Correlating Conformational Shift Induction with Altered Inhibitor Potency in a Multidrug Resistant HIV-1 Protease Variant

Abstract Background BRIGHTE is an ongoing global study evaluating the gp120 attachment inhibitor fostemsavir (FTR) in heavily treatment-experienced (HTE) adults with multidrug resistant (MDR) HIV-1 unable to form a viable antiretroviral (ARV) regimen. An estimated 2 million people living with HIV-1 have been infected with SARS-CoV-2. Those with HIV viremia and/or low CD4+ counts are at increased risk of serious adverse outcome. We describe the reported COVID cases in a clinical trial population of people living with MDR HIV and immune suppression. Methods At the start of the COVID pandemic, all ongoing BRIGHTE subjects had achieved ≥ 192 weeks on FTR and optimized background ARVs; results through Week 96 were presented previously. Investigators used WHO guidelines for COVID diagnosis and reported exposure, testing results and symptom presence. Figure 1. BRIGHTE Study Design Results 371 subjects [272 Randomized Cohort (RC), 99 Non-Randomized Cohort (NC)] were enrolled; 44% were ≥ 50 years of age and 86% had an AIDS history. Median CD4+ count at study start of was 80 cells/mm3 (IQR 11–202); 30% with ≤ 20 cells/mm3. 250 subjects remained in BRIGHTE at pandemic start. By April 2021, 17 subjects (14 RC, 3 NC) had confirmed COVID infection (positive PCR test). Severity was Grade 1-3, all cases resolved with no deaths. Six subjects were hospitalized (Table 1); most recent CD4+ count prior to COVID were 293-1641 cells/mm3 and 5/6 subjects were virologically suppressed. Treatments often included prophylactic anticoagulants and supplemental oxygen; no cART changes were made. The remaining 11/17 confirmed cases were managed outpatient. Five more subjects had suspect COVID not confirmed by PCR and 2 subjects had negative PCR tests. Table 1. Characterization of Participants with Serious AEs of Confirmed COVID-19 Infections – All Hospitalizations Conclusion A total of 22/250 COVID-19 cases (17 confirmed, 5 unconfirmed) have been reported in BRIGHTE. Outcomes were reassuring with no deaths or known persistent sequelae, despite having advanced HIV and comorbid diseases at baseline associated with poorer COVID outcomes. Outcomes may have benefitted from immunologic improvement during the trial. Disclosures Shiven Chabria, MD, Viiv Healthcare (Employee) Stephane De Wit, MD, Gilead (Grant/Research Support)Janssen (Grant/Research Support)Merck Sharpe & Dohme (Grant/Research Support)ViiV Healthcare (Grant/Research Support) Amy Pierce, BS, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Bronagh M. Shepherd, PhD, GlaxoSmithKline (Employee, Shareholder) Michael Warwick-Sanders, BM BSc DPM MFPM, GSK (Employee) Marcia Wang, PhD, GlaxoSmithKline (Employee, Shareholder) Andrew Clark, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Peter Ackerman, MD, GSK/ViiV Healthcare (Employee, Shareholder)

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Primary HIV drug resistance among newly HIV type-1 diagnosed patients in St. Petersburg

HIV Infection and Immunosuppressive Disorders ◽

10.22328/2077-9828-2021-13-1-70-79 ◽

2021 ◽

Vol 13 (1) ◽

pp. 70-79

Author(s):

Thierry Ingabire ◽

A. V. Semenov ◽

E. V. Esaulenko ◽

E. B. Zueva ◽

A. N. Schemelev ◽

...

Keyword(s):

Drug Resistance ◽

Reverse Transcriptase ◽

Direct Sequencing ◽

Population Level ◽

Multidrug Resistant ◽

Antiretroviral Drugs ◽

Drug Resistant ◽

Resistant Virus ◽

Primary Drug Resistance ◽

Hiv 1

There is concern that the widespread use of antiretroviral drugs (ARV) to treat human immunodeficiency virus 1 (HIV-1) infection may result in the emergence of transmission of drug-resistant virus among persons newly infected with HIV-1. Russia is one of a growing number of countries in the world where drug-resistant HIV is becoming a serious health problem because it has the potential to compromise the efficacy of antiretroviral therapy (ART) at the population level.Materials and methods. We performed a genetic analysis of the HIV-1 plasma derived pol gene among the newly diagnosed ART-naïve HIV-1 infected patients during the period from November 2018 to October 2019 in the St. Petersburg Clinical Infectious Diseases Hospital named after S.P. Botkin. We used reverse transcriptase polymerase chain reaction (RT-PCR) followed by direct sequencing of PCR products to determine the prevalence of primary drug resistance (PDR) conferring mutations. HIV-1 genotypes were determined by phylogenetic analysis.Results. The predominant HIV-1 subtype was A1 (87.2%), followed by B (11.8%) and CRF06_cpx (1%). The overall prevalence of PDR was 11%. Virus with known resistance-conferring mutations to any nucleoside reverse transcriptase inhibitors (NRTIs) was found in 8 individuals, to any non NRTIs in 5 subjects, and to any protease inhibitors in 1 case. Multidrug-resistant virus was identified in 2 individuals (2%).Conclusion. The distribution of HIV-1 genotypes in St. Petersburg, Russia is diverse. The emerging prevalence of PDR in ART-naïve patients demonstrates the significance of constant monitoring due to the challenges it presents towards treatment.

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Activity against Human Immunodeficiency Virus Type 1, Intracellular Metabolism, and Effects on Human DNA Polymerases of 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00277-07 ◽

2007 ◽

Vol 51 (8) ◽

pp. 2701-2708 ◽

Cited By ~ 72

Author(s):

Hirotomo Nakata ◽

Masayuki Amano ◽

Yasuhiro Koh ◽

Eiichi Kodama ◽

Guangwei Yang ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Transcriptase Inhibitor ◽

Multidrug Resistant ◽

Wild Type ◽

Immunodeficiency Virus ◽

Reverse Transcriptase Inhibitor ◽

Hiv 1

ABSTRACT We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) of a nucleoside reverse transcriptase inhibitor, 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA), which has potent activity against wild-type and multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 μM [3H]EFdA or [3H]3′-azido-2′,3′-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/109 cells, while that of AZT was 396.5 pmol/109 cells. When CEM cells were exposed to 10 μM [3H]EFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/109 cells), while the amount of [3H]AZT-TP increased only moderately by 2.4-fold (970 pmol/109 cells). The intracellular half-life values of EFdA-TP and AZT-TP were ∼17 and ∼3 h, respectively. When MT-4 cells were cultured with 0.01 μM EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1NL4-3, and cultured for an additional 5 days, the protection values were 75 and 47%, respectively, after 24 and 48 h with no drug incubation, while those with 1 μM AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases α, β, and γ were >100 μM, >100 μM, and 10 μM, respectively, while those of ddA-TP were >100 μM, 0.2 μM, and 0.2 μM, respectively. These data warrant further development of EFdA as a potential therapeutic agent for those patients who harbor wild-type HIV-1 and/or multidrug-resistant variants.

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