Cabotegravir – global access to long-acting pre-exposure prophylaxis for HIV

doi:10.21203/rs.3.rs-2198548/v2

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Cabotegravir – global access to long-acting pre-exposure prophylaxis for HIV

https://doi.org/10.21203/rs.3.rs-2198548/v2

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A novel injectable pre-exposure prophylaxis, cabotegravir, has greater efficacy and acceptability than oral TDF/FTC for prevention of HIV infection. Cabotegravir is currently priced at $22,200 per year, 370-times higher than the potential $60 estimated cost-effectiveness threshold for MICs. Following civil society pressure, ViiV agreed access to generic versions in 90 countries with the Medicines Patent Pool (MPP), including all African nations. However, several MICs outside Africa have rapidly growing HIV epidemics. We analysed the ViiV-MPP deal to assess population covered and Gross Domestic Product (GDP) per capita. There were 38 countries excluded from the ViiV-MPP deal despite having a GDP per Capita lower than the highest earning African country. These countries include 2.4 billion people (30% global population), with an incidence of 122 thousand (8%). For cabotegravir to have a significant impact on HIV infections, millions will need to be treated at affordable prices in a wide range of countries.

Infectious Diseases

Preventive Medicine

PrEP

Cabotegravir

access

HIV

63 people must be treated with CAB-LA (currently marketed at $22,000 per year) instead of TDF/FTC to prevent 1 HIV infection. The ViiV-MPP deal, which excludes 37 MICs (total incidence 122 thousand), requires expansion to make CAB-LA cost-effective globally.

Antiretroviral therapy (ART) has reached 28.7 million people, with virologic suppression minimising transmission risk of HIV(1). However, inequalities maintain incidence at 1.5 million (2021) (1,2). Oral PrEP (TDF/FTC) has been revelatory in combating incidence; the iPrEx and IPERGAY studies proved efficacy, and it is cheap and readily available (3,4). Most governments now recommend its use (5). However, poor adherence to TDF/FTC, particularly in young and heterosexual female populations, limits its effectiveness(6). Cabotegravir (CAB-LA), the first long-acting injectable PrEP, produced by ViiV, eliminates timely pill-taking and so could improve uptake for many.

CAB-LA has superior efficacy to TDF/FTC, showing 66% risk reduction in the HPTN083 trial in cisgender men and transgender women, and 88% in HPTN084 for cisgender women (7,8). Both were stopped due to efficacy. CAB-LA has the potential to substantially reduce new HIV infections over the next 50 years if used widely, as shown by the 27% reduction in HIV incidence over 20 years in patients using CAB-LA in South Africa (9). This is promising as incidence currently matches mortality, so that the number of PLWH remains stable, sustaining the pandemic (1).

ViiV markets CAB-LA at $22,200 (USD) per year in the US, and £7100 per year in the UK (10), vastly outpricing CAB-LA for most PLWH. Conversely, generic TDF/FTC is available in the UK at £168 per year (11), and $55 per year via the Pan-American Health Organisation (12). From July 2021-July 2022, there were £95m CAB-LA sales in the US (4,279 patient years) (13) .

For CAB-LA to reach PLWH across LMICs, significant health system strengthening is needed across infrastructure, training, and primary care. These structural conditions for health are highly politicised, slowing mobilisation. As a result, even tiered costs for branded CAB-LA would be untenable. While ViiV suggest a cost price of $1440 per year, South African cost-effectiveness and threshold analysis suggests an annual cost between $60-$119 per year would be cost-effective (9). Estimates for lowest possible pricing are around $16 per year (14). ViiV have responded to civil society pressure (15) to agree a voluntary licence with the Medicines Patent Pool (MPP) (16).The deal, enabling 90 countries to procure generic CAB-LA, has drawn criticism for its delay and exclusivity, ignoring many MICs (16)(17).

Here, we calculate the number needed to treat to show benefit (NNTB) for cabotegravir compared to oral PrEP, analyse the ViiV-MPP deal in terms of GDP, population, and global incidence, and summarise the latest data on global CAB-LA pricing.

To calculate NNTB for CAB-LA, data on infection rates were extracted from the HPTN083/084 studies (7,8) to give relative risk of infection for extrapolation to sales figures and ViiV-MPP deal analysis.

We gathered incidence data across 178 countries from the UNAIDS AIDSinfo database; 41 nations did not have 2021 data (18). All 178 countries were classified by 2021 World Bank income statu , and inclusion/exclusion from the ViiV-MPP deal (16,19).

Country level data on 2021 population and GDP was then extracted from the World Bank database for all 178 countries (20). GDP per capita was calculated as GDP/population. As the African continent was included in the ViiV-MPP deal (bar Libya) we analysed GDP per Capita of high incidence nations excluded from the deal compared to the highest GDP per Capita African nations included, to assess the appropriateness of exclusion.

Yearly pricing figures pertain to 6 doses, 2-monthly, whereas an extra dose is given in the first year of treatment.

Population level data showed that 47% of the global population (3.7 billion people) live in countries not covered by the ViiV-MPP deal, 31% of whom (2.5 billion) live in MICs.

Figure 1a shows countries who may access generic CAB-LA via ViiV-MPP. Figures 1b and 1c show the additional countries who would have access to generic versions based on a GDP per Capita lower than that of Mauritius ($8,800) and the Seychelles ($13,300) - the two richest African nations currently included. Mauritius as the decisive GDP per Capita includes 24 countries excluded from the ViiV-MPP deal, including Thailand and Brazil. The Seychelles, higher again, includes a further 14 nations currently excluded, to a total of 38, including China, Argentina and the Russian Federation.

Of these 38 countries across 5 continents, 1 was an LMIC and the remaining 37 were UMICs. These 38 countries had a total population of 2.4 billion people (30%). There were 122 thousand estimated infections across these 38 countries, 8% of global incidence. This estimate does not account for poorly documented rates in Russia and China, home to over 1.5 billion people; most recent national estimates of their combined incidence give a conservative 145 thousand (21,22). Their inclusion makes 267 thousand excluded infections, 18% of global incidence. These estimates, however, are difficult to verify and have thus been excluded from analysis.

Table 1 shows that the ViiV-MPP deal does not discriminate by national wealth; 6 African nations have a higher GDP per capita than excluded high-incidence nations. The ten richest African nations included show a similar average GDP per Capita to ten high-incidence excluded MICs (mean $6936 versus $8418), and a total incidence of 240 thousand versus 109 thousand. However, South Africa is a major outlier in incidence, bearing 87% of infections for the ten richest African nations (210 thousand). Excluding South Africa, there are only 30 thousand infections across these countries. Furthermore, the top 5 high incidence nations excluded have a caseload of 88.6 thousand compared to just 15 thousand for the 5 highest GDP African nations.

With the most up-to-date numbers from HPTN083/084, there were 95/4797 infections on TDF/FTC (1.98%), versus 19/4818 on CAB-LA (0.39%) (Table 2), an incidence reduction of 1.59%, or 63 patients on CAB-LA to prevent 1 infection compared to TDF/FTC (NNTB) (Table 2). Applying this reduction to $95 million CAB-LA sales in the US (4,279 patient years), just 68 infections would have been prevented compared to the same population receiving oral PrEP. Subsequently, to prevent 1.5 million annual infections, CAB-LA must reach 946 million people. To cover 122 thousand infections across nations excluded from the ViiV-MPP deal (excluding China and Russia), nearly 7.8 million people would have to be treated annually at branded prices.

Our analysis reveals that access to CAB-LA by the ViiV-MPP deal is arbitrary, motivated by neither incidence nor national wealth. African nations have been included indiscriminately (bar Libya) while 38 MICs were excluded from the deal despite similar GDP per Capita to included African nations and often higher incidence of new HIV infections (table 1). Examples include Thailand, home to nearly half a million PLWH, of whom 1 in 4 are untreated, and Brazil, where CAB-LA clinical trials were conducted (23,24) (table 1).

While GDP per Capita is useful for ascertaining industrial wealth of nations, it does not correlate to health expenditure or wellbeing. Neither are inequalities in healthcare accounted for, rife in many excluded nations despite high GDP per Capita. Databases for alternative measures are unfortunately incomplete, outdated, or difficult to analyse (25,26). Summarily, GDP per Capita is used as a basic measure of national wealth correlated roughly to buying power, and to question justification of the deal.

Branded CAB-LA will not be cost-effective. High NNTB means that CAB-LA will only be a feasible alternative to TDF/FTC if prices are dramatically cut. ViiV currently claim a lowest price of $1440 per year, 16-times higher than cost-effectiveness estimates and 100-times higher than lowest possible pricing estimates (9,14). ViiV is seeking regulatory approval in several excluded countries where clinical trials were conducted, such as Brazil, spiking further ethical questions around post-trial access.

Overall, arbitrary decisions on licensing cause unmet PrEP needs in nations that are no more able to afford CAB-LA than included nations. Within excluded MICs, populations structurally disempowered from achieving suppression on ART due to inequitable services and stigma will be unable to use injectable PrEP, despite it being more effective and tolerable, worsening inequalities (2). In 2021, 39% of all new HIV cases were in sub-Saharan Africa, 63% of whom were women or girls (18), while the ADVANCE trial in South Africa has shown that unemployed patients are less likely to achieve viral suppression due to precarity (27).

The structures that limit adherence to ART and oral PrEP will reduce access to CAB-LA, more so where high prices limit capacity or will to address important determinants of access beyond procurement. The necessity for advocacy on unfair licensing detracts from a global need and responsibility to address structural causes of sustained HIV incidence for progress towards the 95-95-95 goals.

Despite greater efficacy and higher reported acceptability in risk populations, 63 people must be treated with CAB-LA instead of oral PrEP to prevent 1 HIV infection, so only cheap generic production can unlock any benefit. The current ViiV-MPP deal must be widened. 2.4 billion (30%) people live in countries excluded from the deal despite having a lower GDP per Capita than the Seychelles, the highest earning African nation included, so that 122-267 thousand (8-18% global) new cases of HIV are missed. Truly equitable public procurement must be coupled with improvement on wider health determinants like infrastructure, primary care, and social protection. Overall, there is limited justification for the ViiV-MPP deal on CAB-LA, which should be expanded to all MICs.

1. UNAIDS. Global HIV & AIDS statistics — Fact sheet | UNAIDS [Internet]. 2021 [cited 2022 Aug 30]. Available from: https://www.unaids.org/en/resources/fact-sheet

2. World Health Organisation. CONSOLIDATED GUIDELINES ON HIV PREVENTION, DIAGNOSIS, TREATMENT AND CARE FOR KEY POPULATIONS. WHO Libr [Internet]. 2016 [cited 2022 Aug 30]; Available from: https://apps.who.int/iris/bitstream/handle/10665/246200/9789241511124-eng.pdf

3. Rosenberg Z. iPrEx Clinical Trial Demonstrates 44 Percent Protection Against HIV | International Partnership For Microbicides [Internet]. 2010 [cited 2022 Aug 30]. Available from: https://www.ipmglobal.org/publications-media/iprex-clinical-trial-demonstrates-44-protection-against-hiv

4. Molina J-M, Capitant C, Spire B, Pialoux G, Cotte L, Charreau I, et al. On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection. N Engl J Med [Internet]. 2015 Dec 3 [cited 2022 Aug 30];373(23):2237–46. Available from: https://www.aidsmap.com/news/dec-2015/ipergay-prep-study-results-published

5. World Health Organisation. Global data shows increasing PrEP use and widespread adoption of WHO PrEP recommendations [Internet]. 2021 [cited 2022 Aug 30]. Available from: https://www.who.int/news-room/feature-stories/detail/global-data-shows-increasing-prep-use-and-widespread-adoption-of-who-prep-recommendations

6. Yun K, Xu J-J, Zhang J, Li J-M, Hu Q-H, Chu Z-X, et al. Female and younger subjects have lower adherence in PrEP trials: a meta-analysis with implications for the uptake of PrEP service to prevent HIV. Sex Transm Infect [Internet]. 2018 [cited 2022 Aug 30];94:163–8. Available from: http://sti.bmj.com/

7. Landovitz RJ, Donnell D, Clement ME, Hanscom B, Cottle L, Coelho L, et al. Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women. N Engl J Med [Internet]. 2021 Aug 12 [cited 2022 Aug 30];385(7):595–608. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2101016

8. Delany-Moretlwe S, Hughes JP, Bock P, Dadabhai S, Gadama D, Hunidzarira P, et al. Long acting injectable cabotegravir: updated efficacy and safety results from HPTN 084. In: AIDS [Internet]. Montreal; 2022 [cited 2022 Aug 30]. Available from: https://www.hptn.org/sites/default/files/inline-files/220803 IAS 2022 HPTN 084 for HPTN website revised_0.pdf

9. Jamieson L, Johnson LF, Nichols BE, Delany-Moretlwe S, Hosseinipour MC, Russell C, et al. The relative cost-effectiveness of long-acting injectable cabotegravir versus oral pre-exposure prophylaxis A modelled economic evaluation and threshold analysis in South Africa based on the HPTN 083 and 084 trials HE RO 2. In: AIDS [Internet]. 2022 [cited 2022 Aug 30]. Available from: https://thembisa.org

10. BNF Medicinal Forms, Cabotegravir - Prolonged Release Suspension for Injection | NICE [Internet]. [cited 2022 Sept 8]. Available from: https://bnf.nice.org.uk/drugs/cabotegravir/medicinal-forms/#prolonged-release-suspension-for-injection

11. Drugs and pharmaceutical electronic market information tool (eMIT) | Gov.uk [Internet]. [cited 2022 Aug 31]. Available from: https://www.gov.uk/government/publications/drugs-and-pharmaceutical-electronic-market-information-emit

12. PAHO Strategic Fund Long Term Agreements Price List | PAHO [Internet]. [cited 2022 Sept 8]. Available from: https://www.paho.org/en/documents/paho-strategic-fund-long-term-agreements-price-list-updated-4212022

13. Press Release Second Quarter 2022 | GSK [Internet]. [cited 2022 Aug 31]. Available from: https://www.gsk.com/media/9386/q2-2022-results-announcement.pdf

14. Long-Acting PreP is a Necessity, Not a Luxury: ViiV’s Greed is Still Blocking Global Access to Injection that Could Transform HIV Prevention and Help End the Pandemic – Health GAP (Global Access Project) [Internet]. [cited 2022 Aug 30]. Available from: https://healthgap.org/press/long-acting-prep-is-a-necessity-not-a-lu xury-viivs-greed-is-still-blocking-global-access-to-injection-that-could-transform-hiv-prevention-and-help-end-the-pandemic/

15. Cabotegravir: What are we waiting for? | Médecins Sans Frontières Access Campaign [Internet]. [cited 2022 Aug 30]. Available from: https://msfaccess.org/cabotegravir-what-are-we-waiting

16. CABOTEGRAVIR LONG-ACTING (LA) FOR HIV PRE-EXPOSURE PROPHYLAXIS (PrEP) - MPP [Internet]. [cited 2022 Aug 30]. Available from: https://medicinespatentpool.org/licence-post/cabotegravir-long-acting-la-for-hiv-pre-exposure-prophylaxis-prep

17. ViiV Healthcare to allow 90 countries to access generic versions of HIV prevention shot | aidsmap [Internet]. [cited 2022 Aug 30]. Available from: https://www.aidsmap.com/news/jul-2022/viiv-healthcare-allow-90-countries-access-generic-versions-hiv-prevention-shot

18. UNAIDS. AIDSinfo [Internet]. 2021 [cited 2022 Aug 30]. p. UNAIDS data 2021. Available from: https://aidsinfo.unaids.org/

19. World Bank. WDI - The World by Income and Region [Internet]. 2021 [cited 2022 Aug 30]. Available from: https://datatopics.worldbank.org/world-development-indicators/the-world-by-income-and-region.html

20. Bank W. Gross domestic product 2021. 2021 [cited 2022 Aug 30]; Available from: https://databankfiles.worldbank.org/data/download/GDP.pdf

21. Information on HIV infection in Russia – Federal Scientific and Methodological Center for the Prevention and Control of AIDS [Internet]. [cited 2022 Sep 10]. Available from: http://www.hivrussia.info/dannye-po-vich-infektsii-v-rossii/

22. National Bureau of Statistics of China. National HIV statistics. China Statistical Yearbook. 2017 [cited 2022 Sep 10]. Available from: http://www.stats.gov.cn/tjsj/ndsj/2017/indexeh.htm

23. UNAIDS. Focus on: Thailand. AIDSinfo. [Internet] 2021 [cited 2022 Sep 10]. Available from: https://www.unaids.org/en/20200117_country_focus_Thailand

24. Zhang C, Liu Y, Moyo E, Murewanhema G, Musuka G, Dzinamarira T. Long-Acting Injectable Drugs for HIV-1 Pre-Exposure Prophylaxis: Considerations for Africa. Trop Med Infect Dis 2022, Vol 7, Page 154 [Internet]. 2022 Jul 29 [cited 2022 Aug 30];7(8):154. Available from: https://www.mdpi.com/2414-6366/7/8/154/htm

25. WHO. Global Health Expenditure Database [Internet]. 2021 [cited 2022 Aug 30]. Available from: https://apps.who.int/nha/database/Home/Index/en

26. OECD. Health Expenditure [Internet]. 2021 [cited 2022 Aug 30]. Available from: https://www.oecd.org/health/health-expenditure.htm

27. Venter WDF, Moorhouse M, Sokhela S, Fairlie L, Mashabane N, Masenya M, et al. Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV. N Engl J Med [Internet]. 2019 Aug 29 [cited 2022 Jul 27];381(9):803–15. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa1902824

Funding: This work was supported by the International Treatment Preparedness Coalition, Make Medicines Affordable campaign

Conflict of Interest: The authors declare no conflict of interest

[Table 1. Population, PLWH, and incidence of HIV infection in richest African nations included in deal, and highest incidence nations excluded from the deal with a lower GDP per Capita than the Seychelles, ranked by GDP per capita]

Country*	Population (millions)	PLWH	Incidence	GDP per Capita (USD)
Seychelles	0.1	600	75	13,307
Malaysia	32.8	82,000	5,500	11,371
Argentina	45.8	140,000	5,000	10,729
Khazakhstan	19.0	35,000	3,500	10,041
Mexico	13.0	360,000	18,000	9,926
Mauritius	1.3	12,000	1,000	8,812
Dominican Republic	11.0	78,000	4,200	8,603
Equatorial Guinea	1.5	66,000	5,200	8,462
Gabon	2.3	47,000	1,700	8,017
Brazil	214.0	960,000	50,000	7,521
Botswana	2.4	360,000	7,200	7,348
Thailand	70.0	520,000	6,500	7,233
South Africa	60.0	7,500,000	210,000	6,994
Peru	33.4	98,000	5,500	6,692
Colombia	51.3	170,000	8,600	6,131
Ecuador	17.9	47,000	2,000	5,935
Namibia	2.6	220,000	6,600	4,729
Eswatini	1.1	220,000	6,900	4,215
Tunisia	11.9	5,400	500	3,924
Morocco	37.3	23,000	1,000	3,554
Highest GDP per capita African nations
Total	120,573,480	845,400	240,175
Mean				6,936
Median			3,450	7,171
Top incidence nations excluded from ViiV-MPP deal**
Total	625,201,470	2,490,000	108,800
Mean				8,419
Median			5,500	8,062

*African nations in blue **bar China and Russia as incidence figures are out of date

[Table 2. Data from HPTN 083/084 trials on infection rate by treatment arm, extrapolated across to give risk reduction on cabotegravir versus TDF/FTC, and number needed to treat to cause benefit as a result]

	Infection rate		Risk reduction	NNTB*
Trial	TDF/FTC	Cabotegravir	Risk reduction	NNTB*
HPTN 083	39/3187 (1.22%)	13/3205 (0.41%)	0.81%	124
HPTN 084	56/1610 (3.48%)	6/1613 (0.37%)	3.11%	33
Both	95/4797 (1.98%)	19/4818 (0.39%)	1.59%	63

*NNTB = number needed to treat to cause benefit (prevention of 1 infection), calculated by 100 divided by risk reduction

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Cabotegravir – global access to long-acting pre-exposure prophylaxis for HIV

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