What HPTN 083 and 084 teaches us about Injectable LA ARV’s: What have we learned, and what do we need to learn next? What to do about the tail? How to avoid oral formulations at the end of LA PrEP strategies?

Rapporteur: Andy Kaytes, Rapporteur for Focus Group 2

Summarized the discussion surrounding the HPTN 083 and 084 trials of LAI CAB for HIV PrEP. The discussion leaders, Raphael J. Landovitz (UCLA) and Beatriz Grinsztejn (Oswaldo Cruz  Foundation), structured the session around the following questions: What have we learned from HPTN 083 and 084? What do we need to learn next? What to do about the “tail”? How do we avoid using oral formulations at the end of LA PrEP strategies?

Overview of HPTN 083 and 084 – LA CAB (5 weeks of oral CAB, then LA CAB IM every 8 weeks, then oral TDF/FTC to cover tail) vs daily oral TDF/FTC. 
Both trials were unblinded early due to superiority of LA CAB arm. HPTN 083 (cisgender men and transgender women who have sex with men) had 52 incident HIV infections (LAI CAB 13 vs oral TDF/FTC 39; 66% risk reduction), and HPTN 084 (cisgender women in sub-Saharan Africa) had 40 incident HIV infections (LAI CAB 4 vs oral TDF/FTC 36; 89% risk reduction). Incident HIV infections were classified into letter groups A–D; D were puzzling cases where HIV was acquired despite CAB arm and receiving every dose on time. 

Lessons learned from HPTN 083 and 084. 
1) LA CAB appears to have an advantage over oral agents for HIV PrEP.
2) There was no significant toxicity, hypersensitivity or discontinuations associated with CAB in the trial setting – Oral lead in (OLI) will be optional in the open-label extension.
3) HIV diagnostics are delayed in oral PrEP and could be at least as challenging for LA formulations, making it difficult to determine the timing of HIV acquisition.
4) Determining oral adherence at study visits is limited – adherence monitoring via plasma, dried blood spots, saliva, urine, and hair assays may be alternatives.
5) Implementation challenges exist.

Lingering questions about the risk of developing resistance from breakthrough infections (D cases) and during the PK tail and whether the OLI should be obligatory. 
Resistance data are limited, but encouraging (to be presented at CROI 2021). Concerns were raised about scenarios where the tail is not covered – If there is an HIV exposure during the CAB PK tail, would drug concentrations be high enough to select for resistance? What are the implications for global TLD use or BIC or DTG-based regimens in high-income countries to treat LA PrEP breakthrough cases? The group discussed whether the trial data give enough confidence to remove OLI in the context of HIV prevention – numbers are small, and safety may not be generalizable. Risk/benefit analysis is more stringent for prevention than treatment. Is there a period of vulnerability with direct-to-inject – cannot yet accurately determine the time-to-protection after first injection, as current understanding of the correlates of protection and PK variability is incomplete. In contrast, could OLI be considered a liability due to sub-optimal adherence to oral PrEP? Is there any scenario where you would cover the “nose” – double-dose TDF/FTC or TAF/FTC as in IPERGAY study?

Implications for pregnant and breastfeeding women, considerations for LMICs and real-world acceptability. 
Data remain limited in pregnant and breastfeeding women – women who become pregnant on protocol will be given the option to remain on LAI CAB in the open-label extension. In LMICs, the OLI would add complexity and costs to care – ViiV Healthcare plans to make LA CAB available in LMICs and RLS, but what are the mechanisms and pricing structure? Given that the LA approach is Q8 weeks vs 4 times per year for oral PrEP, will LA CAB be acceptable, particularly among youth, transgender, and other key populations that have not seen benefits from existing oral PrEP?

Strategic agenda. 
1) PK: need mechanisms for interrogating the PK tail more systematically and should leverage knowledge about PK variability from other LA nano-crystalized formulations.
2) Real-world data are needed to understand resistance implications, either via surveillance conducted with demonstration projects or relegate assessment to a location with a national healthcare system – Will need to identify strategies to minimize resistance to INSTIs if break-through infections are seen.
3) More robust HIV diagnostics: are they needed and what are the implications for resource-limited settings?
4) Pregnant and breast feeding women: more data are needed.
5) Real-world implementation: need to understand how to generate product demand and acceptability outside of clinical trials and how to access specific populations who stand to benefit most, including youth, Black, Latinx, trans-gender females.

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