy and resistance.

Topics: Animals; Dideoxynucleosides; Drug Combinations; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

Antiretroviral therapy has evolved dramatically and more potent, safer and convenient drugs have replaced former compounds. Dolutegravir (DTG) is the most recently approved integrase inhibitor. It displays attractive properties such as one pill once daily (QD) dosing, high barrier to resistance and clean safety profile. Moreover, it is planned to be marketed, co-formulated with abacavir (ABC) and lamivudine (3TC) as a single-tablet regimen (STR). The availability of this QD single pill represents a significant step further for a large number of HIV-infected persons.. Updated summary of evidence-based information on efficacy and safety of DTG along with ABC and 3TC. All information available on antiretrovirals in the most advanced stages of clinical development reported in peer-reviewed journals or at international meetings has been reviewed.. The combination of DTG, ABC and 3TC displays a high efficacy, superior to many other antiretroviral combinations, including other convenient STR. The good safety profile, low potential for drug interactions and high resistance barrier of DTG- ABC-3TC are unique features than make this co-formulation the preferred choice as HIV therapy in multiple clinical scenarios, including most treatment-naïve and treatment-experienced patients, as part of switch strategies, and in patients with underlying serious medical conditions such as kidney abnormalities, liver disease, metabolic disturbances or neuropsychiatric conditions.

Topics: Anti-HIV Agents; Clinical Trials as Topic; Dideoxynucleosides; Drug Resistance, Viral; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

With longer life expectancy in people living with HIV (PLWH) on antiretroviral therapy, cardiovascular disease (CVD) has become a common cause of mortality among them. Abacavir has been associated with an increased risk of myocardial infarction, but the mechanism is unknown. Additionally, abacavir may be obesogenic which could mediate an additional risk factor of CVD. We aim to investigate if discontinuation of abacavir will have a favourable impact on body weight and cardiac parameters in PLWH.. Randomised, controlled, superiority trial of virologically suppressed PLWH on dolutegravir, abacavir and lamivudine (DTG/ABC/3TC) for ≥6 months. In total, 70 PLWH will be randomised 1:2 to either continue DTG/ABC/3TC or to switch to dolutegravir and lamivudine (DTG/3TC) providing the power of 80% at alpha 5% to detect a mean difference in weight change of 2 kg (Δ) given an SD of 2.7 kg. Follow-up will be 48 weeks. Data will be collected at baseline and week 48. Primary outcome will be change in mean body weight from baseline to week 24 and 48 evaluated in a linear mixed model. Secondary outcomes will be changes in cardiac, inflammatory and metabolic parameters, fat distribution, coagulation, endothelial, platelet function, quality of life and virological control from baseline to week 48. Measurements include CT of thorax and abdomen, external carotid artery ultrasound, liver elastography and dual energy X-ray absorptiometry and blood analysis. Plasma HIV RNA will be measured at baseline, week 4, 24 and 48. Forty participants (20 from each arm) will be included in a substudy involving cardiac MRI at baseline and week 48. Twenty non-HIV-infected controls will be included with a single scan to compare with baseline scan data.. Result from this study will lead to a better understanding of the association between antiretroviral therapy and the impact on weight and risk of CVD. Findings will be useful for both clinicians and PLWH in the guidance of a more individualised HIV treatment. Results from the main study and the substudies will be submitted for publication in a peer-reviewed journal(s). The AVERTAS study is approved by the Ethics Committee of the Capital Region, Denmark (H-20011433), Danish Medicines Agency (EudraCT no. 2019-004999-19) and Regional Data Protection Centre (P-2020-207).. Pre-results registration at ClinicalTrials.gov Identifier: NCT04904406, registered 27 May 2021.. Protocol version 9.0, 4 April 2023, approved 10-05-2023 by Ethics Committee of the Capital Region, Denmark (H-20011433). Danish Medicines Agency (EudraCT no. 2019-004999-19). Regional Data Protection Centre (P-2020-207) ClinicalTrials.gov.

Topics: Body Composition; Body Weight; Cardiovascular Diseases; Denmark; HIV Infections; Humans; Lamivudine; Quality of Life

Tenofovir disoproxil fumarate (TDF) is associated with reduced bone mineral density (BMD). The aim of the study was to evaluate changes in BMD in women who switched from TDF, emtricitabine and a nonnucleoside reverse transcriptase inhibitor (TDF/FTC/NNRTI) to abacavir, lamivudine and dolutegravir (ABC/3TC/DTG).. We conducted a randomized controlled trial in which women aged ≥ 40 years were randomized 1:2 to continue TDF/FTC/NNRTI or switch to ABC/3TC/DTG. We analysed changes in BMD at the hip and lumbar spine from baseline to week 96 using linear regression, and markers of bone turnover and kidney function using repeated measures mixed effects models with multiple imputation for missing data. We conducted exploratory analyses of weight, mental health, sleep and symptoms attributed to HIV infection and antiretroviral therapy.. Ninety-one women [mean (standard deviation) age 50.4 (6.6) years] were randomized. Women who switched to ABC/3TC/DTG maintained viral suppression and experienced improvements in BMD at the lumbar spine (but not the neck of the femur or the total hip), bone resorption markers and proteinuria (total protein, albumin and retinol-binding protein) and modest weight gain without changes in body mass index. Although mean anxiety, depression and sleep scores did not differ between the two study arms, anxiety, depression and sleep disturbance at baseline predicted ABC/3TC/DTG discontinuation for neuropsychiatric side effects [odds ratios (95% confidence intervals) 11.9 (2.0-71.6), 16.0 (2.6-97.9) and 10.0 (1.8-56.0), respectively].. Switching from TDF/FTC/NNRTI to ABC/3TC/DTG improved the BMD of the lumbar spine and kidney function. These benefits need to be balanced against modest weight gain and the need for antiretroviral therapy substitutions in a proportion of participants.

Topics: Adult; Anti-HIV Agents; Bone Density; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Kidney; Lamivudine; Middle Aged; Oxazines; Patient Reported Outcome Measures; Piperazines; Pyridones; Reverse Transcriptase Inhibitors; Tenofovir

In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies.. We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov, NCT02607930 and NCT02607956.. 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference -2·6%, 95% CI -8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference -1·9%, -7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (-0·1 vs -0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study.. These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance.. Gilead Sciences.

Topics: Adenine; Adult; Aged; Alanine; Dideoxynucleosides; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; RNA, Viral; Tenofovir; Treatment Outcome; Young Adult

The WHO recently recommended the use of a new first-line ART containing dolutegravir. We investigated the efficacy of NRTI backbones (tenofovir or abacavir with a cytosine analogue) in low- and middle-income countries where there is significant prior exposure to antiretrovirals and drug resistance to NRTIs.. Within the treatment-as-prevention study in South Africa, we selected participants with available next-generation sequencing (NGS) data for the HIV-1 pol gene at trial entry; they were either ART initiators (n = 1193) or already established on ART (n = 94). NGS of the HIV-1 pol gene was carried out using MiSeq technology; reverse transcriptase drug resistance mutations (DRMs) were detected at 5% (DRM5%) and 20% (DRM20%) for all 1287 participants. Genotypic susceptibility was assessed using the Stanford HIVDB resistance interpretation algorithm.. NRTI DRM20% and DRM5% were detected among 5/1193 (0.4%) and 9/1193 (0.8%) of ART initiators, respectively. There was tenofovir exposure in 73/94 (77.7%) of those established on ART, with full susceptibility to abacavir in 57/94 (60.6%) and 56/94 (59.6%) for DRM20% and DRM5%, respectively, while 67/94 (71.3%) and 64/94 (68.1%) were fully susceptible to tenofovir, respectively. The differences between tenofovir and abacavir were not statistically significant at the 20% or 5% variant level (P = 0.16 and 0.29, respectively). NGS detection of variants at the 5% level increased detection of K65R in both naive and treated groups. One of 607 integrase sequences carried a DRM20% (Q148R).. Dolutegravir with a cytosine analogue plus tenofovir or abacavir appears to have similar efficacy in South Africans naive to ART. NGS should be considered in HIV drug resistance surveillance.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cytosine; Dideoxynucleosides; Drug Combinations; Drug Resistance, Viral; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV-1; Humans; Male; Middle Aged; Mutation; Oxazines; Piperazines; Pyridones; South Africa; Tenofovir; Viral Load; Young Adult

We investigated whether dolutegravir (DTG) monotherapy could be used to maintain virological suppression in people living with human immunodeficiency virus (HIV) on a successful dolutegravir-based triple therapy.. MONCAY (MONotherapy of TiviCAY) was a 48-week, multicentric, randomized, open-label, 12% noninferiority margin trial. Patients with CD4 nadir >100/μL, plasma HIV-1 RNA <50 copies/mL for ≥12 months, and stable regimen with DTG/abacavir (ABC)/lamivudine (3TC) were 1:1 randomized to continue their regimen or to DTG monotherapy. The primary endpoint was the proportion of patients with HIV RNA <50 copies/mL at week 24 in intention-to-treat snapshot analysis. Virologic failure (VF) was defined as 2 consecutive HIV RNA >50 copies/mL within 2 weeks apart.. Seventy-eight patients were assigned to DTG monotherapy and 80 to continue DTG/ABC/3TC. By week 24, 2 patients in the DTG group experienced VF without resistance to the integrase strand transfer inhibitor (INSTI) class; 1 patient discontinued DTG/ABC/3TC due to an adverse event. The success rate at week 24 was 73/78 (93.6%) in the DTG arm and 77/80 (96.3%) in the DTG/ABC/3TC arm (difference, 2.7%; 95% confidence interval [CI], -5.0 to 10.8). During subsequent follow-up, 5 additional VFs occurred in the DTG arm (2 of which harbored emerging resistance mutation to INSTI). The cumulative incidence of VF at week 48 was 9.7% (95% CI, 2.8 to 16.6) in the DTG arm compared with 0% in the DTG/ABC/3TC arm (P = .005 by the log-rank test). The Data Safety Monitoring Board recommended to reintensify the DTG arm with standardized triple therapy.. Because the risk of VF with resistance increases over time, we recommend avoiding DTG monotherapy as a maintenance strategy among people living with chronic HIV infection.. NCT02596334 and EudraCT 2015-002853-36.

Topics: Adult; Anti-HIV Agents; Confidence Intervals; Dideoxynucleosides; Drug Resistance, Viral; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Mutation; Oxazines; Piperazines; Pyridones

Bictegravir co-formulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination is recommended for treatment of HIV-1-infection and might be better tolerated than other integrase inhibitor-based single-tablet regimens, but long-term outcomes data are not available. We assessed the efficacy, safety and tolerability of bictegravir, emtricitabine, and tenofovir alafenamide compared with co-formulated dolutegravir, abacavir, and lamivudine at week 96.. This ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial was done at 122 outpatient centres in nine countries. We enrolled adults (aged ≥18 years) living with HIV who were treatment naive and HLA-B*5701 negative, did not have hepatitis B virus infection, and had an estimated glomerular filtration rate of at least 50 mL/min. We randomly assigned participants (1:1) to receive co-formulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (the bictegravir group) or co-formulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (the dolutegravir group), each with matching placebo, once daily for 144 weeks. Treatment allocation was masked to all participants and investigators. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. We previously reported the primary endpoint. Here, we report the week 96 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 96 by US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. This study was registered with ClinicalTrials.gov, number NCT02607930.. Between Nov 13, 2015, and July 14, 2016, we screened 739 participants, of whom 108 were excluded and 631 enrolled and randomly assigned to bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or dolutegravir, abacavir, and lamivudine (n=315). Two participants in the bictegravir group did not receive at least one dose of their assigned drug and were excluded from analyses. At week 96, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to dolutegravir, abacavir, and lamivudine, with 276 (88%) of 314 participants in the bictegravir group versus 283 (90%) of 315 participants in the dolutegravir group achieving HIV-1 RNA less than 50 copies per mL (difference -1·9%; 95% CI -6·9 to 3·1). The most common adverse events were nausea (36 [11%] of 314 for the bictegravir group vs 76 [24%] of 315 for the dolutegravir group), diarrhoea (48 [15%] vs 50 [16%]), and headache (41 [13%] vs 51 [16%]). 36 (11%) participants in the bictegravir group versus 39 (12%) participants in the dolutegravir group had a serious adverse event. Two individuals died in the bictegravir group (recreational drug overdose and suicide, neither of which was treatment related) and none died in the dolutegravir group. No participants discontinued because of adverse events in the bictegravir group compared with five (2%) of 315 in the dolutegravir group. Study drug-related adverse events were reported for 89 (28%) participants in the bictegravir group and 127 (40%) in the dolutegravir group.. These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with HIV-1 with no emergent resistance.. Gilead Sciences, Inc.

Topics: Adenine; Alanine; Amides; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Lamivudine; Male; Oxazines; Piperazines; Pyridones; Tenofovir; Treatment Outcome; Viral Load

Bictegravir, co-formulated with emtricitabine and tenofovir alafenamide, has shown good efficacy and tolerability, and similar bone, renal, and lipid profiles to dolutegravir, abacavir, and lamivudine, in treatment-naive adults with HIV-1 infection, without development of treatment-emergent resistance. Here, we report 48-week results of a phase 3 study investigating switching to bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir, abacavir, and lamivudine in virologically suppressed adults with HIV-1 infection.. In this multicentre, randomised, double-blind, active-controlled, non-inferiority, phase 3 trial, HIV-1-infected adults were enrolled at 96 outpatient centres in nine countries. Eligible participants were aged 18 years or older and on a regimen of 50 mg dolutegravir, 600 mg abacavir, and 300 mg lamivudine (fixed-dose combination or multi-tablet regimen); had an estimated glomerular filtration rate of 50 mL/min or higher; and had been virologically suppressed (plasma HIV-1 RNA <50 copies per mL) for 3 months or more before screening. We randomly assigned participants (1:1), using a computer-generated randomisation sequence, to switch to co-formulated bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg; herein known as the bictegravir group), or to remain on dolutegravir, abacavir, and lamivudine (herein known as the dolutegravir group), once daily for 48 weeks. The investigators, participants, study staff, and individuals assessing outcomes were masked to treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or higher at week 48 (according to the US Food and Drug Administration snapshot algorithm); the prespecified non-inferiority margin was 4%. The primary efficacy and safety analyses included all participants who received at least one dose of study drug. This study is ongoing but not actively recruiting participants and is in the open-label extension phase, wherein participants are given the option to receive bictegravir, emtricitabine, and tenofovir alafenamide for an additional 96 weeks. This trial is registered with ClinicalTrials.gov, number NCT02603120.. Between Nov 11, 2015, and July 6, 2016, 567 participants were randomly assigned and 563 were treated (282 received bictegravir, emtricitabine, and tenofovir alafenamide, and 281 received dolutegravir, abacavir, and lamivudine). Switching to the bictegravir regimen was non-inferior to remaining on dolutegravir, abacavir, and lamivudine for the primary outcome: three (1%) of 282 in the bictegravir group had HIV-1 RNA of 50 copies per mL or higher at week 48 versus one (<1%) of 281 participants in the dolutegravir group (difference 0·7%, 95·002% CI -1·0 to 2·8; p=0·62). Treatment-related adverse events were recorded in 23 (8%) participants in the bictegravir group and 44 (16%) in the dolutegravir group. Treatment was discontinued because of adverse events in six (2%) participants in the bictegravir group and in two (1%) participants in the dolutegravir group.. The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide might provide a safe and efficacious option for ongoing treatment of HIV-1 infection.. Gilead Sciences.

Topics: Adult; Aged; Amides; Anti-HIV Agents; Dideoxynucleosides; Double-Blind Method; Drug Substitution; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV Seropositivity; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Sustained Virologic Response; Tenofovir; Viral Load; Young Adult

The fixed-dose combination (FDC) tablet formulation of abacavir/dolutegravir/lamivudine is indicated for the treatment of HIV-1 infection in adults and pediatric patients weighing ≥40 kg. Alternative formulations with acceptable palatability and convenient dosing are needed for children who require smaller doses and have difficulty swallowing tablets.. A phase 1, open-label, randomized study was conducted in healthy adults to evaluate the relative bioavailability of a novel dispersible FDC tablet of abacavir 150 mg/dolutegravir 10 mg/lamivudine 75 mg administered under 4 different dosing conditions compared with dolutegravir plus abacavir/lamivudine nondispersible, film-coated tablets.. The test treatments were 4 dispersible FDC tablets reconstituted in water with high- or zero-mineral content and administered either immediately or after a 30-minute delay. The reference treatment was 4 nondispersible dolutegravir 10-mg tablets plus 1 nondispersible abacavir 600-mg/lamivudine 300-mg tablet administered with zero-mineral content water. The primary endpoints were area under the concentration-time curve from time 0 extrapolated to infinity and the maximum observed plasma concentration.. Following administration of dispersible abacavir/dolutegravir/lamivudine, the relative bioavailability of dolutegravir was approximately 50% higher. Abacavir and lamivudine demonstrated bioequivalence when administered as the dispersible FDC tablet compared with coadministration of dolutegravir plus abacavir/lamivudine nondispersible, film-coated tablets. Neither the mineral content of the water nor dosing times affected the pharmacokinetics of individual components. The dispersible tablet was safe and well tolerated, and the palatability was acceptable.. These pharmacokinetic results support further development of a dispersible FDC tablet of abacavir/dolutegravir/lamivudine for future use in pediatric patients.

Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Biological Availability; Dideoxynucleosides; Drug Combinations; Female; Healthy Volunteers; Heterocyclic Compounds, 3-Ring; Humans; Lamivudine; Male; Middle Aged; Minerals; Oxazines; Piperazines; Pyridones; Tablets; Water; Young Adult

Combination abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) is approved as a first-line treatment for antiretroviral naïve patients. This report investigated the immunovirological outcome and total HIV-1 DNA decay in a small cohort of naïve HIV-1-positive patients treated with this regimen. In the presence of viral suppression and increased lymphocyte T CD4+ cells, the quantitative analysis of total HIV-1 DNA content revealed a significant decay after 12 months of treatment. Subsequently, we deintensificated the treatment of these patients from (ABC/3TC/DTG) to lamivudine plus dolutegravir (3TC/DTG) after 12 months of virological suppression, as a strategy of "induction-maintenance" therapy. The analysis of HIV-1 RNA viral load, total HIV-1 DNA, CD4+ T lymphocyte count and CD8+ HLA-DR+ T lymphocyte percentage after a mean 3.5 months of therapy deintensification showed no significant difference with respect to data detected after 12 months of ABC/3TC/DTG treatment in the presence of continuous viral suppression. These results indicate that the deintensification of highly active antiretroviral therapy (HAART) from ABC/ 3TC/DTG to 3TC/DTG effectively controls HIV-1 replication and in the early period does not induce any significant variations of total HIV-1 DNA. This suggests that HAART deintensification might be proposed as a therapeutic evolution in the treatment of HIV-1 infection.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Cohort Studies; Dideoxynucleosides; DNA, Viral; Drug Therapy, Combination; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Viral Load; Young Adult

Simplified dosing regimens are important for patients who face challenges in adhering to HIV-1 therapy. We investigated the safety and virological efficacy of switching to once-daily abacavir/dolutegravir/lamivudine (ABC/DTG/3TC).. The STRIIVING study was a randomized, open-label, Phase IIIb study in adults with HIV-1 RNA <50 copies/ml on antiretroviral therapy (ART) at enrolment (ClinicalTrials.gov identifier, NCT02105987). Subjects were randomly assigned to switch to ABC/DTG/3TC once daily for 48 weeks (early-switch group) or continue current ART for 24 weeks and then switch to ABC/DTG/3TC (late-switch group). The primary end point was the proportion of subjects with HIV-1 RNA <50 copies/ml at week 24.. Of 553 subjects enrolled, 275 were randomly assigned to switch immediately to ABC/DTG/3TC and 278 continued on current ART. At week 24, 85% and 88% of subjects who switched to ABC/DTG/3TC or remained on current ART, respectively, were virologically suppressed, indicating that ABC/DTG/3TC was non-inferior (difference in proportion, -3.4%; 95% CI -9.1, 2.4). At week 48, 83% and 92% were virologically suppressed in the early- and late-switch groups, respectively. Adverse events were reported more frequently with ABC/DTG/3TC (66%) than with current ART (47%) by week 24, and in the late-switch group, 60% of subjects reported adverse events post-switch. Pharmacokinetic data supported immediate switch. HIV Treatment Satisfaction Questionnaire scores improved in participants switching to ABC/DTG/3TC versus current ART.. Data demonstrating non-inferiority of switching to ABC/DTG/3TC versus continuing current ART support ABC/DTG/3TC as an option when considering switch regimens in HIV-1-infected adults with stable viral suppression.

Topics: Adult; Aged; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Canada; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Substitution; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; RNA, Viral; Treatment Outcome; United States; Viral Load

Dolutegravir is a once-daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection. Because women are often under-represented in HIV clinical trials, we addressed the safety and efficacy of dolutegravir in women with HIV-1.. The ARIA study is a randomised, open-label, multicentre, active-controlled, parallel-group, non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia. Eligible participants were women aged 18 years or older who had HIV-1 RNA viral loads of 500 copies per mL or greater, had received 10 days or less of previous antiretroviral therapy, and had tested negative for the HLA-B*5701 allele. Pregnant women were excluded. Eligible women were randomly assigned (1:1) to receive either a single-tablet regimen of dolutegravir plus abacavir and lamivudine once a day (dolutegravir group) or a three-tablet combination of ritonavir-boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day (atazanavir group). Random treatment group assignment was stratified by plasma HIV-1 RNA viral loads and CD4 cell count at baseline. The primary endpoint was the proportion of participants with HIV-1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication (intention-to-treat exposed population). We used a non-inferiority margin of -12%. Investigators monitored adverse events to assess safety. This study is registered with ClinicalTrials.gov, number NCT01910402.. Between Aug 22, 2013, and Sept 22, 2015, of 705 women assessed, 499 were randomly assigned to either the dolutegravir group (n=250) or the atazanavir group (n=249); two participants from each group were randomised to treatment but did not receive study medication. At week 48, 203 (82%) of 248 participants in the dolutegravir group compared with 176 (71%) of 247 in the atazanavir group had HIV-1 RNA viral loads of less than 50 copies per mL (mean difference 10·5%, 95% CI 3·1-17·8, p=0·005). One participant in the atazanavir group had nucleoside reverse transcriptase inhibitor-associated resistance that led to reduced emtricitabine susceptibility. Adverse events were similar between the dolutegravir and atazanavir groups; the most common were nausea (46 [19%] of 248 in the dolutegravir group vs 49 [20%] of 247 in the atazanavir group) and headache (28 [11%] vs 32 [13%]). Fewer participants in the dolutegravir group than the atazanavir group reported drug-related adverse events (83 [33%] vs 121 [49%]) or adverse events that led to discontinuation (ten [4%] vs 17 [7%]). One death was reported in each treatment group, but neither was considered related to the study medications.. The non-inferior efficacy and similar safety profile of the dolutegravir combined regimen compared with the atazanavir regimen support the use of dolutegravir for HIV-1 infection in treatment-naive women.. ViiV Healthcare.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Middle Aged; Oxazines; Piperazines; Pyridones; Tenofovir; Treatment Outcome

There is no known reason to suspect an adverse drug interaction between dolutegravir-based antiretroviral therapy and sofosbuvir, simeprevir, or ledipasvir. There is a paucity of clinical data for this combination.. Prospective, open-label study of patients with HIV well controlled on dolutegravir, abacavir, and lamivudine, who were co-infected with HCV genotype 1, and required therapy with simeprevir plus sofosbuvir or sofosbuvir/ledipasvir single-tablet regimen (STR) for 12 weeks. The two primary endpoints were percentage of patients achieving sustained virologic response (SVR) at 12 weeks post-treatment and percentage of patients with a HIV-1 viral load <50 copies/ml at end of the combination therapy.. Twenty-eight subjects were enrolled from August 2014 to September 2015. Thirteen patients were treated with simprevir plus sofosbuvir, and 15 subjects were treated with sofosbuvir/ledipasvir. 23 genotype 1a, and 5 genotype 1b were included. Nineteen were treatment naïve, and 2 patients had compensated cirrhosis. The mean age was 59 years (95% CI 58.21-59.78 years). The mean age was 59 years (95% CI: 58.21-59.78 years), and 25 patients were black. Out of the 28 patients who completed this study, SVR 12 was achieved in 27 of 28 patients (96%, 95% CI 89.6-100.0%), and all patients had an HIV virus load <50 copies/ml at week 12 of therapy, for an intent-to-treat rate of 100%. No patients ended therapy secondary to adverse events.. Our study suggests a good safety and efficacy for the combination of a dolutegravir, abacavir, and lamivudine with sofosbuvir-based DAA therapy.

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Coinfection; Dideoxynucleosides; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Sofosbuvir; Treatment Outcome; Viral Load

The integrase inhibitor dolutegravir and nucleoside analogues abacavir and lamivudine are once-daily treatment options for HIV. This study (NCT01622790) evaluated, first, the bioequivalence (BE) of a fixed-dose combination (FDC) tablet containing dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (dolutegravir/abacavir/lamivudine FDC) vs coadministered dolutegravir 50 mg and abacavir/lamivudine combination tablets (Epzicom) and, second, the effect of food on the dolutegravir/abacavir/lamivudine FDC tablet.. Study part A (66 healthy subjects) was a single-dose, open-label, randomized, 2-period crossover study to evaluate the BE of the dolutegravir/abacavir/lamivudine FDC tablet and dolutegravir + abacavir/lamivudine tablets in the fasted state. In study part B, 12 subjects from part A received the dolutegravir/abacavir/lamivudine FDC tablet with a high-fat meal. BE and food effect were assessed by analysis of variance to determine the ratio of geometric least squares means and associated 90% confidence intervals for key pharmacokinetic parameters for each of dolutegravir, abacavir, and lamivudine.. Sixty-two subjects completed part A. The dolutegravir/abacavir/lamivudine tablet was bioequivalent to the dolutegravir + abacavir/lamivudine tablets; 90% confidence intervals for the geometric least squares mean ratios fell within the 0.8-1.25 BE criteria. The effect of food on the dolutegravir/abacavir/lamivudine FDC tablet was similar to previous food effects observed with the separate formulations. The safety profile was comparable between treatments, with no observed serious or grade 3/4 adverse events.. The BE of the dolutegravir/abacavir/lamivudine FDC tablet was demonstrated; it may be administered without regard to meals.

Topics: Adult; Anti-HIV Agents; Cross-Over Studies; Dideoxynucleosides; Dietary Fats; Drug Combinations; Female; Food-Drug Interactions; Heterocyclic Compounds, 3-Ring; Humans; Lamivudine; Male; Oxazines; Piperazines; Pyridones; Therapeutic Equivalency; Vaginal Creams, Foams, and Jellies; Young Adult

Dolutegravir (S/GSK1349572), a once-daily, unboosted integrase inhibitor, was recently approved in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. Dolutegravir, in combination with abacavir-lamivudine, may provide a simplified regimen.. We conducted a randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1000 copies per milliliter or more. Participants were randomly assigned to dolutegravir at a dose of 50 mg plus abacavir-lamivudine once daily (DTG-ABC-3TC group) or combination therapy with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine once daily (EFV-TDF-FTC group). The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. Secondary end points included the time to viral suppression, the change from baseline in CD4+ T-cell count, safety, and viral resistance.. A total of 833 participants received at least one dose of study drug. At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (88% vs. 81%, P=0.003), thus meeting the criterion for superiority. The DTG-ABC-3TC group had a shorter median time to viral suppression than did the EFV-TDF-FTC group (28 vs. 84 days, P<0.001), as well as greater increases in CD4+ T-cell count (267 vs. 208 per cubic millimeter, P<0.001). The proportion of participants who discontinued therapy owing to adverse events was lower in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (2% vs. 10%); rash and neuropsychiatric events (including abnormal dreams, anxiety, dizziness, and somnolence) were significantly more common in the EFV-TDF-FTC group, whereas insomnia was reported more frequently in the DTG-ABC-3TC group. No participants in the DTG-ABC-3TC group had detectable antiviral resistance; one tenofovir DF-associated mutation and four efavirenz-associated mutations were detected in participants with virologic failure in the EFV-TDF-FTC group.. Dolutegravir plus abacavir-lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz-tenofovir DF-emtricitabine. (Funded by ViiV Healthcare; SINGLE ClinicalTrials.gov number, NCT01263015 .).

Topics: Adult; Aged; Aged, 80 and over; Anti-Retroviral Agents; Dideoxynucleosides; Double-Blind Method; Drug Therapy, Combination; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; RNA, Viral; Young Adult

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate (EVG/c/FTC/TAF) and dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) are currently available for HIV patients.. This study evaluated modifications in the renal safety profile in a large real-world cohort of patients who had received EVG/c/FTC/TAF or DTG/ABC/3TC.. A retrospective observational study of HIV-infected patients who received EVG/c/FTC/TAF or DTG/ABC/3TC between March 2015 and June 2019 at a reference hospital in north-western Spain was conducted. Epidemiological, clinical, immunovirological data and information regarding antiretroviral therapy were recorded. The statistical differences between treatments were calculated.. A total of 457 patients were evaluated, 266 using EVG/c/FTC/TAF and 191 using DTG/ABC/3TC. Up to week 120, serum creatinine improved in both study groups among experienced patients (EVG/c/FTC/TAF 1.01±0.24 vs 0.91±0.19, p<0.001; DTG/ABC/3TC 1.08±0.24 vs 1.02±0.31, p<0.001), while in naïve patients serum creatinine remained stable compared with baseline. Statistically significant differences were found in serum creatinine when comparing both treatments at week 48 in experienced (0.94±0.21 vs 1.09±0.28, p<0.001) and naïve patients (0.89±0.16 vs 1.06±0.20, p=0.001), and among experienced patients at week 120 (0.91±0.19 vs 1.02±0.31, p=0.015) for the EVG/c/FTC/TAF and DTG/ABC/3TC groups, respectively. During the follow-up, 39 patients in EVG/c/FTC/TAF and 33 in DTG/ABC/3TC (p=0.449) discontinued treatment. The main reason for stopping treatment was adverse events, which were similar in both groups.. During the follow-up, patients experienced changes that were not clinically relevant in both treatment groups. Differences in renal events were not found.

Topics: Anti-HIV Agents; Cobicistat; Creatinine; Emtricitabine; Fumarates; HIV Infections; Humans; Lamivudine

Herein, a simple spectrophotometric method coupled with chemometric techniques i.e. partial least square (PLS) and genetic algorithm (GA) were utilized for the simultaneous determination of the vital ternary antiretroviral therapy dolutegravir (DTG), lamivudine (LMV), and abacavir (ACV) in their combined dosage form. Calibration (25 samples) and validation (13 samples) sets were prepared for these drugs at different concentrations via implementing partial factorial experimental designs. The zero order UV spectra of calibration and validation sets were measured and then subjected for further chemometric analysis. Partial least squares with/without variable selection procedures i.e. genetic algorithm (GA) were utilized to untangle the UV spectral overlapping of these mixtures. Cross-validation and external validation methods were applied to compare the performance of these chemometric techniques in terms of accuracy and predictive abilities. It was found that six latent variables were optimum for modelling DTG, four latent variables for modelling LMV and three latent variables for modelling ACV. Although, good recoveries with prompt predictive ability were attained by these PLS, GA-PLS showed better analytical performance owing to its capability to remove redundant variables i.e. the number of absorbance variables have been reduced to about 21-29%. The proposed chemometric methods can be reliably applied for simultaneous determination of DTG, LMV, and ACV in their laboratory prepared mixtures and pharmaceutical preparation posing these chemometric methods as worthy and substantial analytical tools in in-process testing and quality control analysis of many antiretroviral pharmaceutical preparations.

Topics: Calibration; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Least-Squares Analysis; Oxazines; Piperazines; Pyridones; Spectrophotometry; Spectrophotometry, Ultraviolet

Topics: Anti-HIV Agents; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

Topics: Alanine; Amides; Anti-HIV Agents; Dideoxynucleosides; Emtricitabine; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; Tenofovir; Weight Gain

Dolutegravir (DTG) plus lamivudine (2-DR) is suggested as an initial and switch option in HIV-1 treatment.. To analyze the effectiveness, durability, and safety of 2-DR compared with DTG plus abacavir/lamivudine (3-DR).. This was an observational, ambispective study that included all treatment-naïve (TN) and treatment-experienced (TE) patients who started 2-DR or 3-DR between July 1, 2018, and November 30, 2020. The primary end point was noninferiority, at 24 and 48 weeks, of 2-DR versus 3-DR regarding the percentage of patients with viral load (VL)≥50 and 200 copies/mL in TN (4% margin) and VL<50 and 200 copies/mL in TE (margin 12%). Durability of response, and safety were also measured.. 242 patients were included (53 TN and 189 TE). Two TN patients on 2-DR had VL≥50 copies/mL and 1 had VL≥200 copies/mL at week 24. In TE patients on 2-DR, 90.2% achieved VL<200 copies/mL at week 24 (difference: 3.8%; 95% CI = -6.3% to 14%) and 91.8% at week 48 (difference: 0.06%; 95% CI = -9% to 10%), meeting noninferiority criteria. Among the 53 TN patients, only 1 VF was observed in 2-DR. In TN patients, the risk of treatment discontinuation was similar between groups (hazard ratio [HR] = 0.37;. Our results did not show noninferiority in terms of virological effectiveness. Nevertheless, all effectiveness measures support the use of 2-DR in a real-life cohort of TN and TE. Additionally, durability and safety of 2-DR were confirmed to be similar to that of 3-DR.

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; Viral Load

Evaluate differences in weight change by regimen among people living with HIV (PLWH) initiating antiretroviral therapy (ART) in the current era.. Between 2012 and 2019, 3232 ART-naïve PLWH initiated ≥3-drug ART regimens in 8 Centers for AIDS Research Network of Integrated Clinical Systems sites. We estimated weight change by regimen for 11 regimens in the immediate (first 6 months) and extended (all follow-up on initial regimen) periods using linear mixed models adjusted for time on regimen, interaction between time and regimen, age, sex, race/ethnicity, hepatitis B/C coinfection, nadir CD4, smoking, diabetes, antipsychotic medication, and site. We included more recently approved regimens [eg, with tenofovir alafenamide fumarate (TAF)] only in the immediate period analyses to ensure comparable follow-up time.. Mean follow-up was 1.9 years on initial ART regimen. In comparison to efavirenz/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), initiating bictegravir/TAF/FTC {3.9 kg [95% confidence interval (CI): 2.2 to 5.5]} and dolutegravir/TAF/FTC [4.4 kg (95% CI: 2.1 to 6.6)] were associated with the greatest weight gain in the immediate period, followed by darunavir/TDF/FTC [3.7 kg (95% CI: 2.1 to 5.2)] and dolutegravir/TDF/FTC [2.6 kg (95% CI: 1.3 to 3.9)]. In the extended period, compared with efavirenz/TDF/FTC, initiating darunavir/TDF/FTC was associated with a 1.0 kg (95% CI: 0.5 to 1.5) per 6-months greater weight gain, whereas dolutegravir/abacavir/FTC was associated with a 0.6-kg (95% CI: 0.3 to 0.9) and dolutegravir/TDF/FTC was associated with a 0.6-kg (95% CI: 0.1 to 1.1) per 6-months greater gain. Weight gain on dolutegravir/abacavir/FTC and darunavir/TDF/FTC was significantly greater than that for several integrase inhibitor-based regimens.. There is heterogeneity between regimens in weight gain following ART initiation among previously ART-naïve PLWH; we observed greater gain among PLWH taking newer integrase strand transfer inhibitors (DTG, BIC) and DRV-based regimens.

Topics: Adult; Alanine; Alkynes; Anti-HIV Agents; Anti-Retroviral Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Tenofovir; Weight Gain

Topics: Dideoxynucleosides; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Insulin; Lamivudine; Menopause; Nitriles; Oxazines; Piperazines; Pyridones; Pyrimidines; Raltegravir Potassium; Waist Circumference; Weight Gain

The time at which the protective effect of starting ART is achieved in male rectal and genital reservoirs is not clearly established.. To quantify HIV-1 RNA decay towards virological suppression in rectal mucosa and semen in MSM starting dolutegravir/abacavir/lamivudine (DTG/ABC/3TC).. A longitudinal cohort study of ART-naive HIV-positive MSM was performed. HIV-1 RNA was quantified in rectal mucosa and seminal plasma samples at day 1 of ART initiation (baseline) and every 4 weeks until week 20 (w20; all participants) and week 64 (w64; 6 of 12 participants).. Twelve MSM, with median (IQR) age 36 (33-40) years and baseline CD4+ count 449 (411-503) cells/mm3, were included. At baseline, HIV-1 RNA was detectable in all plasma and seminal samples and 10/12 rectal samples. All participants achieved plasma virological suppression by w20, whereas HIV-1 RNA was detectable in 42% and 50% of seminal and rectal samples, respectively. At w64, HIV-1 RNA was detectable in 1/6 seminal and 1/6 rectal samples. A relationship of baseline seminal and rectal HIV-1 RNA levels with viral shedding in reservoirs (HIV-1 RNA >200 copies/mL or copies/swab) was found. In addition, a significant association of baseline plasma viral load with time to rectal HIV-1 RNA <200 copies/swab was found (P=0.025).. Viral decay after initiating DTG/ABC/3TC is slower in rectal mucosa and semen than in plasma. Approximately half of patients achieved undetectable HIV-1 RNA levels in rectal and genital secretions at w20 and in some patients viral shedding persisted for up to 1 year. Initial plasma viral load influences time to rectal suppression.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Homosexuality, Male; Humans; Lamivudine; Longitudinal Studies; Male; Oxazines; Piperazines; Pyridones; RNA Stability; RNA, Viral; Sexual and Gender Minorities; Viral Load

Bariatric surgery is increasingly performed in morbidly obese HIV patients. Limited data exist regarding antiretroviral drug exposure after bariatric surgery. We report a case of a morbidly obese HIV patient who underwent sleeve gastrectomy. Abacavir, lamivudine, and dolutegravir therapeutic drug monitoring was performed at several time points pre- and postsurgery. Significantly increased levels were measured, particularly for abacavir, whose levels increased ∼12-fold. Several mechanistic explanations for these findings are discussed.

Topics: Adult; Anti-Retroviral Agents; Bariatric Surgery; Dideoxynucleosides; Drug Monitoring; Gastrectomy; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Male; Obesity, Morbid; Oxazines; Piperazines; Pyridones

Topics: Adult; Alanine; Anti-HIV Agents; Deglutition Disorders; Dideoxynucleosides; Drug Therapy, Combination; Emtricitabine; Eosinophilic Esophagitis; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Male; Oxazines; Piperazines; Pyridones; Tenofovir; Treatment Outcome; Viral Load

M184V/I NRTI resistance mutations can be selected by either lamivudine/emtricitabine or abacavir. There are controversies about the use of abacavir/lamivudine/dolutegravir combinations in HIV-1-infected treatment-experienced patients with a fully suppressed HIV viral load (VL) and harbouring M184V/I.. We assessed the efficacy of abacavir/lamivudine/dolutegravir when used in HIV-infected pretreated patients with an undetectable VL who previously harboured M184V/I as a unique NRTI resistance mutation in a genotypic resistance test and had no resistance to integrase inhibitors.. A total of 154 patients with a fully suppressed HIV-1 plasma VL (<50 copies/mL) treated with tenofovir disoproxil fumarate/emtricitabine/boosted PI or abacavir/lamivudine/boosted PI who switched to an abacavir/lamivudine/dolutegravir regimen and had M184V/I as a unique NRTI resistance mutation in their therapeutic history were retrospectively analysed up to 12 months after the switch to abacavir/lamivudine/dolutegravir. Assessment of residual viraemia was performed at Months 1, 3, 6 and 12. Plasma VL with undetectable HIV-1 RNA corresponded to an absence of residual viraemia.. During the 12 months of follow-up, three patients had a blip of VL (53, 62 and 106 copies/mL) at Month 3 followed by a subsequent VL <50 copies/mL. No patient harboured a virological failure during the follow-up. Moreover, there was no change in residual viraemia during the follow-up.. M184V/I as a unique NRTI resistance mutation, regardless of possible selection by regimens containing lamivudine/emtricitabine or abacavir, does not affect the virological response of well-controlled patients who switched to abacavir/lamivudine/dolutegravir for at least 12 months.

Topics: Anti-HIV Agents; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; Retrospective Studies; Viral Load

Topics: Adenine; Adult; Alanine; Anti-HIV Agents; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Oxazines; Pandemics; Piperazines; Pneumonia, Viral; Pyridones; Ritonavir; SARS-CoV-2; Tenofovir; Transgender Persons

Bone mineral density (BMD) decreases with ART initiation with a tenofovir disoproxil fumarate-containing regimen, although bone tissue quality increases. The impact of dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC)-based ART initiation on bone health parameters is not clear.. To study the impact of DTG/ABC/3TC-based therapy on bone health parameters in ART-naive individuals with HIV after 48 weeks of treatment.. An observational, prospective and analytical study of treatment-naive patients with HIV undergoing a DTG/ABC/3TC-based regimen at 48 week follow-up. Changes in bone strength parameters (BMD, bone microarchitecture and bone tissue quality) were assessed with non-parametric methods.. Sixteen HIV-infected ART-naive patients starting DTG/ABC/3TC were included. BMD in the lumbar spine showed a significant decrease of -2.25% (P = 0.007) and -4.1% in the femoral neck (P = 0.007). Bone microarchitecture, as measured by trabecular bone score, also decreased significantly by -2.5% (P = 0.03). In contrast, bone quality [bone material strength index (BMi)], as measured by microindentation, significantly increased with respect to baseline after 48 weeks of treatment, showing better bone properties of +6.53% (P < 0.001). No significant changes were found in bone turnover markers. In addition, a positive significant correlation between the CD4/CD8 cell count ratio at baseline and changes in BMSi after 48 weeks of treatment was observed (Spearman's rho = 0.4974; P = 0.04).. After a 48 week treatment with DTG/ABC/3TC-based ART, BMD and trabecular bone score decreased while bone tissue quality, as measured by microindentation, improved significantly. The state of the immune system at ART initiation is related to bone quality recovery. An overarching approach to assess bone toxicity in ART-treated patients is needed.

Topics: Anti-HIV Agents; Bone Density; Dideoxynucleosides; Drug Combinations; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Prospective Studies; Pyridones

A 26-year-old male living with human immunodeficiency virus (HIV) and who had previously been treated for ocular syphilis presented to the Emergency Department with progressive vision loss and uveitis. The efficacy of standard management for neurosyphilis in HIV and recurrence was examined.

Topics: Adult; AIDS-Related Opportunistic Infections; Dideoxynucleosides; Eye Infections, Bacterial; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Male; Neurosyphilis; Oxazines; Penicillin G; Piperazines; Pyridones; Syphilis; Syphilis Serodiagnosis; Treatment Outcome; Treponema pallidum; Uveitis; Visual Acuity

Topics: Adult; Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Illinois; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Prisoners; Prisons; Pyridones; Retrospective Studies; Treatment Outcome

Alternative modes of antiretroviral administration are sought for people with impaired intestinal passage and/or absorption. We present a case of late HIV diagnosis (CD4+ count 160 cells/µL) with gastric outlet obstruction due to stomach adenocarcinoma. Co-morbidities included oesophageal candidiasis, Helicobacter pylori-positive duodenal ulcers and cytomegalovirus duodenitis. The gastric outlet obstruction required total parenteral nutrition and parenteral medication during four weeks of diagnostic work-up leading to pyloric resection. Crushed dolutegravir, abacavir and lamivudine were administered during this time in the evening via nasogastric tube, which was kept clamped overnight. The tube was unclamped in the morning and stomach content was drained during the daytime. This mode of administration resulted in rapid and sustained viral load suppression (from 300,000 to 115 copies per mL in 28 days, 81 copies/mL after 42 days of treatment and less than 40 copies/mL thereafter). Therapeutic drug monitoring confirmed sufficient antiretroviral plasma levels during this mode of administration. The absorption of crushed dolutegravir, abacavir and lamivudine in the stomach may be considered in people with questionable gastrointestinal passage or impaired gastric emptying to achieve viral load suppression.

Topics: Adenocarcinoma; Anti-Retroviral Agents; Dideoxynucleosides; Gastric Outlet Obstruction; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Intubation, Gastrointestinal; Lamivudine; Male; Middle Aged; Oxazines; Parenteral Nutrition; Piperazines; Pyridones; Stomach Neoplasms; Sustained Virologic Response; Treatment Outcome

No single-tablet antiretroviral (ARV) regimens (STRs) are approved for patients with human immunodeficiency virus (HIV) and end-stage renal disease (ESRD) on hemodialysis (HD). Based on known pharmacokinetic (PK) properties, abacavir (ABC)/lamivudine (3TC)/dolutegravir (DTG) STR may represent a promising option. This case series presents the safety and efficacy of ABC/3TC/DTG STR in patients with HIV and ESRD on HD. Patients were included if they were HIV-positive, maintained on intermittent HD for ESRD, switched to an ARV regimen containing ABC/3TC/DTG, and had at least one set of virologic data before and after the switch. Average age (±standard deviation) was 59 (±8) years. The majority of patients were cis-gender male and non-Hispanic Black. Only one demonstrated clinically significant resistance at baseline. All were on multiple-tablet regimens prior to the switch. Five patients (83%) achieved undetectable HIV-RNA after the switch while only four patients (46%) were undetectable immediately prior. No decline in immune function was noted. ABC/3TC/DTG STR was well tolerated. Only one patient self-reported an adverse event (nausea), which resolved without drug discontinuation. Based on these data, it appears that ABC/3TC/DTG may be a safe and effective ARV-STR option for patients with HIV and ESRD on HD. A larger trial including a PK analysis is needed to confirm these findings.

Topics: Adult; Aged; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Dideoxynucleosides; Drug Combinations; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Kidney Failure, Chronic; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Renal Dialysis; Tablets; Treatment Outcome; Viral Load

Topics: Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV; HIV Infections; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

Concerns about dolutegravir (DTG) tolerability in the real-life setting have recently arisen. We aimed to estimate the risk of treatment discontinuation and virological failure of DTG-based regimens from a large cohort of HIV-infected individuals.. We performed a multicentre, observational study including all antiretroviral therapy (ART)-naïve and virologically suppressed treatment-experienced (TE) patients from the Icona (Italian Cohort Naïve Antiretrovirals) cohort who started, for the first time, a DTG-based regimen from January 2015 to December 2017. We estimated the cumulative risk of DTG discontinuation regardless of the reason and for toxicity, and of virological failure using Kaplan-Meier curves. We used Cox regression model to investigate predictors of DTG discontinuation.. About 1679 individuals (932 ART-naïve, 747 TE) were included. The one- and two-year probabilities (95% CI) of DTG discontinuation were 6.7% (4.9 to 8.4) and 11.5% (8.7 to 14.3) for ART-naïve and 6.6% (4.6 to 8.6) and 7.6% (5.4 to 9.8) for TE subjects. In both ART-naïve and TE patients, discontinuations of DTG were mainly driven by toxicity with an estimated risk (95% CI) of 4.0% (2.6 to 5.4) and 2.5% (1.3 to 3.6) by one year and 5.6% (3.8 to 7.5) and 4.0% (2.4 to 5.6) by two years respectively. Neuropsychiatric events were the main reason for stopping DTG in both ART-naïve (2.1%) and TE (1.7%) patients. In ART-naïve, a concomitant AIDS diagnosis predicted the risk of discontinuing DTG for any reason (adjusted relative hazard (aRH) = 3.38, p = 0.001), whereas starting DTG in combination with abacavir (ABC) was associated with a higher risk of discontinuing because of toxicity (aRH = 3.30, p = 0.009). TE patients starting a DTG-based dual therapy compared to a triple therapy had a lower risk of discontinuation for any reason (adjusted hazard ratio (aHR) = 2.50, p = 0.037 for ABC-based triple-therapies, aHR = 3.56, p = 0.012 for tenofovir-based) and for toxicity (aHR = 5.26, p = 0.030 for ABC-based, aHR = 6.60, p = 0.024 for tenofovir-based). The one- and two-year probabilities (95% CI) of virological failure were 1.2% (0.3 to 2.0) and 4.6% (2.7 to 6.5) in the ART naïve group and 2.2% (1.0 to 3.3) and 2.9% (1.5 to 4.3) in the TE group.. In this large cohort, DTG showed excellent efficacy and optimal tolerability both as first-line and switching ART. The low risk of treatment-limiting toxicities in ART-naïve as well as in treated individuals reassures on the use of DTG in everyday clinical practice.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Italy; Male; Middle Aged; Oxazines; Piperazines; Prospective Studies; Pyridones; Retrospective Studies; Tenofovir; Treatment Outcome

Topics: Adenine; Alanine; Amides; Dideoxynucleosides; Double-Blind Method; Emtricitabine; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Lamivudine; Oxazines; Piperazines; Pyridones; Tenofovir

Poor antiretroviral penetration may contribute to human immunodeficiency virus (HIV) persistence within the brain and to neurocognitive deficits in opiate abusers. To investigate this problem, HIV-1 Tat protein and morphine effects on blood-brain barrier (BBB) permeability and drug brain penetration were explored using a conditional HIV-1 Tat transgenic mouse model. Tat and morphine effects on the leakage of fluorescently labeled dextrans (10-, 40-, and 70-kDa) into the brain were assessed. To evaluate effects on antiretroviral brain penetration, Tat+ and Tat- mice received three antiretroviral drugs (dolutegravir, abacavir, and lamivudine) with or without concurrent morphine exposure. Antiretroviral and morphine brain and plasma concentrations were determined by LC-MS/MS. Morphine exposure, and, to a lesser extent, Tat, significantly increased tracer leakage from the vasculature into the brain. Despite enhanced BBB breakdown evidenced by increased tracer leakiness, morphine exposure led to significantly lower abacavir concentrations within the striatum and significantly less dolutegravir within the hippocampus and striatum (normalized to plasma). P-glycoprotein, an efflux transporter for which these drugs are substrates, expression and function were significantly increased in the brains of morphine-exposed mice compared to mice not exposed to morphine. These findings were consistent with lower antiretroviral concentrations in brain tissues examined. Lamivudine concentrations were unaffected by Tat or morphine exposure. Collectively, our investigations indicate that Tat and morphine differentially alter BBB integrity. Morphine decreased brain concentrations of specific antiretroviral drugs, perhaps via increased expression of the drug efflux transporter, P-glycoprotein.

Topics: Animals; Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Blood-Brain Barrier; Capillary Permeability; Corpus Striatum; Dextrans; Dideoxynucleosides; Female; Fluorescein-5-isothiocyanate; Heterocyclic Compounds, 3-Ring; Hippocampus; HIV Infections; HIV-1; Lamivudine; Mice; Mice, Transgenic; Models, Biological; Morphine; Neurocognitive Disorders; Oxazines; Piperazines; Pyridones; tat Gene Products, Human Immunodeficiency Virus

Trends in resistance to antiretroviral drugs for HIV-1 may inform clinical support and drug development. We evaluated drug resistance mutation (DRM) trends for nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), and integrase strand transfer inhibitor (INSTI) in a large U.S. reference laboratory database. DRMs with a Stanford HIV Drug Resistance Database mutation score ≥10 from deidentified subtype B NRTI/NNRTI/PI specimens (2006-2017; >10,000/year) and INSTI specimens (2010-2017; >1,000/year) were evaluated. Sequences with NRTI, NNRTI, or PI single- or multiclass DRMs declined from 48.9% to 39.3%. High-level dual- and triple-class resistance declined from 43.3% (2006) to 17.1% (2017), while sequences with only single-class DRMs increased from 40.0% to 52.9%. The prevalence of DRMs associated with earlier treatment regimens declined, while prevalence of some DRMs associated with newer regimens increased. M184V/I decreased from 48.3% to 29.4%. K103N/S/T declined from 42.5% in 2012 to 36.4% in 2017. Rilpivirine and etravirine DRMs E138A/Q/R and E138K increased from 4.9% and 0.4% to 9.7% and 1.7%, respectively. Sequences with ≥1 darunavir DRM declined from 18.1% to 4.8% by 2017. INSTI DRM Q148H/K/R declined from 39.3% (2010) to 13.8% (2017). Prevalence of elvitegravir-associated DRMs T66A/I/K, E92Q, S147G, and the dolutegravir-associated DRM R263K increased. For a subset of patients with serial testing, 50% (2,646/5,290) of those who initially had no reportable DRM subsequently developed ≥1 DRM for NRTI/NNRTI/PI and 49.7% (159/320) for INSTI. These trends may inform the need for baseline genotypic resistance testing. The detection of treatment-emergent DRMs in serially tested patients confirms the value of genotypic testing following virologic failure.

Topics: Anti-HIV Agents; Darunavir; Dideoxynucleosides; Drug Resistance, Viral; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Mutation; Nitriles; Oxazines; Piperazines; Pyridazines; Pyridones; Pyrimidines; Reverse Transcriptase Inhibitors; Rilpivirine

Topics: Adolescent; Adult; Aged; Amyotrophic Lateral Sclerosis; Biomarkers; Cohort Studies; Dideoxynucleosides; Disease Progression; Drug Combinations; Female; Heterocyclic Compounds, 3-Ring; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Young Adult

Dolutegravir (DTG) is recommended as part of first-line antiretroviral therapy (ART) for people living with HIV(PLHIV). We sought to determine the rate of adverse events (AEs) and discontinuations among Thais treated during acute HIV infection (AHI) and switched to DTG-based regimens.. Thai participants in the SEARCH010/RV254 cohort who initiated ART during AHI and switched to DTG for at least 48 weeks were prospectively observed and included in the analysis. Rates and characteristics of DTG-related AEs and discontinuations were described.. A total of 313 Thai participants were included in the analysis. The median age was 29 years, 96% were male, 64% had a Bachelor's degree or higher and 16% had a body mass index (BMI) <18.5 kg/m. DTG was well tolerated with few discontinuations in this cohort of young men. Incident hepatitis C virus infection was a driver of liver-related AEs leading to discontinuations. In populations at risk, regular testing for hepatitis C virus during ART is recommended to anticipate possible AEs, guide management and improve safety.

Topics: Adult; Anti-HIV Agents; Cohort Studies; Dideoxynucleosides; Female; Hepatitis C; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Risk Factors; Thailand; Young Adult

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Chemical and Drug Induced Liver Injury; Cholestasis; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Male; Middle Aged; Oxazines; Piperazines; Pyridones

HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines evolve.. An expert panel was created to provide recommendations for the update of the Stanford HIV Drug Resistance Database (HIVDB) GRT-IS. The panel was polled on the ARVs to be included in a GRT report, and the drug-resistance interpretations associated with 160 drug-resistance mutation (DRM) pattern-ARV combinations. The DRM pattern-ARV combinations included 52 nucleoside RT inhibitor (NRTI) DRM pattern-ARV combinations (13 patterns x 4 NRTIs), 27 nonnucleoside RT inhibitor (NNRTI) DRM pattern-ARV combinations (9 patterns x 3 NNRTIs), 39 protease inhibitor (PI) DRM pattern-ARV combinations (13 patterns x 3 PIs) and 42 integrase strand transfer inhibitor (INSTI) DRM pattern-ARV combinations (14 patterns x 3 INSTIs).. There was universal agreement that a GRT report should include the NRTIs lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir disoproxil fumarate; the NNRTIs efavirenz, etravirine, nevirapine, and rilpivirine; the PIs atazanavir/r, darunavir/r, and lopinavir/r (with "/r" indicating pharmacological boosting with ritonavir or cobicistat); and the INSTIs dolutegravir, elvitegravir, and raltegravir. There was a range of opinion as to whether the NRTIs stavudine and didanosine and the PIs nelfinavir, indinavir/r, saquinavir/r, fosamprenavir/r, and tipranavir/r should be included. The expert panel members provided highly concordant DRM pattern-ARV interpretations with only 6% of NRTI, 6% of NNRTI, 5% of PI, and 3% of INSTI individual expert interpretations differing from the expert panel median by more than one resistance level. The expert panel median differed from the HIVDB 7.0 GRT-IS for 20 (12.5%) of the 160 DRM pattern-ARV combinations including 12 NRTI, two NNRTI, and six INSTI pattern-ARV combinations. Eighteen of these differences were updated in HIVDB 8.1 GRT-IS to reflect the expert panel median. Additionally, HIVDB users are now provided with the option to exclude those ARVs not considered to be universally required.. The HIVDB GRT-IS was updated through a collaborative process to reflect changes in HIV drug resistance knowledge, treatment guidelines, and expert opinion. Such a process broadens consensus among experts and identifies areas requiring further study.

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Drug Resistance, Viral; Genotype; Heterocyclic Compounds, 3-Ring; HIV-1; Lamivudine; Lopinavir; Nelfinavir; Oxazines; Piperazines; Pyridones; Reverse Transcriptase Inhibitors; Ritonavir; Zidovudine

Fixed-dose combinations of antiretroviral drugs have meant an important step forward in simplifying treatment and improving compliance and has led to an increased effectiveness of therapy, a viral load decrease and improving the quality of life of patients. The single-table formulation of dolutegravir with abacavir and lamivudine (DTG/ABC/3TC) is a highly efficacious and well-tolerated once-daily regimen for HIV-infected patients. The objective of the study was to assess the incremental cost-utility ratio of the fixed-dose combination of (DTG/ABC/3TC) versus the combinations emtricitabine/tenofovir/efavirenz (FTC/TDF/EFV), and darunavir/r (DRV/r) or raltegravir (RAL) with emtricitabine/tenofovir (FTC/TDF) or abacavir/lamivudine (ABC/3TC) as initial antiretroviral therapy in patients infected with HIV-1 from the perspective of the Spanish National Health System.. The ARAMIS model, which uses a microsimulation approach to simulate the individual changes in each patient from the start of treatment to death through a Markov chain of descriptive health states of the disease, was adapted to Spain. The alternatives used for comparison were the fixed-dose combination of emtricitabine/tenofovir/efavirenz (FTC/TDF/EFV), and the fixed- dose combinations of emtricitabine/tenofovir (FTC/TDF) or abacavir/lamivudine (ABC/3TC) with darunavir/r (DRV/r) or raltegravir (RAL). The probability of achieving virological suppression by the treatments included in the model was obtained from clinical trials SINGLE, SPRING-2 and FLAMINGO and the costs were expressed in € (2015). The model use the perspective of the Spanish National Health System, with a lifetime horizon and a discount rate of 3% was applied to cost and effectiveness.. Treatment initiation with DTG/ABC/3TC was dominant when it was compared with treatment initiation with all the comparators: vs. FTC/TDF/EFV (-67 210.71€/QALY), vs. DRV/r + FTC/TDF or ABC/3TC (-1 787 341.44€/QALY), and vs. RAL + FTC/TDF or ABC/3TC (-1 005 117.13€/QALY). All the sensitivity analyses performed showed the consistency of these findings.. With the premises considered, treatment initiation with DTG/ABC/3TC STR appears to be the most cost-effective option in ARTnaïve HIV infected patients from the Spanish Health System perspective.. Objetivo: Las combinaciones a dosis fijas de medicamentos antirretrovirales han significado un importante paso adelante en la simplificación del tratamiento y la mejora del cumplimiento, así como hacia una mayor eficacia de la terapia, una disminución de la carga viral y una mejora de la calidad de vida de los pacientes. La formulación de un comprimido único una vez al día con dosis fijas de dolutegravir, abacavir y lamivudina (DTG/ABC/3TC) para pacientes infectados con VIH es un régimen altamente eficaz y bien tolerado. El objetivo del estudio fue evaluar la relación coste- utilidad incremental de la combinación de dosis fija de (DTG/ABC/3TC) versus las combinaciones de emtricitabina/tenofovir/efavirenz (TDF/FTC/EFV) y darunavir/r (DRV/r) o raltegravir (RAL) con emtricitabina/tenofovir (FTC/TDF) o abacavir/lamivudina (ABC/3TC) como tratamiento antirretroviral inicial en pacientes infectados con VIH-1 desde la perspectiva del Sistema Nacional de Salud Español.Método: Se adaptó en España el modelo ARAMIS. Este utiliza un enfoque de microsimulación para emular los cambios individuales en cada paciente desde el inicio del tratamiento hasta su muerte mediante una cadena de Markov de estados de salud descriptivos de la enfermedad. Las alternativas empleadas para la comparación fueron la combinación de dosis fijas de emtricitabina/tenofovir/efavirenz (TDF/FTC/EFV) y las combinaciones de dosis fijas de emtricitabina/tenofovir (FTC/TDF) o abacavir/lamivudina (ABC/3TC) con darunavir/r (DRV/r) o raltegravir (RAL). La probabilidad de lograr la supresión virológica mediante los tratamientos incluidos en el modelo se ha obtenido de ensayos clínicos individuales, SPRING2 y FLAMINGO, y los costes fueron expresados en € (2015). El uso del modelo de la perspectiva del Sistema Nacional de Salud español, con un horizonte de vida útil y una tasa de descuento del 3% se, aplicó a coste y efectividad.Resultados: El inicio de tratamiento con DTG/ABC/3TC fue dominante cuando se comparó con el inicio del tratamiento con el resto de comparadores: frente a TDF/FTC/EFV (-67.210,710 € / AVAC) vs DRV/r FTC/TDF o ABC/3TC (-1,787,341.44 € / AVAC) y vs RAL FTC/TDF o ABC/3TC (-1,005,117.13 € / AVAC). Todos los análisis de sensibilidad realizados demostraron la consistencia de estos hallazgos.Conclusiones: Con las premisas consideradas, el inicio del tratamiento con la combinación a dosis fijas de DTG/ABC/3TC parece ser la opción más rentable para el tratamiento de pacientes infectados con

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cost-Benefit Analysis; Dideoxynucleosides; Drug Combinations; Drug Compounding; Female; Heterocyclic Compounds, 3-Ring; HIV Seropositivity; Humans; Lamivudine; Male; Oxazines; Piperazines; Pyridones; Reverse Transcriptase Inhibitors; Spain

We report this case to highlight the possibility of a severe hypersensitivity reaction as an important potential consequence of couples, living with HIV, sharing anti-retroviral treatment. An HIV-1 positive and carrier of HLA-B*57:01 allele, treatment experienced man was commenced one pill Regimen Stribild (tenofovir, emtricitabine, elvitegravir and cobicistat) in July 2015. On running short of medication, he admitted to sharing his partner's treatment (Triumeq; abacavir, lamivudine and dolutegravir). On the second occasion, re-introduction resulted in whole body rash 4 h post dose and was associated with fever, respiratory symptoms, headache and vomiting. On examination, he was pyrexic, tachyponeic, tachycardiac and hypotensive. Hypersensitivity to abacavir can cause significant morbidity. Re-challenge can result in a more rapid, severe and potentially life-threatening reaction. This potentially could become an increasing problem with more couples, living with HIV, sharing medication.

Topics: Anti-HIV Agents; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; HLA-B Antigens; Humans; Lamivudine; Oxazines; Piperazines; Pyridones

While HIV-2 is a causative agent for AIDS in addition to the better studied HIV-1, there is currently no suitable animal model for experimental studies for HIV-2 infection and evaluating promising drugs in vivo. Here we evaluated humanized mice for their susceptibility to HIV-2 infection and tested a single-pill three drug formulation of anti-retrovirals (NRTIs abacavir and lamivudine, integrase inhibitor dolutegravir) (trade name, Triumeq

Topics: Animals; Anti-HIV Agents; CD4-Positive T-Lymphocytes; Dideoxynucleosides; Disease Models, Animal; Drug Therapy, Combination; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-2; Humans; Lamivudine; Mice; Mice, Inbred BALB C; Oxazines; Piperazines; Pyridones

The combination of Abacavir, Lamivudine and Dolutegravir is an anti-retroviral formulation that displays high efficacy and superiority in comparison to other anti-retroviral combinations. Analysis of related substances in this combination drug product was very challenging due to the presence of nearly thirty peaks including the three active pharmaceutical ingredients (APIs), eleven known impurities and other pharmaceutical excipients. Objective of this study was to develop a single, selective, and robust high performance liquid chromatography method for the efficient separation of all peaks. Initially, one-factor-at-a-time (OFAT) approach was adopted to develop the method. But, it could not resolve all the critical peaks in such complex matrix. This led to the advent of two different HPLC methods for the determination of related substances, one for Abacavir and Lamivudine and the other for Dolutegravir. But, since analysis of a single sample using two methods instead of one is time and resource consuming and thus expensive, an attempt was made to develop a single and robust method by adopting quality by design (QbD) principles. Design of Experiments (DoE) was applied as a tool to achieve the optimum conditions through Response surface methodology with three method variables, pH, temperature, and mobile phase composition. As the study progressed, it was discovered that establishment of the design space was not viable due to the completely distant pH requirements of the two responses, i.e. (i) retention time for Lamivudine carboxylic acid and (ii) resolution between Abacavir impurity B and unknown impurity. Eventually, neglecting one of these two responses each time, two distinguished design spaces have been established and verified. Edge of failures at both design spaces indicate high probability of failure. It therefore, becomes very important to identify the most robust zone or normal operating range (NOR) within the design space with low risk of failure and high quality assurance. For NOR establishment, Monte Carlo simulation was performed on the basis of which process capability index (Cpk) was derived. Finally, the selectivity issue problem faced due to the pH dependency and the dissimilar pH needs of the two critical responses was resolved by introducing pH gradient into the program. This new ternary gradient program has provided a single robust method. Thus, two HPLC methods for the analysis of the combination drug product have been replaced with a

Topics: Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; Lamivudine; Monte Carlo Method; Oxazines; Pharmaceutical Preparations; Piperazines; Pyridones; Temperature

Topics: Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Drug Combinations; Drug Hypersensitivity; Drug Interactions; Drug Resistance, Viral; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Emtricitabine, Rilpivirine, Tenofovir Drug Combination; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Mental Disorders; Oxazines; Piperazines; Pyridones; Viral Load

Topics: Adolescent; Anti-HIV Agents; Black or African American; Dideoxynucleosides; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Lamivudine; Male; Oxazines; Pancreatitis, Acute Necrotizing; Piperazines; Pyridones