Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study

Clotet, Bonaventura; Feinberg, Judith; Lunzen, Jan van; Khuong-Josses, Marie Aude; Antinori, Andrea; Dumitru, Irina Magdalena; Pokrovskiy, Vadim; Fehr, Jan; Ortiz, Roberto; Saag, Michael S.; Harris, Julia; Brennan, Clare; Fujiwara, Tamio; Min, Sherene

doi:10.1016/s0140-6736(14)60084-2

Cited by 450 publications

(426 citation statements)

References 24 publications

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“…Virological failure in ARV-naive individuals receiving DTG was not associated with the emergence of drug resistance substitutions against either DTG or other drugs that were coadministered with it (3)(4)(5)(6). In contrast, drug resistance has been reported against other INSTIs, i.e., raltegravir (RAL) and elvitegravir (EVG), in treatment-naive and treatment-experienced individuals (7).…”

mentioning

confidence: 98%

Combination of the R263K and M184I/V Resistance Substitutions against Dolutegravir and Lamivudine Decreases HIV Replicative Capacity

Singhroy

Wainberg

Mésplède

2015

Antimicrob Agents Chemother

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bWe investigated the effect of combining the dolutegravir-specific R263K integrase resistance substitution with either M184I or M184V, two reverse transcriptase drug resistance substitutions that are frequently detected in individuals failing therapeutic regimens containing either lamivudine or emtricitabine. The presence of R263K and M184I/V in a single virus resulted in substantial further decreases in the viral replicative capacity compared to that in the presence of single substitutions alone. In treatment-naive individuals, human immunodeficiency virus type 1 (HIV-1) has been able to develop resistance substitutions against all new antiretrovirals (ARVs) tested to date, with the exception of the integrase strand-transfer inhibitor (INSTI) dolutegravir (DTG) (1, 2). Virological failure in ARV-naive individuals receiving DTG was not associated with the emergence of drug resistance substitutions against either DTG or other drugs that were coadministered with it (3-6). In contrast, drug resistance has been reported against other INSTIs, i.e., raltegravir (RAL) and elvitegravir (EVG), in treatment-naive and treatment-experienced individuals (7). The emergence of resistance substitutions against reverse transcriptase inhibitors coadministered with RAL and EVG has also been reported (4,8,9), as has the occurrence of relevant resistance substitutions in patients failing treatment with protease inhibitors (10).DTG robustness against the emergence of resistance substitutions in treatment-naive individuals may be related to the fact that the most common resistance substitution that has been selected by DTG in tissue culture and in treatment-experienced individuals has been R263K, which is associated with a decrease in HIV-1 replicative capacity (11,12). Moreover, no compensatory substitution for R263K has been reported (2, 13-17), and the appearance of R263K in two INSTI-naive, treatment-experienced individuals who failed DTG treatment did not lead to the occurrence of other resistance substitutions within integrase, despite the fact that therapy with DTG was continued even after detection of the R263K substitution (13).This contrasts with the generation of multiple integrase substitutions in treatment-experienced individuals who have failed treatment with DTG after having previously failed treatment with either RAL or EVG (18), which led us to hypothesize that the R263K substitution may represent an evolutionary dead end for HIV and that this may explain the absence of resistance to DTG in treatment-naive individuals (2). DTG is now coformulated with two nucleoside reverse transcriptase inhibitors (NRTIs), lamivudine (3TC) and abacavir (ABC) (http://content.govdelivery.com /accounts/USFDA/bulletins/cb6dfa), and treatment failure with these NRTIs has commonly led to the appearance of the M184I/V substitutions that are associated with resistance against 3TC and emtricitabine (FTC) (19,20). M184V is also associated with a lower incidence of thymidine analogue substitutions and with increased susceptibility to some rever...

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confidence: 98%

Combination of the R263K and M184I/V Resistance Substitutions against Dolutegravir and Lamivudine Decreases HIV Replicative Capacity

Singhroy

Wainberg

Mésplède

2015

Antimicrob Agents Chemother

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“…The most recently approved INSTI dolutegravir (DTG) is for once-daily dosing without a pharmacokinetic booster and shows efficacy for treatment-naive subjects and treatment-experienced but INSTI-naive subjects, as well as subjects who failed RAL and EVG treatment (9)(10)(11)(12)(13). DTG was approved by the U.S. FDA in August 2013 for treatment-naive and treatment-experienced INSTI-naive adults, as well as for INSTI-resistant adults.…”

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confidence: 99%

Effects of Raltegravir or Elvitegravir Resistance Signature Mutations on the Barrier to Dolutegravir Resistance In Vitro

Seki

Suyama-Kagitani

Kawauchi-Miki

et al. 2015

Antimicrob Agents Chemother

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cThe recently approved HIV-1 integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) (S/GSK1349572) has overall advantageous activity when tested in vitro against HIV-1 with raltegravir (RAL) and elvitegravir (EVG) resistance signature mutations. We conducted an in vitro resistance selection study using wild-type HIV-1 and mutants with the E92Q, Y143C, Y143R, Q148H, Q148K, Q148R, and N155H substitutions to assess the DTG in vitro barrier to resistance. No viral replication was observed at concentrations of >32 nM DTG, whereas viral replication was observed at 160 nM RAL or EVG in the mutants. In the Q148H, Q148K, or Q148R mutants, G140S/Q148H, E138K/Q148K, E138K/Q148R, and G140S/Q148R secondary mutations were identified with each INSTI and showed high resistance to RAL or EVG but limited resistance to DTG. E138K and G140S, as secondary substitutions to Q148H, Q148K, or Q148R, were associated with partial recovery in viral infectivity and/or INSTI resistance. In the E92Q, Y143C, Y143R, and N155H mutants, no secondary substitutions were associated with DTG. These in vitro results suggest that DTG has a high barrier to the development of resistance in the presence of RAL or EVG signature mutations other than Q148. One explanation for this high barrier to resistance is that no additional secondary substitution of E92Q, Y143C, Y143R, or N155H simultaneously increased the fold change in 50% effective concentration (EC 50 ) to DTG and infectivity. Although increased DTG resistance via the Q148 pathway and secondary substitutions occurs at low concentrations, a higher starting concentration may reduce or eliminate the development of DTG resistance in this pathway in vitro.

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“…55 Discovery of one of the newer classes of antiretroviral drugs known as integrase strand transfer inhibitor agents (InSTIs) has been a major step forward and regimens based on this class of drug are currently viewed as optimal for initial therapy. 56 These drugs are highly effective at virological suppression in comparison with other classes of antiretroviral drugs 58,59 and are extremely well tolerated. 60 In addition to the new drugs themselves, clinical trials have shown the benefits of beginning antiretroviral therapy early after infection, 56 benefiting not only the individual patients but also making them significantly less infectious to their partners, 61 thereby integrating treatment and prevention.…”

Section: Hivmentioning

confidence: 99%

No longer 'written off' – times have changed for the BBV-infected dental professional

et al. 2017

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There is a recognised potential risk of transmission of blood-borne viruses (BBVs) from infected healthcare workers to patients during exposure prone procedures (EPPs). The restrictions placed on performance of EPPs by infected clinicians in the UK have had a particularly significant impact on dentists, because of the exposure-prone nature of most dental procedures and the difficulties in identifying alternative career pathways in the profession that do not involve EPPs. More recently, the significant positive impact of antiviral drugs on viral load together with a re-categorisation of EPPs in dentistry have resulted in evolution of the guidance with a consequent significant improvement to the career prospects of dentists infected with BBVs. This paper provides an update for practitioners on the progress that has been made and outlines the current position with respect to practice restrictions.

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Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study

Cited by 450 publications

References 24 publications

Combination of the R263K and M184I/V Resistance Substitutions against Dolutegravir and Lamivudine Decreases HIV Replicative Capacity

Combination of the R263K and M184I/V Resistance Substitutions against Dolutegravir and Lamivudine Decreases HIV Replicative Capacity

Effects of Raltegravir or Elvitegravir Resistance Signature Mutations on the Barrier to Dolutegravir Resistance In Vitro

No longer 'written off' – times have changed for the BBV-infected dental professional

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