CROI 2022: Injectable PrEP: impressive results, new viral load monitoring – but price questions access

Simon Collins, HIV i-Base

Two oral presentations at CROI 2022 provided follow-up data on injectable PrEP using long-acting cabotegravir. [1, 2]

One study reported that CAB-LA continued to be highly effective at preventing HIV transmission in the HPTN 083 study, including in full data from the planned three year study as well as from the open-label roll-over from the subsequent unblinded year.

The other study recommended routine monitoring with viral load testing to limit drug resistance in the few breakthrough infections that were either missed at baseline or had delayed diagnoses during the study.

The large international randomised phase 3 HPTN 083 study was previously reported in detail after the IAS 2000 conference. It is a notable success that due to prespecified enrolment criteria, the study included people at high risk of HIV: 12% of participants were transgender and 67% were younger than 30, and 50% of US participants were Black.

After a median of only 1.4 years, significantly fewer infections were reported among the 4700 gay men and transgender women by those in the CAB-LA vs oral TD/FTC arms: 13 vs 39 respectively [HR: 0.34 (95% CI: 0.18 to 0.62), p=0.0005]. [3]

Similar results were reported in the slightly smaller HPTN-084 study in African women, with 4 vs 34 new infections in the injectable vs oral arms respectively. [4]

The updated results, presented by Raphael Landovitz from UCLA, now includes four new infections from the initial blinded period (two in each arm) plus 48 new infections from the unblinded year (11 with CAB-LA and 37 in TDF/FTC). This maintains almost identical results as the initial report [HR: 0.33 (95% CI: 0.17 to 0.56).

However, overall incidence in both arms was approximately 1.5-fold higher than during the blinded period, lined to lower adherence in both arms, including CAB-LA coverage dropping from 91% to 79%: accounting for 40% of the increased cases. Most of the additional 60% was explained by higher HIV background incidence in Latin American study sites who made up a greater proportion and the follow-up data (from 32% to 54%).

Both incident infections on CAB-LA during the final blinded period and four during the unblinded period were classified as D. The remaining 7/11 infections occurred more than 6 months since last prescription.         

There were no new safety concerns.

Open-label extensions continue but now with optional oral lead-in dosing and viral load monintoring for HIV detection.

This last point was the focus of the second oral presentation from HPTN 083 by Susan Eshleman from Johns Hopkins University. [2]

Although breakthrough HIV infections while using injectable PrEP were uncommon in HPTN 083/084, some HIV diagnoses were delayed (median time: 60 days; range 35 to 117). The longer time is associated with a higher risk of resistance developing to cabotegravir and cross-resistance to other integrase inhibitors.

The seven acute infections reported from HPTN 083 included INSTI resistance in 6/7 and modelling the outcomes from using viral load (sensitive to <30 copies/mL) would have detected HIV before INSTI resistance in 4/6 cases and before accumulted INSTI resistance in the remaining 2/6.

This led researchers to recommend routine HIV monitoring using viral load rather than antibody testing, in settings where this is an option.

However, the study also concluded that access to CAB-LA PrEP should not be restricted in settings where viral load testing is not easily available.

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As with oral PrEP, HTB has reported the remarkable scientific development of long-acting injectable PrEP over nine years – from initial animal studies through to US approval two months ago in December 2021. [5, 6]

Additional regulatory submissions have been submitted to Australia, Brazil and six countries in southern Africa – but, at least in the CROI 2022 talk, the EU was noticeably missing. [1, 8]

Global access will need CAB-LA to be affordable in settings where oral PrEP uses generic TDF/FTC, recognising that injectable formulations are likely to always be more expensive to manufacture than tablets. If ViiV/GSK supports generic licenses for CAB-LA (similar to the way it supported this for dolutegravir) it might still delay access for many years. Pricing for these settings has not yet been disclosed. 

The suggested US list price of $22,000 is a difficult signal to community organisations in other countries who otherwise support the importance of PrEP and new formulations. 

Even allowed for discounts, the US list price is significantly higher than for the CAB-LA when used as treatment, when the expectation that greater demand for PrEP should make this much less expensive. It is also considerably higher than the price for TAF/FTC (Descovy), the newer version of Gilead’s oral PrEP that was withdrawn from EU regulatory approval due to lack of a financial market, even though the registrational studies included European study sites.

EU countries use social health care systems and even the wiliest health economist hasn’t been able to  support list price TAF/FTC over generic TDF/FTC.

ViiV provided the following response when asked about registration in the EU, including a weblink for future updates.
“ViiV Healthcare remains committed to working collaboratively and transparently to develop new approaches that are sustainable, relevant, address public health needs, and deliver for the people that need them. We are on track with our submissions to other Global regulatory authorities outside of the US.” [7]

References

1. Landovitz RJ et al. Updated efficacy, safety, and case studies IN HPTN 083: CAB-LA vs TDF/FTC for PrEP, CROI 2022, 12–16 and 22–24 February, virtual meeting. Oral abstract 96.
   https://www.croiconference.org/abstract/updated-efficacy-safety-and-case-studies-in-hptn-083-cab-la-vs-tdf-ftc-for-prep/
2. Eshleman S et al. CAB-LA PrEP: early detection of HIV infection may reduce INSTI resistance risk. CROI 2022, 12–16 and 22–24 February, virtual meeting. Oral abstract 95.
   https://www.croiconference.org/abstract/cab-la-prep-early-detection-of-hiv-infection-may-reduce-insti-resistance-risk/
3. Long-acting cabotegravir injections are effective as HIV PrEP in gay men and transgender women: results from HPTN 083. IAS 2000 reports. HTB (July 2000).
   https://i-base.info/htb/38534
4. Two-monthly cabotegravir injections prevent HIV infection in African women: HPTN 084 study recommends early unblinding. HTB (11 November 2020).
   https://i-base.info/htb/39327
5. Monthly injection protects macaques from rectal exposure: results should fast-track human studies for advanced PrEP options. HTB (1 April 2013).
   https://i-base.info/htb/21072
6. US FDA approves long-acting cabotegravir injections for PrEP. HTB (December 2021).
   https://i-base.info/htb/41890
7. ViiV Healthcare. Improving access to HIV Medicines).
   https://viivhealthcare.com/ending-hiv/viiv-improve-access-to-hiv-medicine
   https://viivhealthcare.com/content/dam/cf- (link page)
   viiv/viivhealthcare/master/files/cab-prep-wwrs-10-jan-2022-for-external-use.pdf (PDF)

This report was first published on 20 February 2022.