Exploring low-level viraemia:
Are DTG-based two-drug regimens as good as three?

Authored by

Jan van Lunzen MD PhD 
    
Head of Translational Research ViiV Healthcare


 

Chris Parry PhD     
Global Director Medical Virology
ViiV Healthcare

What you need to know in three minutes

  • DTG-based two-drug regimens (2DRs) show similar efficacy to three- or four-drug regimens (3DRs; 4DRs) in both virologically suppressed and treatment-naïve patients, based on the widely used measure of viral suppression to <50 copies of HIV RNA per mL of plasma (c/mL) at 48 weeks.
  • More stringent assessment of lower-level viraemia (below 50 c/mL), and of viral blips above it, found no differences between DTG-based 2DRs and 3DR/4DR comparators.
  • The fact that DTG-based 2DRs and 3DRs achieve similar levels of suppression in both treatment-naïve and virologically suppressed patients, even below the 50 c/mL threshold, through 96 weeks is highly reassuring.

DTG at the core of two-drug regimens

REGIMENS USED IN GEMINI, TANGO AND SWORD

STUDY 2DR ARM
(PROPORTION OF TREATMENT ARM,%)
COMPARATOR ARM OR THIRD AGENT CLASS
(PROPORTION OF TREATMENT ARM,%)
GEMINI: DTG + 3TC1 DTG + 3TC (100) DTG + TDF/FTC (100)
TANGO2 DTG + 3TC (100) INI (80a)
    NNRTI (13b)
    PI (8c)
SWORD3


 DTG + RPV (100)

 INI (19d)

    NNRTI (54e)
    PI (27f)

 

Third agent, proportion of treatment arm: aEVG/c, 67%; bRPV, 12%; cbDRV, 7%; dRAL, 1%; eEFV, 12%; fbDRV, 1%

In the post-HAART era, we have come to expect high levels of virologic efficacy, with the vast majority of PHIV achieving levels of HIV-1 RNA <50 c/mL (the currently accepted standard measure of ART efficacy) when effective ARV combinations are taken as prescribed. The potency and high barrier to resistance of some newer ARVs, particularly INIs, have opened up the possibility that similar high rates of virologic suppression could be achieved with two carefully selected ARVs rather than three. This is supported by the fact that intensification studies (adding a fourth active ARV to an effective 3DR) have shown no clear treatment benefit.4,5 Studies with boosted PIs acted as proof of principle for an effective 2DR.6–10 However, so far, only 2DRs with DTG at the core have been tested in large-scale, well-powered, registrational trials.1,3

DTG/3TC IS NOW A
RECOMMENDED INITIAL
REGIMEN IN THE RECENTLY
UPDATED EACS GUIDELINES
(EACS GUIDELINES VERSION 10.0)

DTG-based 2DRs of DTG + RPV (SWORD-1 and -2 studies) and DTG + 3TC (GEMINI-1 and -2, and TANGO studies) were non-inferior to 3- and 4-DRs, as measured by standard efficacy parameters (HIV-1 RNA <50 c/mL at Week 48).1–3 JULUCA(DTG/RPV) has since received marketing authorisation in virologically suppressed patients,* and DOVATO (DTG/3TC) in virologically suppressed and treatment-naïve patients.11–14 DTG/3TC is now a recommended initial regimen in the recently updated EACS guidelines.15

*JULUCA is indicated for HIV-1 virologically suppressed adults on a stable regimen for at least 6 months with no history of virologic failure and no known or suspected resistance to any NNRTI or INI. †DOVATO is indicated for the treatment of HIV-1 in adults and adolescents above the age of 12 years weighing at least 40 kg, with no known or suspected resistance to the integrase inhibitor class, or lamivudine.

Low- and very-low-level viraemia during ART

VIRAL LOAD AND VIRAEMIA TERMS EXPLAINED

  • HIV-1 RNA <50 c/mL: The currently accepted standard definition of virologic success, used as cut-off in the FDA Snapshot algorithm.16
  • Persistent low-level viraemia: Consistent HIV-1 plasma viral load above the level of detection of the assay used (e.g. 20–50 c/mL) but below 500 c/mL or 1,000 c/mL.17
  • Very-low-level viraemia: HIV-1 plasma viral load measured as <50 c/mL, but viral target detected.
  • Residual viraemia: HIV-1 plasma viral load that is typically in the 1–10 c/mL range and unaffected by treatment intensification.18,19

As ARVs have evolved, so too has our ability to detect very low viral loads; current research assays can detect even a single copy of HIV-1 RNA per mL of plasma.20 As such, we are now able to examine levels of viraemia below the standard 50 c/mL cut-off used in clinical trials. SWORD-1 and -2, GEMINI-1 and -2 and TANGO used the Abbott RealTime HIV-1 assay, which measures viral load quantitatively from 40 c/mL to 10,000,000 c/mL and provides a qualitative output of target (virus RNA) detected or target not detected for viral load <40 c/mL.21

  • Viral blip: Transient episode of HIV-1 viraemia above the level of detection of the assay used (e.g. 20–50 c/mL) followed by a subsequent measurement of viral load below the level of detection of the assay.
  • Target detected and target not detected: Below the viral load assay limit of quantification, there may be a weak signal indicating that HIV-1 RNA is detectable but can’t be quantified. This is described as target detected (TD). Target not detected (TND) means that, in addition to being below the threshold where it is possible to quantify the virus, HIV-1 RNA cannot be detected in the sample at all (no signal).

Low- and very-low-level viraemia in DTG-based 2DR trials

In treatment-naïve patients (GEMINI-1 and -2), the proportion of participants with blips (viral loads 50–200 c/mL with adjacent values <50 c/mL) or TND, and the median time to TND, were similar between the DOVATO‡ and 3DR arms through 48 weeks of treatment.22,23 None of the participants with confirmed virologic withdrawal (CVW) at Week 48 in either arm had blips prior to CVW, or had treatment-emergent resistance.22 Results at Week 96 were consistent with those seen at Week 48; indeed, the Snapshot 96-week analysis found that DOVATO and TIVICAY (DTG) + TDF/FTC had similar proportions of TND across all timepoints tested.23 These data reinforce the efficacy and potency of DOVATO in treatment-naïve patients.23

In virologically suppressed patients (HIV-1 RNA <50 c/mL) who switched to DOVATO (TANGO) or JULUCA§ (SWORD-1 and -2), the incidence of viral blips through 48 weeks was low and similar between patients who received a DTG-based 2DR and those who continued their previous regimen.24,25 In the SWORD studies, incidence of blips was similar between treatment arms at Week 48.24 This low level of blips was maintained over 100 weeks in the JULUCA arm.24 Similar proportions of SWORD participants had TND (no virus detected) at each visit through Week 48, regardless of whether they continued their previous regimen or switched to JULUCA.26 Viral blips were not associated with meeting the criteria for CVW in either TANGO or SWORD.24,25 These data indicate that DOVATO and JULUCA 2DRs control viral load as effectively as 3- or 4-DRs in virologically suppressed patients.

2DRS WITH DTG AT THE CORE
ACHIEVED SIMILAR VIROLOGIC
EFFICACY TO 3- OR 4-DRS IN
TREATMENT-NAÏVE AND VIROLOGICALLY
SUPPRESSED PATIENTS, USING BOTH THE
TRADITIONAL DEFINITION OF VIROLOGIC
SUPPRESSION (HIV-1 RNA <50 C/ML)
AND MORE STRINGENT DEFINITIONS,
SUCH AS TND

Overall, the GEMINI, TANGO and SWORD studies show that DTGbased 2DRs achieve similar virologic efficacy to 3- or 4-DRs in treatment-naïve patients (DOVATO) and virologically suppressed patients (DOVATO and JULUCA) using more stringent definitions of virologic suppression, such as TND, compared with the traditional standard definition of efficacy (HIV-1 RNA <50 c/mL).

‡Patients in the GEMINI studies received DTG 50 mg + 3TC 300 mg once daily
§Patients in the SWORD studies received DTG 50 mg + RPV 25 mg once daily

Implications: what is the clinical relevance of low-level viraemia?

We know that suppression of viral load to <50 c/mL prevents HIV disease transmission, progression and the development of AIDS. As such, we use viral load results to guide clinical decisions.

ALTHOUGH WE ARE ABLE TO MEASURE
LOW-LEVEL VIRAEMIA AND VIRAL BLIPS,
THE CLINICAL RELEVANCE (IF ANY) OF
SUCH EVENTS REMAINS UNCLEAR

In contrast, although we are able to measure low-level viraemia <50 c/mL and viral blips >50 c/mL, the clinical relevance (if any) of such events remains unclear. Essentially, viral loads up to 49 c/mL represent something of a black box – we can generate data, but we do not know what these data mean for our patients. For example, recent data from the Swiss Cohort have shown that viral blips and low-level viremia are associated with a slower viral reservoir decay; however, the clinical significance of this in the day to day management of PHIV is not known.27 There is currently no confirmed link between low-level viraemia or blips and subsequent virologic failure or development of resistance.22,24,25,28–30

This may be, at least partly, because interpretation of results from the various available studies is not straightforward. For example, Doyle et al. found that patients with a viral load of 40–49 c/mL were more likely to develop virologic rebound >50 c/mL than patients with <40 c/mL.28 However, as highlighted in a commentary by Ghandi and Deeks, this could have been influenced by differences between groups in the duration of virologic suppression.29 Patients with long-term virologic suppression are less likely to rebound than those with shorter durations of suppression, and patients with viral load <40 c/mL in this study had been on ART much longer (median 1.3–2.8 years) than those with viral load 40–49 c/mL (median 0.2 years).29 In fact, we would expect all patients to have low but detectable HIV-1 RNA during the first months of suppressive therapy; many of the patients with 40–49 c/mL in this study could still have been in the process of viral decay, before achieving robust, steady-state viral suppression.29,31

Summary and future directions

DTG-based 2DRs showed non-inferior efficacy to 3- or 4-DRs based on the standard measure of viral suppression to <50 c/mL at 48 weeks, with powerful efficacy maintained through each milestone timepoint reached (48 weeks for TANGO, 96 weeks for GEMINI, and 3 years for SWORD).

WHETHER BLIPS AND VIRAL LOW-LEVEL
VIRAEMIA <50 C/ML PROVE TO HAVE
CLINICAL RELEVANCE OR NOT, THE
FACT THAT DTG-BASED 2DRS AND 3DRS
ARE SIMILAR AT MORE STRINGENT
LEVELS OF VIRAL CONTROL IS HIGHLY
REASSURING AND SHOULD PROVIDE
FURTHER CONFIDENCE IN
PRESCRIBING DTG-BASED 2DRS

More stringent assessment of viral suppression and low-level viraemia/blips still found that there were no notable differences between DTGbased 2DRs and standard 3- or 4DRs through Week 96. Whether blips and viral low-level viraemia <50 c/mL prove to have clinical relevance or not, the fact that DTG-based 2DRs and 3- or 4-DRs have similar outcomes with regards to more stringent measurements of viral control is highly reassuring and should provide further confidence in prescribing DTG-based 2DRs.

Glossary
2DR, two-drug regimen
3DR, three-drug regimen
3TC, lamivudine
4DR, four-drug regimen
ART, antiretroviral therapy
ARV, antiretroviral
bDRV, boosted darunavir
c/mL, copies per mL
CVW, confirmed virologic withdrawal
DTG, dolutegravir
EACS, European AIDS Clinical Society
EFV, efavirenz
EVG/c, cobicistat-boosted elvitegravir
 


FDA, Food and Drug Administration
FTC, emtricitabine
HAART, highly active ART
INI, integrase inhibitor
NNRTI, non-nucleoside reverse
            transcriptase inhibitor
PHIV, people living with HIV
PI, protease inhibitor
RAL, raltegravir
RPV, rilpivirine
TD, target detected
TDF, tenofovir disoproxil fumarate
TND, target not detected

DOVATO and JULUCA Prescribing Information
TIVICAY Prescribing Information

References

  1. Cahn P, Madero JS, Arribas JR, 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;393:143-155.
  2. van Wyk J, Ajana F, Bisshop F, et al. Switching to DTG + 3TC fixed dose combination (FDC) is non-inferior to continuing a TAF-based regimen (TBR) in maintaining virologic suppression through 24 weeks (TANGO Study). 10th IAS Conference on HIV Science (IAS); July 21–24, 2019; Mexico City, Mexico. Oral WEAB0403LB.
  3. Llibre JM, Hung CC, Brinson C, 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;391:839-849.
  4. Cheret A, Nembot G, Melard A, et al. Intensive five-drug antiretroviral therapy regimen versus standard triple-drug therapy during primary HIV-1 infection (OPTIPRIM-ANRS 147): a randomised, open-label, phase 3 trial. Lancet Infect Dis 2015;15:387-396.
  5. Kityo C, Szubert AJ, Siika A, et al. Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: a randomised controlled trial. PLoS Med 2018;15:e1002706.
  6. Cahn P, Andrade-Villanueva J, Arribas JR, et al. Dual therapy with lopinavir and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, non-inferiority GARDEL trial. Lancet Infect Dis 2014;14:572-580.
  7. Raffi F, Babiker AG, Richert L, et al. Ritonavir-boosted darunavir combined with raltegravir or tenofovir-emtricitabine in antiretroviral-naive adults infected with HIV-1: 96 week results from the NEAT001/ANRS143 randomised non-inferiority trial. Lancet 2014;384:1942-1951.
  8. Reynes J, Trinh R, Pulido F, et al. Lopinavir/ritonavir combined with raltegravir or tenofovir/emtricitabine in antiretroviral-naive subjects: 96-week results of the PROGRESS study. AIDS Res Hum Retroviruses 2013;29:256-265.
  9. Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008;358:2095-2106.
  10. Sued O, Figueroa MI, Gun A, et al. Dual therapy with darunavir/ritonavir plus lamivudine for HIV-1 treatment initiation: Week 24 results of the randomized ANDES study. 9th IAS Conference on HIV Science; July 23–26, 2017; Paris, France. Oral MOAB0106LB
  11. ViiV Healthcare. DOVATO EU Summary of Product Charcteristics, July 2019.
  12. ViiV Healthcare. DOVATO US Prescribing Information, October 2019.
  13. ViiV Healthcare. JULUCA EU Summary of Product Characteristics, January 2019.
  14. ViiV Healthcare. JULUCA US Prescribing Information, October 2019.
  15. European AIDS Clinical Society. EACS Guidelines, Version 10.0, November 2019. https://www.eacsociety.org/files/2019_guidelines-10.0_final. pdf. Accessed November 2019.
  16. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Human Immunodeficiency Virus-1 Infection: Developing Antiretroviral Drugs for Treatment Guidance for Industry. 2015. https://www.fda.gov/media/86284/download. Accessed November 2019.
  17. Ryscavage P, Kelly S, Li JZ, Harrigan PR, Taiwo B. Significance and clinical management of persistent low-level viremia and very-low-level viremia in HIV-1-infected patients. Antimicrob Agents Chemother 2014;58:3585-3598.
  18. Dinoso JB, Kim SY, Wiegand AM, et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A 2009;106:9403-9408.
  19. Li JZ, Gallien S, Ribaudo H, Heisey A, Bangsberg DR, Kuritzkes DR. Incomplete adherence to antiretroviral therapy is associated with higher levels of residual HIV-1 viremia. AIDS 2014;28:181-186.
  20. Tosiano MA, Jacobs JL, Shutt KA, Cyktor JC, Mellors JW. A simpler and more sensitive single-copy HIV-1 RNA assay for quantification of persistent HIV-1 viremia in individuals on suppressive antiretroviral therapy. J Clin Microbiol 2019;57:e01714-18.
  21. Abbott Laboratories. Abbot RealTime HIV-1 Package Insert https://www.molecular.abbott/sal/en-us/staticAssets/realtime-hiv-1-package-insert.pdf. Accessed November 2019.
  22. Underwood M, Wang R, Horton J, et al. Dolutegravir (DTG) plus lamivudine (3TC) versus DTG plus tenofovir/emtricitabine (TDF/FTC) fixed-dose combination in the GEMINI studies – viral load rebound including ‘blips’ through 48 weeks. 10th IAS Conference on HIV Science (IAS); July 21–24, 2019; Mexico City, Mexico. Poster MOPEB231.
  23. Underwood M, Urbaityte R, Wang R, et al. Assessments of very low level HIV replication for dolutegravir+lamivudine (DTG+3TC) vs dolutegravir+tenofovir disoproxil/emtricitabine (DTG+TDF/FTC) in the GEMINI 1&2 studies through week 96. 17th European AIDS Conference (EACS); November 6–9, 2019; Basel, Switzerland. Oral PS8/2.
  24. Wang R, Underwood M, Koteff J, 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. HIV Glasgow 2018; October 28–31, 2018; Glasgow, UK. Poster P313.
  25. Wang R, Horton J, Wright J, et al. Switching from a 3-drug tenofovir alafenamide (TAF)-based regimen (TBR) to a 2-drug dolutegravir/ lamivudine (2DR, DTG/3TC FDC) was not associated with a higher frequency of intermittent viremia in suppressed patients in the TANGO study. 17th European AIDS Conference (EACS); November 6–9, 2019; Basel, Switzerland. Poster PE3/15.
  26. Underwood M, Angelis K, Wang R, 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. HIV Glasgow 2018; October 28–31, 2018; Glasgow, UK. Poster 311.
  27. Bachmann N, von Siebenthal C, Vongrad V, et al. Determinants of HIV-1 reservoir size and long-term dynamics during suppressive ART. Nat Commun 2019;10:3193.
  28. Doyle T, Smith C, Vitiello P, et al. Plasma HIV-1 RNA detection below 50 copies/ml and risk of virologic rebound in patients receiving highly active antiretroviral therapy. Clin Infect Dis 2012;54:724-732.
  29. Gandhi RT, Deeks SG. Plasma HIV-1 RNA levels during antiretroviral therapy: how low is low enough? Clin Infect Dis 2012;54:733-735.
  30. Henrich TJ, Wood BR, Kuritzkes DR. Increased risk of virologic rebound in patients on antiviral therapy with a detectable HIV load <48 copies/mL. PLoS One 2012;7:e50065.
  31. Andrade A, Rosenkranz SL, Cillo AR, et al. Three distinct phases of HIV-1 RNA decay in treatment-naive patients receiving raltegravir-based antiretroviral therapy: ACTG A5248. J Infect Dis 2013;208:884-891.

 

 PM-GB-HVX-WCNT-190010 January 2020