Exploring low-level viraemia:
Are DTG-based two-drug regimens as good as three?
Jan van Lunzen MD PhD
Head of Translational Research ViiV Healthcare
Chris Parry PhD
Global Director Medical Virology
(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)|
Third agent, proportion of treatment arm: aEVG/c, 67%; bRPV, 12%; cbDRV, 7%; dRAL, 1%; eEFV, 12%; fbDRV, 1%
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.
‡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
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).
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.
2DR, two-drug regimen
3DR, three-drug regimen
4DR, four-drug regimen
ART, antiretroviral therapy
bDRV, boosted darunavir
c/mL, copies per mL
CVW, confirmed virologic withdrawal
EACS, European AIDS Clinical Society
EVG/c, cobicistat-boosted elvitegravir
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
- ViiV Healthcare. DOVATO EU Summary of Product Charcteristics, July 2019.
- ViiV Healthcare. DOVATO US Prescribing Information, October 2019.
- ViiV Healthcare. JULUCA EU Summary of Product Characteristics, January 2019.
- ViiV Healthcare. JULUCA US Prescribing Information, October 2019.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Gandhi RT, Deeks SG. Plasma HIV-1 RNA levels during antiretroviral therapy: how low is low enough? Clin Infect Dis 2012;54:733-735.
- 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.
- 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