Disease Analysis: HIV Treatment

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, 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), 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. 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.
• The HIV treatment market in the US, Japan, and five major European markets (France, Germany, Italy, Spain, and the UK) is expected to continue to expand through to 2025, driven primarily by increases in disease prevalence and continued uptake of Gilead’s Biktarvy and ViiV Healthcare’s portfolio of two-drug regimens. Uptake of new premium-priced therapies (Rukobia and lenacapavir) in heavily treatment-experienced (HTE) individuals will also drive growth, though their impact will be limited by the relatively low number of patients in the salvage setting. However, a plethora of products undergoing patent expiry across the forecast period will tip the market into decline from 2026, particularly Descovy, which is the preferred nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone, as physicians and payers will be provided with the ability to construct lower-cost once-daily regimens with generic Descovy and a generic third antiretroviral agent (such as dolutegravir, which will lose exclusivity in the US in 2027).
• Integrase strand transfer inhibitor (INSTI)-based regimens have become the top drug class due to their excellent efficacy and tolerability profiles as well as their very high barriers to resistance. Both US and EU guidelines now favor INSTI-based regimens as initial “recommended” regimens, which has driven a steady decline in the market share of protease inhibitor (PI)- and non-nucleoside reverse transcriptase (NNRTI)-based regimens in the first-line setting in recent years. PIs suffer from the requirement for co-administration with a pharmacokinetic boosting agent, which increases the risk of drug-drug interactions and adverse events, while NNRTIs suffer from low barriers to resistance. In the maintenance setting, the recent launches of Juluca, Dovato, and Cabenuva will further drive consolidation to INSTI-based regimens by offering patients the opportunity to simplify their treatment regimens from three drugs to two.
• Gilead’s flagship single-tablet regimen (STR) Biktarvy will continue to experience strong growth through to at least 2025. Biktarvy outpaced rival STRs to gain market-leader status in 2020, with sales amounting to $7.3bn. Further success in the HIV market will primarily be driven by patients switching over from Gilead’s older STRs (Genvoya, Stribild, Atripla, Complera, and Odefsey), its continued uptake in treatment-naïve patients, increasing HIV prevalence, and price rises in the US. While Biktarvy has suppressed its main rival Triumeq, the drug will face competition from other assets in ViiV Healthcare’s portfolio, most notably two-drug regimens Dovato, Juluca, and Cabenuva. Additional competition will come in 2025 following the launch of low-cost generics for Descovy, which makes up the NRTI backbone of Biktarvy. Coupling generic Descovy with an INSTI such as Tivicay will allow physicians to make their own less expensive three-drug regimens.
• ViiV Healthcare has maintained its second-place position in the HIV treatment market and is likely to grow its revenues due to new INSTI-based drug launches. Despite a continued decline for the company’s flagship three-drug regimen Triumeq, a shift in focus to the recently launched two-drug regimens Cabenuva, Dovato, and Juluca will be key in growing ViiV Healthcare’s revenues. The two-drug regimens have the advantage of potentially improved long-term tolerability and safety (although this is unproven), as well as a lower cost, giving them a competitive advantage. While initial uptake was muted due to physician concerns over resistance generation, long-term data demonstrating that resistance generation is minimal should allay these concerns. Both Dovato and Juluca have seen strong year-on-year growth, despite delays in patient switching due to the COVID-19 pandemic. Cabenuva has the advantage of a two-monthly injectable dosing schedule (recently extended from monthly); however, it is expected to gain only a minority of market share because it must be administered as two separate intramuscular injections by a physician, which will be a deterrent to some patients as well as posing a logistical challenge for primary care physicians by increasing the number of patient visits required.
• Remaining unmet needs in the HIV space include longer-acting drugs, simplified dosing regimens, and more treatment options for HTE patients. Initially, ViiV Healthcare’s two-drug regimens had a muted uptake due to a hypothetical lower barrier to resistance; however, uptake is now accelerating. Cabenuva, which has a two-monthly dosing regimen, has the benefit of being the first-to-market long-acting injectable (LAI); however, Gilead’s pipeline asset lenacapavir, which has a more attractive six-monthly dosing schedule, is likely to be a major challenger. Assuming a positive response from the FDA, lenacapavir could gain approval in December 2022 to become the second marketed LAI. Moreover, a partnership between Gilead and Merck & Co to develop a dual-combination therapy of islatravir/lenacapavir as a long-acting oral (LAO) and LAI is another major threat; however, this partnership is materially at risk owing to safety concerns surrounding islatravir (low lymphocyte and T-cell counts).
• With a significant proportion of treatment-experienced patients generating resistance to multiple drug classes, there is a major unmet need for new mechanisms of action. There are three drugs in late-phase development for the treatment of HTE patients, namely lenacapavir (capsid inhibitor), islatravir/doravirine (reverse transcriptase translocation inhibitor), and Vyrologix (CCR5 inhibitor).
• With Isentress being downgraded in US treatment guidelines, Merck & Co’s success in the HIV space largely rests on islatravir, a novel nucleoside reverse transcriptase translocation inhibitor, which has been selected to be the backbone drug for the company’s next generation of combination therapies. In November 2021, the FDA decided to place a clinical hold on trials of islatravir based on observations of a dose-dependent decline in levels of lymphocytes and CD4+ T-cells. The depletion of lymphocytes and T-cells is the opposite of the desired effect of a HIV treatment, and therefore Datamonitor Healthcare believes that this represents a potentially insurmountable safety hurdle for islatravir to overcome. Our base-case scenario is that development will continue once protocols have been amended to monitor lymphocytes and CD4+ T-cells, however, it is hard to imagine that there will be much interest for a HIV drug that requires routine monitoring and is associated with T-cell toxicity.