In summary, the global ARV optimization framework was initially focused on improving global access to key ARV drugs available at that time by reducing cost and simplifying manufacturing processes, aiming the rapid reduction in mortality from HIV, preservation of life and prevention of progression to AIDS and the risk of HIV transmission at the population level. With the evolving science of HIV treatment in the last decade, new steps were taken to ensure a transition to new drugs and formulations with better efficacy, lower toxicity, limited contraindications and higher durability against drug resistance, to reduce the need to switch to more complex and expensive regimens and also to reduce the risk of HIV transmission at population level.
POLICY TRANSITION TO NEW ARV OPTIONS: OPPORTUNITIES AND CHALLENGES
The most recent drug optimization meetings have emphasized the importance of programmatic data to inform benefits and challenges in introducing and scaling up DTG as the preferred first-line regimen [7,10]. There was discussion on low-dose EFV (EFV 400 mg) as an alternative first-line option in the event that DTG is unavailable or patients face tolerability issues. Several fixed-dose DTG dual therapy regimens have recently been developed, notably DTG combined with rilpivirine and DTG with DRV/r. These were not given a priority at that time, as existing clinical trial data with these regimens were limited, particularly with respect to populations of concern in resource-limited settings.
Medium-term opportunities include the role of regimens including the new tenofovir prodrug (TAF) and new DRV formulations, with critical research focusing on the efficacy/safety, switch regimens, dose-reduction and/or the use of nanoformulations, particularly for DRV. Long-term goals include long-acting formulations of new compounds, maturation and capsid inhibitors and biologicals. Key research is also needed to evaluate the efficacy and safety of different second-line ART options [8▪].
Furthermore, harmonization of adult and paediatric and key populations has been a goal for HIV treatment, ideally as FDCs. DTG offers great potential as a first-line regiment options, particularly as a generic fixed dose combination – requires less quantity of active pharmaceutical ingredient, once daily dosing, favourable side-effect profile compared to EFV .
In the future, however, it may be useful to expand the idea of target populations, particularly in the further scale-up of HIV treatment to reach the 90-90-90 targets by 2020 . Upon reaching the global 90-90-90 target, a large number of individuals will be on life-long therapy. Developing a robust, cross applicable treatment regimen having evaluated an expanded safety requirement in addition to efficacy at the level of clinical trials will be of great utility and the importance of such pragmatic clinical trials, particularly when considering pregnancy, TB/HIV coinfection, teratogenicity, early birth defects as well as the effects of polypharmacy in aging populations [9▪,17].
LOOKING TO THE FUTURE: HOW TREATMENT OPTIMIZATION WILL LOOK LIKE?
Given the high efficacy, safety, tolerability and convenience of current ARV therapy, it can be challenging to identify where and to what extent further improvements can be made. New agents under investigation are challenging the current treatment paradigm of three active antiretroviral medications taken orally every day to maintain viral suppression . Several two-drug therapy options are under study and may simplify treatment and reduce cost [19,20]. Long-acting medications dosed every week or month, or longer, may be easier for some patients, improve medication adherence and increase cost-effectiveness . A few longer acting ARVs in development will provide additional oral therapy options, but the majority of novel regimens will likely be delivered via alternative drug delivery systems. This includes the potential delivery of some new agents such as cabotegravir and rilpivirine as long-acting injectable formulations or as a subdermal implant . These methods of drug, while new for HIV treatment, are common in other therapeutic areas such as hormonal contraception and psychiatry and may represent an additional way to improve medication adherence and effective treatment. These agents, along with the recent approval of ibalizumab (a novel anti-CD4 monoclonal antibody), may provide future therapeutic options, particularly for those with heavy treatment experience  (Table 3).
Future ARV optimization will move towards inclusion of new drugs classes, new technologies in process chemistry and formulations and new therapeutic strategies. How to retain the public health approach and guarantee equitable access to these innovations in all settings remains an important challenge.
Additional patient populations should also be considered in the future development of optimal ARVs. With the significant decrease in the mortality and establishment of HIV as a chronic disease, aging populations with HIV will form a significant proportion of the people on ART in the near future, and is already know that they at an elevated risk of cardiovascular disease, type 2 diabetes and other comorbidities when compared with general population . Greater integration is expected in the future between HIV, TB, hepatitis, sexual/reproductive health and noncommunicable diseases [25–27]. Close coordination between the innovators and these disease areas will further enhance considerations for safety and applicability.
In this context, enhanced pharmacovigilance is a critical component to ensuring patient safety. Clinical trials have limited scope to discover rare but important adverse/side-effects – the recent example of a potential safety issue with DTG is a difficult lesson demonstrating the importance of having established networks for outcome surveillance . In the absence of the ongoing study, such a signal would be unlikely to have been detected, with potential serious consequences. Surveillance systems should also be in place when considering drug–drug interactions, pregnancy and elderly/geriatric populations on ARVs.
Finally, treatment optimization goes beyond of pharmacological/patient adherence interventions. Improvement in the efficiency and quality of treatment programs and the promotion of innovative, comprehensive strategies and actions to eliminate HIV-related stigma and discrimination are essential to improve the outcomes and reach global HIV elimination targets. Several challenges need to be overcome. These include increased testing uptake, and sustained high levels of treatment coverage, adherence and retention in care. Cost implications at the regional and country levels will also vary and need to be further explored. Additional ARV drug costs may be at least partially offset by increased efficiencies, such as implementation of the differentiated care approach, task shifting and integration of HIV and related services.
The optimization of ARV drugs in the last decades has dramatically improved both treatment and prevention outcomes of HIV infection globally. Continued development of compounds and formulations that improve the efficacy, safety and tolerability of HIV drugs will provide additional progress in this area. Notwithstanding, these extraordinary achievements, important challenges to consolidate the treatment optimization agenda still remain, considering that as of the end of 2017, still some 15 million HIV positive individuals were not receiving treatment . Therefore, drug innovations should be combined with innovative care delivery models to ensure durable, efficacious and safe treatment for all PLHIV. Innovators should consider the ease of administration and scale-up of a new ARV in low/middle-income settings in addition to the framework laid down by the CADO process. Sequencing of first-line, second-line and third-line regimens will also allow better planning, rationalize the number of regimen that programmes need to procure and minimize the risk of ARV stock outs.
Financial support and sponsorship
This work was supported by the Department of HIV and Global Hepatitis Programme, World Health Organization, Geneva, Switzerland.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
antiretroviral therapy; fixed-dose combinations; integrase inhibitors; long-acting formulations; tenofovir alfenamide