Switching to a two-drug regimen for HIV-1– SALSA and TANGO CROI 2022 updates

Dr. Mark Underwood
ViiV Healthcare, Research Triangle Park
North Carolina, US
Dr. Ruolan Wang
ViiV Healthcare, Research Triangle Park
North Carolina, US
19 Apr 2022
Switching to a two-drug regimen for HIV-1– SALSA and TANGO CROI 2022 updates

Based on the noninferior antiviral activity of dolutegravir/lamivudine (DTG/3TC) vs tenofovir alafenamide (TAF)–based three- or four-drug regimens demonstrated in the TANGO study at 48 weeks, international guidelines recommend DTG/3TC use in adults with HIV-1 infection in the viral suppression setting. DTG/3TC updates presented at the Conference on Retroviruses and Opportunistic Infections (CROI) 2022 included stringent viral load measures and archived resistance.

SALSA: Stringent noninferiority, including M184V/I
In the phase III, open-label SALSA trial, people with HIV-1 (PWH) on a three- or four-drug regimen with HIV-1 RNA <50 copies/mL for >6 months were randomized to switch to DTG/3TC (n=246; female, 44 percent; median age, 45 years; Asian, 13 percent) or continue their current antiretroviral therapy (ART) regimen (CAR; n=247; female, 34 percent; median age, 45 years; Asian, 16 percent). [Llibre J, et al, IAS Conference on HIV Science 2021, abstract OALB0303] Historic genotypic resistance results were submitted if available, and participants were excluded if International AIDS Society (IAS)–USA 2019 DTG-associated or major nucleoside reverse transcriptase inhibitor (NRTI) resistance was present.

“The clinical implications of genotypic resistance mutations in archived proviral DNA need to be better understood, as proviral resistance is sometimes used where plasma levels of HIV-1 are below standard resistance testing levels,” said poster presenter, Dr Mark Underwood of ViiV Healthcare, Research Triangle Park, North Carolina, US.

The post hoc analysis presented at CROI 2022 assessed the proportion of baseline participant samples with archived resistance and virologic response through 48 weeks, using the stringent viral load measure of <40 copies/mL and target not detected (TND). Virologic outcomes were determined using the FDA Snapshot algorithm at week 48 based on the last on-treatment HIV-1 RNA viral load. Baseline proviral DNA genotypes were generated for 196/224 and 189/216 of available samples in the DTG/3TC and CAR arms, respectively. [Underwood M, et al, CROI 2022, poster 481]

Of samples with baseline genotypes, 192 and 185 fit proviral resistance analysis population (PRAP) criteria, defined as all participants in the intention-to-treat–exposed (ITT-E) population with at least one post-baseline on-treatment viral load result, and not meeting protocol deviation criteria. In the PRAP, time from first ART to study start was 66.1 months among those receiving DTG/3TC and 74.4 months among CAR recipients.

The impact of archived baseline resistance with DTG/3TC was assessed. Frequency of any overall major class resistance was similar across treatment arms, with 54 instances among 192 samples from DTG/3TC recipients (28 percent) and 40 of the 185 CAR samples (22 percent).

“M184V/I mutation was similarly distributed between the arms, with 3 percent frequency across both DTG/3TC [five instances of M184V] and CAR [four M184V and one M184I occurrence(s)] recipients. M184V/I with 1 major resistance mutation was present in two participants on DTG/3TC and three participants on CAR,” reported Underwood.

At week 48, proportions of participants with viral load <40 copies/mL and TND were overall similar across arms and by key and most frequent baseline resistance mutations, including M184V/I. Four out of five M184V/I samples in the DTG/3TC arm and three out of five samples in the CAR arm had a viral load <40 copies/mL. In samples with major integrase strand transfer inhibitor (INSTI) resistance mutations, viral load <40 copies/mL and TND were achieved in one out of one and four out of four cases in the DTG/3TC and CAR arms, respectively. These proportions were eight out of eight and four out of five for minor INSTI mutations in the respective arms. (Table)

HK-GLA-398md_01  

While the overall proportions of participants with viral load <50 copies/mL at last available on-treatment reading were 99 percent vs 98 percent in the DTG/3TC vs CAR arm, 81 percent vs 83 percent had both viral load <40 copies/mL and TND. By week 48, no participants in either arm met confirmed virologic withdrawal (CVW) criteria.

“The clinical implications for very low-level viraemia measures remain exploratory, and resistance testing of archived proviral DNA should be used with caution,” noted Underwood. [Clin Infect Dis 2019;68:177-187] “Further work may help inform the use of these measures in clinical management of HIV-1.

“With high and similar proportions of TND across the DTG/3TC and CAR arms, whether assessed by baseline resistance mutations or by baseline class resistance categories, DTG/3TC demonstrated noninferior efficacy compared with CAR over 48 weeks. The overall TND frequency findings are consistent with previously reported data and are supportive of the efficacy and potency of DTG/3TC in suppressed switch participants,” he concluded. [Wang R, et al, CROI 2020, poster 489]

TANGO: TD/TND and elevated viral load through week 144
In the phase III, open-label TANGO trial, PWH with HIV-1 RNA <50 copies/mL for >6 months, no prior virological failure and no documented NRTI or INSTI resistance were randomized 1:1 to switch to DTG/3TC (n=369; female, 7 percent; median age, 40 years; Asian, 4 percent) or remain on a tenofovir alafenamide (TAF)–based three- or four-drug regimen (TBR; n=372; female, 9 percent; median age, 39 years; Asian, 3 percent). Noninferior virologic efficacy (HIV-1 RNA ≥50 copies/mL by FDA Snapshot algorithm) of switching to DTG/3TC vs continuing TBR was demonstrated through week 114. [Clin Infect Dis 2020;71:1920-1929; Osiyemi O, et al, IDWeek 2021, poster 900]

“Viral load <50 copies/mL has unknown clinical influence, with low-level viraemia potentially depending on pre-treatment viral load and proviral DNA load set points. Previous assessment of low-level viraemia using TND or target detected [TD] measures showed that more participants on DTG/3TC than those continuing TBR had TND at all visits through week 96,” said poster presenter, Dr Ruolan Wang of ViiV Healthcare, Research Triangle Park, North Carolina, US. “In this post hoc analysis, we present the longer-term HIV-1 RNA data with TD/TND and elevated viral load through week 144.

The proportion of participants per visit with viral load <40 copies/mL and TND through week 144 was high (approximately 6580 percent) and comparable in both treatment arms. (Figure) [Wang R, et al, CROI 2022, poster 484]

HK-GLA-398md_02

Across the baseline viral load categories of at least one measurement 50 copies/mL, at least one between 40 copies/mL and <50 copies/mL, at least one <40 copies/mL and TD, and all viral loads <40 copies/mL and TND, proportions of participants with TND at all visits through week 144 were 33 percent in the DTG/3TC arm vs 27 percent in the TBR arm. “More participants with TND at baseline had post-baseline TND at all visits compared with participants in higher baseline viral load categories,” noted Wang.

The occurrence of elevated viral load events remained low and similar across arms through week 144, at 7.6 percent among DTG/3TC recipients vs 11.3 percent in the TBR arm. At 5 percent in the DTG/3TC group and 7 percent among TBR recipients, the most frequently observed viral load rebounds were so-called blips, defined as viral loads of 50200 copies/mL with adjacent values of <50 copies/mL. Four participants in the TBR arm had two or more consecutive viral loads of 50 copies/mL with at least one viral load 200 copies/mL; three of them met CVW criteria (defined as two consecutive viral load measurements of 50 copies/mL with the second viral load 200 copies/mL) by week 144.

“None of the participants with archived M184V/I mutation [all detected as mixture with wild-type; four in the DTG/3TC arm and three in the TBR arm] experienced an elevated viral load event through week 144,” highlighted Wang.

According to the results of the ITT-E Snapshot analysis, at week 144, similar proportions of participants had TND in the DTG/3TC and TBR arms (76 percent vs 72 percent; adjusted treatment difference, 3.9 percent; 95 percent confidence interval, -2.5 to 10.2). Virologic failure occurred in 11.1 percent vs 14.2 percent of cases, while no virologic data were available for the remaining study participants.

“Using the more stringent viral load of <40 copies/mL and TND threshold, the two-drug regimen showed noninferior efficacy to TBR. The 144-week long-term virologic data continued to demonstrate the high potency and durability of DTG/3TC in maintaining viral suppression,” concluded Wang.

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