The future of preexposure prophylaxis (PrEP) is here, according to interim study results demonstrating the superiority of long-acting, injectable cabotegravir (CAB-LA) over the current workhorse, daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC).
In a prospective, phase 2b-3 randomized, double-blind, double-dummy, active-controlled trial among 4566 cisgender MSM (men who have sex with men) and transgender women, CAB-LA was shown to reduce risk for HIV infection by 66%. The study was terminated early, owing to strong evidence of efficacy in the first preplanned interim endpoint analysis. The study findings were published on August 11 in The New England Journal of Medicine.
"The lesson is not that TDF-FTC doesn’t work or has major problems; it is a very safe, very well-tolerated agent and astonishingly effective if taken as prescribed," Raphael Landovitz, MD, MDC, lead author and co-director of the Center for HIV Identification, Prevention, and Treatment Services at the University of California, Los Angeles, told Medscape Medical News.
Instead, "The reason that we were able to show that cabotegravir was superior is because we enrolled a very young, very highly at-risk, very underresourced, underrepresented, highly sexually active group who weren't able to take PrEP the way it was prescribed," he said.
Study participants were assigned to receive either active CAB 600 mg intramuscularly with TDF-FTC placebo or active TDF-FTC (300 mg/200 mg) with a CAB procedure in three phases:
an oral-tablet 5-week lead-in phase, a blinded injection phase beginning at week 5, followed by
an injection at week 9 and every 8 weeks thereafter through week 153, and
an open-label "tail" phase consisting of oral TDF/FTC to provide ongoing HIV PrEP for participants discontinuing injections.
The median age of study participants was 26 years (interquartile range [IQR], 22 – 32 years); 12.5% (570) of participants identified as transgender women; 49.8% (845/1698) of US participants were Black patients.
During follow-up, HIV infections were identified in 57 participants, including 52 who acquired HIV infections after enrollment (13 CAB group, incidence 0.41 per 100 person-years, vs 39 TDF-FTC group, incidence 1.22 per 100 person-years). The hazard ratio for incident HIV infection was 0.34 (95% CI, 0.18 – 0.62) CAB vs TDF-FTC (P < .001). Consistent effects were observed across prespecified subgroups and populations.
Among participants in the CAB group, integrase strand-transfer inhibitor resistance mutations were detected in 1 of 4 of the baseline HIV infection cases. Among participants in the TDF-FTC group, 2 of 39 incident infections occurred despite drug concentration measurements that indicated good PrEP adherence.
Although injection site reactions were reported in 81.4% (1724) of the CAB group, only 2.4% of patients (50) discontinued treatment. Most reactions began a median of 1 day (IQR, 0 – 2 days) post injection. They were of mild to moderate severity (60.8% pain, 23.7% tenderness) and lasted a median of 3 days (IQR, 2 – 6 days). Injection site reactions were reported in 31.3% of the participants in the TDF-FTC group who received at least one placebo injection.
Rates of severe adverse effects (grade 3 or higher) were similar between participants in the CAB and TDF-FTC groups. They consisted mostly of an increase in creatine kinase level (14.2% with CAB vs 13.5% with TDF-FTC) and a decrease in creatinine clearance (7.0% with CAB vs 8.3% with TDF-FTC).
In a post hoc analysis, the mean annualized weight increase was 1.23 kg/y (95% CI, 1.05 – 1.42) in the CAB group, compared with 0.37 kg/y (95% CI, 0.18 – 0.55) in the TDF-FTC group. Most of these differences were observed during the first 40 weeks and were driven by weight loss among TDF-FTC participants; weight changes between groups were similar thereafter (~1 kg/y for both groups).
New Modality, New Challenges
"We're constantly searching for new modalities to expand our repertoire of what we can provide patients, especially those folks with the highest need for PrEP," Lina Rosengren-Hovee, MD, MPH, assistant professor of medicine and infectious disease specialist at UNC-Health, Chapel Hill, North Carolina, told Medscape Medical News. "Being able to offer an injectable option is going to be a game changer, but it will be critical to pinpoint structural factors that affect adherence," she added.
Rosengren-Hovee also pointed to cases of integrase inhibitor resistance (both in the study and the larger clinical arena), which she believes are concerning. "It's still a conversation that you'll want to have with a patient; I wonder if we need more discussion about how we handle that in the clinical setting, even if it's fairly uncommon," she said.
When asked, Landovitz emphasized the rarity of breakthrough cases but acknowledged that there appears to be a pattern whereby the first breakthrough occurs with a trickle of virus and then bursts out with higher levels of virus at some point.
"CDC is actually thinking very hard about whether these long-acting PrEP agents obligate a change to the HIV screening process [eg, a viral load or RNA-based test] rather than a conventional HIV test," Landovitz said. He went on to say that in the ongoing, open-label portion of the study, investigators hope to learn whether one can avoid resistance by catching the first breakthrough earlier. That would help inform clinical implementation, he explained. He said that he challenges practitioners and healthcare communities to avoid some of the mistakes made with the oral PrEP rollout, namely, universal access without proper implementation of planning and testing protocols.
"By default, PrEP is much more decentralized and demedicalized, especially in primary care," said Rosengren-Hovee. "We need more studies looking at real-world scenarios."
Rosengren-Hovee reports no relevant financial relationships. Landovitz has consulting relationships with Gilead, Janssen, Roche, and Cepheus.
N Engl J Med. 2021;385:595-608.
Liz Scherer is an independent journalist specializing in infectious and emerging diseases, cannabinoid therapeutics, neurology, oncology, and women's health.
Medscape Medical News © 2021
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Cite this: Injectable Cabotegravir PrEP Superior to Oral TDF-FTC; Trial Halted Early - Medscape - Aug 11, 2021.