CADO 4/PADO 5: Approach to delivery of LA ARVs for HIV treatment
and Prevention in LMICs – Cabotegravir as a precedent-setting case study
Speaker: David Ripin, Executive Vice President of Infectious Diseases and
Chief Science Officer at Clinton Health Access Initiative (CHAI)
Discussed outputs from these recently held conferences and used Cabotegravir to illustrate how LA ARVs can be delivered in LMICs.
Highlights from CADO 4 (Conference on ARV Drug Optimization) – a forum convened by WHO, JHU and CHAI to set priorities for investment in the development of new products for HIV treatment and prevention.
- Priority List (impact within 5 years): LA CAB (HIV prevention) and LA LEN (HIV prevention and treatment). Watch List (impact in 5-10 years): once 6-monthly SC injectable 2-drug regimen or 1-2 year acting implantable 2-drug regimen.
- What led to the overwhelming prioritization of investment in LA products –
- Convenience and particular benefit for key populations (ease of adherence and discretion)
- Assumed to be affordable, easy to deliver and cost-competitive with products on the market.
- Assumed the generic supply model could be reproduced for LA products (the massive scale up of implantable and injectable contraceptives provides adequate precedent that this is possible).
Background for CAB case study – CHAI independent analysis.
- HIV prevention remains an unmet need despite oral PrEP.
- The global burden of new HIV infections was 3-fold higher than the UNAIDS fast-track target in 2020 (1.5 million vs 500,000).
- Key populations are disproportionately affected (65% of new infections) and can be targeted for HIV prevention – young women in sub-Saharan Africa (SSA) are at particularly high risk (6 of 7 new infections among adolescents).
- Oral PrEP is effective, but poses challenges (daily pills not preferred, adherence, stigma, fragmented roll out), and uptake is insufficient to meet the UNAIDS target – only 1,000,000 users in LMICs, yet > 13 million adolescents in SSA (15-24y) experienced symptoms of a sexually transmitted infection in past year.
- Uptake of LA CAB would need to grow by many orders of magnitude to impact HIV prevention – product preference research and scale up of LA product comparators suggest that delivery to scale may be possible to drive a step-change.
- Young women aged 18-30y in South Africa indicate a preference for infrequent injections (every 2-3 months) over daily pills (93% probability).
- Scale up of this magnitude has been accomplished in the family planning space with long-acting reversible contraception (LARC).
- Around 36 million women (15-49y) in SSA are using LARC or an injectable contraception – this user base informs the target for scale from which to calculate cost of LA CAB.
CHAI CAB cost of goods (COGs) calculation is a conservative estimate for a generic manufacturer in a low-cost location (built from cost of API, cost to formulate finished dosage form and cost to irradiate).
- API pricing – based on DTG (due to similar molecular structure) and assumes price decrease over time as volume increases from launch to scale (20kg DTG imported [from China to India] @$3232/kg in 2016 vs 3MT DTG imported @$774/kg in 2019).
- CAB API cost at launch ($3000/kg) – $1.80 for 600mg of CAB – $10.80 PPPY (6 vials).
- CAB API cost at scale ($1000/kg) – $0.60 for 600mg of CAB – $3.60 PPPY (6 vials).
- Capital expansion (CapEx) and development considerations.
- Specialized Nanomill (API to nanoparticulate) – $2,000,000 (2-fold above market cost).
- Bioequivalence (BE) studies – $1,000,000 (5-fold higher than BE for an oral daily product due to the study duration and number of enrolled patients required).
- Other development costs – $5,000,000 (5-fold higher than typical development costs).
- Finished dosage form (FDF) – generics will likely need to invest in high-volume sterile fill/finish lines, but upgrade cost would be relevant to a variety of HIV and non-HIV related products.
- $2.00 per vial x 6 vials – $12.00 PPPY (formulation cost for injectables made at very large scale is ~$0.50 per vial).
- Gamma irradiation for sterilization of CAB API and FDF.
- $0.70/kg – $0.04 PPPY (can be done at industrial scale).
- CAB COGs estimate (API + formulation + irradiation): $22.84 PPPY at launch to $15.64 PPPY at scale.
- Cost per infection averted calculation highlights CAB-LA cost-effectiveness, which is comparable to voluntary male medical circumcision (CAB $722-$962 vs VMMC $555-$4.4K).
Timing and delivery considerations.
- Earlier licensing is critical to meet market expectations (BE and development of LA products takes longer – estimate for CAB-LA is 3-4 years to market).
- Operational research and design of delivery systems should be conducted in parallel with product development to ensure market uptake when generics are available (IM injections are more expensive and require more highly trained staff).
- Financial risk sharing mechanisms will be critical to investment (new product class with a new delivery system required).