In July 2012, WHO released a discussion study ‘The strategic use of antiretrovirals to help end the HIV epidemic’ that summarizes the current WHO guidance on the use of ARVs, and highlights progress in implementation of the Treatment 2.0 strategy, the use of ART as prevention, and WHO's work on the next generation of normative guidelines [10▪▪]. With more than 8 million people on ART in low- and middle-income countries, coverage now stands at 54%, based on WHO's 2010 guidelines for ART initiation at a CD4 cell count 350 cells/μl or less [6▪▪]. Whereas an estimated fifteen million people currently are eligible for ART based on a CD4 cell count 350 cells/μl or less, 22 million could be eligible if ART were offered to all HIV-positive partners in serodiscordant couples, HIV-positive pregnant and breast-feeding women and key populations (MSM, IDU and sex workers) irrespective of CD4 cell count. (Fig. 3) In addition, raising the CD4 cell count threshold for ART initiation to 500 cells/μl and the scaling up treatment as prevention have the potential to increase the pool of people eligible for ART in low-income and middle-income countries to 32 million [10▪▪].
Goal: Effective, affordable, one pill, once daily potent antiretroviral regimens with minimal toxicities or drug interactions and high barriers to resistance are available in resource limited settings.
The Treatment 2.0 strategy has defined the optimal target product profile for simplified, safe and effective ARV drug regimens. Achieving this ideal regimen over the next 10 years will require intensified, targeted research and development, reduced time from research to market, optimization of currently available drugs, and the development of new drugs and therapeutic classes [13,14].
Initiatives launched, or supported, by WHO over the last 2 years related to treatment optimization include the Conference on Antiretroviral Drug Optimization (CADO), a meeting on the short-term priorities for ARV drug optimization and two meetings convened by WHO on the Strategic Use of Antiretrovirals for Treatment and Prevention (SUFA).
In 2010, CADO was convened by the Clinton Health Access Initiative (CHAI) in collaboration with Johns Hopkins University and the Bill and Melinda Gates Foundation. The conference brought together process chemists, clinical pharmacologists, pharmaceutical scientists, physicians, pharmacists, community, regulatory specialists, implementers and normative agencies to explore strategies for the reduction of antiretroviral drug prices without compromising efficacy [15▪▪]. Cost-saving approaches identified at the conference included: alternative sources of raw materials to generate market competition and drive down cost, the use of novel drug formulation technology, drugs with improved bioavailability (permitting dose reduction), drugs with extended shelf-life, studies to reduce the approved doses of current ARVs and the wider use of generic drugs and fixed-dose combinations (FDCs).
In April 2011, WHO, with the support of the Pangaea Global AIDS Foundation, convened a meeting to establish short-term priorities for the optimization of first-line and second-line ARV regimens . On the basis of efficacy and toxicity, available compounds and the preferred first-line options in the 2010 WHO ART adult guidelines, meeting participants recommended the prioritization of the FDC of tenofovir–lamivudine (or emtricitabine) and efavirenz in first-line and atazanavir/ritonavir (ATV/r) as a heat stable FDC combined with a backbone of two nucleoside reverse transcriptase inhibitors (NRTIs) in second-line therapy . With respect to pediatric ART, it was proposed to move away from liquid formulations, sprinkles, heat stable tablets and scored adult strength dispersible formulations were prioritized.
WHO convened two multidisciplinary consultations on the Strategic Use of Antiretrovirals for Treatment and Prevention (SUFA 1 and SUFA 2) in November 2011 and May 2012 [10▪▪,17]. SUFA 1 endorsed a roadmap and architecture for the development of global consolidated guidelines to be launched in 2013, which would include an expansion of the scope to address clinical, operational and programmatic guidance, a consolidation of guidance for different populations (infants, children, adolescents, adults, pregnant women, older adults, key populations) and of interventions (treatment and prevention, treatment of major co-infections). SUFA 2 addressed operational and programmatic issues related to the development of consolidated ARV guidelines. Six themes were addressed: strategic and programmatic decision-making processes in countries; modeling of epidemiology, costs and impact; ethics, equity and human rights; health systems requirements; policy formulation and prioritization; and interventions and resources.
One pill, once-daily formulations suitable for most populations have the potential to reduce drug and program costs, improve adherence and treatment success, simplify procurement and reduce risk of drug stock outs. In mid-2012, WHO released three technical updates in support of the one pill once daily principle. The first technical update provides a balanced assessment of the clinical and programmatic issues relating to the safety of efavirenz (EFV) in pregnancy. Early data from animal studies and case reports led to concerns about the safety of efavirenz in pregnancy, with the consequence that women of childbearing age and in early pregnancy were not initiated on efavirenz, whereas women who became pregnant on EFV were being switched to nevirapine and in some instances pregnancy was terminated. Programmatically, this results in increased complexity and cost due to the need to stock multiple regimens. On the basis of the available data and a public health perspective, this technical update supports the use of efavirenz to optimize and simplify first-line treatment, including among pregnant women and those of reproductive age [18▪▪].
The second technical update provided guidance to countries, programs and manufacturers that, despite limited direct comparisons, the available data support the clinical and programmatic interchangeability of 3TC and FTC . This has important cost saving implications in the optimization of both first-line and second-line regimens. The lowest 2011 generic price for FTC was US$=61 per year compared with US$24 per year for 3TC . In May 2012, the ceiling price from CHAI for tenofovir/FTC was US$97 per year compared with US$ 70 per year for tenofovir/3TC .
Finally, guidance to countries on the use of tenofovir for the treatment of children and adolescents with HIV was provided . Being able to use tenofovir in children and adolescents would harmonize tenofovir-containing pediatric and adult regimens and pave the way for a one pill once daily pediatric FDC. The US Food and Drug Administration has approved tenofovir for use in adolescents and children in the USA above the age of 2 years. In this context, monitoring for tenofovir toxicity (relating to concerns about decreased bone mineral density and glomerular and renal tubular dysfunction) is possible. However, such monitoring is problematic in resource limited settings. This technical update concluded that tenofovir is efficacious in children and adolescents aged 2–18 years but cautioned that the benefits need to be weighed against the potential risk of toxicity and that long-term pharmacovigilance is needed as tenofovir is rolled out for children and adolescents.
Goal: a package of simple, affordable, reliable, quality assured point-of-care (POC) and other simplified diagnostics is available and accessible.
WHO is working to standardize performance and quality requirements, increase research and development, and reduce barriers to bring new diagnostics tools to market . WHO and UNITAID (Tous Unis pour Aider)/IDPF (International Drug Purchase Facility) are working with technical experts to identify the ideal package of diagnostics and the required regulatory processes to bring these to market. UNITAID has reviewed diagnostic technologies based on the WHO assured criteria: affordable, sensitive, specific, user friendly, robust and rapid, equipment free, and deliverable [23▪]. WHO has identified the technologies that need be deployed now, and products that need to be developed in the short, medium and long term to promote competition and reduce prices.
Globally, less than 40% of people living with HIV know their serologic status . Increased deployment of HIV rapid tests and novel approaches to delivering them, including home-based testing and community mobile testing, are being rolled out to bring testing and linkages to care into communities [23▪,24▪,25]. A focus of the work is POC CD4 cell count testing as a way to link HIV testing to eligibility assessment for initiation of ART. The technology is available and is being adopted, with field assessments showing a benefit in terms of reduced patient attrition and improved time to ART initiation . The first generation technologies are device based and need an electricity connection or battery/solar power. New technology is being developed which aims to be device free, single use and disposable.
There is increasing evidence to support the use of viral load as a preferred method of monitoring the success or failure of ART [27▪,28,29]. WHO has called for expanded access to viral load testing to improve the early detection of treatment failure, reduce inappropriate switching to second-line ART, and preserve second-line treatment options . Access to viral load testing is limited in most resource-limited countries (exceptions include South Africa, Thailand and Brazil). Simplified viral load platforms and assays are in development, at least one of which may come to market in 2012 [23▪].
In December 2010, WHO endorsed automated nucleic acid amplification test technology for the detection of tuberculosis (TB) and rifampin resistance. This technology is available in the form of the self-contained, cartridge-based GeneXpert MTB/RIF (Cepheid, Sunnyvale, California, USA). In addition to cartridges for TB and rifampicin resistance, cartridges for the Xpert device are available for detecting other pathogens, including Chlamydia, Neisseria gonorrhoeae and multidrug-resistant Staphylococcus aureus. In collaboration between the Foundation for Innovative New Diagnostics, the manufacturer of GeneXpert, is developing a cartridge to measure HIV viral load .
The use of dried blood spots (DBS) for collection and transport of specimens to a central laboratory has become standard of care in many early infant diagnosis programs. There is good correlation between plasma and DBS viral load and, while POC viral load is awaited, DBS samples can be collected in the clinic and sent to a central laboratory for vial load estimation . Finally, there is a need for improved, simpler technologies to monitor ART adverse events and to monitor the emergence of population level drug resistance.
Goal: High quality HIV care and treatment programs are available at the lowest possible cost with optimal efficiency.
UNAIDS has estimated that the cost of putting 15 million people on ART by 2015 will be US$22–24 billion . HIV programs are already under enormous financial pressure. While more resources are needed from donor countries and those countries most affected by the epidemic, efficiencies need to be found which can drive down costs without compromising quality. Given the global financial crisis and competing health priorities, advocacy is needed to demonstrate that increasing investments in expanded ART and preexposure prophylaxis of HIV acquisition (PrEP) will result in long-term public health, economic and development benefits. Modeling indicates that increasing coverage of ART would be cost effective in the short term and could even be cost saving in the longer term [10▪▪]. Commodity costs can be reduced by pooled procurement and simplified manufacturing processes, and programs can deliver more services to more people through task shifting, integration of HIV services into primary care and other public health programmers, and expanding the role of communities in service delivery . As part of ongoing work to reduce costs, UNDP, UNAIDS and WHO have released guidance on policy options for countries in employing trade-related aspects of intellectual property rights (TRIPS) flexibilities to ensure that patents do not hinder access to affordable medicines (UNDP/UNAIDS. The Potential Impact of Free Trade Agreements on Public Health, Geneva May, 2012 http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2012/JC2349_Issue_Brief_Free-Trade-Agreements_en.pdf) .
Goal: people living with HIV and key populations are fully involved in the demand creation, planning, delivery and evaluation of quality assured, rights based HIV care and treatment programs.
Partnerships between communities, HIV programs and health workers serve to increase access, improve adherence, retention, efficiency and sustainability, and reduce stigma and discrimination. In March 2012, WHO and the Ministry of Health and Child Welfare of Zimbabwe, with the support of the Pangaea Global AIDS Foundation, cohosted a consultation on Optimizing HIV treatment access and retention in care: linking community level interventions with healthcare delivery systems. The goals of the meeting were to consult community organizations, networks of people living with HIV and civil society, and to review best practice of community service delivery models and to inform the service delivery component of the 2013 WHO consolidated ARV guidelines. Key recommendations from the meeting were the need to estimate the costs of community mobilization and provide sustainable funding streams to support community based organizations and networks working in the roll-out and scale-up of Treatment 2.0. Launched at the 2012 International AIDS Conference, the Robert Carr Civil Society Networks Fund aims to provide secure funding flows for civil society networks. The Carr Fund is expected to raise US$21 million in its first 3 years to support global and regional civil society networks (http://www.aidsfonds.nl/rc-nf/robertcarrfund.htm.).
A similar consultation was held in Bangkok, Thailand, in September 2012, with the aim of identifying the needs, challenges and best practices of providing services to key populations in low and concentrated epidemics, with the participation of a wide range of community-based organization and networks.
Adapting delivery systems
Goal: HIV care and treatment programs are decentralized and appropriately integrated with other health services, with increased community engagement and improved retention in care.
Less than 30% of people diagnosed with HIV infection in resource limited settings receive the full cascade of care, from HIV testing through to initiation of ART and long-term retention in care [35▪▪,36]. Substantial attrition and mortality follow HIV diagnosis and, in some settings, less than half of those eligible for ART initiate it within 12 months . Under the Treatment 2.0 pillars of adapting service delivery and community mobilization, WHO is developing comprehensive guidance on the role of decentralization and integration of HIV services in improving access to and retention in ART care .
Current WHO HIV treatment guidelines articulated evidence-based recommendations for HIV prevention, diagnosis, care and treatment. The new consolidated ARV guidelines that will be issued in 2013 will include programmatic and service delivery recommendations to inform countries not only of what to do but also how to do it and to guide prioritization and allocate decisions. The consolidated guidelines will address HIV during the life course (pregnant women, infants, children, adolescents, adults, older adults), include guidance for key affected populations, and address priority comorbidities [10▪▪]. In the lead up to 2013, support to countries has been provided in a series of targeted guidelines, and programmatic and technical updates. (Fig. 4)
Treatment 2.0 in action
An increasing number of countries and regions are adopting the Treatment 2.0 framework for their national plans. One example is Vietnam, where the HIV epidemic is concentrated amongst key populations at higher risk of HIV exposure, that is, people who inject drugs, female sex workers and MSM. Sentinel surveillance in 2010 found a prevalence of 17.2% among people who inject drugs, 4.6% among female sex workers and 0.26% amongst antenatal women. The Vietnamese Administration of HIV/AIDS Control, with support from the Joint United Nations Team on HIV, international partners and donors, has initiated a Treatment 2.0 pilot program, making Vietnam one of the first countries to adapt the principles of Treatment 2.0 to the local epidemic [39▪]. The pilot aims to increase the CD4 cell count at which most people in Vietnam initiate ART from the current norm of less than 100 cells/μl, phase out stavudine as recommended by WHO, and institute HIV rapid testing for key populations. Community mobilization is the fundamental component of the pilot, with decentralization of HIV services for isolated communities in the north of the country, integration of HIV testing and ART delivery with commune level services for tuberculosis, methadone maintenance treatment, and antenatal care, and efforts to reduce stigma and discrimination. Success of the pilot will require engagement of multiple stakeholders to move away from the current model of centralized HIV service delivery [39▪].
Another example is given by a recent publication by the Pan American Health Organization (PAHO) titled Antiretroviral Treatment in the Spotlight: 2012 A Public Health Analysis in Latin America and the Caribbean . At the end of 2010, 521 000 people were receiving ART in Latin America and the Caribbean, with a regional ART coverage of approximately 63%. The objective of the report was to critically evaluate ART programs, assessing their strengths and weaknesses to guide the application of the principles of Treatment 2.0 in Latin America and the Caribbean. With 12 different adult first-line regimens and 15 s line regimens being employed in countries in the region, the potential for optimization is significant. In 2011, 14 out of 26 countries reported at least one stock-out episode, 92 of which averaged 40 days. Eleven countries, mostly from the Caribbean region, were almost 100% dependent on external funding for ART. Key recommendations in the report were to simplify regimens, reduce stock-outs and foreign donor dependency, increase HIV testing and retention in treatment, and strengthen prevention. This is the first in a series in which PAHO will monitor regional progress towards achieving the goals of Treatment 2.0, universal access and the Millennium Development Goals.
In 2011, more than 8 million people living with HIV in low-income and middle-income countries were receiving ART, a 20% increase since 2010. To sustain the momentum, affordable and sustainable mechanisms to foster pharmaceutical and diagnostics innovation need to be pursued, TRIPS agreement flexibilities need to be maximized to ensure more equitable pricing for essential drugs and Treatment 2.0 needs to evolve with the full involvement of people living with HIV and affected communities . In addition to sustained support from donor nations, local solutions need to explore diversified funding sources and reduced dependency on imported commodities . To this end, WHO will work with regional and national partners to support the integration of the Treatment 2.0 framework into national responses.
Bill and Melinda Gates Foundation.
Chris Duncombe is employed by the Bill and Melinda Gates Foundation.
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
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 75).
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One of a series of three policy and practice changing technical updates released by WHO in 2012 as a prelude to the 2013 consolidated guidelines
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; cost–effectiveness; HIV; Treatment 2.0