Impact of Integrase Sequences From HIV-1 Subtypes A6/A1 on the In Vitro Potency of Cabotegravir or Rilpivirine

The FLAIR study demonstrated noninferiority of monthly long-acting cabotegravir + rilpivirine vs daily oral dolutegravir/abacavir/lamivudine for maintaining virologic suppression. Three participants who received long-acting therapy had confirmed virologic failure (CVF) at Week 48, and all had HIV-1 that was originally classified as subtype A1 and contained the baseline integrase polymorphism L74I; updated classification algorithms reclassified all 3 as HIV-1 subtype A6. Retrospectively, the impact of L74I on in vitro sensitivity and durability of response to cabotegravir in HIV-1 subtype B and A6 backgrounds was studied. Site-directed L74I and mutations observed in participants with CVF were generated in HIV-1 subtype B and a consensus integrase derived from 3 subtype A6 CVF baseline sequences. Rilpivirine susceptibility was assessed in HIV-1 subtype B and A1 containing reverse transcriptase mutations observed in participants with CVF. HIV-1 subtype B L74I and L74I/G140R mutants and HIV-1 subtype A6 I74L and I74/G140R mutants remained susceptible to cabotegravir; L74I/Q148R double mutants exhibited reduced susceptibility in HIV-1 subtypes B and A6 (half maximal effective capacity fold change, 4.4 and 4.1, respectively). Reduced rilpivirine susceptibility was observed across HIV-1 subtypes B and A1 with resistance-associated mutations K101E or E138K (half maximal effective capacity fold change, 2.21 to 3.09). In cabotegravir breakthrough experiments, time to breakthrough was similar between L74 and I74 viruses across HIV-1 subtypes B and A6; Q148R was selected at low cabotegravir concentrations. Therefore, the L74I integrase polymorphism did not differentially impact in vitro sensitivity to cabotegravir across HIV-1 subtype B and A6 integrase genes (ClinicalTrials.gov identifier: NCT02938520).

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73. Interim Resistance Analysis of Long-Acting Lenacapavir in Treatment-Naïve People with HIV at 28 Weeks

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.073 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S48-S48

Author(s):

Laurie VanderVeen ◽

Nicolas Margot ◽

Vidula Naik ◽

Silvia Chang ◽

Ross Martin ◽

...

Keyword(s):

Virologic Failure ◽

Amino Acid Residues ◽

Resistance Analysis ◽

Treatment And Prevention ◽

Subtype B ◽

Treatment Naïve ◽

Long Acting ◽

Hiv 1 ◽

Prevention Of Hiv

Abstract Background Lenacapavir (LEN) is a first-in-class HIV-1 capsid (CA) inhibitor in clinical development for treatment and prevention of HIV-1 infection. CALIBRATE is an ongoing, phase 2 clinical study evaluating subcutaneous (SC) or oral LEN, in combination with other antiretrovirals, in treatment-naïve people with HIV-1. High rates of virologic success (HIV-1 RNA < 50 copies/mL) were achieved with LEN-based regimens by FDA Snapshot analysis at Week 28. Here, we present interim resistance analyses through Week 28. Methods Participants were randomized (2:2:2:1) to treatment groups (TG) (Figure): SC LEN + oral daily emtricitabine/tenofovir alafenamide (F/TAF); at Week 28, participants switch F/TAF to oral TAF (TG-A) or bictegravir (B, BIC) (TG-B); oral daily LEN + F/TAF (TG-C), or oral daily B/F/TAF (TG-D). Genotypic analyses (population sequencing) of HIV-1 reverse transcriptase and integrase, and genotypic (deep sequencing)/phenotypic analyses for CA were performed at screening; genotypic and phenotypic analyses were conducted at confirmed virologic failure. Figure CALIBRATE Study Design Results 182 participants were randomized and dosed in TG-A to D (n=52, 53, 52, 25). Most participants had subtype B HIV-1 (92.9%). Sequence analysis of baseline samples found 65% of amino acid residues were conserved with < 1% variation across CA overall, and 55% of residues were fully conserved. No mutations were detected at 6 positions in CA associated with reduced susceptibility to LEN in vitro; residues were fully conserved at 5 positions (L56, M66, Q67, K70, N74), and < 2% variation was observed at 1 position (T107). Three participants met the criteria for resistance analysis: 2 participants resuppressed to < 50 copies/mL while continuing treatment. One participant on SC LEN + F/TAF developed emergent resistance to LEN (Q67H+K70R) and emtricitabine (M184M/I), followed by resuppression after starting dolutegravir, zidovudine + lamivudine, tenofovir disoproxil fumarate. Conclusion Emergent resistance to LEN was uncommon in treatment-naïve participants receiving SC or oral LEN (0.6%, 1/157). These interim resistance findings support the ongoing evaluation of LEN for treatment and prevention of HIV. Disclosures Laurie VanderVeen, PhD, Gilead Sciences (Employee, Shareholder) Nicolas Margot, MA, Gilead Sciences (Employee, Shareholder) Vidula Naik, MSc, Gilead Sciences (Employee, Shareholder) Silvia Chang, Masters, Gilead Sciences, Inc (Employee, Shareholder) Ross Martin, PhD, Gilead Sciences, Inc (Employee, Shareholder) Hadas Dvory-Sobol, PhD, Gilead Sciences (Employee, Shareholder) Martin Rhee, MD, Gilead Sciences (Employee, Shareholder) Christian Callebaut, PhD, Gilead Sciences (Employee, Shareholder)

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833. Efficacy and Safety of Long-Acting Cabotegravir + Rilpivirine in Participants with HIV/HCV Co-infection: ATLAS-2M 48-Week Results

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1029 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S508-S509

Author(s):

Ronald D’Amico ◽

Paul Benn ◽

Shanker Thiagarajah ◽

Susan L Ford ◽

Eileen Birmingham ◽

...

Keyword(s):

Research And Development ◽

Injection Site ◽

Virologic Failure ◽

Hcv Rna ◽

Virologic Suppression ◽

Efficacy And Safety ◽

Modes Of Transmission ◽

Long Acting ◽

Chronic Hcv ◽

Hiv 1

Abstract Background The phase IIIb ATLAS-2M study demonstrated non-inferiority of long-acting (LA) cabotegravir (CAB) + rilpivirine (RPV) dosed every 8 weeks (Q8W) compared with every 4 weeks (Q4W) for maintenance of virologic suppression. Hepatitis C virus (HCV) co-infection occurs in ~6% of people with HIV due to shared modes of transmission. We report efficacy and safety of CAB + RPV LA in participants with HIV/HCV co-infection in ATLAS-2M. Methods Participants with HIV-1 RNA < 50 c/mL receiving CAB + RPV LA Q4W (transitioned from ATLAS [NCT02951052]) or oral comparator ART were randomized 1:1 to receive CAB + RPV LA Q4W or Q8W. Baseline HCV RNA was assessed by polymerase chain reaction. Participants with symptomatic chronic HCV infection requiring treatment within 12 months or liver enzymes not meeting entry criteria were excluded. Week 48 assessments included proportion with HIV-1 RNA ≥50 and < 50 c/mL (Snapshot algorithm), general and hepatic safety, and pharmacokinetics. Results HIV/HCV co-infection was present in 10 (1%) of 1045 participants, 60% of whom were female at birth. At Week 48, 9/10 (90%) and 972/1035 (94%) participants with HIV/HCV co-infection and HIV mono-infection, respectively, had HIV-1 RNA < 50 c/mL (adjusted difference, 4.1; 95% CI, −14.5 to 22.6). No participants with HIV/HCV co-infection had HIV-1 RNA ≥50 c/mL (vs 14/1035 [1%] with HIV mono-infection) or confirmed virologic failure through Week 48 (vs 10 [1%] with HIV mono-infection); 1/10 (10%) discontinued for reasons other than adverse events (AEs). Excluding injection site reactions (ISRs), AEs and serious AEs were reported in 4 (40%) and 0 participants with HIV/HCV co-infection, respectively; the only AE reported in >1 participant was injection site pain (n=5; 50%). In participants with HIV/HCV co-infection, all ISRs were grade 1/2; none led to withdrawal. No hepatic laboratory abnormalities were reported in participants with HIV/HCV co-infection through Week 48; rates were low in those with HIV mono-infection (Table). Plasma CAB and RPV concentrations were similar between groups. Conclusion CAB + RPV LA was effective and well tolerated in this small cohort of participants with HIV and asymptomatic HCV co-infection. Disclosures Ronald D’Amico, DO, MSc, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Paul Benn, MB ChB FRCP, ViiV Healthcare (Employee) Shanker Thiagarajah, MB ChB, GlaxoSmithKline (Employee, Shareholder) Susan L. Ford, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Eileen Birmingham, MD, MPH, Janssen Research and Development (Employee, Shareholder) Ojesh R. Upadhyay, MPH, MBA, GlaxoSmithKline (Employee) Louise Garside, PhD, GlaxoSmithKline (Employee) Rodica Van Solingen-Ristea, MD, Janssen Research and Development (Employee)ViiV Healthcare (Employee) Kati Vandermeulen, M.SC., Janssen Research and Development (Employee) William Spreen, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

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877. North American Phase 3/3b Experience with Long-Acting Cabotegravir and Rilpivirine: Efficacy, Safety, and Virologic Outcomes

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1072 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S530-S531

Author(s):

Babafemi O Taiwo ◽

Darrell Tan ◽

Parul Patel ◽

Paula Teichner ◽

Joseph Polli ◽

...

Keyword(s):

Treatment Guidelines ◽

Virologic Failure ◽

Descriptive Analysis ◽

Injection Site Reaction ◽

Treatment Preference ◽

Virologic Suppression ◽

Research Support ◽

Phase 3 ◽

Long Acting ◽

Hiv 1

Abstract Background Cabotegravir (CAB) plus rilpivirine (RPV) is the first complete long-acting (LA) regimen recommended by treatment guidelines for the maintenance of HIV-1 virologic suppression. CAB+RPV LA dosed every 4 weeks (Q4W) or every 8 weeks (Q8W) demonstrated noninferior efficacy in multinational Phase 3/3b trials. This post hoc descriptive analysis summarizes efficacy, virologic outcomes, safety, and treatment preference for US and Canadian (CAN) participants through Week (W) 48. Methods This analysis focuses on data for US/CAN participants naive to CAB+RPV (n=376) from the larger pooled population of the ATLAS, FLAIR, and ATLAS-2M Phase 3/3b studies (N=1245). Endpoints included the proportion of participants with plasma HIV-1 RNA ≥ 50 and < 50 c/mL at W48 (FDA Snapshot algorithm), incidence of confirmed virologic failure (CVF; 2 consecutive HIV-1 RNA ≥ 200 c/mL), safety, and treatment preference through W48. Results 376 US/CAN participants received CAB+RPV LA Q4W or Q8W. Median (range) age was 39y (20–74); 14.9% were female, 66.0% were White. At W48, 93.1% (350/376) maintained virologic suppression (HIV-1 RNA < 50 c/mL), 1.9% (7/376) had HIV-1 RNA ≥ 50 c/mL, and 0.8% (3/376) met the CVF criterion, consistent with the overall global pooled population (Table 1). Two of the three participants with CVF had ≥ 2 of the three baseline factors (archived RPV resistance-associated mutations [RAMs], HIV subtype A6/A1, body mass index [BMI] ≥ 30 kg/m2) previously associated with CVF. Among the US/CAN participants with a single baseline factor, none met CVF. Overall, archived RPV RAMs were observed in 3.2% (12/376), HIV subtype A6/A1 in 1.1% (4/376), and BMI ≥ 30 kg/m2 in 26.3% (99/376) of participants. Safety and injection site reaction findings were similar to the overall pooled population (Table 2). Most participants (120/134, 89.6%) preferred LA over oral dosing (7/134, 5.2%). Table 1. Snapshot outcomes following CAB+RPV LA Q4W and Q8W at Week 48 in participants naive to CAB+RPV from ATLAS, FLAIR, and ATLAS-2M (ITT-E population) Table 2. Safety summary through Week 48 following CAB+RPV LA Q4W and Q8W or comparator ART in participants naive to CAB+RPV from ATLAS, FLAIR, and ATLAS-2M Conclusion In US/CAN Phase 3/3b trial participants, CAB+RPV LA was highly effective and well tolerated, with outcomes consistent with the overall pooled population. Baseline prevalence of archived RPV RAMs and subtype A6/A1 was low and aligned with regional prevalence/surveillance data. CAB+RPV LA provides a tolerable and effective injectable LA treatment option for virologically suppressed US/CAN individuals with HIV. Disclosures Babafemi O. Taiwo, MBBS, Gilead (Consultant)Merck (Consultant)ViiV Healthcare (Consultant) Darrell Tan, MD PhD, Abbvie (Grant/Research Support)Gilead (Grant/Research Support)GlaxoSmithKline (Scientific Research Study Investigator)ViiV Healthcare (Grant/Research Support) Parul Patel, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Paula Teichner, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Joseph Polli, PhD, FAAPS, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Louise Garside, PhD, GlaxoSmithKline (Employee) Ronald D’Amico, DO, MSc, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Christine L. Talarico, M.S., GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Rodica Van Solingen-Ristea, MD, Janssen Research and Development (Employee)ViiV Healthcare (Employee) Bryan Baugh, MD, Janssen, Johnson & Johnson (Employee, Shareholder) William Spreen, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Michael Aboud, MBChB, MRCP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Matthew Bosse, DO, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

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Clinical and Virologic Outcomes Following Initiation of Antiretroviral Therapy Among Seroconverters in the Microbicide Trials Network-020 Phase III Trial of the Dapivirine Vaginal Ring

Clinical Infectious Diseases ◽

10.1093/cid/ciy909 ◽

2018 ◽

Vol 69 (3) ◽

pp. 523-529 ◽

Cited By ~ 2

Author(s):

Sharon A Riddler ◽

Jennifer E Balkus ◽

Urvi M Parikh ◽

John W Mellors ◽

Carolyne Akello ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Disease Progression ◽

Virologic Failure ◽

Vaginal Ring ◽

Phase Iii ◽

Virologic Suppression ◽

Cell Counts ◽

The Impact ◽

Hiv 1

Abstract Background A vaginal ring containing dapivirine, a non-nucleoside human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitor (NNRTI), was safe and effective in preventing HIV-1 infection in African women. We examined the impact of dapivirine ring use at the time of HIV-1 acquisition on subsequent HIV-1 disease progression and responses to NNRTI-containing antiretroviral therapy (ART). Methods HIV-1 disease progression and virologic failure following initiation of ART were assessed among women who acquired HIV-1 while participating in Microbicide Trials Network–020, a randomized, placebo-controlled trial of a monthly, dapivirine vaginal ring. Results Among the 158 participants who acquired HIV-1 (65 dapivirine, 93 placebo), no differences between dapivirine and placebo participants were observed in CD4+ cell counts or plasma HIV-1 RNA over the first year after infection (prior to ART). During follow-up, 100/158 (63%) participants initiated NNRTI-containing ART (dapivirine: 39/65; placebo: 61/93); the median time to HIV-1 RNA <200 copies/ml was approximately 90 days for both dapivirine and placebo ring recipients (log-rank P = .40). Among the 81 participants with at least 6 months of post-ART follow-up, 19 (24%) experienced virologic failure (dapivirine: 6/32, 19%; placebo: 13/39, 27%; P = .42). Conclusions The acquisition of HIV-1 infection during dapivirine or placebo treatment in ASPIRE did not lead to differences in HIV-1 disease progression. After the initiation of NNRTI-containing ART, dapivirine and placebo participants had similar times to virologic suppression and risks of virologic failure. These results provide reassurance that NNRTI-based ART regimens are effective among women who acquired HIV-1 while receiving the dapivirine vaginal ring. Clinical Trials Registration NCT016170096 and NCT00514098.

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Highly prevalent Russian HIV-1 V3-loop sequence variants are susceptible to maraviroc

Antiviral Chemistry and Chemotherapy ◽

10.1177/20402066211025156 ◽

2021 ◽

Vol 29 ◽

pp. 204020662110251

Author(s):

ME Lewis ◽

B Jubb ◽

P Simpson ◽

A Lopatukhin ◽

D Kireev ◽

...

Keyword(s):

Amino Acid ◽

Virologic Failure ◽

Natural Resistance ◽

V3 Loop ◽

Amino Acid Residues ◽

Subtype B ◽

Loop Sequence ◽

Hiv 1 ◽

Amino Acid Variants

Introduction Maraviroc inhibits CCR5-tropic HIV-1 across different subtypes in vitro and has demonstrated efficacy in clinical trials. V3-loop amino acid variants observed in individual maraviroc-resistant viruses have not been found to be predictive of reduced susceptibility. Sequence-database searches have demonstrated that approximately 7.3% of viruses naturally encode these variants, raising concerns regarding potential pre-existing resistance. A study from Russia reported that combinations of these same amino acids are present in the V3 loops of the Russian variant subtype A (IDU-A, now A6) with a much greater prevalence (range: 74.4%–92.3%) depending on the combination. However, these studies and database searches did not include phenotypic evaluation. Methods Sixteen Russian HIV-1 isolates (including sub-subtype A6 viruses) were assessed for V3 loop sequence and phenotypic susceptibility to maraviroc. Results All 12 of the A6 viruses and 2/4 subtype B isolates encoded V3-loop variants that have previously been identified in individual virus isolates with reduced susceptibility to maraviroc. However, despite the prevalence of these V3-loop amino acid variants among the tested viruses, phenotypic sensitivity to maraviroc was observed in all instances. Similarly, reduced susceptibility to maraviroc was not found in virus from participants who experienced virologic failure in a clinical study of maraviroc in Russia (A4001101, [NCT01275625]). Discussion Altogether, these data confirm that the presence of individual or combinations of V3-loop amino acid residues in sub-subtype A6 viruses alone does not predict natural resistance to maraviroc and that V3-loop genotype analysis of R5 virus prior to treatment is not helpful in predicting clinical outcome.

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Impact of HIV subtype on response and resistance in antiretroviral-naïve adults comparing treatment with once daily versus twice daily ritonavir boosted fosamprenavir in combination with Abacavir/Lamivudine

Drugs and Therapy Studies ◽

10.4081/dts.2012.e1 ◽

2011 ◽

Vol 2 (1) ◽

pp. 1

Author(s):

Lisa L. Ross ◽

Marjorie D. Robinson ◽

Giampiero Carosi ◽

Adriano Lazzarin ◽

Hans-Juergen Stellbrink ◽

...

Keyword(s):

Virologic Failure ◽

Resistance Mutation ◽

Virologic Response ◽

Fixed Dose ◽

Combination Tablet ◽

Once Daily ◽

Hiv Rna ◽

Subtype B ◽

The Impact ◽

Hiv 1

The impact of HIV-1 subtype on resistance mutation selection and on virologic response to fosamprenavir in combination with once-daily (QD) versus twice-daily (BID) dosing of ritonavir was examined in a prospective, open label, randomized study in antiretroviral-naïve, HIV-1 infected subjects. We studied APV109141 compared QD fosamprenavir/ritonavir (1400mg/100mg) to BID fosamprenavir/ritonavir (700mg/100mg), administered in combination with a QD fixed-dose abacavir/lamivudine (600 mg/300 mg) combination tablet through 48 weeks in ART-naïve subjects. HIV genotypes were obtained from all subjects at screen. Subjects with virologic failure (VF) were also genotyped at baseline and VF. HIV subtypes observed in the ITT (n=214) population were A or AE or AG circulating recombinant forms (CRFs) 19%; B 62%; BF or BG CRFs 2%; C or CPX CRFs 7%; D 2%; F1 7%; G <1%. By TLOVR (ITT-exposed), 86/106 (81%) of subjects on QD study arm and 87/106 (82%) in the BID arm achieved plasma HIV-RNA<400 copies/mL at Week 48. Three subjects met VF criteria, 2 receiving QD fosamprenavir/ritonavir; 1 receiving BID fosamprenavir/ritonavir; (HIV subtype B, F1 A1, respectively). Baseline drug resistance was detected in 2/3 VFs: Subject 1-RT: K103K/N, T215C; major PI: V82A, L90M; and Subject 2-RT: M41L, L74V. Only virus from one subject with VF selected for any treatment-emergent mutation (Subject 1; M184V). Post-VF, Subject 3 (subtypeA1) suppressed HIV-RNA >400 copies/mL through 48 weeks. Subtype appeared to have no preferential impact on virologic response or selection for specific resistance mutations in subjects receiving fosamprenavir/ritonavir. Virologic failure rate was rare (3 subjects; each from different subtypes). At VF, virus from only one subject selected any HIV NRTI mutation (M184V); none selected major protease mutations.

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887. Implementation of Long-acting Injectable Cabotegravir/Rilpivirine for HIV-1 Treatment at a Ryan White-funded Clinic in the U.S. South

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1082 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S535-S535

Author(s):

Lauren F Collins ◽

Della Corbin-Johnson ◽

Meron Asrat ◽

Tonya Rankins ◽

...

Keyword(s):

Virologic Failure ◽

Panel Member ◽

Proton Pump Inhibitor Therapy ◽

Source Distribution ◽

Virologic Suppression ◽

Screening Criteria ◽

Medication Access ◽

Ryan White ◽

Long Acting ◽

Hiv 1

Abstract Background In January 2021, the first ever long-acting injectable (LAI) antiretroviral therapy (ART), cabotegravir/rilpivirine (CAB/RPV), was approved for maintenance HIV-1 treatment in select patients with virologic suppression. LAI-ART has the potential to improve ART adherence, reduce HIV stigma, and promote equity in care outcomes, however, implementation in real-world settings has yet to be evaluated. Methods We launched a pilot LAI-ART program at the largest Ryan White-funded HIV clinic in the Southeast. From 4/14/21 to 5/14/21, providers referred patients interested and willing to switch to LAI-CAB/RPV who met screening criteria. Our interdisciplinary LAI team (Clinician-Pharmacy-Nursing) verified clinical eligibility (HIV-1 < 200 c/ml ≥6 months and no history of virologic failure, resistance to either drug, or chronic HBV infection) and pursued medication access for 28-day oral lead-in and monthly injectable CAB/RPV. We describe demographic and clinical variables of referred PWH and early outcomes in accessing LAI-ART. Results Among 42 referrals, median age was 40.5 (Q1-Q3, 32-52) years, 83% were men, and 76% Black. Payor source distribution was 26% Private, 19% Medicare, 10% Medicaid, and 45% ADAP. At the time of referral, median CD4 count was 583 (Q1-Q3, 422-742) cells/mm3 and median sustained HIV-1 RNA < 200 c/ml was 1427 (Q1-Q3, 961-2534) days. A total of 35 patients (74%) met clinical eligibility for LAI-CAB/RPV, including 4 patients who required a transition off proton pump inhibitor therapy to accommodate oral RPV. Ineligible PWH were excluded due to evidence of RPV resistance (n=5), possible RPV hypersensitivity (n=1), and HIV non-suppression (n=1). The table summarizes the process of pursuing LAI-ART access for the initial 10 enrollees by insurance status. Conclusion Our experience implementing LAI-ART at a Ryan White-funded HIV clinic in the Southern U.S. has been challenged by substantial human resource capital to attain drug, delayed therapy initiation due to insurance denials, and patient ineligibility primarily due to concern for potential RPV resistance. These barriers may perpetuate disparities in ART access and virologic suppression among PWH and need to be urgently addressed so that LAI-ART can be offered equitably. Disclosures Lauren F. Collins, MD, MSc, Nothing to disclose Bradley L. Smith, Pharm.D., AAHIVP, Gilead Sciences, Inc (Advisor or Review Panel member) Wendy Armstrong, MD, Nothing to disclose Jonathan Colasanti, MD, Integritas CME (Consultant, develop and deliver CME content around Rapid Entry/Rapid ART)

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Racial Disparities in Virologic Failure and Tolerability During Firstline HIV Antiretroviral Therapy

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz022 ◽

2019 ◽

Vol 6 (2) ◽

Cited By ~ 1

Author(s):

Priya Bhagwat ◽

Shashi N Kapadia ◽

Heather J Ribaudo ◽

Roy M Gulick ◽

Judith S Currier

Keyword(s):

Antiretroviral Therapy ◽

Adverse Events ◽

Socioeconomic Factors ◽

Ethnic Groups ◽

Virologic Failure ◽

Virologic Suppression ◽

Factors Associated ◽

Race Ethnicity ◽

The Impact ◽

Racial Ethnic

Abstract Background Racial/ethnic disparities in HIV outcomes have persisted despite effective antiretroviral therapy. In a study of initial regimens, we found viral suppression varied by race/ethnicity. In this exploratory analysis, we use clinical and socioeconomic data to assess factors associated with virologic failure and adverse events within racial/ethnic groups. Methods Data were from AIDS Clinical Trial Group A5257, a randomized trial of initial regimens with either atazanavir/ritonavir, darunavir/ritonavir, or raltegravir (each combined with tenofovir DF and emtricitabine). We grouped participants by race/ethnicity and then used Cox-proportional hazards regression to examine the impact of demographic, clinical, and socioeconomic factors on the time to virologic suppression and time to adverse event reporting within each racial/ethnic group. Results We analyzed data from 1762 participants: 757 self-reported as non-Hispanic black (NHB), 615 as non-Hispanic white (NHW), and 390 as Hispanic. The proportion with virologic failure was higher for NHB (22%) and Hispanic (17%) participants compared with NHWs (9%). Factors associated with virologic failure were poor adherence and higher baseline HIV RNA level. Prior clinical AIDS diagnosis was associated with virologic failure for NHBs only, and unstable housing and illicit drug use for NHWs only. Factors associated with adverse events were female sex in all groups and concurrent use of medications for comorbidities in NHB and Hispanic participants only. Conclusions Clinical and socioeconomic factors that are associated with virologic failure and tolerability of antiretroviral therapy vary between and within racial and ethnic groups. Further research may shed light into mechanisms leading to disparities and targeted strategies to eliminate those disparities.

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Phenotypic Susceptibility to Bevirimat in Isolates from HIV-1-Infected Patients without Prior Exposure to Bevirimat

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01784-09 ◽

2010 ◽

Vol 54 (6) ◽

pp. 2345-2353 ◽

Cited By ~ 39

Author(s):

Nicolas A. Margot ◽

Craig S. Gibbs ◽

Michael D. Miller

Keyword(s):

Recombinant Viruses ◽

Gag Polyprotein ◽

New Class ◽

Major Mutation ◽

Hiv Drugs ◽

The Impact ◽

First Time ◽

Hiv 1

ABSTRACT Bevirimat (BVM) is the first of a new class of anti-HIV drugs with a novel mode of action known as maturation inhibitors. BVM inhibits the last cleavage of the Gag polyprotein by HIV-1 protease, leading to the accumulation of the p25 capsid-small peptide 1 (SP1) intermediate and resulting in noninfectious HIV-1 virions. Early clinical studies of BVM showed that over 50% of the patients treated with BVM did not respond to treatment. We investigated the impact of prior antiretroviral (ARV) treatment and/or natural genetic diversity on BVM susceptibility by conducting in vitro phenotypic analyses of viruses made from patient samples. We generated 31 recombinant viruses containing the entire gag and protease genes from 31 plasma samples from HIV-1-infected patients with (n = 21) or without (n = 10) prior ARV experience. We found that 58% of the patient isolates tested had a >10-fold reduced susceptibility to BVM, regardless of the patient's ARV experience or the level of isolate resistance to protease inhibitors. Analysis of mutants with site-directed mutations confirmed the role of the V370A SP1 polymorphism (SP1-V7A) in resistance to BVM. Furthermore, we demonstrated for the first time that a capsid polymorphism, V362I (CA protein-V230I), is also a major mutation conferring resistance to BVM. In contrast, none of the previously defined resistance-conferring mutations in Gag selected in vitro (H358Y, L363M, L363F, A364V, A366V, or A366T) were found to occur among the viruses that we analyzed. Our results should be helpful in the design of diagnostics for prediction of the potential benefit of BVM treatment in HIV-1-infected patients.

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1021. HIV-1 RNA Blips and Low-Level Replication During Phase III/IIIb Cabotegravir + Rilpivirine Long-Acting Studies Are Similar to Oral 3-Drug Therapy and Not Associated with Week 48 Virologic Outcome

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1207 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S540-S541

Author(s):

Christine L Talarico ◽

Sterling Wu ◽

Ojesh R Upadhyay ◽

Marty St Clair ◽

Veerle Van Eygen ◽

...

Keyword(s):

Viral Load ◽

Virologic Failure ◽

Phase Iii ◽

Individual Study ◽

Treatment Groups ◽

Qualitative And Quantitative ◽

Low Level ◽

Long Acting ◽

Study Participants ◽

Hiv 1

Abstract Background Phase III/IIIb studies demonstrated cabotegravir (CAB) + rilpivirine (RPV) long-acting (LA) dosed every 4 weeks (Q4W) was noninferior to current antiviral regimen (CAR) (FLAIR and ATLAS) and CAB + RPV LA dosed every 8 weeks (Q8W) was noninferior to Q4W (ATLAS-2M) through Week 48 (W48). HIV-1 ribonucleic acid (RNA) blips (viral load [VL] ≥50 to < 200 c/mL) are common during antiretroviral therapy (ART) and generally not associated with subsequent virologic failure (2 consecutive HIV-1 RNA ≥200 c/mL). We compared the frequency of HIV-1 RNA blips and low-level qualitative and quantitative HIV-1 RNA replication among participants treated with CAB+RPV LA and oral CAR and assessed impact on virologic outcome. Methods Plasma samples collected at study visits were analyzed for HIV-1 RNA viral load using the Abbott RealTime HIV-1 assay and qualitative target detected (TD) or target not detected (TND) outcomes were provided for HIV-1 RNA < 40 c/mL. The HIV-1 SuperLow assay (bioMONTR Labs) was used to measure HIV-1 RNA < 2 c/mL at Baseline and W48. Results The proportion of participants with HIV-1 RNA blips was similar overall between Q4W CAB + RPV LA and CAR arms in FLAIR (38/283 [13%] vs 39/283 [14%]) and ATLAS (17/308 [6%] vs 23/308 [7%]). Presence of HIV-1 RNA blips in either arm was not associated with virologic non-response at W48 (HIV-1 RNA ≥50 c/mL per US Food and Drug Administration Snapshot). In ATLAS-2M, HIV-1 RNA blips were observed in 32/523 (6%; Q4W) and 18/522 (3%; Q8W) of participants, with W48 virologic nonresponse in 2 Q4W and 0 Q8W participants. TD outcomes at individual study visits were comparable between study arms for the 3 studies. At W48, the proportion of participants with HIV-1 RNA < 2 c/mL was similar to Baseline and similar between treatment groups in all studies. Conclusion The proportions of study participants with HIV-1 RNA blips, TD viral load results, and HIV-1 < 2 c/mL were similar between the Q4W and Q8W CAB+RPV LA and the oral 3-drug CAR arms through W48 in phase III/IIIb studies. HIV-1 RNA blips did not predict virologic nonresponse (Snapshot analysis) at W48. Disclosures Christine L. Talarico, M.S, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Sterling Wu, PhD, GlaxoSmithKline (Employee, Shareholder) Marty St. Clair, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Veerle Van Eygen, MSc, Janssen Pharmaceutica NV (Employee) Krischan J. Hudson, PhD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Sandy Griffith, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Conn M. Harrington, BA, ViiV Healthcare (Employee) Jan van Lunzen, MD, PhD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) David Margolis, MD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) William Spreen, PharmD, ViiV Healthcare (Employee, Shareholder)

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