ART Barrier to Resistance:
Is it quantity or quality of ARVs that counts?

Authored by
Dr José Gatell      Senior Global Medical Director at ViiV Healthcare

Treating HIV-1 today, we have the luxury of selecting a regimen from a number of potent and well-tolerated drugs. However, whilst potency may be assumed, the resilience of that potency (resilience being how long an ARV remains effective in the face of the rapid and error prone replication of HIV), which is driven by the barrier to resistance, differs between ARVs.1-3 Among first generation INSTIs, EVG and RAL both have a low barrier to resistance; furthermore, EVG requires a PK booster.2,4-7 Second-generation INSTIs, DTG (dolutegravir▼) and BIC, have been developed to offer potency without boosting, together with a high resistance barrier.1,2,8,9 Similarly, second generation PIs, for example boosted DRV, are more potent and more resilient than first-generation unboosted PIs such as SQV and NFV.10,11

Barrier to resistance of ARVs
So, what factors are at play in determining the barrier to resistance of an ARV? A simple summary would be potency (a virus that cannot replicate cannot select resistance mutations), PK, genetic barrier (or the number of mutations required for a phenotypic effect and what that effect is) and the relationships between these factors – though, of course, the devil is in the detail and the interplay may be complex. From the potency and PK perspective, a drug with a minimum plasma concentration that is well above the IC90 of wild-type virus throughout the dosing period will have a high pharmacological barrier to resistance, a concept captured in part by the inhibitory quotient (IQ: ratio of drug exposure to concentration needed to inhibit viral replication by 90%).12 In addition to these concentration-related parameters, target-binding time, or drug residency may play a part, as this potentially allows the drug a greater opportunity to have an effect.13 In vitro, INSTI residence time has been qualitatively associated with both potency and barrier to resistance.13

The role of mutations
How this picture changes when drug-resistance mutations are thrown into the mix is crucial, as a higher IC90 acts to reduce the pharmacologic barrier to resistance by decreasing the IQ.12 If phenotypic resistance to a drug is induced by a single mutation that is easily accrued, that drug will have a low barrier to resistance; if several mutations must be accrued before resistance manifests, then a drug will have a high barrier to resistance, particularly if those mutations accumulate only slowly. However, mutations do not only affect drug susceptibility: some mutations affect replicative fitness, rendering a virus less able to compete.14


Barrier to resistance of DTG
Let me use DTG, an ARV acknowledged as having a high barrier to resistance by numerous treatment guidelines,1,2,7 to illustrate these concepts. DTG is a potent ARV, even as monotherapy, and understanding that DTG monotherapy is not recommended for clinical use, DTG 50 mg delivers a 2.46 log10 decrease in viral load after ten days of treatment.15 The potency of DTG is reinforced by a high IQ; 24 hours post-dosing, plasma concentrations of DTG remain 19 times higher than the protein-adjusted IC90 throughout the QD dosing interval and DTG plasma concentrations remain above the IC90 in 94% of patients 72 hours after dosing.16,17 In addition, DTG is subject to few DDIs with potential to reduce circulating plasma levels.18,19


Phenotypic resistance to DTG requires a minimum of two mutations, typically G140S/Q148R/H, whereas resistance to RAL or EVG arises from one or two mutations that may occur across three (N155H±E92Q; Q148H/R/K±G140S/A; and Y143C/R) and two (N155H±E92Q and Q148H/R/K±G140SA) resistance pathways, respectively. 20,21 Furthermore, in vitro, selection of DTG-resistance mutations is slow relative to EVG and RAL resistance mutations.22

As one would expect, DTG’s high potency and genetic barrier to resistance are underpinned by its structural characteristics; the metal-chelating scaffold of DTG, which is shared by BIC, has a more streamlined shape than the architecture of RAL and EVG, which have protruding functional groups.13,20,23 This streamlined structure allows DTG to fit securely into the HIV integrase active site, prolonging residency (the dissociation half-life from wild-type integrase DNA is 71 hours, slower than RAL [8.8 hours] and EVG [2.7hours]).13,23


Barrier to resistance of regimens
The ultimate proof of a high barrier to resistance is clinical record. The robustness of DTG is evidenced by the fact that there have been no INSTI-resistance mutations in DTG + 2 NRTI clinical trials conducted in treatment-naïve participants (SPRING-2, SINGLE, FLAMINGO and ARIA),24-27 and few reports of DTG-resistance in more than a million patient–years of exposure to DTG in real-world clinical practice.28-33

However, in reality, these findings reflect the robustness of DTG-based regimens, specifically triple therapy in the DTG trials listed above. What determines the barrier to resistance of a regimen? Is it the number of drugs? We know that even a drug as potent and robust as DTG is not robust enough to use as monotherapy. Clearly, a 3DR is more robust than monotherapy, but is it the number of drugs or the specific drugs that matter? Might two well-selected drugs also comprise an ART regimen with a high barrier to resistance? It is, after all, reasonable to assume that the overall barrier of a regimen comprising fewer selected agents (2DR), could be as high, or higher, than that of a regimen comprising more agents that have not been chosen for their combined barrier to resistance (3DR).

Clinical data: SWORD-1 and -2
Recently, DTG 2DRs have been evaluated in the large SWORD-1 and -2 and GEMINI-1 and -2 clinical trials.

Click to access SWORD study designs



SWORD-1 and -2 compared the antiviral efficacy of switching to DTG + RPV versus continuing a fully suppressive 3DR.34 The twin studies enrolled a total of 513 participants who switched to DTG + RPV at study start, whilst 511 continued CAR.34 At Week 48, DTG + RPV demonstrated non-inferiority to CAR (snapshot analysis) in both studies. Two participants receiving DTG + RPV met the criteria for CVW (a viral load of ≥50 copies/mL and a second, confirmatory viral load of 200 copies/mL); no INSTI-resistance mutations were detected among participants treated with DTG + RPV, although one subject with documented nonadherence had an NNRTI resistance-associated mutation (K101K/E) identified with no decreased sensitivity to RPV.34

For comparison, a number of studies have reported switching virologically suppressed participants from a 3DR to a RPV-based 3DR. For example, one study switching 438 PLHIV suppressed on EFV/FTC/TDF to RPV/FTC/TAF resulted in six cases of confirmed virologic rebound over 48 weeks; none were associated with treatment-emergent resistance35 In contrast, in the SPIRIT study, where 469 participants suppressed on a boosted PI + 2 NRTIs were switched to RPV/FTC/TDF, seven participants were assessed for resistance in the Week 48 analysis.36 Four (4/469) had NRTI-resistance mutation M184V/I, of whom three also had NNRTI-resistance mutations (E138E/K; L100I + K103N with preexisting V90V/I; V108V/I + E138K with preexisting K103N and V179V/I).36

Returning to SWORD-1 and -2, the proportion of patients with TND (target-not-detected; no detectable HIV-1 RNA) was similar between the DTG + RPV and CAR groups over 48 weeks.37 Patients who initially continued CAR switched to DTG + RPV at Week 52.38 ‘Blips’ (at least one incident of VL >50 but <200 c/mL, with adjacent VL <50 c/mL) were infrequent, and occurred at similar rates during 48 weeks of treatment with DTG + RPV (6%, 34/513) and CAR (5%, 28/511).39 Through Week 100 there was a low number of CVWs (1%, 10/990; defined as VL ≥50 copies/mL and a second, confirmatory VL ≥ 200 copies/mL); there were no CVWs with INSTI mutations (resistance results were available for six participants) and CVWs with NNRTI mutations were rare (0.3%; 3/990 through Week 100), with minimal impact on future treatment options.38

The SWORD-1 and -2 data led to the approval of JULUCA▼, a fixed dose combination of DTG/RPV to replace the current ARV regimen in virologically suppressed adults, in 2017 in the US and 2018 in the EU.40,41 However, I do think we should remember that participants in SWORD-1 and -2 had been suppressed on CAR for at least 6 months before switching, had no history of virologic failure on previous ART and no pre-existing resistance to INSTIs, NRTIs, NNRTIS or PIs.34 In clinical practice, one must assume that interpretation of resistance testing of archived proviral DNA is difficult to interpret and therefore not recommended.

Clinical data: GEMINI-1 and -2
Treatment-naïve PLHIV may have high viral loads – control of which is a completely different prospect from maintaining pre-existing viral suppression.3 The large, randomized Phase III GEMINI-1 and -2 studies are investigating DTG + 3TC (EPIVIR) versus DTG + TDF/FTC for HBV-negative treatment-naïve adults with VL 1,000–500,000 c/mL and no evidence of pre-existing resistance to NRTIs, NNRTIS or PIs.3,42-44

Click to access GEMINI study designs


Enrollment across the two studies was 716 and 717 in the 2DR and 3DR arms, respectively.42 Given the treatment-naïve study population, the first question has to be: are DTG + 3TC potent enough for rapid suppression of elevated viral load? Data at Week 48 indicate that they are. The Week 48 primary endpoint confirmed non-inferiority of DTG + 3TC to DTG + TDF/FTC, and the magnitude and speed of viral load decline were similar between arms, irrespective of baseline viral load.42,45 CVWs were <1% in each treatment arm (6/716 for DTG + 3TC and 4/717 for DTG + TDF/FTC) with no treatment-emergent INSTI or NRTI resistance mutations observed.42 Likewise, the proportion of patients with TND was similar between the DTG + 3TC and DTG + TDF/FTC at 48 weeks (77% (553/716) vs 73% (525/717), respectively; adjusted difference, 3.8%; 95% CI, −0.6% to 8.2%).46

To my mind, DTG + 3TC is a particularly interesting combination that potentially offers more than simply blocking two stages of the HIV lifecycle, as do traditional three-drug regimens. Plasma concentrations of DTG and intracellular concentrations of 3TC triphosphate decay at a similar rate.47-49 As noted above, DTG remains above its protein-adjusted IC90 for 72-hours.16,17 Likewise, the concentration of intracellular 3TC triphosphate with 300 mg QD remains within the range observed with 150 mg BID dosing.47-49 Additionally, as the plasma concentrations of DTG and the intracellular concentrations of 3TC triphosphate decay at a similar rate, the PK profiles of the two are well-matched,18,47-49 This is important as it minimises the likelihood of functional monotherapy).

However, 3TC does have an Achilles heel, in that a single mutation, M184V, commonly selected by 3TC (and FTC) reduces HIV susceptibility to 3TC by more than 100-fold.50,51 On the plus side, M184V enhances HIV-1 reverse transcriptase fidelity, thereby reducing spontaneous HIV mutagenesis, and decreases replicative fitness.50-52 In vitro data suggest that resistance mutations against NRTIs, including M184V, antagonise the development of HIV-1 resistance against DTG (but not RAL or EVG),53 and resistance mutations against DTG can delay development of HIV-1 resistance against 3TC,54 raising the possibility that this is a mutually beneficial pairing.

This concept is reinforced by clinical data documenting the time-course of HIV-1 RNA levels in response to 3TC monotherapy and DTG + 3TC.45,55 Back in 1995, 3TC monotherapy was associated with a rapid emergence of resistance (Week 4) that prevented adequate assessment of its maximum antiviral potency.55 In GEMINI-1 and -2, the combination of DTG and 3TC decreased plasma HIV-1 RNA by nearly three logs (log10 scale) at the Week 4 timepoint, and suppression was maintained through Week 48,45 which suggests that DTG prevents the emergence of 3TC resistance, thereby allowing 3TC to reinforce the antiviral potency of DTG.

A vision for the future
Longer-term data from GEMINI-1 and -2 are eagerly awaited, but currently available data suggest the DTG-based 2DRs may prove to be resilient. Going back to the assumption that a regimen comprising fewer ARVs with high barriers to resistance might present a higher barrier to resistance than a regimen comprising a greater number of ARVs with lower barriers to resistance, at this point the question that springs to mind is how great a barrier to resistance is enough – how much of a barrier do you actually need?

The answer to that question depends on the person you are treating, and perhaps, rather than arguing the merits of the barrier to resistance of three drugs versus two, we should be evaluating the needs of the person sitting in front of us.

2DR, two-drug regimen
3DR, three-drug regimen
3TC, lamivudine
ART, antiretroviral treatment
ARV, antiretroviral
BIC, bictegravir
CAR, current antiretroviral regimen
Cmax, minimum plasma concentration
CVW, confirmed virologic withdrawal
DDIs, drug-drug interactions
DRV, darunavir
DTG, dolutegravir
EVG, elvitegravir
HBV, hepatitis B virus
IC90, concentration to achieve 90% inhibition

, integrase strand transfer inhibitor
IQ, inhibitory quotient
NLF, nelfinavir
NRTI, nucleoside reverse transcriptase inhibitor
NNRTI, non-nucleoside reverse transcriptase inhibitor
PI, protease inhibitor
PK, pharmacokinetics
PLHIV, people living with HIV
QD, once daily
RAL, raltegravir
RPV, rilpivirine
SQV, saquinavir
TND, target not detected
VL, viral load


  1. European AIDS Clinical Society. EACS Guidelines, Version 9.1, 2018. Available from: Accessed Feb 2019.
  2. United States Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV, October 2018. Available from: Accessed Feb 2019.
  3. Coffin J, Swanstrom R. HIV pathogenesis: dynamics and genetics of viral populations and infected cells. Cold Spring Harb Perspect Med 2013;3(1):a012526.
  4.  ISENTRESS 600mg Summary of Product Characteristics, Oct 2018.
  5. STRIBILD Summary of Product Characteristics, Dec 2018.
  6. GENVOYA Summary of Product Characteristics, Nov 2018.
  7. Saag MS, Benson CA et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2018 Recommendations of the International Antiviral Society-USA Panel. JAMA 2018;320(4):379-396.
  8. BIKTARVY Prescribing Information, Feb 2018.
  9. BIKTARVY Summary of Product Characteristics, Jun 2018.
  10. De Meyer S, Azijn H et al. TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother 2005;49(6):2314-2321.
  11. Renjifo B, van Wyk J et al. Pharmacokinetic enhancement in HIV antiretroviral therapy: a comparison of ritonavir and cobicistat. AIDS Rev 2015;17(1):37-46.
  12. University of Liverpool. Liverpool Disposition of ARV – PIs and boosting, 2019. Available from: Accessed Feb 2019.
  13. Hightower KE, Wang R et al. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob Agents Chemother 2011;55(10):4552-4559.
  14. Quiñones-Mateu ME, Arts EJ. HIV-1 Fitness: Implications for Drug Resistance, Disease Progression, and Global Epidemic Evolution. HIV Sequence database. Available from: Accessed Feb 2019 
  15. Min S, Sloan L et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS 2011;25(14):1737-1745.
  16. van Lunzen J, Maggiolo F et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis 2012;12(2):111-118.
  17. Elliot E, Amara A et al. Pharmacokinetics of once-daily dolutegravir and elvitegravir/cobicistat following drug cessation. Abstract 13 presented at 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, Washington, DC., USA, 26–28 May 2015.
  18. TIVICAY Prescribing Information, Sep 2018.
  19. TIVICAY Summary of Product Characteristics, Nov 2018.
  20. Tsiang M, Jones GS et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother 2016;60(12):7086-7097.
  21. Clutter DS, Jordan MR et al. HIV-1 drug resistance and resistance testing. Infect Genet Evol 2016;46:292-307.
  22. Kobayashi M, Yoshinaga T et al. In Vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother 2011;55(2):813-821.
  23. DeAnda F, Hightower KE et al. Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics. PLoS One 2013;8(10):e77448.
  24. Molina JM, Clotet B et al. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV 2015;2(4):e127-136.
  25. Orrell C, Hagins DP et al. Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study. Lancet HIV 2017;4(12):e536-e546.
  26. Raffi F, Jaeger H et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2013;13(11):927-935.
  27. Walmsley S, Baumgarten A et al. Brief Report: dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr 2015;70(5):515-519.
  28. Fulcher JA, Du Y et al. Emergence of Integrase Resistance Mutations During Initial Therapy Containing Dolutegravir. Clin Infect Dis 2018;67(5):791-794.
  29. Lepik KJ, Harrigan PR et al. Emergent drug resistance with integrase strand transfer inhibitor-based regimens. AIDS 2017;31(10):1425-1434.
  30. Lübke N, Jensen B et al. Failure of dolutegravir-containing first-line regimen. Poster presented at 16th European Meeting on HIV & Hepatitis, Rome, Italy, 30 May–1 Jun 2018.
  31. Pena-Lopez M, Chueca N et al. Virological failure through the R263K pathway to a first line Doluegravir containing regimen. Poster THPE041 presented at 22nd International AIDS Conference, Amsterdam, the Netherlands, 23–27 Jul 2018.
  32. ViiV Healthcare. DTG patient exposure derived from IMS data from July 2013 – March 2018. Data on File: VIIV/TRIM/0020/17c.
  33. Wiesmann F, Däumer M et al. Development of T66I-mediated integrase inhibitor cross-resistance against elvitegravir under dolutegravir-containing first-line therapy. Poster 364 presented at International Congress of Drug Therapy in HIV Infection, Glasgow, UK, 23–26 Oct 2016.
  34. Llibre JM, Hung CC et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet 2018;391(10123):839-849.
  35. DeJesus E, Ramgopal M et al. Switching from efavirenz, emtricitabine, and tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study. Lancet HIV 2017;4(5):e205-e213.
  36. Palella FJ, Jr., Fisher M et al. Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants. AIDS 2014;28(3):335-344.
  37. Underwood M, Angelis M et al. Comparison of viral replication below 50 copies/mL for two-drug (DTG+RPV) versus three-drug current antiretroviral regimen (CAR) therapy in the SWORD-1 and SWORD-2 studies. Poster P311 presented at International Congress of Drug Therapy in HIV Infection, Glasgow, UK, 28–31 Oct 2018.
  38. Aboud M, Orkin C et al. Durable suppression 2 years after switch to DTG+RPV 2-drug regimen: SWORD 1&2 studies. Poster THPEB047 presented at 22nd International AIDS Conference, Amsterdam, the Netherlands, 23–27 Jul 2018.
  39. Wang R, Underwood M et al. Comparison of HIV-1 Intermittent Viremia for Two Drug (DTG+RPV) vs Three Drug Current Antiretroviral Therapy in the SWORD-1 and SWORD-2 Studies. Poster P313 presented at International Congress of Drug Therapy in HIV Infection, Glasgow, UK, 28–31 Oct 2018.
  40. JULUCA Prescribing Information, Sep 2018.
  41. JULUCA Summary of Product Characteristics, Feb 2019.
  42. Cahn P, Madero JS et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet 2019;393(10167):143-155.
  43. NCT02831673. Available from: Accessed Feb 2019.
  44. NCT02831764. Available from: Accessed Feb 2019.
  45. Eron JJ. Oral presentation 7 at HIV DART and Emerging Viruses 2018, Miami, USA, 27–29 Nov.
  46. Underwood M. HIV replication at <40 c/mL for DTG + 3TC vs DTG + TDF/FTC in the GEMINI-1 & -2 studies. Poster 490 presented at Conference on Retroviruses and Opportunistic Infections, Seattle, USA, 4–7 Mar 2019.
  47. Moore KH, Barrett JE et al. The pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells from patients infected with HIV-1. AIDS 1999;13(16):2239-2250.
  48. Yuen GJ, Lou Y et al. Equivalent steady-state pharmacokinetics of lamivudine in plasma and lamivudine triphosphate within cells following administration of lamivudine at 300 milligrams once daily and 150 milligrams twice daily. Antimicrob Agents Chemother 2004;48(1):176-182.
  49. Song I, Chen S et al. Pharmacokinetic (PK) and pharmacodynamic (PD) relationship of S/GSK1349572, a next generation integrase inhibitor (INI), in HIV-1 infected patients. Poster WEPEB250 presented at 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, Sotuh Africa, 19–22 Jul 2009.
  50. Gallant JE. The M184V mutation: what it does, how to prevent it, and what to do with it when it's there. The AIDS reader 2006;16(10):556-559.
  51. Stanford University. HIV Drug Resistance Database. Available from: Accessed Aug 2018.
  52. Paredes R, Sagar M et al. In vivo fitness cost of the M184V mutation in multidrug-resistant human immunodeficiency virus type 1 in the absence of lamivudine. J Virol 2009;83(4):2038-2043.
  53. Oliveira M, Ibanescu RI et al. The M184I/V and K65R nucleoside resistance mutations in HIV-1 prevent the emergence of resistance mutations against dolutegravir. AIDS 2016;30(15):2267-2273.
  54. Oliveira M, Mesplede T et al. Resistance mutations against dolutegravir in HIV integrase impair the emergence of resistance against reverse transcriptase inhibitors. AIDS 2014;28(6):813-819.
  55. Eron JJ, Benoit SL et al. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. North American HIV Working Party. N Engl J Med 1995;333(25):1662-1669.


November 2019 PM-GB-2DR-WCNT-190001