Polly Clayden leads us on a brisk, bracing walk through the changing landscape of ART optimization in her 2016 "Fit for Purpose: Antiretroviral Treatment Optimization" chapter. "Since the 2015 Pipeline Report global antiretroviral treatment (ART) guidelines have moved to recommending "treat all" HIV positive people. With this recommendation comes the massive task of starting and keeping everyone with HIV on ART. ART optimization is one of many critical steps to universal access to HIV treatment that is: safe, effective, tolerable, durable, simple and affordable. Antiretrovirals can sometimes be optimized by dose reduction. Reducing an approved dose of a drug might be possible, because when new ones are developed, the highest tolerated doses in phase II are usually selected for phase III and approval. In some cases lower doses might have equivalent efficacy and better tolerability – as has been shown with efavirenz (EFV). But since discussions on treatment optimization began the field has evolved and newer, better, and lower dose antiretrovirals have been approved. With a couple of exceptions, treatment optimization has shifted away from making older drugs more efficient. Speeding up the introduction of generic versions of newer drugs – in appropriate regimens and formulations – into low-and middle-income countries (LMIC) – is now the main focus of ART optimization.
"Experts now agree on a short list of antiretrovirals that have shown superior or non-inferior efficacy compared to existing recommended ones. These drugs offer improved durability and tolerability, higher bioavailability, lower pill burden, and the potential for fewer side effects. The antiretrovirals are: dolutegravir (DTG), tenofovir alafenamide (TAF), efavirenz (EFV) 400 mg, and darunavir/ritonavir (DRV/r)."
As Clayden points out, the 2015 WHO guidelines now include dolutegravir and efavirenz 400mg; generic formulations of dolutegravir are on the way; and the FDA has begun to approve TAF-containing regimens to replace those with tenofovir disoproxil fumarate (TDF). WHO second-line recommended alternative regimens now "include ritonavir-boosted darunavir (DRV/r) or raltegravir (RAL) as alternatives to boosted lopinavir (LPV/r)."
New generic formulations of dolutegravir (DTG), DTG/TDF/3TC, efavirenz 400mg/TDF/3TC, and DRV/r will ]come on-line in the next year; see Table 3: New generic antiretrovirals available 2016/2017 for adults. "By the end of 2025 the introduction of TAF, EFV 400 mg, and DTG into ART programs in LMIC could mean 3 Executive Summary savings up to a whopping US $3 billion" – please see Table 5: Table 5: Market share and cumulative savings 2025.
Clayden reviews studies investigating dolutegravir or efavirenz at 400mg as global first-line ART anchor drugs (see Table 6: New first-line regimen studies), first-line pregnancy studies (see Table 7: First-line pregnancy studies), reviews the urgent case of first-line ART in combination with tuberculosis co-treatment (see Table 8: First-line HIV/TB co-treatment studies), and considers the potential use of darunavir/r/dolutegravir in secondline therapy (see Table 9: Low dose DRV/r studies).
This chapter provides a long view of what to expect in the coming decade and how research can provide answers which will make it easier to treat all of the world's 37 million HIV-infected persons.