The unexpected success of NRTIs in second-line treatment
Authors: Andrew M Hill, Francois Venter
Journal: The Lancet Infectious Diseases (2017)

Genotype-defined resistance to antiretrovirals supposedly predicts future virological failure. Findings from clinical studies, including the 144 week results from the EARNEST trial, published in The Lancet Infectious Diseases,1Hakim JG Thompson J Kityo C et al.Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial.Lancet Infect Dis. 2017; (published online Nov 3)http://dx.doi.org/10.1016/S1473-3099(17)30630-8Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar challenge this decades-long dogma, certainly when it comes to nucleoside analogues. WHO currently recommends second-line treatment with two nucleoside reverse-transcriptase inhibitors (NRTIs) and a boosted protease inhibitor.2WHOConsolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection.June, 2016http://www.who.int/hiv/pub/arv/arv-2016/en/Google Scholar However, there is evidence for widespread resistance to NRTIs after virological failure of first-line treatment in low-income countries, which might limit future treatment options.3TenoRes Study GroupGlobal epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study.Lancet Infect Dis. 2016; 16: 565-575Summary Full Text Full Text PDF PubMed Scopus (188) Google Scholar The EARNEST trial1Hakim JG Thompson J Kityo C et al.Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial.Lancet Infect Dis. 2017; (published online Nov 3)http://dx.doi.org/10.1016/S1473-3099(17)30630-8Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar was set up to evaluate alternatives for second-line treatment, including the current WHO recommendation, which involves sequencing without genotype guidance using virological, immunological, and clinical failure. The novel combination of two drug classes, the integrase inhibitor raltegravir with the boosted protease inhibitor ritonavir-boosted lopinavir (LPV/r), was predicted to outperform the control of two NRTIs plus LPV/r. Patients in the EARNEST trial, identified through the WHO definitions of failure retrospectively, had extensive resistance at randomisation, 95% of patients had at least one NRTI mutation, and 59% of patients had no active NRTIs. Despite extensive NRTI resistance, the control of NRTIs plus LPV/r outperformed the other non-NRTI groups, with 317 (86%) of 426 patients having HIV RNA suppression below 400 copies per mL by week 144, compared with 312 (81%) of 433 patients in the LPV/r plus raltegravir group and 292 (78%) of 418 patients in the LPV/r monotherapy group.1Hakim JG Thompson J Kityo C et al.Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trial.Lancet Infect Dis. 2017; (published online Nov 3)http://dx.doi.org/10.1016/S1473-3099(17)30630-8Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar Findings from two other randomised trials, SELECT4La Rosa AM Harrison LJ Taiwo B et al.Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study.Lancet HIV. 2016; 3: e247-e258Summary Full Text Full Text PDF PubMed Scopus (55) Google Scholar and SECOND-LINE,5Boyd MA Moore CL Molina JM et al.Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: an exploratory analysis.Lancet HIV. 2015; 2: e42-e51Summary Full Text Full Text PDF PubMed Scopus (60) Google Scholar have also shown no benefits for protease inhibitor plus integrase inhibitor second-line combinations. These results suggest that NRTIs are retaining high levels of efficacy despite the predictions of failure from genotypic resistance. In a subgroup analysis of the NRTI plus LPV/r group of EARNEST,6Paton NI Kityo C Thompson J et al.Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial.Lancet HIV. 2017; 4: e341-e348Summary Full Text Full Text PDF PubMed Scopus (60) Google Scholar patients who were taking NRTIs with no predicted activity had the highest levels of viral suppression. This effect was also seen in two other randomised trials of NRTI plus protease inhibitor (with ritonavir) combinations as second-line treatment (table).5Boyd MA Moore CL Molina JM et al.Baseline HIV-1 resistance, virological outcomes, and emergent resistance in the SECOND-LINE trial: an exploratory analysis.Lancet HIV. 2015; 2: e42-e51Summary Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 7Sension M Cahn P Domingo P et al.Subgroup analysis of virological response rates with once- and twice-daily darunavir/ritonavir in treatment-experienced patients without darunavir resistance-associated mutations in the ODIN trial.HIV Med. 2013; 14: 437-444Crossref PubMed Scopus (14) Google Scholar In the SELECT trial,4La Rosa AM Harrison LJ Taiwo B et al.Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): a randomised, phase 3, non-inferiority study.Lancet HIV. 2016; 3: e247-e258Summary Full Text Full Text PDF PubMed Scopus (55) Google Scholar which also evaluated NRTI plus LPV/r as second-line treatment, there was no benefit from resistance testing before starting second-line treatment. These negative correlations between viral suppression and number of active NRTIs were independent of potential confounding effects of adherence levels or baseline viral load in multivariate analysis of SELECT, EARNEST, and SECOND-LINE.TableHIV RNA suppression rates by number of active NRTIs, in four randomised trialsTreatmentActive NRTIsHIV RNA suppressionEARNESTTwo NRTIs plus0176/198 (89%)(HIV RNA <400 copies per mL; week 144)ritonavir-boosted lopinavir195/112 (85%)220/26 (77%)SECOND-LINETwo NRTIs plus0–0·7561/66 (92%)(HIV RNA <500 copies per mL; week 96)ritonavir-boosted lopinavir169/80 (86%)1·25–356/69 (81%)ODINTwo NRTIs plus031/34 (91%)(HIV RNA <50 copies per mL; week 48)ritonavir-boosted darunavir1101/128 (79%)2 or more276/412 (67%)DAWNINGTwo NRTIs plus dolutegravir<2212/251 (84%)(HIV RNA <50 copies per mL; week 24)245/61 (74%)DAWNINGTwo NRTIs plus<2180/248 (73%)(HIV RNA <50 copies per mL; week 24)ritonavir-boosted lopinavir235/64 (55%)NRTIs=nucleoside reverse-transcriptase inhibitors. Open table in a new tab NRTIs=nucleoside reverse-transcriptase inhibitors. Investigators of the DAWNING study8Aboud M Kaplan M Lombaard J et al.Superior efficacy of dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) compared with lopinavir/ritonavir (LPV/RTV) plus 2NRTIs in second-line treatment: interim data from the DAWNING study.in: 9th International AIDS Society Conference on HIV Science. 2017: 8Google Scholar compared the standard second-line combination of two NRTIs plus LPV/r with two NRTIs (at least one of which had efficacy, according to genotyping) plus the integrase inhibitor dolutegravir. DAWNING was stopped early after the NRTI plus dolutegravir group showed viral suppression rates higher than the control group (82% vs 69% at week 24, p<0·001). Patients in the DAWNING study taking fewer than two active NRTIs had higher rates of suppression compared with those taking two fully active NRTIs, consistent again with studies of treatment based on protease inhibitor (with ritonavir; table). Fixed-dose combinations of tenofovir, lamivudine, and dolutegravir are now available for US$75 per person-year in low-income countries, a price far below the standard price of protease inhibitors, or current first-line therapy.9UnitaidNew high-quality antiretroviral therapy to be launched in South Africa, Kenya and over 90 low- and middle-income countries at reduced price.Sept 21, 2017https://unitaid.eu/news-blog/new-high-quality-antiretroviral-therapy-launched-south-africa-kenya-90-low-middle-income-countries-reduced-price/#enGoogle Scholar Dolutegravir was safer and more effective than LPV/r in DAWNING. So, should the single-dose combination of tenofovir–lamivudine–dolutegravir become the new WHO-recommended second-line treatment, over two NRTIs plus protease inhibitor? There are two key unanswered questions. First, the DAWNING study excluded patients with no active NRTIs at baseline. Can we be sure that the high retained efficacy of NRTIs combined with protease inhibitors will also be seen when NRTIs are combined with dolutegravir? Secondly, a high percentage of patients in low-income countries will be taking first-line tenofovir plus lamivudine and efavirenz, so a switch to second-line tenofovir–lamivudine–dolutegravir will involve changing only one antiretroviral. Will the benefits of recycled NRTIs be retained in this situation—ie, will dolutegravir behave like a protease inhibitor? The transition to tenofovir–lamivudine–dolutegravir for both first-line and second-line treatment, which has started in countries like Botswana (for first-line) and likely to expand across the region in 2018, has the potential to be a important step forward in simplifying HIV treatment with improved tolerability and adherence at a cheaper cost.10Clinton Health Access InitiativeHIV market report 2016.https://clintonhealthaccess.org/content/uploads/2017/09/2017-ARV-Market-Report_Final.pdfGoogle Scholar Real-time resistance surveillance systems will be essential to ensure that this transition is a success.11WHOTransition to new antiretrovirals in HIV programmes.July, 2017http://apps.who.int/iris/bitstream/10665/255888/1/WHO-HIV-2017.20-eng.pdf?ua=1Google Scholar The results from EARNEST and other similar clinical trials suggest that NRTIs will retain efficacy in second-line treatment when used with protease inhibitors. We now need to ensure that this protective effect also allows newer drugs such as dolutegravir to be used with recycled NRTIs in second-line treatment. Finally, the interpretation and use of routine genotype resistance testing, an expensive and complex test to interpret, requires reappraisal in the context of modern antiretroviral combinations. FV reports grants from United States Agency for International Development, Unitaid, South African Medical Research Council, and Bill & Melinda Gates Foundation; personal fees and non-financial support from Gilead Sciences; non-financial support from Viiv Health; and personal fees from Aspen, Mylan, Adcock Ingram, and MSD, outside the submitted work. AMH declares no competing interests. Lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of HIV (EARNEST): 144-week follow-up results from a randomised controlled trialProtease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings. Full-Text PDF Open Access