Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1

Hassounah, Said; Alikhani, Ahmad; Oliveira, Maureen; Bharaj, Simrat; Ibanescu, Ruxandra-Ilinca; Osman, Nathan; Xu, Hongtao; Brenner, Bluma G.; Mésplède, Thibault; Wainberg, Mark A.

doi:10.1128/aac.01695-17

Cited by 36 publications

(22 citation statements)

References 51 publications

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“…We previously showed that the results obtained with this assay are concordant with those seen in spreading infections of immortalized T-cell lines, as demonstrated for the INIs raltegravir (17), dolutegravir (21), and cabotegravir (22). In addition, other groups have used similar single-cycle assays to quantify the activity of various INIs against HIV-1 and simian immunodeficiency virus (SIV) (33,(36)(37)(38)(39)(40).…”

supporting

confidence: 58%

Comparison of the Antiviral Activity of Bictegravir against HIV-1 and HIV-2 Isolates and Integrase Inhibitor-Resistant HIV-2 Mutants

Smith

Raugi

et al. 2019

Antimicrob Agents Chemother

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We compared the activity of the integrase inhibitor bictegravir against HIV-1 and HIV-2 using a culture-based, single-cycle assay. Values of 50% effective concentrations ranged from 1.2 to 2.5 nM for 9 HIV-1 isolates and 1.4 to 5.6 nM for 15 HIV-2 isolates. HIV-2 integrase mutants G140S/Q148R and G140S/Q148H were 34- and 110-fold resistant to bictegravir, respectively; other resistance-associated mutations conferred ≤5-fold changes in bictegravir susceptibility. Our findings indicate that bictegravir-based antiretroviral therapy should be evaluated in HIV-2-infected individuals.

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supporting

confidence: 58%

Comparison of the Antiviral Activity of Bictegravir against HIV-1 and HIV-2 Isolates and Integrase Inhibitor-Resistant HIV-2 Mutants

Smith

Raugi

et al. 2019

Antimicrob Agents Chemother

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“…We have reported previously on the effects of E92Q, Q148K, G118R, and R263K on the antiretroviral drug susceptibility of SIV, as these mutations confer low-level (2-to 12-fold) resistance to DTG in vitro (22,29). Here, to explore the importance of viral fitness on treatment failure versus viral suppression, we documented the replicative capacities of wild-type (WT), E92Q mutant, and G118R mutant viruses in monkey peripheral blood mononuclear cells (PBMCs) over 12 days (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dolutegravir Monotherapy of Simian Immunodeficiency Virus-Infected Macaques Selects for Several Patterns of Resistance Mutations with Variable Virological Outcomes

Rompay

Hassounah

Keele

et al. 2019

J Virol

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Drug resistance remains a major concern for human immunodeficiency virus (HIV) treatment. To date, very few resistance mutations have emerged in first-line combination therapy that includes the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG). In vitro, DTG selects for several primary mutations that induce low-level DTG resistance; secondary mutations, while increasing the level of resistance, however, further impair replication fitness, which raised the idea that DTG monotherapy may be feasible. The simian immunodeficiency virus (SIV) rhesus macaque model of HIV infection can be useful to explore this concept. Nine macaques were infected with virulent SIVmac251 and started on DTG monotherapy during either acute (n = 2) or chronic infection (n = 7). Within 4 weeks of treatment, all animals demonstrated a reduction in viremia of 0.8 to 3.5 log RNA copies/ml plasma. Continued treatment led to overall sustained benefits, but the outcome after 10 to 50 weeks of treatment was highly variable and ranged from viral rebound to near pretreatment levels to sustained suppression, with viremia being 0.5 to 5 logs lower than expected based on pretreatment viremia. A variety of mutations previously described to confer low-level resistance of HIV-1 to DTG or other INSTI were detected, and these were sometimes followed by mutations believed to be compensatory. Some mutations, such as G118R, previously shown to severely impair the replication capacity in vitro, were associated with more sustained virological and immunological benefits of continued DTG therapy, while other mutations, such as E92Q and G140A/Q148K, were associated with more variable outcomes. The observed variability of the outcomes in macaques warrants avoidance of DTG monotherapy in HIV-infected people. IMPORTANCE A growing number of anti-HIV drug combinations are effective in suppressing virus replication in HIV-infected persons. However, to reduce their cost and risk for toxicity, there is considerable interest in simplifying drug regimens. A major concern with single-drug regimens is the emergence of drug-resistant viral mutants. It has been speculated that DTG monotherapy may be a feasible option, because DTG may have a higher genetic barrier for the development of drug resistance than other commonly used antiretrovirals. To explore treatment initiation with DTG monotherapy, we started SIV-infected macaques on DTG during either acute or chronic infection. Although DTG initially reduced virus replication, continued treatment led to the emergence of a variety of viral mutations previously described to confer low-level resistance of HIV-1 to DTG, and this was associated with variable clinical outcomes. This unpredictability of mutational pathways and outcomes warns against using DTG monotherapy as initial treatment for HIV-infected people.

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“…In the study of Quashie et al, site-directed mutagenesis analysis showed that R263K did confer very low-level resistance to DTG (Fold Change (FC) = 1.06), a slight increased for EVG (FC = 1.75) and no change for RAL (FC = 0.63) [ 2 ]. More recently, it has been shown that in both single and multiple rounds of HIV-1 infections, bictegravir (BIC) and cabotegravir (CAB), two INIs currently under development, remained active against R263K mutant [ 7 ].…”

Section: R263k Integrase Mutationmentioning

confidence: 99%

“…Interestingly, regarding both INI currently under development, BIC and CAB, they remained active against R263K-M50I and R263K-E138K double-mutants with less than ≤4-fold increase in phenotypic resistance level [ 7 ].…”

Section: R263k Integrase Mutationmentioning

confidence: 99%

Resistance to HIV Integrase Inhibitors: About R263K and E157Q Mutations

Charpentier

Descamps

2018

Viruses

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The use of integrase inhibitors (INI) is increasing in antiretroviral therapies (ART) and INI are not all equal regarding genetic barrier to resistance. The aim of this manuscript was to review main in vivo and in vitro knowledge about two particular integrase resistance-associated mutations: R263K and E157Q. The R263K mutation was the first mutation rarely found selected at time of virological failure in patients failing a first-line dolutegravir-based treatment. Further in vitro studies on R263K mutants showed a moderate increase in phenotypic resistance level and a drastic reduction in viral replicative capacity. No compensatory mutations were evidenced. The E157Q mutation is polymorphic, found between 1.7% and 5.6% of viral sequences issued from ART-naïve patients depending on the viral subtype; as well as acquired resistance emerging at failure of a raltegravir-based regimen in two case reports. We reported data on phenotypic resistance level of E157Q mutants and virological response of patients harboring a E157Q virus initiating an INI-based regimen, showing that dolutegravir might be the most recommended INI in such patients. These findings show that there is still a need for a better understanding of resistance mechanisms to INI and emphasized the importance of genotypic background in viral evolution under drug pressure.

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Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1

Cited by 36 publications

References 51 publications

Comparison of the Antiviral Activity of Bictegravir against HIV-1 and HIV-2 Isolates and Integrase Inhibitor-Resistant HIV-2 Mutants

Comparison of the Antiviral Activity of Bictegravir against HIV-1 and HIV-2 Isolates and Integrase Inhibitor-Resistant HIV-2 Mutants

Dolutegravir Monotherapy of Simian Immunodeficiency Virus-Infected Macaques Selects for Several Patterns of Resistance Mutations with Variable Virological Outcomes

Resistance to HIV Integrase Inhibitors: About R263K and E157Q Mutations

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