Background: Study 1844 demonstrated the safety and noninferior efficacy of switching to bictegravir/ emtricitabine/tenofovir alafenamide (B/F/TAF) from dolutegravir/abacavir/lamivudine (DTG/ABC/3TC). Here we present resistance, viral blips, and virologic outcomes through the end of the study. Methods: Virologically suppressed adults switched to B/F/TAF or continued DTG/ABC/3TC in a double‐blind (DB) manner through Week (W) 48; then all remaining participants received B/F/TAF in an open‐label (OL) extension. Preexisting HIV‐1 drug resistance was determined by cumulative historical genotypes and retrospective baseline proviral DNA genotyping. Viral blips and outcomes based on last available on‐treatment HIV‐1 RNA were assessed for all participants with ≥1 on‐treatment HIV‐1 RNA measurement. Results: 562 participants had HIV‐1 RNA data in the DB phase (281 B/F/TAF, 281 DTG/ABC/3TC), and 545 participants received B/F/TAF and had post‐switch data in the DB and/or OL phases (B/F/TAF duration median 96 weeks, maximum 168 weeks). Cumulative baseline genotypic data from historical (n=271) and/or proviral DNA (n=499) genotypes were available for 96% (522/545) of B/F/TAF‐treated participants. The average frequency of viral blips was 1% per timepoint with 25 participants (10 B/F/TAF, 15 DTG/ABC/3TC) experiencing ≥1 viral blip through W48 and 9 on B/F/TAF experiencing blips after W48. Viral blips were not associated with any baseline characteristic, preexisting resistance, or virologic failure. Through 168 weeks of B/F/TAF treatment, 98% (535/545) had HIV‐1 RNA <50 copies/mL at last visit, including 99% (159/161) with preexisting resistance. No participant developed drug resistance. Conclusion: Virologic suppression was maintained for ≥2 years of B/F/TAF treatment, including in those with preexisting resistance or viral blips. Long‐term suppression and the absence of treatment‐emergent resistance demonstrate the durable efficacy of B/F/TAF.

The SINGLE study was a randomized, double-blind, noninferiority study that evaluated the safety and efficacy of 50 mg dolutegravir + abacavir/lamivudine versus efavirenz/tenofovir/emtricitabine in 833 ART-naive HIV-1 + participants. Of 833 randomized participants, 71% in the dolutegravir + abacavir/lamivudine arm and 63% in the efavirenz/tenofovir/emtricitabine arm maintained viral loads of <50 copies per milliliter through W144 (P = 0.01). Superior efficacy was primarily driven by fewer discontinuations due to adverse events in the dolutegravir + abacavir/lamivudine arm [dolutegravir + abacavir/lamivudine arm, 16 (4%); efavirenz/tenofovir/emtricitabine arm, 58 (14%)] through W144 [corrected]. No treatment-emergent integrase or nucleoside resistance was observed in dolutegravir + abacavir/lamivudine recipients through W144.

Background: Tenofovir has been associated with a decrease in bone mineral density (BMD). However, data on changes in BMD after discontinuing tenofovir are lacking. Methods: We performed a two-centre randomized pilot study in virologically suppressed HIV-infected patients receiving tenofovir with osteopenia/osteoporosis (OsteoTDF study, ClinicalTrials.gov number NCT 01153217). Fifty-four patientswere randomly assigned to switch from tenofovir to abacavir (n = 26) or to continue with tenofovir (n = 28). Changes in lumbar and total hip BMD were evaluated at Week 48 from baseline. Results: Five patients discontinued the study (three from the tenofovir group and two from the abacavir group). No significant differences were detected between the groups at Week 48 (P = 0.229 for total hip and P = 0.312 for lumbar spine). However, hip BMD improved by 2.1% (95% CI -0.6 to 4.7) (P = 0.043) in the abacavir group and 0.7% (95% CI -0.9 to 2.4) (P = 0.372) in the tenofovir group. Lumbar spine BMD varied by -0.7% (95% CI -3.8 to 3.3) (P ≤ 0.001) in the abacavir group and -1.2% (95% CI -3.8 to 0.4) (P < 0.001) in the tenofovir group. Conclusions: Switching from tenofovir to abacavir led to a slight improvement in femoral BMD although no differences were detected between groups. Larger studies are necessary before firm recommendations can be made on the discontinuation of tenofovir in patients with a low BMD. © The Author 2014.

OBJECTIVE:

To assess the antiviral efficacy, safety and adherence in patients switched to an abacavir‐containing nucleoside reverse transcriptase inhibitor (NRTI) regimen after long‐term HIV‐1 RNA suppression with a dual NRTI/protease inhibitor (PI) combination.

METHODS:

In an open‐label, multicentre study, patients receiving 2NRTI plus PI for at least 6 months, with a history of undetectable plasma HIV‐1 RNA since the initiation of therapy and plasma HIV‐1 RNA < 50 copies/ml at screening, were randomly assigned to replace the PI with abacavir (n = 105) or continue the same treatment (n = 106). Clinical assessments included plasma HIV‐1 RNA, chemistry, haematology, lymphocyte counts, and adverse event reports. Adherence to treatment was assessed by patient self‐report.

RESULTS:

A significantly longer time to treatment failure was demonstrated in the abacavir arm compared with the PI arm (P = 0.03) while treatment failure was experienced by significantly more patients in the PI arm: 24 (23%) versus 12 (12%) (P = 0.03). Therapy‐limiting toxicity led to treatment failure in eight versus 14 cases in the abacavir and PI arms, respectively, whereas virological rebound was the cause in four versus two cases. Significant reductions in cholesterol and non‐fasting triglyceride plasma levels at 48 weeks were observed in the abacavir arm (P < 0.001 andP = 0.035, respectively). The number of patients reporting no difficulty in taking their therapy showed a marked increase from baseline in the abacavir arm.

CONCLUSION:

The replacement of PI by abacavir in a triple combination regimen following prolonged suppression of plasma HIV‐1 RNA provides continued virological suppression, significant improvements in lipid abnormalities and enhanced ease of dosing.

To assess the safety, tolerance, and efficacy of amprenavir (APV) plus abacavir (ABC) in patients who have previously failed antiretroviral treatment containing a protease inhibitor (PI). To provide open-label, pre-approval access to APV for adults and adolescents with HIV-1 infection and limited treatment options.

This study is being conducted to provide open-label APV to patients in danger of HIV disease progression, as well as those who may benefit beyond the expected outcomes of current anti-retroviral therapies. Despite unapproved status, APV may prove highly efficacious in combatting HIV progression and may help those in need, prior to regulatory approval.

Enfuvirtide is a novel antiretroviral that blocks HIV-1 cell fusion and viral entry. This Phase II, controlled, open-label, randomized, multicentre dose-ranging trial explored the safety, antiviral activity and pharmacokinetics of enfuvirtide, administered by subcutaneous (s.c.) injection, in 71 HIV-1-infected, protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive adults for 48 weeks. Study participants were randomized to receive enfuvirtide at a deliverable dose of 45, 67.5 or 90 mg twice daily; the 45 mg twice daily dose required 2 injections/day, while the higher doses required 4 injections/day. A background oral antiretroviral (ARV) regimen of abacavir (300 mg twice daily), amprenavir (1200 mg twice daily), ritonavir (200 mg twice daily) and efavirenz (600 mg once daily) was provided with enfuvirtide. A control group received the background ARV regimen alone. All potential participants underwent an HIV genotype at screen to ensure a homogenous population and to exclude patients with evidence of genotypic resistance to NNRTIs. Overall, the tolerability of the combination of abacavir, amprenavir, ritonavir, efavirenz and enfuvirtide was generally comparable to control through 48 weeks. No enfuvirtide dose-dependent adverse events (AEs) were observed across treatment groups. Injection site reactions (ISRs) occurred at least once in 68.5% of the enfuvirtide-treated population, and most ISRs were mild to moderate in severity, with no apparent dose relationship. Excluding ISRs, the most common treatment-emergent AEs were nausea, diarrhoea, dizziness and fatigue; with no clinically significant differences in the incidence of AEs observed between the control and enfuvirtide groups. Each treatment group benefited from ARV therapy, with a trend of increasing antiviral and immunological activity associated with increasing enfuvirtide dose. At 48 weeks, the median HIV-1 RNA change from baseline for the ITT population was -2.24 log10 copies/ml for the combined enfuvirtide groups compared with -1.87 log10 copies/ml for the control group. In addition, 54.9% of patients in the enfuvirtide group achieved HIV-1 RNA < or = 400 copies/ml versus 36.8% of patients in the control group. These results indicate that enfuvirtide has a favourable safety profile and is a promising new antiviral agent for HIV-infected patients who have been on previously failing ARV regimens.

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INTERVENTION:

Trade Name: ISENTRESS Pharmaceutical Form: Tablet INN or Proposed

INN:

Raltegravir Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 400‐

CONDITION:

HIV ; MedDRA version: 12.0 Level: HLT Classification code 10038997 Term: Retroviral infections

PRIMARY OUTCOME:

Main Objective: 1) To verify the persistent control of the virus replication at 48 weeks after the simplification to tenofovir + emtricitabina + raltegravir or to lamivudine+abacavir+raltegravir in patients with optimal virological suppression without any virological failure to previous combined antiretroviral therapies Primary end point(s): proportion of patients with virological failure (two consecutive HIV‐RNA levels > 50 copies/mL or a single value >1000 copies/mL) within 48 weeks at intention‐to.treat analysis Secondary Objective:  Time to virological failure (two consecutive HIV‐RNA levels > 50 copies/mL or a single value >1000 copies/mL) at survival analysis;  Proportion of patients with viral load lower than 50 copies/mL at 48 weeks at the intention to treat analysis;  Evolution of CD4 cell count during the 48 weeks of study;  Evolution of adherence and quality of life during the 48 weeks of study;  Evolution of raltegravir plasma concentrations during the 48 weeks of study;  Evolution of metabolic parameters during the 48 weeks of study;  Change of the results of neurocognitive tests at 48 weeks of study;  Change of bone density and of adipose tissue by DEXA analysis at 48 weeks of study

INCLUSION CRITERIA:

Patients treated with a combined antiretroviral therapy from at least 1 year Aged 18 years or older With one or more of the following conditions:  Grade 3 or 4 Dyslipidemia  Any Hyperglicemia  Lipodystrophy (patient?s self report, confirmed by physician?s physical examination)  Moderate/severe cardiovascular risk, defined as a calcium score higher than 40 or a Framingham score higher than 10 (estimated 10 years cardiovascular risk: 10%)  Diarrhea (at least 3 emissions of loose stool every day for at least 3 days every week) With at least two HIV‐RNA levels <50 copies/mL on two consecutive determinations at least 3 months apart With CD4 cell count >200 cells/ μL for at least 6 months and absence of any opportunistic infection or AIDS‐related disease during the last year before screening. Who gave informed consent to the participation to the study Are the tri

INTERVENTION:

Product Code: GSK1349752 Pharmaceutical Form: Tablet CAS Number: 1051375‐19‐9 Current Sponsor code: GSK1349752 Concentration unit: IU/mg international unit(s)/milligram Concentration type: equal Concentration number: 10‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Product Code: GSK1349752 Pharmaceutical Form: Tablet CAS Number: 1051375‐19‐9 Current Sponsor code: GSK1349752 Concentration unit: IU/mg international unit(s)/milligram Concentration type: equal Concentration number: 25‐ Pharmaceutical form of the placebo: Tablet Route of administration of the placebo: Oral use Pharmaceutical Form: Tablet INN or Proposed

INN:

Efavirenz Concentration unit: IU/mg international unit(s)/milligram Concentration type: equal Concentration number: 600‐ Pharmaceutical Form: Tablet INN or Proposed

INN:

Combinations Concentration unit: IU/mg international unit(s)/milligram Concentration type: equal Concentration number: 445‐ Pharmaceutical Form: Tablet INN or Proposed

INN:

Combinations Concentration unit: IU/mg international unit(s)/milligram Concentration type: equal Concentration number: 445‐ Pharmaceutical Form: Tablet INN or Proposed

INN:

Combinations Concentration unit: IU/mg international unit(s)/milligram Concentration type: equal Concentration number: 900‐ Pharmaceutical Form: Tablet INN or Proposed

INN:

Combinations Concentration unit: IU/mg international unit(s)/milligram Concentration type: equal Concentration number: 900‐

CONDITION:

HIV‐1 infected antiretroviral therapy naïve adult subjects ; MedDRA version: 12.0 Level: LLT Classification code 10064456 Term: HIV infection WHO clinical stage

IV PRIMARY OUTCOME:

Main Objective: To select a GSK1349572 once daily dose for further evaluation in Phase III based on a comparison of the Week 16 antiviral activity and tolerability of a range of oral doses of GSK1349572 in HIV‐1 infected therapy‐naïve adult subjects Primary end point(s): Proportion of subjects with HIV‐1 RNA <50 c/ml through Week 16 using the TLOVR algorithm. Dose selection will be based primarily on antiviral activity and tolerability in conjunction with immunologic, safety and PK measures will also be considered Secondary Objective: To evaluate the effect of various GSK1349572 doses on selected virological and immunological markers of HIV infection through Week 16 To evaluate the safety and tolerability of GSK1349572 doses through Week 16 To characterize the PK parameters of GSK1349572 using intensive and sparse PK sampling strategies and to explore exposure‐response relationships To confirm the Week 16 GSK1349572 once daily selected dose at Week 24 based on antiviral activity in conjunction with immunologic, safety and PK measures To assess the development of viral resistance to GSK1349572 and other on‐study ARTs in subjects experiencing virological failure To evaluate the effect of various demographic factors on exposure‐response parameters of GSK1349572 To assess the HIV‐1 RNA decay rate over the initial 2 weeks of treatment To evaluate the antiviral activity, safety, tolerability and development of viral resistance of the selected dose of GSK1349572 relative to EFV over time

INCLUSION CRITERIA:

1.HIV‐1 infected males or females of non‐childbearing potential ≥18 years of age.For the purposes of this trial, a woman is considered of non‐childbearing potential if she is physiologically incapable of becoming pregnant.This includes pre‐menopausal females with a documented tubal ligation, hysterectomy or bilateral oophorectomy or post‐menopausal women (defined as 12 months of spontaneous amenorrhea) 2.HIV‐1 infection with a screening plasma HIV‐1 RNA ≥1000 c/mL 3. CD4+ cell count ≥100 cells/mm3 (or higher as local guidelines dictate) 4. ART‐naive defined as having <10 days of prior therapy with any antiretroviral agent.Any previous exposure to an HIV integrase inhibitor other than GSK1349572 will be exclusionary. 5.Subject has no evidence of genotypic or phenotypic viral resistance to any antiretroviral drug indicative of primary transmitted resistance in screening genotype or phenotype or historical resistance test result 6.Able

BACKGROUND:

Abacavir and tenofovir alafenamide offer reduced bone toxicity compared with tenofovir disoproxil fumarate. We aimed to compare safety and efficacy of tenofovir alafenamide plus emtricitabine with that of abacavir plus lamivudine.

METHODS:

In this randomised, double-blind, active-controlled, non-inferiority phase 3 trial, HIV-1-positive adults (≥18 years) were screened at 79 sites in 11 countries in North America and Europe. Eligible participants were virologically suppressed (HIV-1 RNA <50 copies per mL) and on a stable three-drug regimen containing abacavir plus lamivudine. Participants were randomly assigned (1:1) by a computer-generated allocation sequence (block size 4) to switch to fixed-dose tablets of tenofovir alafenamide (10 mg or 25 mg) plus emtricitabine (200 mg) or remain on abacavir (600 mg) plus lamivudine (300 mg), with matching placebo, while continuing to take the third drug. Randomisation was stratified by the third drug (boosted protease inhibitor vs other drug) at screening. Investigators, participants, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary endpoint was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 48 (assessed by snapshot algorithm), with a 10% non-inferiority margin. We analysed the primary endpoint in participants enrolled before May 23, 2016 (when target sample size was reached), and we analysed safety in all enrolled participants who received at least one dose of study drug (including patients enrolled after these dates). This study was registered with ClinicalTrials.gov, number NCT02469246.

FINDINGS:

Study enrolment began on June 29, 2015, and the cutoff enrolment date for the week 48 primary endpoint analysis was May 23, 2016. 501 participants were randomly assigned and treated. At week 48, virological suppression was maintained in 227 (90%) of 253 participants receiving tenofovir alafenamide plus emtricitabine compared with 230 (93%) of 248 receiving abacavir plus lamivudine (difference -3·0%, 95% CI -8·2 to 2·0), showing non-inferiority. Few participants discontinued treatment because of adverse events: 12 (4%) of 280 participants in the tenofovir alafenimide plus emtricitabine group and nine (3%) of 276 in the abacavir plus lamivudine group. Three participants had serious, treatment-related adverse events: one each with renal colic and neutropenia in the tenofovir alafenamide plus emtricitabine group, and one myocardial infarction in the abacavir plus lamivudine group. There were no treatment-related deaths.

INTERPRETATION:

Tenofovir alafenamide, in combination with emtricitabine and various third drugs, maintained high efficacy with a renal and bone safety profile similar to that of abacavir. In virologically suppressed patients, a regimen containing tenofovir alafenamide could be an alternative to those containing abacavir, without concern for new onset of renal or bone toxicities or hyperlipidaemia.

FUNDING:

Gilead Sciences Inc.