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EACS 2019 update: Increasing role of two-drug regimens in HIV

Dr. Chloe Orkin
Barts Health NHS
Trust, London, UK
Dr. Juan Berenguer
Hospital General
Universitario Gregorio
Marañón, Madrid, Spain
Dr. Carlo Federico Perno
Università degli Studi
di Milano, Milan, Italy
13 Jan 2020
GEMINI
Three- and four-drug regimens have been the mainstay of treatment for patients with HIV infection, but recent data indicated noninferiority of two-drug regimens compared with three-drug regimens. At a symposium held during the 17th European AIDS Conference (EACS 2019) in Basel, Switzerland, experts discussed current evidence for dolutegravir (DTG)-lamivudine (3TC) combination therapy, the only two-drug regimen listed in the EACS 2019 guidelines as a recommended initial combination therapy for antiretroviral therapy (ART)-naïve adults living with HIV, and one of the recommended two-drug switch strategies for virologically suppressed individuals.

DTG-3TC therapy recommended in EACS 2019 guidelines

“The efficacy of first-line treatment in patients with HIV has increased from 77 percent to >82 percent with the introduction of integrase inhibitors [INIs],” said Dr Chloe Orkin of the Barts Health NHS, London, UK. [PLoS One 2014;9:e97482; Lancet 2019;393:143-155; Lancet 2017;390:2063-2072; Lancet 2017;390:2073-2082; Lancet 2015;385:2606-2615; Lancet 2014;383:2222-2231; Lancet 2012;379:2429-2438; Lancet 2013;381:735-743; Lancet Infect Dis 2011;11:907-915; N Engl J Med 2013;369:1807-1818; Lancet 2012;379:2439-2448; Lancet 2009;374:796-806; Lancet 2017;4:e536-e546]

“All guidelines recommend INI-based three-drug regimens for treatment-naïve adults. Two-drug regimens were listed as alternative options until recently, when the EACS 2019 guidelines upgraded DTG-3TC combination therapy to one of the recommended regimens,” she continued. [EACS guidelines v10.0: https://www.eacsociety.org/files/2019_guidelines-10.0_final.pdf]

The upgrade of the DTG-3TC regimen from alternative to recommended therapy in ART-naïve patients living with HIV and the inclusion of DTG-3TC as a switch strategy for virologically suppressed individuals represent some of the most notable changes in the ART section of the EACS 2019 guidelines. [EACS guidelines v10.0: https://www.eacsociety.org/files/2019_guidelines-10.0_final.pdf]

Two-drug vs three-drug regimens

In the phase III GEMINI-1 and -2 trials, DTG-3TC combination therapy demonstrated promising efficacy vs the three-drug comparator regimen of DTG plus tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) in ART-naïve patients, including those with high viral loads and low CD4+ T-cell counts at baseline.

In the trials, 1,441 ART-naïve adults with HIV-1 infection and HIV-1 RNA of 1,000 and ≤500,000 copies/mL were randomized to receive once-daily DTG 50 mg plus 3TC 300 mg or DTG 50 mg plus TDF 300 mg and FTC 200 mg. [Lancet 2019;393:143-155]

Long-term durability, efficacy

“As shown in GEMINI-1 and -2, the percentage of patients achieving HIV-1 RNA <50 copies/mL with DTG-3TC was noninferior to that with DTG-TDF-FTC at all timepoints throughout 96 weeks,” said Orkin. [Cahn P, et al, IAS 2019, abstract WEAB0404LB]

The response rates were high and similar between the two treatment arms in patients with baseline viral load of 100,000 and >100,000 copies/mL. “Most patients with baseline HIV-1 RNA 100,000 copies/mL [87 percent of patients on DTG-3TC vs 90 percent of patients on DTG-TDF-FTC] and >100,000 copies/mL [84 percent of patients on DTG-3TC vs 86 percent of patients on DTG-TDF-FTC] achieved HIV-1 RNA <50 copies/mL at week 96,” Orkin highlighted. [van Wyk J, et al, ID Week 2019, abstract 978] “However, among those with a starting CD4+ T-cell count ≤200 cells/mm3, week-96 sub-50-copy response rates were substantially lower with two vs three drugs [68 percent vs 87 percent].There were three confirmed virologic withdrawals in the DTG-3TC group and two in the DTG-TDF-FTC group.” [Cahn P, et al, IAS 2019, abstract WEAB0404LB]

In a meta-analysis of data from 14 randomized controlled trials involving 14 unique regimens and a total of 10,043 treatment-naïve patients, the mean difference in the proportion of patients achieving virologic suppression at week 48 with DTG-3TC, as compared with the other 13 regimens, ranged from -2.7 percent vs DTG- tenofovir alafenamide (TAF)-FTC (95 percent confidence interval [CI], -5.6 to 11.0) to 7.3 percent vs efavirenz-TDF-FTC (95 percent CI, 0.6 to 13.8). “The meta-analysis demonstrated similar efficacy outcomes over 48 weeks with DTG-3TC compared with traditional three-drug regimens,” said Dr Juan Berenguer of Hospital General Universitario Gregorio Marañón, Madrid, Spain. [AIDS 2019;33:1739-1749]

Using more sensitive viral markers

The efficacy and potency of DTG-3TC were further reinforced by an ad hoc analysis of GEMINI-1 and -2 data presented at EACS 2019, which utilized a more stringent viral load cut-off of 40 copies mL (ie, ≥40 copies mL = target detected, <40 copies/mL = target not detected [TND]). In this analysis, the median time to TND was similar with both regimens across 96 weeks. (Figure 1) At week 96, the median time to TND and the proportion of patients with TND were comparable between both treatment groups regardless of baseline viral load or CD4+ T-cell count. [Underwood M, et al, EACS 2019, abstract PS8/2]

HK-GLA-356md Tivicay + lamivudine IU_4

Blip frequency, time to virologic suppression, resistance

“The GEMINI-1 and -2 studies also showed similar frequencies of blips in both treatment groups by visit week through week 48,” said Orkin. “No patients in either arm had blips prior to confirmed virologic withdrawal.” [Underwood M, et al, IAS 2019, abstract MOPEB231]

The rate and time to virologic suppression were also similar with both treatment groups in the overall cohort and in those with baseline HIV-1 RNA >100,000 copies/mL. [Lancet 2019;393:143-155; Eron J, et al, HIV DART and Emerging Viruses 2018, abstract 7] “Likewise, time to TND was similar between both treatment groups [median, 57 days for both groups],” added Orkin. [Underwood M, et al, CROI 2019, abstract 490]

In a pooled analysis of GEMINI-1 and -2, only 1.5 percent of patients receiving DTG-3TC and 1.0 percent of those receiving DTG-TDF-FTC had confirmed virologic withdrawals at week 96, and no treatment-emergent resistance was noted in either group. [Cahn P, et al, IAS 2019, abstract WEAB0404LB]

Better AE profile

“Overall, the adverse event [AE] profile of the two regimens were similar. However, a lower rate of drug-related AEs was noted with DTG-3TC at week 96 [20 percent vs 25 percent with DTG-TDF-FTC]. The rate of AEs leading to study withdrawal was low, at 3 percent in both treatment groups,” Orkin highlighted. “Post-baseline changes in markers of bone and renal function favoured DTG-3TC.” [Cahn P, et al, IAS 2019, abstract WEAB0404LB]

“In a pooled analysis of eight trials involving a total of 5,680 treatment-naïve patients, TAF was associated with a significantly increased risk of >10 percent weight gain compared with other nucleoside reverse transcriptase inhibitors,” said discussant Dr Carlo-Federico Perno of Università degli Studi di Milano, Milan, Italy. “INIs, particularly bictegravir and DTG, were associated with more weight gain than protease inhibitors [PIs] or non-nucleoside reverse transcriptase inhibitors [NNRTIs].” [Clin Infect Dis 2019, doi: 10.1093/cid/ciz999]

Switching to DTG-3TC from TAF-based regimens

The phase III TANGO trial evaluated the efficacy and safety of switching to DTG-3TC in 741 HIV-1infected adults with virologic suppression for >6 months on a three- or four-drug TAF-based regimen. Participants in the trial were randomized to switch to DTG-3TC therapy (n=369) or continue with the TAF-based regimen (n=372) through week 148. The study’s primary endpoint result, presented previously, showed that switching to DTG-3TC was noninferior to remaining on a TAF-based regimen in patients achieving HIV-1 RNA <50 copies/mL at week 48. [Van Wyk J, et al, IAS 2019, abstract WEAB0403LB]

The key secondary endpoint (ie, snapshot virologic success by baseline drug class of the third agent, demographics and disease characteristics) was presented at EACS 2019. [Ait-Khaled M, et al, EACS 2019, abstract PS7/2]

The proportion of patients achieving HIV-1 RNA <50 copies/mL was comparable between those who switched to DTG-3TC and those who remained on a TAF-based regimen across age groups (<35 years, 35 to <50 years, ≥50 years) (range, 9196 percent vs 92–94 percent), race (white, black or African American, Asian, other) (range, 88–100 percent vs 88–94 percent), sex (female, male) (range, 84–94 percent vs 82–94 percent), baseline third-agent class (NNRTI, integrase strand transfer inhibitor, PI) (range, 93–96 percent vs 88–100 percent), and baseline CD4+ T-cell count (<350 cells/mm3, 350 cells/mm3) (range, 89–94 percent vs 93–97 percent). No confirmed virologic withdrawals or resistance was noted with DTG-3TC through week 48.

The safety profile of DTG-3TC combination therapy was consistent with that reported in other trials. At week 48, a similar adjusted mean 0.8 kg increase in weight from baseline was observed in both treatment groups.

Improvements in lipid, insulin resistance

At week 48, patients who switched to DTG-3TC therapy showed improvements in serum lipids (total cholesterol, LDL-cholesterol, and total cholesterol/HDL-cholesterol ratio) vs those who remained on a TAF-based regimen. (Figure 2)

HK-GLA-356md Tivicay + lamivudine IU_5

Improvements in insulin resistance were also noted in patients who switched to DTG-3TC therapy. (Figure 3) Fewer patients in the DTG-3TC group vs TAF-based regimen group had insulin resistance (defined as homeostasis model assessment insulin resistance [HOMA-IR] score ≥2) at week 48 (65 percent vs 74 percent; odds ratio, 0.59; 95 percent CI, 0.40 to 0.87; p=0.008).

K-GLA-356md Tivicay + lamivudine IU_6.
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