Disease Analysis: HIV Pre-Exposure Prophylaxis (HIV PrEP)

Overview

HIV, or the human immunodeficiency virus, is a lentivirus belonging to the Retroviridae family. HIV infects and destroys cells of the immune system, including cluster of differentiation 4+ (CD4+) T cells, macrophages, and dendritic cells, progressively impairing the infected individual’s ability to respond to subsequent infections. If left untreated for several years, the continued destruction of CD4+ T cells can lead to the development of acquired immunodeficiency syndrome (AIDS) (defined as a CD4+ T-cell count <200 cells/mm3), which is characterized by increased susceptibility to opportunistic infections and cancers. Although HIV infection is currently incurable, there are several effective highly active antiretroviral therapies (HAARTs) available that can suppress viral replication and prevent the progression of infection to AIDS.

Latest key takeaways

• HIV, or the human immunodeficiency virus, infects and destroys cells of the immune system, including cluster of differentiation 4+ (CD4+) T cells, macrophages, and dendritic cells, progressively impairing the infected individual’s ability to respond to subsequent infections. If left untreated for several years, the continued destruction of CD4+ T cells can lead to the development of acquired immunodeficiency syndrome (AIDS). HIV represents a major global clinical and economic burden, with the World Health Organization (WHO) estimating that there were 38.4 million people living with HIV at the end of 2021, 1.5 million of whom were newly infected during that year. The majority of people (54%) living with HIV in 2021 were in East and Southern Africa, where the prevalence of infection is highest.
• Following its initial US and EU approvals for HIV pre-exposure prophylaxis (PrEP) in 2012 and 2016, respectively, the PrEP-specific sales for Gilead Sciences’ Truvada (emtricitabine/tenofovir disoproxil fumarate) steadily rose to a peak in 2019, with estimated PrEP sales of $2,278m in the US and five major European markets (5EU): France, Germany, Italy, Spain, and the UK. This strong performance was driven by its status as the only approved therapy for PrEP until Descovy’s US approval in October 2019, the favorable recommendations for its use in US Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) guidelines, and reimbursement by the healthcare systems of four of the 5EU markets in either national or pilot programs. However, PrEP-specific sales tumbled in 2020 to an estimated $1,281m, driven by the launch of Teva’s generic in the US market in October 2020 and rapid cannibalization by Gilead’s own successor product, Descovy (emtricitabine/tenofovir alafenamide).
• Despite Truvada’s and Descovy’s commercial success, PrEP remains underutilized due to poor awareness and lack of/limited reimbursement in some European countries, though uptake is increasing due to recent favorable reimbursement decisions in Germany, Spain, England, Wales, and Northern Ireland, as well as due to Gilead’s marketing efforts. The US has the highest rate of uptake (estimated at 22% of at-risk individuals in 2020) and generates the majority of global PrEP revenues, though the October 2020 launch of generic versions of Truvada has triggered a steep decline in the drug’s sales. Within the EU and UK, Truvada is the only approved agent for PrEP but generates minimal sales due to generic competition since July 2017. PrEP uptake is also estimated to be much lower in the 5EU markets (4.7% in 2020), due partially to a historical lack of reimbursement in some countries and continued lack of reimbursement in Italy, but also due to social factors.
• In order to protect PrEP revenues from generic versions of Truvada, since October 2019 Gilead has been promoting swapping to Descovy, which has displayed non-inferior efficacy and marginal improvements in bone and renal safety. Despite the COVID-19 pandemic reducing interaction between physicians and their patients, Gilead has successfully converted approximately half of patients to Descovy (46% market share versus 54% for Truvada/generic Truvada as of the end of 2020), due largely to Descovy being priced at parity to Truvada. However, Teva’s launch of the first generic version of Truvada is expected to have severely limited further swapping to Descovy throughout 2021, as widespread use of Descovy in patients with no pre-existing renal or bone risk factors is unlikely to be deemed as cost-effective compared to lower-cost generic Truvada.
• Descovy has a potential growth opportunity from the HIV Women’s Prevention Study, which will support potential US approval in female adolescents and adult women (the FDA refused to approve Descovy for women as the sole pivotal DISCOVER trial only included men who have sex with men [MSM] and transgender women). However, if trial timelines are comparable to the DISCOVER trial, supplementary approval for use in women is unlikely to occur until late 2024, leaving Descovy little time to capitalize on the new indication before its anticipated patent expiry in June 2025. As a result, Gilead’s PrEP development focus is switching to its six-monthly subcutaneously administered lenacapavir, which would be more competitive against long-acting pipeline rivals and has been added to the HIV Women’s Prevention Study. Additionally, in June 2021 Gilead initiated a Phase III trial, PURPOSE 2, to investigate lenacapavir in cisgender men as well as in non-binary and transgender individuals.
• Notable threats to Truvada/Descovy include ViiV Healthcare’s Apretude (cabotegravir), which is dosed intramuscularly every two months (eight weeks) and has demonstrated superior efficacy compared to Truvada in the HIV Prevention Trials Network (HPTN) 083 (cisgender men and transgender women) and HPTN 084 (cisgender women) trials. Apretude’s two-monthly administration could be very attractive to patients who struggle to adhere to daily pills, though its injectable nature and requirement for physician administration will deter some patients, meaning Descovy will still be able to maintain some market share.
• There are currently four agents in clinical development for pharmacological PrEP, comprising three antiretrovirals and a single broadly neutralizing antibody. All the pipeline agents aim to offer less frequent dosing schedules in order to address the issue of suboptimal adherence to once-daily Truvada and Descovy, which can result in impaired effectiveness in real-world practice. Merck & Co’s once-monthly oral drug, islatravir, and Gilead’s six-monthly injectable, lenacapavir, are potential threats to Truvada and Descovy, as both treatment options would offer greatly improved adherence while avoiding the need for physician administration. However, islatravir’s prospects are now more tentative given that the FDA has placed a clinical hold on islatravir trials following observations of low lymphocyte and CD4+ T-cell counts.
• The overall likelihood of approval of a Phase I antiviral asset is 12.3%, and the average probability a drug advances from Phase III is 64.9%. Antiviral assets, on average, take 8.6 years from Phase I to approval, which is slightly less than the average of 9.1 years for the overall infectious disease space.