The treatment landscape for HIV patients has undergone a revolutionary change. HIV, a once deadly infection is now a largely manageable chronic condition owing to several decades of HIV drug innovation. Indeed, HIV patients today are able to successfully reduce their viral load to undetectable levels through daily adherence to highly-active antiretroviral (ARV) regimens consisting of three- or four-drugs, many of which are now available in convenient once-daily single tablets regimens (STRs). Since many HIV therapeutics have attained excellent efficacy, the focus of manufacturers is now shifting towards addressing the need for new agents with improved long-term safety and tolerability in the context of combination therapy, in order to differentiate their therapies in the market.

New HIV therapies need to be suited for long-term use as HIV patients treated with ARVs are living longer than ever before, often with a life expectancy similar to the overall population. The current standard of care for HIV infections is associated with cumulative toxicity over time. Therefore, as patients age, the treatment of patients with age-associated comorbidities will become increasingly important and requires that HIV therapies be amenable to use with such comorbidities (e.g., renal dysfunction, high blood pressure, neurocognitive disorders, etc.). As such, HIV regimens over time have become not only more potent, but also more safe and tolerable, seeking to address the evolving needs of the HIV patient population.

HIV treatment guidelines recommend three-drug regimens composed of two nucleotide reverse transcriptase inhibitors (NRTIs) and a third agent, generally either a protease inhibitor (PI), non-nucleotide reverse transcriptase inhibitor (NNRTI) or, most recently, an integrase stand transfer inhibitor (InSTI). The third agents added to the NRTI backbone are the critical components that provide the bulk of the activity to achieve viral suppression. The NRTI backbone provides an additional level of therapeutic potency, thereby helping to ensure sustained viral suppression and deter the emergence of viral resistance.

The vast improvements in efficacy, safety, and tolerability of third agents over time, most notably seen through the development of InSTIs, are responsible for the high quality of treatment currently available to patients today. While older-generation HIV regimens delayed the devastating progression of the infection to AIDS, they subjected patients to a host of unfavorable side effects (e.g. cardiovascular disease, hepatoxicity, renal toxicity, lipodystrophy, etc.). Additionally, the poor safety and tolerability of older HIV treatments often fueled poor patient compliance, which in turn led to the development of viral resistance. Taken together, these issues associated with older ARV agents created a significant unmet need for better tolerated and safer therapeutic options.

A key step in the evolution of regimen safety was the development of tenofovir, the active form of the NRTI contained in the majority of HIV regimens. Tenofovir was the first ARV to be optimized for HIV therapeutic use through a collaborative effort between Gilead and UCSF in 1997, resulting in the development of the prodrug tenofovir disoproxil fumarate (TDF, marketed as Gilead’s Viread), which has better gut absorption than tenofovir. TDF has been a blockbuster HIV product, largely attributed to its availability as a fixed-dose combination with emtricitabine (marketed as Gilead’s Truvada; FDA approved in 2004). More recently, Gilead has also developed tenofovir alafenamide (TAF) as a safer alternative prodrug compared to TDF, resulting in improved pharmacokinetics. TAF as compared with TDF offers an improved side effect profile, with a significant reduction in bone demineralization and renal toxicity1,2 seen in clinical trials. While the improved side-effect profile of TAF offers many patients significant safety benefits, these benefits are relatively minor compared to those delivered by other new-generation third-agents included in current HIV regimens, such as the InSTI elvitegravir contained in Stribild. As such, it is no surprise that Gilead’s development and commercialization of Stribild preceded launch of TAF-containing compounds. TAF has recently reached the market and is now available as a component of two new STRs that are poised to address some of the safety-focused needs of the aging HIV patient population – Genvoya (elvitegravir/cobicistat/emtricitabine/TAF) and Odefsey (rilpivirine/emtricitabine/TAF).

The launch of TAF-containing compounds so close to the patent expiry date of TDF has garnered some criticism from interviewed experts. However, it is worth considering that including TAF in the development of Stribild would have likely made Gilead’s commercialization of HIV therapies more difficult and limited the number of new therapeutic options brought to the market. Stribild’s submission for approval to the FDA was based on clinical trials designed to compare the novel boosted integrase inhibitor elvitegravir and the NNRTI efavirenz, which was the dominant third-agent on the market at the time. Comparing a novel regimen containing both TAF and elvitegravir against Atripla would have confounded the conclusions on the benefits for individual agents. Therefore, by designing the Genvoya clinical trials as a direct TAF-containing follow up to the TDF-containing Stribild, Gilead was able to use two comparator-controlled clinical programs to provide enough evidence for the marketing of four new products (Striblid, Genvoya, Vitekta (elvitegravir), and Descovy (emtricitabine/TAF), thus providing additional options for patients that require customized regimens.

Overall, the key point to consider is that pharmaceutical developers are only able to focus on improved safety profiles of HIV regimens because of the tremendous improvements in efficacy and safety offered by the latest generation of ARVs. While long-term safety benefits of TAF-containing regimens will require validation through analysis of real world evidence, the hope for patients is that someday a functional cure will move us beyond the need for antiretroviral treatment and provide value to patients on a much larger scale. However, as a functional cure is unlikely to reach the market in the near future, until then, safe and efficacious regimens, which have generally transformed HIV infections into a manageable chronic condition, will maintain market dominance.

For a more in-depth analysis of the HIV market, please see our content here.

 

References:

http://www.gilead.com/news/press-releases/2015/7/gilead-announces-phase-3-results-from-the-first-study-to-evaluate-switching-from-tdfbased-regimens-to-a-tafbased-regimen-containing-elvitegravir-cobicistat-emtricitabine-and-tenofovir-alafenamide-ecftaf

http://www.gilead.com/news/press-releases/2015/10/gilead-announces-phase-3-results-for-genvoya-elvitegravir-cobicistat-emtricitabine-and-tenofovir-alafenamide-an-investigational-oncedaily-single-tablet-regimen-for-hiv

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