Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial

Kambugu, Andrew; Kaimal, Arvind; Castelnuovo, Barbara; Kiiza, Daniel; Kisembo, John; Nsubuga, John; Okwero, Max; Muyise, Rhona; Kityo, Cissy; Nasaazi, Claire; Nakiboneka, D; Mugerwa, Henry; Namusanje, Josephine; Najjuuko, Theresa; Masaba, Timothy; Serumaga, Timothy; Alinaitwe, Adolf; Arinda, Allan; Rweyora, Angela; Ategeka, Gilbert; Kangah, Mary Goretti; Lugemwa, Abbas; Kasozi, Mariam; Tukumushabe, Phionah; Akunda, Rogers; Makumbi, Shafic; Musumba, Sharif; Myalo, Sula; Ahuura, John; Namusisi, Annet Mary; Kibirige, Daniel; Kiweewa, Francis; Mirembe, Grace; Mabonga, Habert; Wandege, Joseph; Nakakeeto, Josephine; Namubiru, Sharon; Nansalire, Winfred; Siika, Abraham; Kwobah, Charles; Mboya, Chris Sande; Mokaya, M; Karoney, Mercy Jelagat; Cheruiyot, Priscilla; Cherutich, Salinah; Njuguna, Simon Wachira; Kirui, Viola Cherotich; Borok, Margaret; Chidziva, Ennie; Musoro, Godfrey; Hakim, James; Bhiri, Joyline; Phiri, Misheck Nkalo; Mudzingwa, Shepherd; Manyanga, Tadios; Kiragga, Agnes; Banegura, Anchilla Mary; Hoppé, Anne; Balyegisawa, Apolo; Agwang, Betty; Isaaya, Brian; Tumwine, Constantine; Laker, Eva; Asienzo, Jesca; Musaazi, Joseph; Paton, Nicholas I.; Senkungu, Peter; Walimbwa, Stephen; Kamara, Yvonne; Amperiize, Mathius; Allen, Elizabeth; Opondo, Charles; Mohammed, Perry; Horst, Willemijn van Rein-van der; Delft, Yvon van; Boateng, Fafa Addo; Namara, Doreen; Kaleebu, Pontiano; Ojoo, Sylvia; Bwakura, Tapiwanashe; Katana, Milly; Venter, François; Phiri, Sam; Walker, Sarah

doi:10.1016/s2352-3018(22)00092-3

Cited by 62 publications

(72 citation statements)

References 23 publications

(46 reference statements)

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“…Darunavir-ritonavir was non-inferior to dolutegravir for the outcome of virologic suppression at week 96 in the NADIA study 5 and is, therefore, a robust alternative to dolutegravir in In summary, dolutegravir in second-line ART with recycled tenofovir is more effective than switching to zidovudine. However, emergent dolutegravir resistance in a small minority of participants raises a public health concern as dolutegravir is recommended in most patients requiring first-line ART.…”

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confidence: 90%

“…Emergent dolutegravir resistance was reported in a small proportion of integrase inhibitor-naïve participants switching to second-line dolutegravir-based ART in randomised trials (9 [4%] of 235 participants by week 96 in NADIA and 6 [2%] of 314 participants by week 159 in DAWNING). 2,5,9 Notably, emergence of protease inhibitor resistance did not occur in either NADIA or DAWNING, indicating that dolutegravir has a lower genetic barrier to resistance than protease inhibitors when dolutegravir is administered with NRTIs potentially compromised by resistance mutations. Risk factors associated with emergent dolutegravir resistance include intermittent adherence, drug-drug interactions, high baseline HIV-1 RNA and active opportunistic infections.…”

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confidence: 99%

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Dolutegravir for second-line treatment: Programmatic implications of new evidence

Zhao

Maartens

Meintjes

2022

South. Afr. j. HIV med.

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confidence: 90%

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Dolutegravir for second-line treatment: Programmatic implications of new evidence

Zhao

Maartens

Meintjes

2022

South. Afr. j. HIV med.

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“…Subsequent to our study being done, the NADIA trial showed that TLD after TDF-FTC-EFV (efavirenz) failure was superior to AZT-3TC-DTG although that was not known at the time of our study. 7 The clinical impact of switching treatment experienced patients to DTG-based regimens was poorly understood at the time, therefore knowing the frequency of reduced predictive efficacy to TLD in children and adolescents is still useful in low- and middle-income countries (LMICs) where genotypic testing before treatment switch is often not available.…”

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confidence: 99%

Minimal Cross-resistance to Tenofovir in Children and Adolescents Failing ART Makes Them Eligible for Tenofovir-Lamivudine-Dolutegravir Treatment

Steegen

Levin

Evans

et al. 2022

Pediatric Infectious Disease Journal

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Background: Fixed-dose combination of dolutegravir (DTG) with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) likely improves adherence and has a favorable resistance profile. We evaluated predicted efficacy of TLD (TDF-3TC-DTG) in children and adolescents failing abacavir (ABC), zidovudine (AZT), or TDF containing regimens. Methods: Drug resistance mutations were analyzed in a retrospective dataset of individuals <19 years of age, failing ABC (n = 293) AZT (n = 288) or TDF (n = 69) based treatment. Pol sequences were submitted to Stanford HIVdb v8.9. Genotypic susceptibility scores were calculated for various DTG-containing regimens. Results: Genotypes were assessed for 650 individuals with a median age of 14 years (IQR 10-17 years). More individuals failed a protease inhibitor (PI)-based (78.3%) than a non-nucleoside reverse transcriptase inhibitors (NNRTI)-based (21.7%) regimen. Most individuals in the AZT group (n = 288; 94.4%) failed a PI-based regimen, compared with 71.0% and 64.2% in the TDF (n = 69) and ABC group (n = 293). Genotypic sensitivity scores <2 to TLD were observed in 8.5% and 9.4% of ABC- and AZT-exposed individuals, compared with 23.2% in the TDF group. The M184V mutation was most often detected in the ABC group (70.6%) versus 60.0% and 52.4% in TDF and AZT groups. The presence of K65R was rare (n = 13, 2.0%) and reduced TLD susceptibility was commonly caused by accumulation of nucleoside reverse transcriptase inhibitor (NRTI) mutations. Conclusions: Cross-resistance to TDF was limited, further reducing concerns about use of transition to TLD in children and adolescents. The NADIA trial has subsequently shown that patients failing a TDF/3TC/EFV regimen can safely be transitioned to a TLD regimen but we do not have data for patients failing an ABC/3TC/NNRTI or PI regimens. Frequent virological monitoring is recommended after switch to DTG, especially in children continuing ABC in the backbone. Clinical studies correlating predicted resistance with clinical outcomes, especially in settings without access to genotyping, are required.

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“…I have a few comments and questions: The first statement in the abstract as well as part of the literature review may need to be updated in view of the recent presentation of data from both the NADIA 1 and VISEND trials. The VISEND trial showed that TLD had superior efficacy to PI/r (LPVr and ATVr) and the NADIA showed that DTG did well even in the absence of a fully active NRTI.…”

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confidence: 99%

“… Indicate the dissemination plan to participants. Update the discussion in the main text to highlight the findings from recently published data 1 , 2 on the use of DTG in 2 nd line ART in sub-Saharan Africa. These recent findings are relevant to the discussion of the protocol and also strengthen the rationale of the ARTIST protocol.…”

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AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir (ARTIST): protocol for a randomised controlled trial

et al. 2021

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Background: Dolutegravir has superior efficacy and tolerability than lopinavir-ritonavir in second-line antiretroviral therapy after failure of a first-line non-nucleoside reverse transcriptase inhibitors-based regimen, when dolutegravir is accompanied by at least one fully active nucleoside reverse transcriptase inhibitor (NRTI). Resistance testing to select NRTIs is not feasible in low- and middle-income countries due to cost and limited laboratory capacity. Evidence suggests that recycling tenofovir plus lamivudine or emtricitabine backbone with dolutegravir could provide an effective second-line option. This study aims to determine the virologic efficacy of tenofovir-lamivudine-dolutegravir (TLD) with and without a lead-in supplementary dose of dolutegravir (to counteract the inducing effect of efavirenz) in patients failing a first-line regimen of tenofovir-emtricitabine-efavirenz (TEE). Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled, Phase II trial, comparing TLD fixed dose combination daily with a lead-in supplementary 50 mg dolutegravir dose versus matching placebo taken 12 hours later for the first 14 days, in patients failing a first-line TEE regimen. The trial will be set in two primary care clinics in Khayelitsha; a large, peri-urban informal settlement in Cape Town, South Africa. We will enrol 130 participants, with follow-up to 48 weeks. The primary endpoint is proportion achieving viral load <50 copies/mL at week 24 using a modified intention-to-treat analysis and the U.S. Food and Drug Administration snapshot algorithm. Secondary endpoints include virologic suppression at weeks 12 and 48, time to suppression, emergence of dolutegravir and new NRTI resistance mutations, safety, and tolerability. Discussion: Impaired viral fitness due to NRTI resistance mutations and dolutegravir’s high barrier to resistance provide rationale for switching patients from a failing TEE regimen to TLD; however, clinical evidence regarding virologic efficacy is lacking. This study provides estimates of such a strategy’s early virologic efficacy with and without a supplementary dolutegravir dosing. Registration: ClinicalTrials.gov NCT03991013 (19/06/2019).

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Efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial

Cited by 62 publications

References 23 publications

Dolutegravir for second-line treatment: Programmatic implications of new evidence

Dolutegravir for second-line treatment: Programmatic implications of new evidence

Minimal Cross-resistance to Tenofovir in Children and Adolescents Failing ART Makes Them Eligible for Tenofovir-Lamivudine-Dolutegravir Treatment

AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir (ARTIST): protocol for a randomised controlled trial

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