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CROI 2021: ART Trials in Spain
CROI 2021: My Picks for Interesting HIV Treatment Data From Spain and Beyond

Released: April 01, 2021

Expiration: March 31, 2022

José R. Arribas
José R. Arribas, MD
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Here I provide my key takeaways from 3 interesting HIV treatment studies presented at the Virtual 2021 Conference on Retroviruses and Opportunistic Infections (CROI 2021)—2 from Spain and 1 from the United States.

DRV/COBI/FTC/TAF vs DTG/ABC/3TC in ART-Naive Patients With HIV
The first trial compared darunavir (DRV)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir alafenamide (TAF) vs dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC) as initial treatment for antiretroviral therapy (ART)–naive patients with HIV. This study was interesting because the FLAMINGO trial demonstrated the superiority of DTG vs DRV/ritonavir (RTV), but the question remained whether the fixed-dose combination of DRV/COBI/FTC/TAF could match the efficacy of a second-generation integrase inhibitor such as DTG. The noninferiority trial (N = 316) was performed during the COVID pandemic, so Podzamczer and colleagues deserve a lot of credit for continuing the trial during this difficult time. Participants’ CD4+ cell counts were slightly lower than those in other recent trials: 26% to 28% of participants had CD4+ cells counts <350 cells/mm3 and 40% had HIV-1 RNA >100,000 copies/mL.

Analysis of the intention-to-treat exposed population (n = 306) demonstrated that 82% of participants randomized to the DTG/ABC/3TC arm (n = 155) had undetectable HIV-1 RNA (<50 copies/mL) after 1 year vs 79% in the DRV/COBI/FTC/TAF arm (n = 151). This 2.4% difference (95% CI: -11.3% to -6.6%; P = .706) did not meet the noninferiority margin of 10%, likely because of the small sample size. However, no participant experienced virologic failure with emergent resistance.

For me, the take-home message is that both combinations are highly potent. In addition, the boosted PI combination in this single-tablet regimen can be given even before receiving baseline genotypic resistance data. In contrast to the FLAMINGO results, in this study, DTG was not superior to DRV. To my knowledge, this is the first comparison between the fixed-dose DRV combination with a second-generation integrase inhibitor.

ADVANZ-4 Trial: DTG/ABC/3TC vs DRV/RTV Plus ABC/3TC in ART-Naive Patients With Advanced HIV
Another unresolved issue in HIV treatment is determining the best treatment for patients with advanced HIV who start therapy with CD4+ cell counts <100 cells/mm3. In Spain, it is estimated that 25% to 30% of patients are diagnosed with advanced disease, and this continues to be a problem worldwide. The ADVANZ-4 trial was a small, randomized study performed in Spain that compared DTG/ABC/3TC (n = 52) with DRV/RTV plus ABC/3TC (n = 52).

Enrolled patients had advanced HIV; although their median baseline HIV-1 RNA was approximately 5.5-5.7 log10 copies/mL, the median baseline CD4+ cell count was only 41 cells/mm3 in the DTG arm and 30 cells/mm3 in the DRV/RTV arm, so these patients were in need of immune reconstitution. The primary endpoint was the increase in CD4+ cell count at 48 weeks, and both arms showed similar results with a median increase in CD4+ cell count of 172 cells/mm3 with DTG vs 157 cells/mm3 with DRV/RTV (P = .430).

The proportion of participants with HIV-1 RNA <50 copies/mL via FDA snapshot at 48 weeks was 77% in the DTG arm and 63% in the DRV arm (P = .191). This difference did not reach statistical significance, again likely because of the small sample size. It was also likely affected by more treatment discontinuations in the DRV/RTV arm compared with the DTG arm (24.5% vs 8.0%, respectively).

The investigators also assessed markers of inflammation (eg, tumor necrosis factor-α, interleukin-6, high-sensitivity C-reactive protein), immune activation (CD8+CD38+ T-cells, CD8+CD38+DR+ T-cells), and apoptosis (annexin-V), which were similar at baseline and declined significantly and similarly in both treatment arms. Of interest, there was a greater reduction in the bacterial translocation marker soluble CD14, which has been linked to immune activation, in patients treated with DTG. In summary, I think this small study in patients with advanced HIV paves the way for other trials such as LAPTOP, an ongoing phase III study comparing bictegravir/FTC/TAF with DRV/COBI/FTC/TAF in patients with advanced HIV disease.

CAPELLA Trial: Antiviral Activity of Capsid Inhibitor Lenacapavir in Heavily ART–Experienced Patients With HIV
Another important and unresolved issue for healthcare professionals is how best to treat patients with multiclass drug resistance and limited options. Although both ibalizumab and fostemsavir are approved by the European Medicines Agency, we need additional drug options for patients with highly resistant HIV. 

At CROI 2021, results were presented from the phase II/III CAPELLA trial that is investigating the first-in-class capsid inhibitor lenacapavir. In the oral lead-in phase, heavily treatment–experienced patients with resistance to 2 or more agents from at least 3 of the 4 main antiretroviral classes were randomized to receive oral lenacapavir or placebo in addition to their failing regimen for 2 weeks.

The primary endpoint was reached with 88% of patients receiving lenacapavir (21/24) achieving an HIV-1 RNA decline of ≥0.5 log10 copies/mL by Day 15 compared with only 17% of patients receiving placebo (2/12) (P < .0001). This demonstrates that lenacapavir has antiviral activity in the majority of patients. After this 14-day oral lead-in phase, patients in all arms were switched to subcutaneous lenacapavir every 6 months plus an optimized background regimen for 52 weeks. At the 26-week follow-up, 73% of all participants had HIV-1 RNA <50 copies/mL.   

Two patients experienced virologic failure with emergent capsid inhibitor resistance, and both participants were resuppressed while continuing lenacapavir—one patient’s optimized background regimen was adjusted and the other’s regimen was not altered. Overall, I think this is good news because not only do we have a new drug that can be beneficial to heavily treatment–experienced patients, but it has a long half-life with injections only required every 6 months.

Your Thoughts
Which studies presented at CROI 2021 did you find most intriguing? Which new drug developments are you most excited about? Join the discussion by posting a comment and share your experiences.

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Data on which of the following ART strategies presented at CROI 2021 will be most beneficial to patients in your practice?
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