HIV-1 Resistance Dynamics in Patients With Virologic Failure to Dolutegravir Maintenance Monotherapy

Wijting, Ingeborg E A; Lungu, Cynthia; Rijnders, Bart J. A.; Ende, Marchina E. van der; Pham, Hanh Thi; Mésplède, Thibault; Pas, Suzan D.; Voermans, Jolanda J.C.; Schuurman, Rob; Vijver, David van de; Boers, Patrick H. M.; Gruters, Rob A.; Boucher, Charles A.; Kampen, Jeroen J. A. van

doi:10.1093/infdis/jiy176

Cited by 73 publications

(53 citation statements)

References 38 publications

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“…This finding suggests that the development of this specific resistance pathway is not sufficient by itself to predict treatment failure. As described earlier (reviewed in reference 16), other host and viral factors may contribute to these different outcomes, including immunological factors (such as the strength of the antiviral immune responses) and also the reservoir size, given that this parameter was recently reported to correlate with virological failure in people using dolutegravir monotherapy as maintenance (13). These G140A and Q148K mutations were not unexpected, considering that HIV-1 mutants with changes at integrase positions 140 and 148 were recently described to emerge in an HIV-infected humanized mouse that was treated with DTG and led to a partial viral rebound (41).…”

Section: Discussionmentioning

confidence: 92%

“…G118R and R263K were both identified during preclinical in vitro selection experiments with HIV under DTG pressure and later found in patients failing DTG-based ART (6,(31)(32)(33). Notably, both G118R and R263K were found to emerge from HIV sequences in the context of dolutegravir monotherapy (6,13). We previously showed that introducing G118R in SIVmac239 integrase caused an 80% decrease in enzymatic efficiency (22,34).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, several studies have investigated DTG monotherapy as a maintenance therapy in HIV-infected patients who have previously achieved virological suppression with combination ART regimens. Despite promising results in several initial small studies, in subsequent larger studies, including the DOMONO study, occasional virological failures associated with the detection of DTG resistance mutations have been reported, raising ethical concerns whether this strategy deserves further consideration (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…However, sequencing of 2-LTR circles, which form at low frequency in the cell nucleus via DNA ligation and thus provide a snapshot of viral DNA end sequences, failed to identify the hypothesized PPT extension (148). PPT mutations have been recorded in one patient who received DTG monotherapy (149), indicating that such changes may very well be clinically relevant. Additional work is required to more fully document the frequency of PPT changes in patients that fail DTG therapy as well as how such changes engender drug resistance.…”

Section: Mechanisms Of Hiv Resistance To Instismentioning

confidence: 99%

“…Despite relatively high barriers, second-generation INSTIs do select for resistance (149,159,163). As exemplified by the clinical successes of the NRTIs and NNRTIs, it would accordingly be highly beneficial to have additional drug classes that inhibit IN activity through novel mechanisms of action.…”

Section: Allinismentioning

confidence: 99%

Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition

Engelman

2019

Journal of Biological Chemistry

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Figure 3. Retroviral intasome structures. A-C, representative intasomes from the spumavirus PFV (A; protein database (PDB) accession code 3OY9), ␤-retrovirus MMTV (B; PDB code 3JCA), and lentivirus MVV (C; PDB code 5M0Q) are color-coded to highlight the CIC. Green and blue, catalytically active IN protomers; cyan, supporting IN CCDs; black, DNA strands. Whereas four PFV IN molecules suffice to form the CIC, both MMTV and MVV require six IN protomers. For MMTV, critical CTDs (magenta) are donated by flanking IN dimers, leading to an overall IN octamer. In MVV, flanking IN tetramers provide the critical CTDs, resulting in an overall IN hexadecamer. Gray coloring in B and C deemphasizes IN elements that do not compose the CIC. D-F, resected CCD and CTD domains from above green IN protomers, oriented to highlight the different CCD-CTD linker regions (dark gray). Associated magenta CTDs from separate IN protomers in E and F assume similar positions as the green CTD in D. Red sticks, DDE catalytic triad residues. JBC REVIEWS: HIV integrase mechanisms and inhibition 15140 Figure 4. INSTI structures and ALLINI chemotypes. A, diagrams of the four FDA-licensed INSTIs as well as investigational second-generation compound 6p (113, 119). B, representative ALLINI chemotypes. Asterisks mark common positions of t-butoxyacid moieties. JBC REVIEWS: HIV integrase mechanisms and inhibition 15142

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Recent Advances in the Development of Integrase Inhibitors for HIV Treatment

et al. 2020

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Purpose of the review-The complex multistep life-cycle of HIV allows it to proliferate within the host and integrate its genome in to the host chromosomal DNA. This provirus can remain dormant for an indefinite period. The process of integration, governed by integrase (IN), is highly conserved across the Retroviridae family. Hence, targeting integration is not only expected to block HIV replication but may also reveal new therapeutic strategies to treat HIV as well as other retrovirus infections.Recent findings-HIV integrase (IN) has gained attention as the most promising therapeutic target as there are no equivalent homologues of IN that has been discovered in humans. Although current nano-formulated long-acting IN inhibitors have demonstrated the phenomenal ability to block HIV integration and replication with extraordinary half-life, they also have certain limitations.Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. http://www.springer.com/gb/openaccess/authors-rights/aam-terms-v1

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HIV-1 Resistance Dynamics in Patients With Virologic Failure to Dolutegravir Maintenance Monotherapy

Abstract: NCT02401828.

Cited by 73 publications

References 38 publications

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

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

Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition

Recent Advances in the Development of Integrase Inhibitors for HIV Treatment

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