Efficacy and safety of the novel capsid inhibitor lenacapavir to treat multidrug-resistant HIV: week 52 results of a phase 2/3 trial.

BACKGROUND: Lenacapavir, a first-in-class HIV-1 capsid inhibitor, is in development as a long-acting agent for treating and preventing HIV-1. We aimed to evaluate the efficacy and safety of lenacapavir with an optimised background regimen in adults living with multidrug-resistant HIV-1 up to 52 weeks. METHODS: This ongoing, international, phase 2/3 trial at 42 sites included adults living with multidrug-resistant HIV-1. In cohort 1, 36 participants were randomly assigned (2:1) to add oral lenacapavir (600 mg, days 1 and 2; 300 mg, day 8) or placebo to an existing failing regimen. At day 15, those on oral lenacapavir received subcutaneous lenacapavir 927 mg every 26 weeks; those on placebo started lenacapavir (2-week oral lead-in then subcutaneous). Cohort 1 started an optimised background regimen on day 15. In cohort 2 (non-randomised), 36 participants started an optimised background regimen concurrent with lenacapavir (oral to subcutaneous). Here we report the secondary endpoints of plasma HIV-1 RNA of less than 50 copies per mL or less than 200 copies per mL at week 52 (US Food and Drug Administration snapshot algorithm) in cohort 1 along with results for cohorts 1 and 2 combined. This trial is registered with ClinicalTrials.gov, NCT04150068, and clinicaltrialregister.eu, EudraCT 2019-003814-16 and is ongoing. FINDINGS: Of 72 participants, 46 (64%) had CD4 counts of less than 200 cells per µL and 38 (53%) had no more than one fully active antiretroviral drug at baseline. In cohort 1, 30 of 36 participants (83%, 95% CI 67-94) had less than 50 HIV-1 RNA copies per mL and 31 of 36 participants (86%, 71-95) had less than 200 HIV RNA copies per mL, at week 52. In all, nine participants (four in cohort 1, five in cohort 2) had emergent lenacapavir resistance; four resuppressed (HIV-1 RNA <50 copies per mL) while maintaining lenacapavir use. One participant discontinued study drug owing to injection site reaction. INTERPRETATION: In participants with multidrug-resistant HIV-1, subcutaneous lenacapavir in combination with an optimised background regimen resulted in a high rate of virological suppression up to 52 weeks. FUNDING: Gilead Sciences.

Lenacapavir administered every 26 weeks or daily in combination with oral daily antiretroviral therapy for initial treatment of HIV: a randomised, open-label, active-controlled, phase 2 trial.

BACKGROUND: Antiretroviral agents with novel mechanisms and dosing intervals could expand treatment options for people with HIV. Lenacapavir, an inhibitor of capsid protein that makes use of a unique mechanism, can be administered orally or subcutaneously. We sought to explore the efficacy of lenacapavir in various combination regimens as initial and maintenance therapy for HIV. METHODS: In a phase 2, randomised, open-label, ongoing study at 41 investigational sites in the USA and Dominican Republic, we randomly assigned adults with HIV who had not previously received antiretrovirals to four groups (2:2:2:1). Randomisation was stratified by plasma HIV-1 RNA load (≤100 000 or >100 000 copies per mL) at screening. Groups 1 and 2 both received lenacapavir (927 mg) subcutaneously every 26 weeks (after 2 weeks of oral loading [600 mg on days 1 and 2, followed by 300 mg on day 8]) with oral daily emtricitabine (200 mg) and tenofovir alafenamide (25 mg) for 28 weeks followed by subcutaneous lenacapavir (927 mg) plus oral daily tenofovir alafenamide (25 mg, group 1) or bictegravir (75 mg, group 2). Group 3 received oral daily lenacapavir (600 mg on days 1 and 2, followed by 50 mg daily) with emtricitabine (200 mg) and tenofovir alafenamide (25 mg). Group 4 received oral daily bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants and investigators were not masked to group assignment. The primary endpoint was the percentage of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 54, analysed in the full analysis set (all randomly assigned participants who received at least one dose of study drug) using only on-treatment data. The safety outcome measures were incidences of treatment-emergent adverse events and graded laboratory abnormalities, analysed in the full analysis set. This study is registered at ClinicalTrials.gov, NCT04143594. FINDINGS: Between Nov 22, 2019, and Aug 27, 2020, 249 people with HIV were screened, 183 participants were randomly assigned and 182 received a dose of antiretroviral drugs (52 in group 1, 53 in group 2, 52 in group 3, and 25 in group 4). 22 participants did not complete the full study course (five in group 1, 12 in group 2, four in group 3, and one in group 4). At week 54, virological suppression was 90% (47 of 52 patients) for group 1 (difference vs group 4: -2·6%, 95% CI -18·4 to 13·2), 85% (45 of 53) for group 2 (-7·1%, -23·4 to 9·3), 85% (44 of 52) for group 3 (-7·2%, -23·5 to 9·1), and 92% (23 of 25) for group 4. The most frequent non-injection-site adverse events with lenacapavir (subcutaneous or oral) were headache (13%, 21 of 157) and nausea (13%, 21 of 157). The most common lenacapavir-related injection-site reactions were erythema (27%, 28 of 105), swelling (23%, 24 of 105), and pain (19%, 20 of 105), which were generally mild or moderate. No serious adverse event related to study treatment occurred. Three participants discontinued subcutaneous lenacapavir because of grade 1 injection-site reactions (two for induration and one for erythema or swelling). INTERPRETATION: Lenacapavir warrants further investigation as a potential antiretroviral used orally and as injection in combination with other antiretroviral drugs. FUNDING: Gilead Sciences.

Indirect Treatment Comparisons of Lenacapavir Plus Optimized Background Regimen Versus Other Treatments for Multidrug-Resistant Human Immunodeficiency Virus.

BACKGROUND/AIMS: Heavily treatment-experienced (HTE) people with human immunodeficiency virus (HIV) (PWH) may not achieve virologic suppression (VS) with combination antiretroviral therapy due to multidrug resistance (MDR), intolerance, and safety concerns. These PWH often receive highly individualized treatment regimens, but these regimens may not enable PWH to achieve VS, thereby halting disease progression. Novel medications are required for treating individuals with MDR HIV. Lenacapavir (LEN), a first-in-class HIV capsid inhibitor, is under investigation for the treatment of HTE individuals with MDR HIV in the phase 2/3 CAPELLA study. This study aimed to compare LEN plus optimized background regimen (OBR) with fostemsavir (FTR) + OBR, ibalizumab (IBA) + OBR, and OBR alone in terms of VS, CD4 cell count change from baseline, immunologic recovery, and discontinuation due to adverse events, using indirect treatment comparisons. METHODS: A systematic review identified clinical evidence on HIV-1 treatments in HTE PWH. A feasibility assessment evaluated the identified studies for indirect treatment comparison analyses based on population characteristics, interventions, comparators, and outcomes of interest. Unanchored simulated treatment comparisons of LEN + OBR versus comparators were conducted. RESULTS: LEN + OBR had 6.57 times higher odds of VS at weeks 24 to 28 than FTR + OBR (95% confidence interval [CI] 1.34-32.28), 8.93 times higher odds of VS than IBA + OBR (95% CI 2.07-38.46), and 12.74 times higher odds of VS than OBR alone (95% CI 1.70-95.37). Change from baseline in CD4 cell count was similar across LEN + OBR, FTR + OBR, and IBA + OBR. CONCLUSION: LEN + OBR has statistically significantly greater odds of VS at weeks 24 to 28 than its comparators and represents a novel treatment for people with MDR HIV.

Resistance Analyses in Highly Treatment-Experienced People With Human Immunodeficiency Virus (HIV) Treated With the Novel Capsid HIV Inhibitor Lenacapavir.

BACKGROUND: Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function in clinical development for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) harboring multidrug resistance (MDR) in combination with an optimized background regimen (OBR). Here we describe resistance analyses conducted in the pivotal phase 2/3 CAPELLA study. METHODS: CAPELLA enrolled viremic HTE PWH with resistance to ≥3 of 4 of the main antiretroviral (ARV) classes and resistance to ≥2 ARV drugs per class. Baseline resistance analyses used commercial assays (HIV-1 protease, reverse transcriptase, integrase genotypic/phenotypic tests). Postbaseline resistance was evaluated in participants experiencing virologic failure. RESULTS: At baseline, 46% of participants had resistance to the 4 main ARV drug classes, with one-third of participants having exhausted all drugs from ≥3 of the 4 main ARV classes. Treatment with LEN + OBR for 26 weeks led to viral suppression in 81% of participants. Postbaseline resistance mutations to lenacapavir occurred in 8 participants (6 with M66I, 1 with K70H, 1 with Q67H + K70R) who were receiving unintended functional LEN monotherapy at the time of resistance selection. CONCLUSIONS: LEN added to OBR led to high efficacy in this HTE patient population with MDR but could select for resistance when used unintentionally as functional monotherapy.

Capsid Inhibition with Lenacapavir in Multidrug-Resistant HIV-1 Infection.

BACKGROUND: Patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection have limited treatment options. Lenacapavir is a first-in-class capsid inhibitor that showed substantial antiviral activity in a phase 1b study. METHODS: In this phase 3 trial, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to the change in the plasma HIV-1 RNA level between the screening and cohort-selection visits. In cohort 1, patients were first randomly assigned in a 2:1 ratio to receive oral lenacapavir or placebo in addition to their failing therapy for 14 days; during the maintenance period, starting on day 15, patients in the lenacapavir group received subcutaneous lenacapavir once every 6 months, and those in the placebo group received oral lenacapavir, followed by subcutaneous lenacapavir; both groups also received optimized background therapy. In cohort 2, all the patients received open-label oral lenacapavir with optimized background therapy on days 1 through 14; subcutaneous lenacapavir was then administered once every 6 months starting on day 15. The primary end point was the percentage of patients in cohort 1 who had a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15; a key secondary end point was a viral load of less than 50 copies per milliliter at week 26. RESULTS: A total of 72 patients were enrolled, with 36 in each cohort. In cohort 1, a decrease of at least 0.5 log10 copies per milliliter in the viral load by day 15 was observed in 21 of 24 patients (88%) in the lenacapavir group and in 2 of 12 patients (17%) in the placebo group (absolute difference, 71 percentage points; 95% confidence interval, 35 to 90). At week 26, a viral load of less than 50 copies per milliliter was reported in 81% of the patients in cohort 1 and in 83% in cohort 2, with a least-squares mean increase in the CD4+ count of 75 and 104 cells per cubic millimeter, respectively. No serious adverse events related to lenacapavir were identified. In both cohorts, lenacapavir-related capsid substitutions that were associated with decreased susceptibility developed in 8 patients during the maintenance period (6 with M66I substitutions). CONCLUSIONS: In patients with multidrug-resistant HIV-1 infection, those who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo. (Funded by Gilead Sciences; CAPELLA ClinicalTrials.gov number, NCT04150068.).

Lenacapavir: a first-in-class HIV-1 capsid inhibitor.

PURPOSE OF REVIEW: This review summarizes available data for lenacapavir, an investigational first-in-class agent that disrupts functioning of HIV capsid protein across multiple steps in the viral life cycle. RECENT FINDINGS: Lenacapavir demonstrated picomolar potency in vitro with no cross resistance to existing antiretroviral classes and potent antiviral activity in persons with HIV-1. In persons with HIV-1, there was no preexisting resistance to lenacapavir regardless of treatment history. Lenacapavir can be administered orally either daily or weekly and subcutaneously up to every 6 months. In heavily treatment-experienced persons with multidrug-resistant HIV-1 and in treatment-naive persons with HIV-1, lenacapavir in combination with other antiretroviral agents led to high rates of virologic suppression and was well tolerated. SUMMARY: Ongoing studies are evaluating long-acting dosing of lenacapavir for treating HIV-1 in combination with other antiretrovirals and preventing HIV-1 as a single agent.

Clinical targeting of HIV capsid protein with a long-acting small molecule.

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.

Tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed HIV-1-infected adults: a randomised, double-blind, active-controlled, non-inferiority phase 3 trial.

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.

Efficacy and safety of emtricitabine/tenofovir alafenamide (FTC/TAF) vs. emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as a backbone for treatment of HIV-1 infection in virologically suppressed adults: subgroup analysis by third agent of a randomized, double-blind, active-controlled phase 3 trial.

BACKGROUND: FTC/TAF was shown to be noninferior to FTC/TDF with advantages in markers of renal and bone safety. OBJECTIVE: To evaluate the efficacy and safety of switching to FTC/TAF from FTC/TDF by third agent (boosted protease inhibitor [PI] vs. unboosted third agent). METHODS: We conducted a 48-week subgroup analysis based on third agent from a randomized, double blind study in virologically suppressed adults on a FTC/TDF-containing regimen who switched to FTC/TAF vs. continued FTC/TDF while remaining on the same third agent. RESULTS: We randomized (1:1) 663 participants to either switch to FTC/TAF (N = 333) or continue FTC/TDF (N = 330), each with baseline third agent stratifying by class of third agent in the prior treatment regimen (boosted PI 46%, unboosted third agent 54%). At week 48, significant differences in renal biomarkers and bone mineral density were observed favoring FTC/TAF over FTC/TDF (p < 0.05 for all), with similar improvements in the FTC/TAF arm in those who received boosted PI vs. unboosted third agents. At week 48, virologic success rates were similar between treatment groups for those who received a boosted PI (FTC/TAF 92%, FTC/TDF 93%) and for those who received an unboosted third agent (97% vs. 93%). CONCLUSIONS: In virologically suppressed patients switching to FTC/TAF from FTC/TDF, high rates of virologic suppression were maintained, while renal and bone safety parameters improved, regardless of whether participants were receiving a boosted PI or an unboosted third agent. FTC/TAF offers safety advantages over FTC/TDF and can be an important option as an NRTI backbone given with a variety of third agents.

Brief Report: Long-Term (96-Week) Efficacy and Safety After Switching From Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in HIV-Infected, Virologically Suppressed Adults.

In a double-blind, phase 3 trial, 663 HIV-infected, virologically suppressed adults were randomized to switch to tenofovir alafenamide (TAF; n = 333) vs. remain on tenofovir disoproxil fumarate (TDF; n = 330), each coformulated with emtricitabine (FTC), while continuing their third agent (boosted protease inhibitor or unboosted third agent). At week 96, 88.6% on FTC/TAF and 89.1% on FTC/TDF had HIV-1 RNA <50 copies per milliliter [adjusted difference -0.5% (95% confidence interval: -5.3 to 4.4%)]. Proteinuria, albuminuria, proximal renal tubular function, and bone mineral density improved after switching to TAF- from TDF-containing regimens. These longer-term data support FTC/TAF as a safe, well-tolerated, and durable nucleotide reverse transcriptase inhibitor backbone.

Safety, efficacy, and pharmacokinetics of single-tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed, HIV-infected children: a single-arm, open-label trial.

BACKGROUND: No once-daily single-tablet regimen is available for HIV-infected children under 12 years. The single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a once-daily, integrase strand transfer inhibitor-based regimen approved in the USA and European Union for individuals aged 12 years or older. In this study, we aimed to assess the pharmacokinetics, safety, and efficacy of this regimen in virologically suppressed, HIV-infected children. METHODS: In this single-arm, open-label trial, we enrolled virologically suppressed, HIV-infected children from five hospital clinics in Uganda, the USA, and Thailand. Eligible participants were aged 6-11 years, weighed 25 kg or more, had virological suppression (<50 copies of HIV-1 RNA per mL) on a stable regimen for at least 6 months, CD4 count of more than 100 cells per µL, and no history of resistance to elvitegravir, emtricitabine, tenofovir alafenamide, or tenofovir. All participants received the available fixed-dose oral formulation of elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg once per day. Primary outcomes were the pharmacokinetic parameters area under the curve (AUC) concentration at the end of the dosing interval (AUCtau) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUClast) of tenofovir alafenamide, treatment-emergent serious adverse events, and all treatment-emergent adverse events. Results from baseline to week 24 are reported, unless specified otherwise. Primary and safety analyses included all enrolled participants who received one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01854775. FINDINGS: Between July 27 and Sept 28, 2015, we screened 26 children, of whom 23 were enrolled and initiated treatment. Median age was 10 years (IQR 8-11), median weight was 30·5 kg (IQR 27·5-33·0), and all participants had virological suppression. The mean AUCtau of elvitegravir was 33 814 ng × h/mL (coefficient of variation 58%), and the mean AUClast of tenofovir alafenamide was 333 ng × h/mL (45%). Exposures to elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide were higher, but modestly so, than those previously reported in adults. All 23 participants tolerated the regimen well; there were no serious adverse events or adverse event-related discontinuations. All participants maintained virological suppression (HIV-1 RNA <50 copies per mL) at week 24. CD4 count decreased by a median of -130 cells per µL (range -472 to 266) with little change in CD4 cell percentage (-2·1%, range -8·4 to 5·9). INTERPRETATION: The fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was efficacious and well tolerated in virologically suppressed, HIV-infected children. Although plasma exposure of all components was higher than has been reported in adults, there were no safety concerns and the overall bone and renal safety profile was favourable. These data support the use of this regimen in children at least 25 kg in weight. FUNDING: Gilead Sciences.

Safety, efficacy, and pharmacokinetics of a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial.

BACKGROUND: The prodrug tenofovir alafenamide is associated with improved renal and bone safety compared with tenofovir disoproxil fumarate. We aimed to assess safety, pharmacokinetics, and efficacy of this single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-infected, treatment-naive adolescents. METHODS: We did a 48 week, single-arm, open-label trial in treatment-naive adolescents with HIV from ten hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants were aged 12-18 years, with plasma HIV-1 RNA of at least 1000 copies per mL, a CD4 count of at least 100 cells per µL, and estimated glomerular filtration rate of at least 90 mL/min per 1·73 m2 by the Schwartz formula, bodyweight of at least 35 kg, and an HIV-1 genotype with sensitivity to elvitegravir, emtricitabine, and tenofovir. Participants received a single-tablet regimen once per day with food (administered by their parent or carer) containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide. Study visits to the clinic occurred at weeks 1, 2, 4, 8, 12, 16, 24, 32, 40, and 48. The coprimary endpoints were the pharmacokinetic parameters of area under the curve (AUC) concentration at the end of the dosing interval (AUCtau) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUClast) for tenofovir alafenamide, incidence of treatment-emergent serious adverse events, and all adverse events that emerged after treatment started (including data for bone mineral density). All participants who received one dose of study drug were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01854775. FINDINGS: Between May 22, 2013, and July 22, 2014, we enrolled 50 participants, and all 50 received the assigned treatment; 24 participated in the intensive pharmacokinetic assessment. 48 patients completed the 48 weeks of treatment; two discontinued (one withdrew consent at week 8, one was lost to follow-up at week 12). The regimen was well tolerated and no discontinuations related to adverse events occurred. The mean AUCtau for elvitegravir was 23 840 ng × h per mL (coefficient of variation [CV] 25·5%), and the mean AUClast for tenofovir alafenamide was 189 ng × h per mL (CV 55·8%). Four participants (8%) had a serious adverse event, one of which (intermediate uveitis) was deemed related to the study regimen but resolved without treatment interruption. The most common study drug-related adverse events were nausea (in ten participants), abdominal pain (in six), and vomiting (in five). Exposures to the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen were similar to those previously noted in adults. INTERPRETATION: The elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen was well tolerated and achieved component plasma pharmacokinetic exposures similar to those in adults. Although non-comparative with a small sample size, these data support the use of this regimen in HIV-infected adolescents and its timely assessment in younger children. FUNDING: Gilead Sciences.

Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial.

BACKGROUND: Emtricitabine with tenofovir disoproxil fumarate is a standard-of-care nucleoside reverse transcriptase inhibitor (NRTI) backbone. However, tenofovir disoproxil fumarate is associated with renal and bone toxic effects; the novel prodrug tenofovir alafenamide achieves 90% lower plasma tenofovir concentrations. We aimed to further assess safety and efficacy of fixed-dose combination emtricitabine with tenofovir alafenamide in patients switched from emtricitabine with tenofovir disoproxil fumarate. METHODS: In this controlled, double-blind, multicentre phase 3 study, we recruited virologically suppressed (HIV RNA <50 copies per mL) patients with HIV aged 18 years and older receiving regimens containing fixed-dose combination emtricitabine with tenofovir disoproxil fumartate from 78 sites in North America and Europe. Patients were randomly assigned (1:1) to switch to fixed-dose 200 mg emtricitabine with 10 mg or 25 mg tenofovir alafenamide or to continue 200 mg emtricitabine with 200 mg or 300 mg tenofovir disoproxil fumarate, while remaining on the same third agent for 96 weeks. Randomisation was done by a computer-generated allocation sequence and was stratified by the third agent (boosted protease inhibitor vs other agent). Investigators, patients, and study staff giving treatment, assessing outcomes, and collecting data were masked to treatment group. The primary outcome was the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the US Food and Drug Administration snapshot algorithm with a prespecified non-inferiority margin of 10%. The primary efficacy endpoint was analysed with the per-protocol analysis set, whereas the safety analysis included all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02121795. FINDINGS: We recruited patients between May 6, 2011, and Sept 11, 2014; 780 were screened and 668 were randomly assigned to receive either tenofovir alafenamide (n=333) or tenofovir disoproxil fumarate (n=330). Through week 48, virological success (HIV-1 RNA <50 copies per mL) was maintained in 314 (94%) of patients in the tenofovir alafenamide group compared with 307 (93%) in the tenofovir disoproxil fumarate group (difference 1·3%, 95% CI -2·5 to 5·1), showing non-inferiority of tenofovir alafenamide to tenofovir disproxil fumarate. Seven patients in the tenofovir alafenamide (2%) and three (1%) in the tenofovir disoproxil fumarate group discontinued due to adverse events. There were no cases of proximal renal tubulopathy in either group. INTERPRETATION: In patients switching from emtricitabine with tenofovir disoproxil fumarate to emtricitabine with tenofovir alafenamide, high rates of virological suppression were maintained. With its safety advantages, fixed-dose emtricitabine with tenofovir alafenamide has the potential to become an important NRTI backbone. FUNDING: Gilead Sciences.

A randomized, open-label study of the safety and efficacy of switching stavudine or zidovudine to tenofovir disoproxil fumarate in HIV-1-infected children with virologic suppression.

BACKGROUND: The safety and efficacy of tenofovir disoproxil fumarate (TDF) in HIV-1-infected children have not been evaluated in a randomized controlled trial. METHODS: Subjects (2 to <16 years) on a stavudine (d4T) or zidovudine (ZDV) containing regimen with HIV-1 RNA <400 copies/mL were randomized to either switch d4T or ZDV to TDF or continue d4T or ZDV. The primary endpoint was the proportion of subjects with HIV-1 RNA < 400 copies/mL at Week 48 with a prespecified noninferiority margin of 15%. After the 48-week randomized phase, eligible subjects were rolled over to an extension phase. RESULTS: Ninety-seven children (48 TDF vs. 49 d4T or ZDV) were randomized and treated. The percent of subjects who maintained virologic suppression in the TDF versus d4T or ZDV group at Week 24 were 93.8% versus 89.8% (difference 4.0%; 95% confidence interval:: -6.9% to 14.9%) and at Week 48 were 83.3% versus 91.8% (difference: -8.5%; 95% confidence interval: -21.5% to 4.5%; missing = failure, intent-to-treat analysis). No subjects discontinued study drug because of an adverse event in the 48 weeks of randomized phase. Four subjects discontinued TDF because of proximal renal tubulopathy in the extension phase. CONCLUSIONS: Our study did not demonstrate noninferiority of TDF versus d4T or ZDV at Week 48. Overall safety and tolerability of TDF in children were consistent with adults. TDF may be considered as an alternative to d4T or ZDV in HIV-infected children.

Week 144 resistance analysis of elvitegravir/cobicistat/emtricitabine/tenofovir DF versus efavirenz/emtricitabine/tenofovir DF in antiretroviral-naive patients.

BACKGROUND: Here, the baseline and emergent resistance to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF) versus efavirenz (EFV)/FTC/TDF in HIV-1-infected antiretroviral-naive adults through 144 weeks from the randomized, ongoing, Phase III study GS-US-236-0102 is described. METHODS: HIV-1 protease (PR) and reverse transcriptase (RT) were sequenced at screening; patients with HIV-1 resistant to EFV, FTC or TDF were excluded. Genotypic/phenotypic analyses were performed at virological failure confirmation and baseline for PR, RT and integrase (IN) for patients with virological failure and for patients with HIV-1 RNA≥400 copies/ml at weeks 48, 96, 144 or early study drug discontinuation. Retrospective, baseline, IN genotyping was conducted for EVG/COBI/FTC/TDF patients. RESULTS: In the EVG/COBI/FTC/TDF group through week 144, HIV-1 from 10 patients (2.9%; 10/348 treated patients) developed primary IN strand transfer inhibitor (n=9) and/or nucleoside RT inhibitor resistance substitutions (n=10). The emergence of resistance decreased over time with 8, 2 and 0 patients developing HIV-1 resistance through week 48, post-week 48-96 and post-week 96-144, respectively. Emergent substitutions were E92Q (n=7), N155H (n=3), Q148R (n=1) and T66I (n=1) in IN, and M184V/I (n=10) and K65R (n=4) in RT. All 10 isolates had reduced susceptibility to EVG, FTC or TDF. Virus with EVG phenotypic resistance had cross-resistance to raltegravir. In the EFV/FTC/TDF group, virus from 14 patients (4.0%; 14/352 treated patients; 4 during weeks 96-144) developed a resistance substitution to EFV (n=14; K103N: n=13), FTC (M184V/I: n=4) or TDF (K65R: n=3). CONCLUSIONS: Resistance development to EVG/COBI/FTC/TDF was infrequent through 144 weeks of therapy and decreased over time, consistent with durable efficacy.

Elvitegravir/cobicistat/emtricitabine/tenofovir DF in HIV-infected patients with mild-to-moderate renal impairment.

In HIV-1-infected treatment-naive patients with mild-to-moderate renal impairment [creatinine clearance (CrCl): 50-89 mL/min], elvitegravir/cobicistat/emtricitabine/tenofovir DF (STB, n = 33) achieved high rates of virologic success (78.8%; 95% confidence interval: 61.1% to 91.0%) and was well tolerated through week 48. Four patients discontinued study drug due to an adverse event and none due to proximal renal tubulopathy. As expected, decreases in CrCl were noted as early as week 2, after which they stabilized. The renal safety profile of STB in patients from this study is consistent with the long-term experience in a large number of patients with CrCl ≥70 mL/min.

Cobicistat-boosted protease inhibitors in HIV-infected patients with mild to moderate renal impairment.

BACKGROUND: Cobicistat (COBI) is a pharmacoenhancer that optimizes systemic exposures of protease inhibitors (PIs) such as atazanavir (ATV) and darunavir (DRV). OBJECTIVE: To evaluate the efficacy and safety of switching ritonavir (RTV) to COBI in patients with creatinine clearance (CrCl) 50 to 89 mL/min who are virologically suppressed on a stable regimen containing ritonavir (RTV)-boosted ATV or DRV. Other components of the regimen remained unchanged. METHODS: A phase 3, non-comparative, open-label clinical trial. RESULTS: Seventy-three patients were enrolled. At week 48, 82% maintained virologic suppression. No emergent resistance developed. Serious adverse events (AEs) occurred in 7%, and study drug discontinuation due to AEs occurred in 10% (7 patients). There were 2 renal discontinuations and no cases of proximal renal tubulopathy. Small reductions in CrCl (median [IQR]) were observed as early as week 2, after which they were nonprogressive through week 48 (-3.8 [-9 to 0.8]). Changes in CrCl by baseline CrCl (< 70 vs ≥ 70) were -1.1 [-6.5 to 6.3] versus -6.6 [-12.4 to -0.7], respectively. CONCLUSIONS: In HIV-1-infected patients with CrCl 50 to 89 mL/min switching from RTV to COBI, COBI-boosted PIs in combination with 2 nucleos(t)ide reverse transcriptase inhibitors were well-tolerated and effective in maintaining virologic suppression. The renal safety profile of COBI in this study was consistent with the long-term data in patients without renal impairment from the phase 3 studies of COBI-containing regimens.

Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults.

OBJECTIVE: To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of short-term monotherapy with tenofovir alafenamide (TAF), a next-generation tenofovir (TFV) prodrug. DESIGN: A phase 1b, randomized, partially blinded, active- and placebo-controlled, dose-ranging study. METHODS: Treatment-naive and experienced HIV-1-positive adults currently off antiretroviral therapy were randomized to receive 8, 25, or 40 mg TAF, 300 mg tenofovir disoproxil fumarate (TDF), or placebo, each once daily for 10 days. RESULTS: Thirty-eight subjects were enrolled. Baseline characteristics were similar across dose groups. Significant reductions in plasma HIV-1 RNA from baseline to day 11 were observed for all TAF dose groups compared with placebo (P < 0.01), with a median decrease of 1.08-1.73 log10 copies per milliliter, including a dose-response relationship for viral load decrease up to 25 mg. At steady state, 8, 25, and 40 mg TAF yielded mean TFV plasma exposures [area under the plasma concentration-time curve (AUCtau)] of 97%, 86%, and 79% lower, respectively, as compared with the TFV exposures observed with 300 mg TDF. For 25 and 40 mg TAF, the mean intracellular peripheral blood mononuclear cell tenofovir diphosphate AUCtau was ∼7-fold and ∼25-fold higher, relative to 300 mg TDF. CONCLUSIONS: Compared with 300 mg TDF, TAF demonstrated more potent antiviral activity, higher peripheral blood mononuclear cell intracellular tenofovir diphosphate levels, and lower plasma TFV exposures, at approximately 1/10th of the dose. This may translate into greater antiviral efficacy, a higher barrier to resistance, and an improved safety profile relative to TDF, supporting further investigation of TAF dosed once daily in HIV-infected patients.