Universal access to effective combination ART is an important component of global efforts to control the HIV pandemic. Concerns about drug resistance, tolerability, toxicity, and cost retard the implementation of universal access. HIV-treatment optimization is a process intended to address all possible issues hindering access to treatment by using the best scientific evidence to remove obstacles and identify innovative, effective public health-based delivery approaches.
There is a common misperception that the main goal of treatment optimization is to reduce costs, thereby expanding the number of treated patients. In fact, treatment optimization, as the name implies, aims to deliver the best possible combinations of antiretroviral drugs to affected populations. The value of recommended interventions is judged by their long-term efficacy, safety, tolerability, adherence, and convenience. Finding the best possible treatments at a cost that allows universal access represents the intersection of the goals of HIV clinical practice and public health, and this is the ultimate objective of treatment optimization.
The best approaches to achieve this objective are subject to discussion and debate. However, most experts recognize that a combination of approaches will be needed to provide optimal HIV treatment to all those in need, a population currently estimated by the WHO at 26 million persons . It is likely that this objective will need to be met without the expenditure of funds substantially in excess of the US$16–18 billion being spent annually to provide ARVs in resource-poor countries. Although additional financing is going to be crucial, particularly through the Global Fund to Fight AIDS, Tuberculosis and Malaria, and from affected countries themselves, recent evidence and opinion indicates that much more can be done within the limits of existing budgets.
WHAT IS THE TARGET PRODUCT PROFILE FOR THE IDEAL ANTIRETROVIRAL DRUG?
Although the ideal Target Product Profile (TPP) for every pharmaceutical includes complete efficacy, convenience, safety, and tolerability, there are special concerns for antiretrovirals (ARVs) that must be considered. As treatment is presumably for life, long-term safety and tolerability are of supreme importance given the large number of equally efficacious drug combinations. At present, there is one marketed ARV, lamivudine, with no proven off-target drug-associated toxicity; as a proof-of-concept, lamivudine is evidence that it is possible to develop a selective antiviral compound taken for decades that produces no adverse effects in diverse populations, discounting the possible consequences of rebound hepatitis B virus if the drug is discontinued in a coinfected patient. Two other approved ARVs, the NRTI emtricitabine and the integrase inhibitor raltegravir, also have few or no significant side-effects .
Additional considerations for ARVs include the need for efficacy and safety in a variety of settings and populations, including children, pregnant women, and individuals of diverse ethnicity and genetics in every region of the world. HIV-associated infections and comorbidities must also be considered. The most problematic of these is tuberculosis, one of the most common life-threatening infections and a frequent partner of HIV. Aside from the obvious combined toxicities of drugs used to treat tuberculosis and HIV, the near universal requirement for rifampin in tuberculosis treatment regimens produces undesirable reductions in concentrations of many co-administered ARVs as a consequence of induction of drug metabolizing enzymes. Of current first-line ARV regimens, only efavirenz-based combinations can be administered with tuberculosis treatment without any need for dose adjustment.
Failure of first-line antiretroviral treatment is nearly always the result of drug discontinuation due to toxicity, or lack of adherence that may result in resistance . The first of these problems is addressed by choosing safer and better tolerated drugs in the regimen. The second problem is addressed by simplifying therapy and choosing more robust drugs that are not impacted by occasional nonadherence. This includes an emphasis on once-daily dosing and fixed-dose combinations (FDCs), preferably a one-pill, once-daily regimen. These tactics were promoted by the UNAIDS and WHO Treatment 2.0 initiative , and resulted in the 2013 WHO Treatment Guidelines for HIV-infected adults recommending a first-line regimen of efavirenz + tenofovir + lamivudine or emtricitabine, preferably as an FDC .
As the vast majority of HIV-infected persons are living in resource-limited countries, cost is an important component of the TPP for antiretroviral drugs when considering public health needs. The availability of low cost generic versions of approved ARVs has revolutionized HIV treatment globally , and strategies to reduce the cost of delivering ARVs to those in need are essential components of public health policy.
The creation of a treatment research agenda that employs new knowledge to deliver better and more sustainable treatments to more patients has been the goal of a number of recent working groups and conferences. This includes two conferences on antiretroviral drug optimization, held in 2010 and 2013.
THE CONFERENCES ON ANTIRETROVIRAL DRUG OPTIMIZATION
The First Conference on Antiretroviral Drug Optimization (CADO) was convened in June, 2010, as a collaborative project between the Clinton Health Access Initiative, the Johns Hopkins University School of Medicine, and the Bill and Melinda Gates Foundation. This unique conference brought together expert scientists in process chemistry and formulation, clinical pharmacology, and infectious diseases, as well as drug regulatory officers, public health specialists, community activists, and medical ethicists, to consider strategies to reduce costs and improve the effectiveness of ARV medications in resource-limited settings [5▪▪].
Two primary approaches were considered: reducing the cost of the active pharmaceutical ingredient (API), which contributes on the order of 65–75% of generic ARV product price, and reducing the amount of API required in the product. Specific examples were reviewed in which API cost efficiencies were improved through alternative raw materials sourcing and manufacturing chemistry optimization. Two complementary approaches could be employed to lower the amount of API required: (1) developing novel strategies in product formulation to improve bioavailability, requiring less API to achieve equivalent plasma concentrations; and (2) reducing API doses, as a number of ARVs from different classes display uncompromised efficacy at doses below the approved dose. Use of lower doses may increase the tolerability of some ARVs, thus improving adherence and leading to more durable virologic suppression. The potential benefits of dose reduction must be balanced against the risks, which include the possibility of a small increase in treatment failures, increased susceptibility of regimens to some adverse pharmacokinetic drug interactions, and the added cost of clinical development and regulatory approvals for new doses.
The First CADO emphasized cost-saving opportunities for the most widely used generic products. The primary recommendations of the First CADO, 2010 are as follows [5▪▪]:
1. Promote the important role of process chemistry in reducing drug costs.
2. Recognize rational therapeutics as a global standard for treating all infected persons.
3. Focus future resources on identifying and developing improved regimens and formulations.
4. Pursue dose reduction as an intermediate optimization strategy.
Utilizing alternate sources of raw materials (e.g., magnesium tert-butoxide in tenofovir synthesis), refining API synthesis, or streamlining API synthesis to fewer steps (e.g., efavirenz) are examples of reducing the costs of producing API for key ARVs [5▪▪]. Innovations in pharmaceutics can create new formulations that improve bioavailability, thus requiring less API to achieve target plasma drug concentrations. For some approved ARVs, there are existing data supporting efficacy at doses below the approved dose. Initiatives like ENCORE and others systematically evaluate the potential for using lower doses of candidate ARVs, which can lead to cost reductions [6▪]. Extending the shelf-life of ARVs is a cost-saving strategy that could be employed by modifying existing procurement and regulatory procedures. Many of these strategies are discussed in greater depth in other articles in this issue of Current Opinion.
Although the first CADO yielded an array of interventions, the potential exists for synergy by combining these interventions, thus maximizing cost savings and expanding the numbers of HIV-patients treated. Employing multiple approaches simultaneously could result in a higher level of cost reduction. All provide concrete means of treating more patients at equivalent or reduced cost without compromising quality of care and in some cases improving it.
In contrast with CADO 1, CADO 2's goal was to identify an HIV-treatment research agenda for resource-limited settings over the next 5–10 years. This conference took place in Cape Town, South Africa, in April, 2013. After reviewing existing compounds in early and later-stage clinical development, the participants of CADO 2 discussed potential approaches to first-line and second-line treatment, as well as the role of new technologies in improving long-term durability and affordability. Primary recommendations of the Second CADO, 2013 are as follows:
1. Identify better, more affordable and sustainable treatments and regimens in the context of a public health approach.
2. Work towards a highly effective and affordable nontoxic, once-daily fixed-dose combination regimen for first-line treatment.
3. Promote minimal sequencing of maximally effective regimens.
4. Recognize the increasing importance of concurrent infections and comorbidities, especially tuberculosis and aging-related diseases.
5. Incentivize R&D innovation in an environment of diminishing industry investment in HIV-treatment research.
A number of top priorities were identified at CADO 2. This included recommendations for developing a new first-line combination regimen embodying all aspects of the TPP for use in resource-limited settings. Special attention was given to drugs with lower daily mass dose, and drugs that could be co-formulated. Two investigational drugs of high interest were the integrase inhibitor dolutegravir (DTG) and the tenofovir prodrug tenofovir alafenamide (TAF). DTG appears to have high efficacy, safety, and tolerability in Phase 3 trials, and is being dosed at 50 mg q.d. , or one-eighth the total daily dose of raltegravir at 400 mg b.i.d.. One particular advantage of using DTG in place of efavirenz in a first-line regimen is its effectiveness against HIV-2, a group of viruses inherently resistant to NNRTIs. In addition, DTG could be administered with rifampin if its dose is doubled during tuberculosis treatment . TAF has shown great promise in early phase clinical trials, and at 25 mg q.d. is less than one-tenth the approved daily dose of tenofovir disoproxil fumarate . Although a fixed-dose combination of DTG + TAF + 3TC or FTC would be attractive for a number of reasons, there are still many clinical and regulatory hurdles to overcome before recommending this as first-line treatment.
Beyond first-line, there is a need to develop simplified once daily FDCs for second-line regimens including boosted HIV protease inhibitors. The combination of darunavir with low-dose ritonavir or cobicistat has special attraction in this regard because of darunavir's high tolerability and low potential for toxicity compared with other HIV protease inhibitors . Other high priority topics for research included strategies for enhancing clinical trial participation, and studies to incorporate the needs of special populations, including girls and women of reproductive age, tuberculosis co-infection, and long-term comorbidities such as diabetes, hypertension, and other cardiovascular diseases. Also discussed were future changes in the HIV-treatment landscape, including the possible impact of long-acting injectable nanoformulated ARVs.
TREATMENT OPTIMIZATION IS ALSO PREVENTION OPTIMIZATION
Although the focus of both CADOs was treatment and not prevention, it is increasingly certain that strategies focused on expanding the number of infected individuals who receive effective therapy will have prevention benefits. For example, provision of effective ART to the infected partner in serodiscordant couples reduced the transmission of HIV by 96% , an effect size greater than that of HIV vaccines, topical microbicides, or pre-exposure prophylaxis employing oral tenofovir . In a more ‘real-world’ setting, adults living in a community in KwaZulu-Natal with up to 40% ARV coverage had an estimated 38% reduction in the risk of HIV acquisition compared with those living in a community with less than 10% coverage [13▪▪].
There is substantial overlap then between strategies being developed to treat HIV infection, and strategies to prevent HIV infection. Optimizing the safety, convenience, and availability of ART will help prevent more HIV infections. Lessons learned in developing the next generation of ARVs for treatment will inform the use of these same agents and formulations in prevention.
The AIDS epidemic is going to be a serious global public health priority for the long term, requiring commitment, investment and innovation. Reaching genuine universal access to HIV treatment means developing combination antiretroviral regimens that approach an ideal target product profile of complete effectiveness, safety, convenience, acceptability, and low cost. New drugs and formulations developed over the past decade come closer to meeting such standards. Significant challenges to treatment optimization include compatibilities of drugs for concurrent infections such as tuberculosis and aging related comorbidities. Harmonization of treatment guidelines for adults, children, and pregnant women is another long-term goal without a simple solution. The weight of evidence needed to change clinical practice is large, and will require investment. Systems of drug regulation are improving in ways that benefit patient access, but unnecessary hurdles persist. Cooperation between legacy and generic pharmaceutical companies, regulators, payers, investigators, and affected communities could be significantly improved. But the pieces are in place to achieve the objectives of treatment optimization, and the next decade is certain to see even greater progress.
We would like to acknowledge all participants in the CADO 1 and CADO 2 meetings that took place in Alexandria, VA, in June, 2010, and Cape Town, SA, in April, 2013. We would also like to acknowledge Keith W. Crawford, PhD, and John Liddy, for their contributions to the summary reports for CADO 1 and CADO 2, respectively.
Conflicts of interest
C.F. reports receiving grant support from GlaxoSmithKline for research unrelated to this manuscript, and has served as a consultant to Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline, Merck, Roche/Genentech, Tobira Pharmaceuticals, and ViiV Healthcare. The Pangaea Global AIDS Foundation has received philanthropic unrestricted funding from Gilead, Roche Molecular Diagnostics, and ViiV Healthcare. D.H.B.R. reports no conflicts.
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
1. Duncombe C, Ball A, Passarelli C, Hirnschall G. Treatment 2.0: catalyzing the next phase of treatment, care and support. Curr Opin HIV AIDS 2013; 8:4–11.
2. Flexner C. HIV drug development: the next 25 years. Nat Rev Drug Disc 2007; 6:959–966.
3. Genberg BL, Wilson IB, Bangsberg DR, et al. MACH14 Investigators. Patterns of antiretroviral therapy adherence and impact on HIV RNA among patients in North America. AIDS 2012; 26:1415–1423.
4. World Health Organization Adult Guideline Development GroupConsolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. Geneva:World Health Organization; 2013.
5▪▪. Crawford KW, Ripin DH, Levin AD, et al. Optimising the manufacture, formulation, and dose of antiretroviral drugs for more cost-efficient delivery in resource-limited settings: a consensus statement. Lancet Infect Dis 2012; 12:550–560.
This publication includes a summary of the First Conference on Antiretroviral Drug Optimization (CADO 1), and provides a comprehensive overview of the concept of HIV-treatment optimization.
6▪. Else LJ, Jackson A, Puls R, et al. Pharmacokinetics of lamivudine and lamivudine-triphosphate after administration of 300 milligrams and 150 milligrams once daily to healthy volunteers: results of the ENCORE 2 study. Antimicrob Agents Chemother 2012; 56:1427–1433.
This is a valuable proof-of-concept demonstrating how a small, well done clinical trial can efficiently lead to go/no-go decisions about whether or not to pursue a dose reduction strategy for a widely used antiretroviral drug.
7. Stellbrink HJ, Reynes J, Lazzarin A, et al. Dolutegravir in antiretroviral-naive adults with HIV-1: 96-week results from a randomized dose-ranging study. AIDS 2013; 27:1771–1778.
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13▪▪. Tanser F, Bärnighausen T, Grapsa E, et al. High coverage of ART associated with decline in risk of HIV acquisition in rural KwaZulu-Natal, South Africa. Science 2013; 339:966–971.
This recent ‘real-world’ analysis of the impact of HIV treatment on regional HIV incidence shows that even modest levels of population coverage with effective ART can significantly decrease seroconversion rates.
© 2013 Lippincott Williams & Wilkins, Inc.