Switch to bictegravir/emtricitabine/tenofovir alafenamide from dolutegravir-based therapy.

OBJECTIVE: To evaluate the efficacy and safety of 96 weeks of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) treatment in participants switching from dolutegravir (DTG)-based therapy. DESIGN: Studies 1489 (NCT02607930) and 1490 (NCT02607956) were phase 3 randomized, double-blind, active-controlled, first-line therapy trials in people with HIV-1. After 144 weeks of DTG-based or B/F/TAF treatment, participants could enter a 96-week open-label extension (OLE) of B/F/TAF. METHODS: A pooled analysis evaluated viral suppression (HIV-1 RNA <50 copies/ml) and changes in CD4 + cell count at OLE Weeks 48 and 96, treatment-emergent resistance, safety, and tolerability after switch from a DTG-based regimen to B/F/TAF. Outcomes by prior treatment were summarized using descriptive statistics and compared by two-sided Wilcoxon rank sum test. RESULTS: At OLE Week 96, participants who switched to B/F/TAF ( N  = 519) maintained high levels of virologic suppression (99.5 and 99.1% in those switching from DTG/abacavir/lamivudine and DTG+F/TAF, respectively) and CD4 + cell count, with no treatment-emergent resistance to B/F/TAF. Twenty-one participants experienced drug-related adverse events after switching, with diarrhea, weight gain, and headache occurring most commonly. There were no cases of proximal renal tubulopathy, drug-related Grade 4 adverse events, or serious adverse events. Two participants discontinued B/F/TAF due to treatment-related adverse events. Participants who switched from DTG/abacavir/lamivudine experienced statistically significant greater weight gain than those who switched from DTG+F/TAF; however, median weight change from the blinded phase baseline to OLE Week 96 was numerically similar across treatment groups. CONCLUSION: This medium-term analysis demonstrates the safety and efficacy of switching to B/F/TAF from a DTG-containing regimen in people with HIV-1.

High efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide in people with suppressed HIV and preexisting M184V/I.

OBJECTIVE: We investigated the prevalence of preexisting M184V/I and associated risk factors among clinical trial participants with suppressed HIV and evaluated the impact of M184V/I on virologic response after switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). DESIGN: Participant data were pooled from six clinical trials investigating the safety and efficacy of switching to B/F/TAF in virologically suppressed people with HIV. METHODS: Preexisting drug resistance was assessed by historical genotypes and/or baseline proviral DNA genotyping. Virologic outcomes were determined by last available on-treatment HIV-1 RNA. Stepwise selection identified potential risk factors for M184V/I in a multivariate logistic regression model. RESULTS: Altogether, 2034 participants switched treatment regimens to B/F/TAF and had follow-up HIV-1 RNA data, and 1825 of these participants had baseline genotypic data available. Preexisting M184V/I was identified in 182 (10%), mostly by baseline proviral DNA genotype ( n  = 167). Most substitutions were M184V ( n  = 161) or M184V/I mixtures ( n  = 10). Other resistance substitutions were often detected in addition to M184V/I ( n  = 147). At last on-treatment visit, 98% (179/182) with preexisting M184V/I and 99% (2012/2034) of all B/F/TAF-treated participants had HIV-1 RNA less than 50 copies/ml, with no treatment-emergent resistance to B/F/TAF. Among adult participants, factors associated with preexisting M184V/I included other resistance, black race, Hispanic/Latinx ethnicity, lower baseline CD4 + cell count, advanced HIV disease, longer duration of antiretroviral therapy, and greater number of prior third agents. CONCLUSION: M184V/I was detected in 10% of virologically suppressed clinical trial participants at study baseline. Switching to B/F/TAF demonstrated durable efficacy in maintaining viral suppression, including in those with preexisting M184V/I.

Brief Report: Bictegravir/Emtricitabine/Tenofovir Alafenamide Efficacy in Participants With Preexisting Primary Integrase Inhibitor Resistance Through 48 Weeks of Phase 3 Clinical Trials.

BACKGROUND: Preexisting drug resistance limits the utility of HIV antiretroviral therapy. Studies have demonstrated safety and efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), including in patients with M184V/I substitutions. SETTING: We investigated virologic outcomes through 48 weeks of B/F/TAF treatment in individuals with preexisting primary integrase strand transfer inhibitor resistance (INSTI-R). METHODS: Preexisting INSTI-R was retrospectively evaluated from 7 B/F/TAF studies. INSTI-R was assessed by historical genotypes and/or baseline RNA or DNA sequencing. Viral loads were measured at all visits. RESULTS: Preexisting primary INSTI-R substitutions were detected in 20 of the 1907 participants (1.0%). The 20 participants were predominantly male (75%), were Black (65%), had HIV-1 subtype B (85%), and had baseline median CD4 counts of 594 cells/mm3 and median age of 52 years. Most of the participants (n = 19) were virologically suppressed at baseline and had one primary INSTI-R substitution, E92G, Y143C/H, S147G, Q148H/K/R, N155S, or R263K, +/-secondary substitutions. All suppressed participants maintained virologic suppression throughout 48 weeks without any viral blips. One treatment-naive participant had virus with Q148H+G140S that was fully sensitive to bictegravir but only partially to dolutegravir (phenotype <2.5-fold change and >4-fold change, respectively). With a baseline viral load of 30,000 copies/mL, this participant was virologically suppressed by week 4 and maintained <50 copies/mL through week 48. CONCLUSIONS: This small cohort with primary INSTI-R achieved and/or maintained virologic suppression through 48 weeks of B/F/TAF treatment. Consistent with the potent in vitro activity of bictegravir against most INSTI-R patterns, B/F/TAF may be a potential treatment option for patients with select preexisting INSTI-R, if confirmed by further studies.

Switching to Bictegravir/Emtricitabine/Tenofovir Alafenamide in Black Americans With HIV-1: A Randomized Phase 3b, Multicenter, Open-Label Study.

BACKGROUND: With the highest rates of HIV/AIDS in the United States, Black Americans are still underrepresented in HIV medical research. SETTING: BRAAVE (NCT03631732) is a randomized, phase 3b, multicenter, open-label US study. METHODS: Adults identifying as Black or African American and virologically suppressed on 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus third agent were randomized (2:1) to switch to open-label bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) once daily or stay on baseline regimen (SBR) for 24 weeks, after which SBR had delayed switch to B/F/TAF. Resistance to non-NRTIs, protease inhibitors, and/or NRTIs was permitted; integrase strand transfer inhibitor resistance was exclusionary. Primary endpoint was proportion of participants with HIV-1 RNA ≥50 copies/mL at week 24 (snapshot algorithm; noninferiority margin of 6%). RESULTS: Of 558 screened, 495 were randomized/treated (B/F/TAF n = 330; SBR n = 165). Overall, 32% were ciswomen, 2% transwomen, and 10% had an M184V/I mutation. At week 24, 0.6% on B/F/TAF vs 1.8% on SBR had HIV-1 RNA ≥50 copies/mL (difference -1.2%; 95% confidence interval -4.8% to 0.9%), demonstrating noninferiority of B/F/TAF vs SBR. Proportions with HIV-1 RNA <50 copies/mL at week 24 were 96% B/F/TAF and 95% SBR and remained high at week 48. No participant had treatment-emergent resistance to study drug. Treatments were well tolerated. Study drug-related adverse events, mostly grade 1, occurred in 10% of participants on B/F/TAF through week 48 and led to discontinuation in 9 participants through week 48. CONCLUSIONS: For Black Americans with HIV, switching to B/F/TAF was noninferior to continuing a variety of regimens, including those with pre-existing NRTI mutations.

Switching to Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) From Dolutegravir (DTG)+F/TAF or DTG+F/Tenofovir Disoproxil Fumarate (TDF) in the Presence of Pre-existing NRTI Resistance.

BACKGROUND: Study 4030 was a phase 3, randomized, double-blinded study of 565 HIV-1 RNA-suppressed participants switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) or dolutegravir (DTG)+F/TAF. Nucleoside reverse transcriptase inhibitor (NRTI), non-NRTI, and protease inhibitor resistance (-R) was allowed, but integrase strand transfer inhibitor-R was excluded. Here, we describe the detailed resistance analysis. METHODS: Historical plasma HIV-1 RNA genotypes and baseline proviral DNA genotypes were analyzed. Documented or investigator-suspected NRTI-R was grouped for stratification into 3 categories of level of resistance. Viral blips were assessed through week 48. Virologic failures had genotypic and phenotypic resistance analyses at week 48, confirmed failure, or last visit, if HIV-1 RNA did not resuppress to <50 copies/mL while on study drug. RESULTS: In total, 83% (470/565) of participants had baseline genotypic data available with NRTI-R detected in 24% (138/565), including 5% (30/565) with K65R/E/N or ≥3 thymidine analog mutations and 19% (108/565) with other NRTI-R mutations. M184V/I was present in 14% (81/565). Pre-existing integrase strand transfer inhibitor-R mutations were found in 4% (20/565) of participants. Primary non-NRTI-R and protease inhibitor-R mutations were present in 21% (118/565) and 7% (38/565) of participants. High rates of viral suppression were maintained in all groups through week 48; blips were observed in only 15 participants (2.7%). Three participants met criteria for resistance analysis (all in DTG+F/TAF arm); none developed treatment-emergent resistance to study drugs. CONCLUSIONS: Participants with baseline NRTI resistance, much of which was previously undocumented, maintained suppression 48 weeks after switching to B/F/TAF or DTG+F/TAF triple therapy. Blips and virologic failure were uncommon using either regimen, with no treatment-emergent resistance.

Switching to bictegravir/emtricitabine/tenofovir alafenamide maintained HIV-1 RNA suppression in participants with archived antiretroviral resistance including M184V/I.

OBJECTIVES: Studies 1878 and 1844 demonstrated non-inferior efficacy of switching suppressed HIV-1-infected adults to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) versus continuing boosted PI-based triple regimens or dolutegravir/abacavir/lamivudine (DTG/ABC/3TC). Here, detailed analyses of pre-existing resistance in the two BIC/FTC/TAF switch studies and efficacy at week 48 are described. METHODS: Pre-existing resistance was assessed from historical genotypes (documented resistance to study drugs was excluded) and by retrospective baseline proviral archive DNA genotyping from whole blood. Outcomes were based on HIV-1 RNA at week 48 with missing values imputed using the last on-treatment observation carried forward method. RESULTS: Cumulative pre-existing resistance data from historical and proviral genotypes were obtained for 95% (543/570) of participants who switched to BIC/FTC/TAF. Altogether, 40% (217/543) had one or more pre-existing primary resistance substitutions in protease, reverse transcriptase and/or integrase. Pre-switch NRTI resistance was detected in 16% (89/543) of BIC/FTC/TAF-treated participants, with M184V or M184I detected by proviral genotyping in 10% (54/543). At week 48, 98% (561/570) of all BIC/FTC/TAF-treated participants versus 98% (213/217) with pre-existing resistance and 96% (52/54) with archived M184V/I had HIV-1 RNA <50 copies/mL. No BIC/FTC/TAF-treated participants developed treatment-emergent resistance to study drugs. CONCLUSIONS: Pre-existing resistance substitutions, notably M184V/I, were unexpectedly common among suppressed participants who switched to BIC/FTC/TAF. High rates of virological suppression were maintained in the overall study population and in those with pre-existing resistance, including M184V/I, for up to 48 weeks of BIC/FTC/TAF treatment with no resistance development. These results indicate that BIC/FTC/TAF is an effective treatment option for suppressed patients, including those with evidence of archived NRTI resistance.

Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide might provide a safe and efficacious option for ongoing treatment of HIV-1 infection. FUNDING: Gilead Sciences.

Efficacy and safety of switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from boosted protease inhibitor-based regimens in virologically suppressed adults with HIV-1: 48 week results of a randomised, open-label, multicentre, phase 3, non-inferiority trial.

BACKGROUND: Switching from therapy based on a boosted protease inhibitor to bictegravir, emtricitabine, and tenofovir alafenamide could avoid drug interactions and unwanted side-effects in virologically suppressed adults with HIV-1 infection, while maintaining a high barrier to resistance and providing a simplified once-daily, single-tablet regimen. Here, we report 48 week results of a phase 3 study investigating this switch. METHODS: In this multicentre, randomised, open-label, active-controlled, non-inferiority, phase 3 trial, adults with HIV-1 infection were enrolled at 121 outpatient centres in ten countries. Eligible participants were aged 18 years or older, had an estimated glomerular filtration rate of 50 mL per min or higher, had been virologically suppressed (plasma HIV-1 RNA <50 copies per mL) for 6 months or more before screening, and were on a regimen consisting of boosted atazanavir or darunavir plus either emtricitabine and tenofovir disoproxil fumarate or abacavir and lamivudine. We randomly assigned participants (1:1), using a computer-generated randomisation sequence, to switch to co-formulated once-daily bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg), herein known as the bictegravir group, or to remain on their baseline boosted protease inhibitor regimen, herein known as the boosted protease inhibitor group, for 48 weeks. Randomisation was stratified by use of tenofovir disoproxil fumarate or abacavir at screening. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or higher at week 48 (by US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 4%. Efficacy and safety analyses included all participants who received at least one dose of study drug. This study is ongoing but not actively recruiting patients and is registered with ClinicalTrials.gov, number NCT02603107. FINDINGS: Between Dec 2, 2015, and July 15, 2016, 578 participants were randomly assigned and 577 were treated (290 in the bictegravir group and 287 in the boosted protease inhibitor group). At week 48, five participants (2%) in the bictegravir group and five (2%) in the boosted protease inhibitor group had plasma HIV-1 RNA of 50 copies per mL or higher (difference 0·0%, 95·002% CI -2·5 to 2·5), thus switching to the bictegravir regimen was non-inferior to continued boosted protease inhibitor therapy. The overall incidence and severity of adverse events was similar between groups, although headache occurred more frequently in the bictegravir group than in the boosted protease inhibitor group. 233 (80%) participants in the bictegravir group and 226 (79%) in the boosted protease inhibitor group had an adverse event. Only two (1%) participants in the bictegravir group and one (<1%) in the boosted protease inhibitor group discontinued treatment because of adverse events. 54 participants (19%) in the bictegravir group had drug-related adverse events compared with six (2%) in the protease inhibitor group. INTERPRETATION: Fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide might be a safe and efficacious alternative to continued boosted protease inhibitor therapy in adults with HIV-1 infection. FUNDING: Gilead Sciences.

Switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir DF from non-nucleoside reverse transcriptase inhibitor plus coformulated emtricitabine and tenofovir DF regimens: Week 96 results of STRATEGY-NNRTI.

BACKGROUND: HIV-1-infected, virologically suppressed adults wanting to simplify or change their non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens may benefit from switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF). OBJECTIVE: We examined differences in the proportion of participants with HIV-1 RNA < 50 copies/mL (Snapshot analysis), change in CD4 cell count, safety, and patient-reported outcomes in participants switching to E/C/F/TDF from an NNRTI + FTC/TDF (TVD) regimen. METHODS: STRATEGY-NNRTI was a 96-week, phase 3b, randomized, open-label, study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF in virologically suppressed individuals (HIV-1 RNA < 50 copies/mL) on an NNRTI + TVD regimen. Participants were randomized to switch or remain on their NNRTI-based regimen (no-switch). RESULTS: At Week 96, 87% (251/290) of switch and 80% (115/143) of no-switch participants maintained HIV-1 RNA < 50 copies/mL (difference 6.1%; 95% CI -1.3 to 14.2%; p = 0.12) according to the FDA-defined snapshot algorithm. Both groups had similar proportions of subjects with virologic failure (2.8% switch, 1.4% no-switch). Discontinuations resulting from adverse events were infrequent (3% [9/291] switch, 2% [3/143] no-switch). Three switch participants (1%) discontinued due to renal adverse events (2 of the 3 before Week 48). Switch participants reported significant improvements in neuropsychiatric symptoms by as early as Week 4, and which were maintained through Week 96. CONCLUSIONS: E/C/F/TDF is safe and effective and reduces NNRTI-associated neuropsychiatric symptoms for virologically suppressed HIV-positive adults switching from an NNRTI plus FTC/TDF-based regimen.

Simplification to single-tablet regimen of elvitegravir, cobicistat, emtricitabine, tenofovir DF from multi-tablet ritonavir-boosted protease inhibitor plus coformulated emtricitabine and tenofovir DF regimens: week 96 results of STRATEGY-PI.

BACKGROUND: Antiretroviral therapy (ART) simplification to a single-tablet regimen can benefit HIV-1-infected, virologically suppressed, individuals on ART composed of multiple pills. OBJECTIVE: We assessed long-term efficacy and safety of switching to co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (E/C/F/TDF) from multi-tablet ritonavir-boosted protease inhibitor (PI + RTV) plus F/TDF (TVD) regimens. METHODS: STRATEGY-PI was a 96-week, phase 3b, randomized (2:1), open-label, non-inferiority study examining the efficacy, safety, and tolerability of switching to E/C/F/TDF from PI + RTV + TVD regimens in virologically suppressed individuals (HIV-1 RNA <50 copies/mL). Participants were randomized to switch to E/C/F/TDF (switch group) or to continue their PI + RTV + TVD regimens (no-switch group). Eligibility criteria included no resistance to F/TDF or history of virologic failure, and estimated creatinine clearance ≥70 mL/min. RESULTS: At week 96, 87% (252/290) of switch and 70% (97/139) of no-switch participants maintained HIV-1 RNA <50 copies/mL (difference: 17%, 95% CI 8.7-26.0%, p < 0.001). Superiority of the switch to E/C/F/TDF vs. no-switch was due to a smaller proportion of both virologic failures (switch, 1% [3/290]; no-switch, 6% [8/139]) and discontinuations for non-virologic reasons (switch, 11% [31/290]; no-switch, 24% [33/139]). No treatment-emergent resistance was observed in switch subjects with virologic failure. Discontinuation rates from adverse events were 3% in both groups (9/293, switch; 4/140, no-switch). Switching from PI + RTV + TVD to E/C/F/TDF was associated with significant improvements in patient-reported outcomes related to gastrointestinal symptoms (nausea and bloating). CONCLUSION: E/C/F/TDF is a safe, effective long-term alternative to multi-tablet PI + RTV + TVD-based regimens in virologically suppressed, HIV-1-infected adults, and improves patient-reported gastrointestinal symptoms.

Clinical Outcomes of Virologically-Suppressed Patients with Pre-existing HIV-1 Drug Resistance Mutations Switching to Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in the SPIRIT Study.

OBJECTIVES: Antiretroviral regimen switching may be considered for HIV-1-infected, virologically-suppressed patients to enable treatment simplification or improve tolerability, but should be guided by knowledge of pre-existing drug resistance. The current study examined the impact of pre-existing drug resistance mutations on virologic outcomes among virologically-suppressed patients switching to Rilpivirine (RPV)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). METHODS: SPIRIT was a phase 3b study evaluating the safety and efficacy of switching to RPV/FTC/TDF in virologically-suppressed HIV-1-infected patients. Pre-existing drug resistance at baseline was determined by proviral DNA genotyping for 51 RPV/FTC/TDF-treated patients with known mutations by historical RNA genotype and matched controls and compared with clinical outcome at Week 48. RESULTS: Drug resistance mutations in protease or reverse transcriptase were detected in 62.7% of patients by historical RNA genotype and in 68.6% by proviral DNA genotyping at baseline. Proviral DNA sequencing detected 89% of occurrences of NRTI and NNRTI resistance-associated mutations reported by historical genotype. Mutations potentially affecting RPV activity, including E138A/G/K/Q, Y181C, and H221Y, were detected in isolates from 11 patients by one or both assays. None of the patients with single mutants had virologic failure through Week 48. One patient with pre-existing Y181Y/C and M184I by proviral DNA genotyping experienced virologic failure. Nineteen patients with K103N present by historical genotype were confirmed by proviral DNA sequencing and 18/19 remained virologically-suppressed. DISCUSSION: Virologic success rates were high among virologically-suppressed patients with pre-existing NRTI and NNRTI resistance-associated mutations who switched to RPV/FTC/TDF in the SPIRIT study. While plasma RNA genotyping remains preferred, proviral DNA genotyping may provide additional value in virologically-suppressed patients for whom historical resistance data are unavailable.

Drug Susceptibility and Viral Fitness of HIV-1 with Integrase Strand Transfer Inhibitor Resistance Substitution Q148R or N155H in Combination with Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Resistance Substitutions.

In clinical trials of coformulated elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF), emergent drug resistance predominantly involved the FTC resistance substitution M184V/I in reverse transcriptase (RT), with or without the tenofovir (TFV) resistance substitution K65R, accompanied by a primary EVG resistance substitution (E92Q, N155H, or Q148R) in integrase (IN). We previously reported that the RT-K65R, RT-M184V, and IN-E92Q substitutions lacked cross-class phenotypic resistance and replicative fitness compensation. As a follow-up, the in vitro characteristics of mutant HIV-1 containing RT-K65R and/or RT-M184V with IN-Q148R or IN-N155H were also evaluated, alone and in combination, for potential interactions. Single mutants displayed reduced susceptibility to their corresponding inhibitor classes, with no cross-class resistance. Viruses with IN-Q148R or IN-N155H exhibited reduced susceptibility to EVG (137- and 40-fold, respectively) that was not affected by the addition of RT-M184V or RT-K65R/M184V. All viruses containing RT-M184V were resistant to FTC (>1,000-fold). Mutants with RT-K65R had reduced susceptibility to TFV (3.3- to 3.6-fold). Without drugs present, the viral fitness of RT and/or IN mutants was diminished relative to that of the wild type in the following genotypic order: wild type > RT-M184V ≥ IN-N155H ≈ IN-Q148R ≥ RT-M184V + IN-N155H ≥ RT-M184V + IN-Q148R ≥ RT-K65R/M184V + IN-Q148R ≈ RT-K65R/M184V + IN-N155H. In the presence of drug concentrations approaching physiologic levels, drug resistance counteracted replication defects, allowing single mutants to outcompete the wild type with one drug present and double mutants to outcompete single mutants with two drugs present. These results suggest that during antiretroviral treatment with multiple drugs, the development of viruses with combinations of resistance substitutions may be favored despite diminished viral fitness.

Reduced viral fitness and lack of cross-class resistance with integrase strand transfer inhibitor and nucleoside reverse transcriptase inhibitor resistance mutations.

The most common pattern of emergent resistance in the phase III clinical trials of coformulated elvitegravir (EVG)-cobicistat (COBI)-emtricitabine (FTC)-tenofovir disoproxil fumarate (TDF) was the EVG resistance substitution E92Q in integrase (IN) with the FTC resistance substitution M184V in reverse transcriptase (RT), with or without the tenofovir (TFV) resistance substitution K65R. In this study, the effect of these IN and RT substitutions alone and in combination in the same genome on susceptibility to antiretroviral inhibitors and viral replication fitness was characterized. Single resistance substitutions (E92Q in IN [IN-E92Q], M184V in RT [RT-M184V], and K65R in RT [RT-K65R]) specifically affected susceptibility to the corresponding inhibitor classes, with no cross-class resistance observed. The IN-E92Q mutant displayed reduced susceptibility to EVG (50-fold), which was not impacted by the addition of RT-M184V or RT-K65R/M184V. Viruses containing RT-M184V had high-level resistance to FTC (>1,000-fold) that was not affected by the addition of IN-E92Q or RT-K65R. During pairwise growth competitions, each substitution contributed to decreased viral fitness, with the RT-K65R/M184V + IN-E92Q triple mutant being the least fit in the absence of drug. In the presence of drug concentrations approaching physiologic levels, however, drug resistance offset the replication defects, resulting in single mutants outcompeting the wild type with one drug present, and double and triple mutants outcompeting single mutants with two drugs present. Taken together, these results suggest that the reduced replication fitness and phenotypic resistance associated with RT and IN resistance substitutions are independent and additive. In the presence of multiple drugs, viral growth is favored for viruses with multiple substitutions, despite the presence of fitness defects.

Baseline antiretroviral resistance mutations and treatment-emergent resistance in HIV-1 RNA-suppressed patients switching to EVG/COBI/FTC/TDF or continuing on their PI-, NNRTI-, or RAL-based regimen.

BACKGROUND: Stably suppressed HIV-1-infected patients that switched to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) from regimens containing FTC/TDF plus a ritonavir-boosted protease inhibitor (PI + RTV), nonnucleoside reverse transcriptase inhibitor (NNRTI), or raltegravir in phase 3 studies STRATEGY-PI, STRATEGY-NNRTI, and GS-US-236-0123 maintained high rates of virologic suppression through 48 weeks. In this article, resistance analyses for these studies are described. METHODS: HIV-1 historical genotypes obtained before therapy initiation were analyzed for preexisting/transmitted resistance (-R) in protease and reverse transcriptase (RT) and subtype. Patients with resistance to FTC/TDF were excluded. Viral isolates with HIV-1 RNA ≥400 copies per milliliter at confirmed virologic failure, discontinuation, or week 48 were analyzed for protease, RT, and integrase genotype and phenotype. RESULTS: Historical genotypes from 626/628 subjects that switched to EVG/COBI/FTC/TDF indicated 25% had ≥1 primary resistance mutation in protease and/or RT. NNRTI-R was identified in 15%, NRTI-R in 8.3%, and PI-R in 3.7% of subjects. Week 48 virologic success rates (HIV-1 RNA <50 copies per milliliter) were 94% for all patients treated with EVG/COBI/FTC/TDF, 94% with preexisting resistance, 93% with subtype B, and 96% with non-B subtypes. Altogether, 2 subjects qualified for postbaseline resistance analyses. Neither had emergent resistance, and both resuppressed to HIV-1 RNA <50 copies per milliliter with no change in therapy. CONCLUSIONS: Switching antiretroviral regimens to EVG/COBI/FTC/TDF in HIV-1 RNA-suppressed FTC/TDF-sensitive patients resulted in maintained virologic suppression through 48 weeks. Similar virologic success rates were achieved irrespective of the presence of preexisting resistance mutations or subtype. The lack of emergent resistance through 48 weeks supports utility of EVG/COBI/FTC/TDF for treatment-experienced patients seeking regimen modification or simplification.

Long-term efficacy and safety of tenofovir disoproxil fumarate in HIV-1-infected adolescents failing antiretroviral therapy: the final results of study GS-US-104-0321.

BACKGROUND: Reports of long-term tenofovir disoproxil fumarate (TDF) treatment in HIV-infected adolescents are limited. We present final results from the open-label (OL) TDF extension following the randomized, placebo (PBO)-controlled, double-blind phase of GS-US-104-0321 (Study 321). METHODS: HIV-infected 12- to 17-year-olds treated with TDF 300 mg or PBO with an optimized background regimen (OBR) for 24-48 weeks subsequently received OL TDF plus OBR in a single arm study extension. HIV-1 RNA and safety, including bone mineral density (BMD), was assessed in all TDF recipients. RESULTS: Eighty-one subjects received TDF (median duration 96 weeks). No subject died or discontinued OL TDF for safety/tolerability. At week 144, proportions with HIV-1 RNA <50 copies/mL were 30.4% (7 of 23 subjects with baseline HIV-1 RNA >1000 c/mL initially randomized to TDF), 41.7% (5 of 12 subjects with HIV-1 RNA <1000 c/mL who switched PBO to TDF) and 0% (0 of 2 subjects failed randomized PBO plus OBR with HIV-1 RNA >1000 c/mL and switched PBO to TDF). Viral resistance to TDF occurred in 1 subject. At week 144, median decrease in estimated glomerular filtration rate was 38.1 mL/min/1.73 m (n = 25). Increases in median spine (+12.70%, n = 26) and total body less head BMD (+4.32%, n = 26) and height-age adjusted Z-scores (n = 21; +0.457 for spine, +0.152 for total body less head) were observed at week 144. Five of 81 subjects (6%) had persistent >4% BMD decreases from baseline. CONCLUSIONS: Some subjects had virologic responses to TDF plus OBR, and TDF resistance was rare. TDF was well tolerated and can be considered for treatment of HIV-infected adolescents.

Impact of primary elvitegravir resistance-associated mutations in HIV-1 integrase on drug susceptibility and viral replication fitness.

Elvitegravir (EVG) is an effective HIV-1 integrase (IN) strand transfer inhibitor (INSTI) in advanced clinical development. Primary INSTI resistance-associated mutations (RAMs) at six IN positions have been identified in HIV-1-infected patients failing EVG-containing regimens in clinical studies: T66I/A/K, E92Q/G, T97A, S147G, Q148R/H/K, and N155H. In this study, the effect of these primary IN mutations, alone and in combination, on susceptibility to the INSTIs EVG, raltegravir (RAL), and dolutegravir (DTG); IN enzyme activities; and viral replication fitness was characterized. Recombinant viruses containing the six most common mutations exhibited a range of reduced EVG susceptibility: 92-fold for Q148R, 30-fold for N155H, 26-fold for E92Q, 10-fold for T66I, 4-fold for S147G, and 2-fold for T97A. Less commonly observed primary IN mutations also showed a range of reduced EVG susceptibilities: 40- to 94-fold for T66K and Q148K and 5- to 10-fold for T66A, E92G, and Q148H. Some primary IN mutations exhibited broad cross-resistance between EVG and RAL (T66K, E92Q, Q148R/H/K, and N155H), while others retained susceptibility to RAL (T66I/A, E92G, T97A, and S147G). Dual combinations of primary IN mutations further reduced INSTI susceptibility, replication capacity, and viral fitness relative to either mutation alone. Susceptibility to DTG was retained by single primary IN mutations but reduced by dual mutation combinations with Q148R. Primary EVG RAMs also diminished IN enzymatic activities, concordant with their structural proximity to the active site. Greater reductions in viral fitness of dual mutation combinations may explain why some primary INSTI RAMs do not readily coexist on the same HIV-1 genome but rather establish independent pathways of resistance to EVG.

HIV-2 antiviral potency and selection of drug resistance mutations by the integrase strand transfer inhibitor elvitegravir and NRTIs emtricitabine and tenofovir in vitro.

BACKGROUND: HIV-2 is susceptible to only a subset of approved antiretroviral drugs. A single tablet regimen containing the integrase strand transfer inhibitor elvitegravir (EVG) boosted by cobicistat plus the nucleoside reverse transcriptase (RT) inhibitors emtricitabine (FTC) and tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) has potent activity against HIV-1 and may have utility against HIV-2. METHODS: HIV-2 susceptibility to EVG, FTC, and tenofovir (TFV) and selection of resistance mutations were characterized in vitro using dose escalation and breakthrough methods. HIV-2 containing the selected mutations was constructed and phenotyped in vitro. RESULTS: The inhibitors EVG, FTC, and TFV had potent activity against HIV-2 with EC50 values of 1.6 nM, 0.99 µM, and 3.5 µM, respectively. In resistance selections, EVG selected E92G/Q and S147N in integrase, FTC selected M184V/I in RT, and TFV selected K65R and Y115F in RT. HIV-2 site-directed mutant (SDM) viruses with E92G and E92Q integrase mutations showed 3.7- and 16-fold reduced susceptibilities to EVG, respectively. The RT M184I and M184V SDM viruses were both highly resistant to FTC (34- and >1000-fold, respectively). The RT K65R SDM virus had 2.2- and 9.1-fold reduced susceptibilities to TFV and FTC, respectively, and the addition of Y115F to K65R further decreased susceptibility to both drugs. CONCLUSIONS: The antiretrovirals EVG, FTC, and TFV showed potent inhibition of HIV-1 and HIV-2 in vitro and selected analogous mutations in HIV-2 and HIV-1. This suggests that the single tablet regimen of EVG/COBI/FTC/TDF should be studied as a treatment option for HIV-2 infection and would likely select for known resistance mutations.

In vitro resistance selections using elvitegravir, raltegravir, and two metabolites of elvitegravir M1 and M4.

Elvitegravir is a strand transfer inhibitor of HIV-1 integrase that is currently undergoing phase 3 clinical testing. The two predominant metabolites of elvitegravir, M1 and M4 (elvitegravir hydroxide and elvitegravir glucuronide), have been shown to inhibit HIV-1 integrase in vitro. While they are markedly less potent than elvitegravir and present only at low levels in plasma clinically, we investigated their potential to select for elvitegravir resistance in vitro. Resistance selection experiments using metabolites M1 and M4 led to the development of the previously reported elvitegravir integrase resistance mutations H51Y, T66A, E92G, and S147G, as well as a novel S153F substitution. Additional resistance selection experiments using elvitegravir led to the development of previously reported integrase inhibitor resistance mutations (T66I, F121Y, and S153Y) as well as a novel R263K integrase mutation. Phenotypic analyses of site-directed mutants with these mutations demonstrated broad cross-resistance between elvitegravir and its M1 and M4 metabolites with more limited cross-resistance to the integrase inhibitor raltegravir. Overall, our in vitro studies demonstrate that the resistance profile of the M1 and M4 metabolites of elvitegravir overlaps with that of the parent molecule elvitegravir; as such, their presence at low levels is not considered clinically relevant.