Virologic suppression in response to antiretroviral therapy despite extensive resistance within HIV-1 reverse transcriptase after the first virologic failure

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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629. High Efficacy of Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) in African American Adults with HIV Including Those with Preexisting Resistance, Viral Blips, and Suboptimal Adherence

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.827 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S418-S418

Author(s):

Kristen Andreatta ◽

Michelle L D'Antoni ◽

Silvia Chang ◽

Aiyappa Parvangada ◽

Ross Martin ◽

...

Keyword(s):

African American ◽

Reverse Transcriptase ◽

Virologic Failure ◽

Pill Count ◽

Controlled Study ◽

Virologic Suppression ◽

African American Adults ◽

Suboptimal Adherence ◽

Tenofovir Alafenamide ◽

Hiv 1

Abstract Background BRAAVE 2020 demonstrated the efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among African American adults with suppressed HIV through Week (W) 48 (Figure 1). We present resistance, viral blips, adherence, and virologic outcomes through W72. Figure 1. BRAAVE 2020 study design (phase 3, randomized, open-label, multicenter [USA], active-controlled study) and virologic suppression at weeks 24 and 48 *Allowed 3rd agents: any FDA-approved protease inhibitor, nonnucleoside reverse transcriptase inhibitor (except etravirine), integrase strand transfer inhibitor (except bictegravir), or maraviroc. Methods Enrollment criteria permitted NNRTI resistance (-R), PI-R, and certain NRTI-R (M184V/I allowed; K65R/E/N, ≥3 thymidine analog mutations [TAMs], or T69-insertions excluded) and excluded known primary INSTI-R. Preexisting drug resistance was assessed with historical genotypes and retrospective baseline proviral DNA genotyping. Adherence was calculated by pill count. Viral blips (transient HIV-1 RNA ≥50 copies/mL) and outcomes based on last available on-treatment HIV-1 RNA were assessed. Results 489 participants received B/F/TAF and had ≥1 post-switch HIV-1 RNA measurement. Baseline genotypic data from cumulative historical and/or proviral genotypes were available for 96% (468/489) in protease/reverse transcriptase and 93% (453/489) in integrase. Preexisting NRTI-R, M184V/I, ≥1 TAMs, NNRTI-R, and PI-R were observed in 15% (68/468), 11% (50/468), 8% (36/468), 22% (101/468), and 13% (61/468), respectively. Primary INSTI-R was detected post-randomization in 2% (11/453); all remained in the study and were included in efficacy analyses. Through W72, 99% (486/489) of participants had HIV-1 RNA < 50 copies/mL at their last study visit, including all with baseline NRTI-R or INSTI-R (Figure 2). Mean frequency of viral blips was 1% per timepoint, and blips were not associated with virologic failure. 112 participants (23%) had < 95% adherence by pill count, 98% (110/112) of whom had HIV-1 RNA < 50 copies/mL at last visit, including 14 of 14 (100%) with < 80% adherence. No participant discontinued due to lack of efficacy or had treatment emergent resistance to study drugs. Figure 2. Virologic suppression by preexisting resistance, viral blips, and adherence Conclusion Virologic suppression was maintained through W72 of B/F/TAF treatment, including those with preexisting resistance, viral blips, and suboptimal adherence. Continued HIV suppression and absence of treatment-emergent resistance demonstrate the efficacy of B/F/TAF in African Americans regardless of adherence or preexisting resistance to NNRTIs, PIs, or non-tenofovir NRTIs. Disclosures Kristen Andreatta, MSc, Gilead Sciences, Inc (Employee, Shareholder) Michelle L. D'Antoni, PhD, Gilead Sciences (Employee, Shareholder)Gilead Sciences, Inc (Employee, Shareholder) Silvia Chang, Masters, Gilead Sciences, Inc (Employee, Shareholder) Aiyappa Parvangada, MS Computational Biology, Gilead Sciences, Inc (Employee, Shareholder) Ross Martin, PhD, Gilead Sciences, Inc (Employee, Shareholder) Christiana Blair, MS, Gilead Sciences, Inc (Employee, Shareholder) Sean E. Collins, MD, MS, Gilead Sciences, Inc (Employee, Shareholder) Kirsten L. White, PhD, Gilead Sciences, Inc (Employee, Shareholder)

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Long-term safety and efficacy of rilpivirine in combination with nucleoside/nucleotide reverse transcriptase inhibitors in HIV-1 infected patients: 336-week rollover study of phase 2b and 3 clinical studies

Antiviral Therapy ◽

10.1177/13596535211062388 ◽

2021 ◽

pp. 135965352110623

Author(s):

Jean Michel Molina ◽

Luminita Ene ◽

Pedro Cahn ◽

Gerd Fätkenheuer ◽

Eric Van Wijngaerden ◽

...

Keyword(s):

Reverse Transcriptase ◽

Cell Count ◽

Virologic Failure ◽

Transcriptase Inhibitor ◽

Virologic Suppression ◽

Reverse Transcriptase Inhibitors ◽

Open Label ◽

Safety And Efficacy ◽

Hiv 1

Background To evaluate the long-term safety and efficacy of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in human immunodeficiency virus (HIV)–infected patients. Methods RPV-treated HIV-infected patients from phase 2b or 3 studies rolled-over into this phase 3, open-label study and received RPV 25 mg once daily (QD) with choice of two NRTIs. Adverse events (AEs), plasma viral load, CD4+ cell count, and antiviral resistance were evaluated. Results Of the 482 patients treated, 437 (>90%) patients discontinued study treatment; 371 (77%) had switched to commercially available RPV, 14 (2.9%) discontinued due to AEs, and 6 (1.2%) had virologic failure. In this rollover study, patients were followed up to week 336, although data was limited beyond 288 weeks. Forty-five (9.3%) patients were still undergoing treatment at the time of data cut-off for the current analysis (8 February 2018). The most frequently reported AEs were pregnancy in 7 (1.5%) patients and syphilis in 5 (1.0%) patients. Grade 3–4 AEs were reported in 17 (3.5%) patients, and AEs possibly related to RPV in 23 (4.8%) patients. Over 288 weeks of treatment, 80.1% (95% CI: 74.9%; 84.3%) of patients maintained virologic suppression (HIV-1 RNA <50 copies/mL). The absolute CD4+ cell count increased over time until week 192 and remained constant thereafter. Conclusions RPV 25 mg QD in combination with an investigator-selected background regimen of two NRTIs demonstrated sustained long-term virologic suppression. The treatment was well-tolerated with no new safety findings.

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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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Impact of long-term antiretroviral therapy on gut and oral microbiotas in HIV-1-infected patients

Scientific Reports ◽

10.1038/s41598-020-80247-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mayumi Imahashi ◽

Hirotaka Ode ◽

Ayumi Kobayashi ◽

Michiko Nemoto ◽

Masakazu Matsuda ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Reverse Transcriptase ◽

Transcriptase Inhibitor ◽

Strand Transfer ◽

Intestinal Dysbiosis ◽

Α Diversity ◽

Reverse Transcriptase Inhibitor ◽

Hiv 1 ◽

Over Time

AbstractIn HIV-1-infected patients, antiretroviral therapy (ART) is a key factor that may impact commensal microbiota and cause the emergence of side effects. However, it is not fully understood how long-term ART regimens have diverse impacts on the microbial compositions over time. Here, we performed 16S ribosomal RNA gene sequencing of the fecal and salivary microbiomes in patients under different long-term ART. We found that ART, especially conventional nucleotide/nucleoside reverse transcriptase inhibitor (NRTI)-based ART, has remarkable impacts on fecal microbial diversity: decreased α-diversity and increased ß-diversity over time. In contrast, dynamic diversity changes in the salivary microbiome were not observed. Comparative analysis of bacterial genus compositions showed a propensity for Prevotella-enriched and Bacteroides-poor gut microbiotas in patients with ART over time. In addition, we observed a gradual reduction in Bacteroides but drastic increases in Succinivibrio and/or Megasphaera under conventional ART. These results suggest that ART, especially NRTI-based ART, has more suppressive impacts on microbiota composition and diversity in the gut than in the mouth, which potentially causes intestinal dysbiosis in patients. Therefore, NRTI-sparing ART, especially integrase strand transfer inhibitor (INSTI)- and/or non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens, might alleviate the burden of intestinal dysbiosis in HIV-1-infected patients under long-term ART.

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HIV‐1 Reverse Transcriptase Connection Domain Mutations: Dynamics of Emergence and Implications for Success of Combination Antiretroviral Therapy

Clinical Infectious Diseases ◽

10.1086/655764 ◽

2010 ◽

Vol 51 (5) ◽

pp. 620-628 ◽

Cited By ~ 21

Author(s):

Viktor von Wyl ◽

Maryam Ehteshami ◽

Lisa M. Demeter ◽

Philippe Bürgisser ◽

Monique Nijhuis ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Reverse Transcriptase ◽

Combination Antiretroviral Therapy ◽

Hiv 1

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Discordant Outcomes following Failure of Antiretroviral Therapy Are Associated with Substantial Differences in Human Immunodeficiency Virus-Specific Cellular Immunity

Journal of Virology ◽

10.1128/jvi.77.10.6041-6049.2003 ◽

2003 ◽

Vol 77 (10) ◽

pp. 6041-6049 ◽

Cited By ~ 20

Author(s):

David A. Price ◽

George Scullard ◽

Annette Oxenius ◽

Ruth Braganza ◽

Simon A. Beddows ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Antiretroviral Therapy ◽

T Lymphocyte ◽

Virologic Failure ◽

Multiple Drug Resistance ◽

Testable Hypothesis ◽

Plasma Virus ◽

Immunodeficiency Virus ◽

Lymphocyte Responses ◽

Hiv 1

ABSTRACT Many individuals chronically infected with human immunodeficiency virus type 1 (HIV-1) experience a recrudescence of plasma virus during continuous combination antiretroviral therapy (ART) due either to the emergence of drug-resistant viruses or to poor compliance. In most cases, virologic failure on ART is associated with a coincident decline in CD4+ T lymphocyte levels. However, a proportion of discordant individuals retain a stable or even increasing CD4+ T lymphocyte count despite virological failure. In order to address the nature of these different outcomes, we evaluated virologic and immunologic variables in a prospective, single-blinded, nonrandomized cohort of 53 subjects with chronic HIV-1 infection who had been treated with continuous ART and monitored intensively over a period of 19 months. In all individuals with detectable viremia on ART, multiple drug resistance mutations with similar impacts on viral growth kinetics were detected in the pol gene of circulating plasma virus. Further, C2V3 env gene analysis demonstrated sequences indicative of CCR5 coreceptor usage in the majority of those with detectable plasma viremia. In contrast to this homogeneous virologic pattern, comprehensive screening with a range of antigens derived from HIV-1 revealed substantial immunologic differences. Discordant subjects with stable CD4+ T lymphocyte counts in the presence of recrudescent virus demonstrated potent virus-specific CD4+ and CD8+ T lymphocyte responses. In contrast, subjects with virologic failure associated with declining CD4+ T lymphocyte counts had substantially weaker HIV-specific CD4+ T lymphocyte responses and exhibited a trend towards weaker HIV-specific CD8+ T lymphocyte responses. Importantly the CD4+ response was sustained over periods as long as 11 months, confirming the stability of the phenomenon. These correlative data lead to the testable hypothesis that the consequences of viral recrudescence during continuous ART are modulated by the HIV-specific cellular immune response.

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A Randomized Switch From Nevirapine-Based Antiretroviral Therapy to Single Tablet Rilpivirine/Emtricitabine/Tenofovir Disoproxil Fumarate in Virologically Suppressed Human Immunodeficiency Virus-1-Infected Rwandans

Open Forum Infectious Diseases ◽

10.1093/ofid/ofw141 ◽

2016 ◽

Vol 3 (3) ◽

Cited By ~ 2

Author(s):

Sean E. Collins ◽

Philip M. Grant ◽

Francois Uwinkindi ◽

Annie Talbot ◽

Eric Seruyange ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Antiretroviral Therapy ◽

Tenofovir Disoproxil Fumarate ◽

Sub Saharan Africa ◽

Current Therapy ◽

Virologic Suppression ◽

Open Label ◽

Immunodeficiency Virus ◽

Sub Saharan ◽

Hiv 1

Abstract Background. Many human immunodeficiency virus (HIV)-infected patients remain on nevirapine-based antiretroviral therapy (ART) despite safety and efficacy concerns. Switching to a rilpivirine-based regimen is an alternative, but there is little experience with rilpivirine in sub-Saharan Africa where induction of rilpivirine metabolism by nevirapine, HIV subtype, and dietary differences could potentially impact efficacy. Methods. We conducted an open-label noninferiority study of virologically suppressed (HIV-1 ribonucleic acid [RNA] < 50 copies/mL) HIV-1-infected Rwandan adults taking nevirapine plus 2 nucleos(t)ide reverse-transcriptase inhibitors. One hundred fifty participants were randomized 2:1 to switch to coformulated rilpivirine-emtricitabine-tenofovir disoproxil fumarate (referenced as the Switch Arm) or continue current therapy. The primary efficacy endpoint was HIV-1 RNA < 200 copies/mL at week 24 assessed by the US Food and Drug Administration Snapshot algorithm with a noninferiority margin of 12%. Results. Between April and September 2014, 184 patients were screened, and 150 patients were enrolled; 99 patients switched to rilpivirine-emtricitabine-tenofovir, and 51 patients continued their nevirapine-based ART. The mean age was 42 years and 43% of participants were women. At week 24, virologic suppression (HIV-1 RNA level <200 copies/mL) was maintained in 93% and 92% in the Switch Arm versus the continuation arm, respectively. The Switch Arm was noninferior to continued nevirapine-based ART (efficacy difference 0.8%; 95% confidence interval, −7.5% to +12.0%). Both regimens were generally safe and well tolerated, although 2 deaths, neither attributed to study medications, occurred in participants in the Switch Arm. Conclusions. A switch from nevirapine-based ART to rilpivirine-emtricitabine-tenofovir disoproxil fumarate had similar virologic efficacy to continued nevirapine-based ART after 24 weeks with few adverse events.

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Evaluation of viral resistance to Reverse Transcriptase Inhibitors (RTI) in HIV-1-infected patients before and after 6 months of single or double antiretroviral therapy

The Brazilian Journal of Infectious Diseases ◽

10.1590/s1413-86702001000400003 ◽

2001 ◽

Vol 5 (4) ◽

Cited By ~ 2

Author(s):

Carlos Brites ◽

Fabianna Bahia ◽

Mark Gilbert ◽

Célia Pedroso ◽

Roberto Badaró

Keyword(s):

Antiretroviral Therapy ◽

Reverse Transcriptase ◽

Viral Resistance ◽

Reverse Transcriptase Inhibitors ◽

Before And After ◽

Hiv 1

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Association of Suboptimal Antiretroviral Therapy Adherence With Inflammation in Virologically Suppressed Individuals Enrolled in the SMART Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx275 ◽

2017 ◽

Vol 5 (1) ◽

Cited By ~ 4

Author(s):

Jose R Castillo-Mancilla ◽

Andrew N Phillips ◽

James D Neaton ◽

Jacqueline Neuhaus ◽

Simon Collins ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Confidence Interval ◽

Cohort Studies ◽

Plasma Concentrations ◽

Virologic Suppression ◽

Art Adherence ◽

Antiretroviral Therapy Adherence ◽

Smart Study ◽

Hiv 1 ◽

D Dimer

Abstract Suboptimal (ie, <100%) antiretroviral therapy (ART) adherence has been associated with heightened inflammation in cohort studies, even among people with virologic suppression. We aimed to evaluate this association among participants in the Strategies for Management of Antiretroviral Therapy (SMART) study who had virologic suppression (HIV-1 VL < 200 copies/mL) at enrollment. Based on self-reported adherence (7-day recall), plasma concentrations of interleukin 6 and D-dimer were 9% (95% confidence interval [CI], 1%–18%; P = .02) and 11% (95% CI, 1%–22%; P = .03) higher in participants who reported suboptimal vs 100% adherence, respectively. These findings confirm previous observations and support the hypothesis that suboptimal ART adherence, even in the context of virologic suppression, may have significant biological consequences. ClinicalTrials.gov number NCT00027352

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