The United Nations High Level Meeting on AIDS in June 2011 has set an ambitious target for dealing with the HIV, ‘fifteen by fifteen’, under which at least 15 million people living with HIV should be on antiretroviral treatment (ART) by 2015. But it is important to ask whether this target is too ambitious or overly cautious and consider what can reasonably be achieved in the next 3 years. The answers to these questions will be critical in assessing how soon we can achieve an ‘AIDS-free generation’ [1▪▪].
THE MAGNITUDE OF THE CHALLENGE
After more than 30 years, we still struggle to control an HIV pandemic in which over 30 million people have already died [2,3▪] and an estimated 34 million people are living with HIV in 2011 [4▪▪]. Of those living with HIV, about seven out of 10 live in sub-Saharan Africa, where most infected people are unaware of their infection, many are unable to access life-saving antiretroviral therapy, and opportunistic infections are common [3▪,5,6▪]. People living with HIV are about 30 times more likely to develop TB [7,8▪] and in 2010 there were an estimated 1.1 million new HIV-associated cases of tuberculosis and 350 000 HIV/TB-related deaths [8▪]. The recent global economic crisis has seriously challenged efforts to address HIV and other significant health problems .
In 2011, over 8 million people were receiving ART [4▪▪] representing an increase of more than 1.4 million from the 6.6 million reported in 2010. This corresponds to 54% of those eligible according to the recommendations of the WHO [4▪▪] (CD4 cell count ≤350 cells/μl). This has significant impact on morbidity and mortality as half of those with a CD4 cell ≤350 per μl would otherwise die within 2 years . Using the 2011 rate of expansion, more than 120 000 people start ART each month. To reach the target of 15 million people by end 2015, expansion will have to be accelerated to around 145 000 additional people living with HIV on ART per month globally.
The rapid expansion of ART is one of the most remarkable achievements in public health history and was accomplished despite doubts and criticism from experts who challenged the feasibility and advisability [11,12] of delivering ART in resource constrained settings, particularly in Africa where less than 8000 people were on therapy in 2001 [12,13]. Delivering daily treatment on this scale through chronically under-funded public health systems required innovative thinking and planning to overcome bureaucratic, financial, infrastructural, and technical challenges. Political commitment to meet these ambitious targets led to the establishment of new financing mechanisms including the World Bank's Multicountry HIV/AIDS Programme, the Global Fund against AIDS, TB and Malaria, and President's Emergency Plan for AIDS Relief (PEPFAR). In 2011 PEPFAR alone reported supporting an estimated 33 million HIV tests and 3.2 million people receiving ART [14▪]. The Global Fund to fight AIDS, TB and Malaria reported supporting similar large-scale global efforts [15▪], with both funding sources increasingly supporting the same programmes through synergistic efforts. Other examples of innovative approaches included collective efforts to dramatically reduce the cost of antiretroviral drugs (ARVs), rationalization of the supply chain which now allows for on-time delivery of daily doses of ART for millions of people living with HIV, and the significant leadership of people living with HIV and affected communities. The imperative to expand treatment to millions of people prompted innovations in service delivery including task shifting and simplified laboratory support to enable lower cadres of medical personnel to prescribe ARVs.
Unfortunately, the world is still not yet keeping pace with new HIV infections and serious challenges remain. In 2011, there were an estimated 2.7 million new HIV infections – roughly two for each person starting treatment – an estimated 1.8 million HIV-related deaths and over 1 million HIV-associated TB cases [4▪▪]. Population-based surveys show that 30–70% of people living with HIV do not know their status [16▪] and 44% of severely immunocompromised people (CD4 cell count ≤350 per μl) are not on ART, leaving only 25% of all people living with HIV on treatment [4▪▪]. Everyone with HIV will eventually need ART to survive. This means that today about 24 million people living in resource constrained settings are not on treatment who will eventually need it, mostly without knowing that they are living with HIV [3▪,5]. There are many challenges to treatment access, including significant social barriers to HIV services due to stigma, poverty, and legal discrimination. Although recent reports provide important insight [14▪–16▪,17▪▪], more work is needed to fully understand the costs and economic impact of continuing and accelerating the expansion of HIV services.
SCIENCE SUPPORTING ART EXPANSION
Much of the scientific evidence supporting the role of ART in reducing HIV and TB morbidity, mortality and transmission is at least a decade old [18–20,21▪]. A full discussion of this evidence is beyond the scope of this article, but it is increasingly apparent that HIV causes inflammatory damage, which begins soon after infection  and that this is mitigated by the use of ART . ART below 350 CD4 cell counts has a significant impact on morbidity, mortality and transmission and evidence suggests that these benefits may extend earlier in the course of disease [21▪,23,24▪▪,25,26▪]. In a recent cohort in the Ivory Coast, extrapolating from data regarding the rate of CD4 decline suggests that there is cumulative risk after infection to a CD4 count of 350 of over 10% for AIDS, serious non-AIDS or death [26▪]. In Zimbabwe, postnatal women living with HIV not on ART were almost six times as likely to die when compared with HIV-negative women even at very high CD4 counts . Although randomized control trials are in progress, HPTN 052 [24▪▪] has already demonstrated a statistically significant clinical benefit to the individual and a marked reduction in HIV transmission to an HIV-negative partner when ART was started immediately for those with CD4 cell counts between 350 and 550 per μl [24▪▪]. Furthermore, a recent meta-analysis of studies in lower income countries found that ART was associated with a 65% decrease in the risk of TB among people living with HIV irrespective of CD4 count [21▪].
Viral load is a key determinant of the risk of sexual transmission of HIV and observational, community and randomized clinical control studies have shown that decreases in viral load are associated with significant reductions in HIV transmission [18,19,20,24▪▪,27–30]. In KwaZulu-Natal, after adjusting for other factors, every 10% increase in ART coverage was associated with a nearly 20% reduction in an individual's risk of acquiring HIV [31▪▪]. Proof-of-concept of the impact of ART on transmission can also be seen in the drastic reduction of maternal-to-child transmission of HIV during pregnancy, delivery and breastfeeding when the women are on ART, as well as virtual elimination of maternal to child transmission (EMTCT) in Europe and the USA .
Many models have been used to project the impact of HIV testing and ART on the course of the epidemic [33–35,36▪,37] and a comparison of these models showed that they all predict a significant impact of ART on HIV transmission but the precise magnitude depends on assumptions about the frequency and scope of HIV testing, ART eligibility criteria and coverage, retention, and duration of acute infection [38▪]. This review of modelling efforts found that the model results were relatively consistent for short-term (8-year) estimations of decreases in incidence associated with treatment. For example, if 80% of individuals were treated after their CD4 cell count reaches 350 cells/μl, the models projected that after 8 years HIV incidence would be reduced by 35–54%, compared with the estimated incidence in the absence of any ART [38▪]. All models reviewed suggested that the existing treatment scale-up in South Africa should have already reduced new infections (incidence in 2011 is estimated to be 17–32% lower than if there had been no ART) [38▪]. However, there was much more variation in long-term (38-year) projections of reductions in incidence depending on the parameterization of the models [38▪]. The consensus among modellers that treatment provided within current guidelines has a prevention benefit is significant and should serve to reinforce the case for continuing to improve access to ART [38▪]. Of course, HIV programmes vary widely in their quality and outcomes and common sense dictates that models that poorer program performance will get poor results . The important role for modeling for policy and program implementation is to better understand what data are missing and the minimum programme parameters necessary to control or eliminate HIV. Modeling efforts have sharpened and expanded our strategic thinking to include the possibility of eliminating HIV in some settings through frequent HIV testing and earlier ART combined with other prevention interventions .
WHO and UNAIDS launched in 2003 the 3 × 5 initiative and the 2010 ART guidelines of WHO recommend ART for all people living with HIV independent of possible symptoms, including pregnant women, if their CD4 cell count is less than 350 per μl. Although the 2010 WHO ART and PMTCT guidelines did not address the issue of treatment as prevention, in 2012 WHO defined treatment as prevention as the impact of ART on HIV and TB morbidity, mortality and transmission, irrespective of the CD4 count [40▪▪]. WHO has issued guidance and programmatic updates in 2012 recommending that ART be offered at CD4 cell counts above 350 per μl for HIV-positive partners within serodiscordant couples, for all pregnant women, and for high-risk sub-groups, such as injection drug users [40▪▪,41▪▪]. National ART guidelines – specifically with regard to the optimal time to initiate therapy – represent a dynamic policy environment: 19 countries have already published recommendations for expanded and earlier access to ART with CD4 cell counts above 350 per μl [42▪], and the United States Department of Human Health Services [43▪▪] recommend to offer immediate initiation of ART regardless of CD4 cell counts. Despite the shift in policy towards earlier treatment, the new science around the benefits of ART may not be translating into HIV programme delivery. Published guidelines from 24 countries still recommended starting ART for CD4 cell counts less than 250 per μl or in some cases less than 200 per μl [42▪]. Although the national context is important when adapting global guidelines there is often a policy adaptation and implementation ‘lag’ of several years in many countries. Achieving consensus around new scientific evidence is complex. However, delaying the adaptation of guidelines may have serious consequences for individual and public health.
FINANCIAL AND POLITICAL COMMITMENT
The need to provide expanded access to ART is now widely accepted and there is a pressing demand for both increased investment and more efficient use of funding in order to achieve and sustain universal access by 2015. This goal was agreed to by all United Nations member states at the High Level Meeting in 2011 [44▪] and UNAIDS estimates that by 2015 an estimated 24 billion per year would be needed for a comprehensive response including access to ART for people living with HIV infection with a CD4 cell count below 350 per μl [45▪▪]. Although there remains a significant gap of about 7 billion USD annually [4▪▪] when compared with current levels of funding, such a gap can be closed within a framework of shared responsibility and global solidarity. Already, the majority of AIDS finding in low and middle-income countries comes from domestic sources [4▪▪]. But more can be done if countries apply increasing gross domestic product to health, live up to their own commitments to achieve the Abuja targets on health resources, and invest in HIV in line with the relative burden if disease. However, it is clear that in particular, the poorest countries with the highest HIV infection rates will not be able to shoulder the cost for comprehensive HIV programmes on their own and renewed efforts are needed on behalf of the donor countries to close the gap and to bring us on the path towards zero. Recent announcements including the statement of the United States Secretary of State on the US commitment to continue its contribution to the global HIV effort with a focus on reducing maternal to child transmission, treatment and male circumcision [1▪▪] are promising.
THE INTERIM FIFTEEN MILLION TARGET
The ART roll out to date has failed to keep pace with new HIV infections and there have been calls to intensify the scale and scope of prevention . As part of a comprehensive approach to prevention, providing ART to 15 million people will continue to contribute to substantial reductions in HIV and TB morbidity, mortality, and transmission. However, the ‘fifteen by fifteen’ target will only reach less than half of the 32 million people living with HIV in resource-constrained settings. Although clearly important for the millions who will be on treatment, reaching 15 million will be insufficient to control or eliminate AIDS or HIV in most settings. To reach people living with HIV earlier, control, and potentially eliminate AIDS and HIV we need a conceptual shift from ‘test and wait until sick’ to ‘offer HIV testing followed by the option of immediate ART’ for all 32 million people living with HIV. The rationale for the conceptual shift includes the following arguments:
- Early initiation of ART is easier to deliver and has clinical benefits: Everyone living with HIV will need treatment to survive. The time it takes CD4 cell counts to fall to 350 per μl often takes only a few months to years whereas the expected duration of ART is measured in up to 50 years [47▪]. The earlier HIV-positive people start treatment, the better the treatment is tolerated, the better and more complete is the CD4 cell count recovery and the better is the overall prognosis. Starting earlier also decreases the likelihood of immune reconstitution inflammatory syndrome. Furthermore immediate treatment maximizes the impact of ART on HIV and TB morbidity, mortality and transmission [21▪,24▪▪,25,48–51]. A number of easy to deliver excellent drug regimens are available and side effects can be managed if alternative regimens are available in the clinics.
- Right to health is a choice and may support adherence: If people are fully informed about the individual health benefits of ART and the protection offered by ART to their partners and their children, many may choose to be tested and to start ART immediately [16▪]. Successful antiretroviral treatment depends on sustained high rates of adherence. More potent regimens can be more forgiving in terms of viral suppression and resistance. But lack of adherence can lead to treatment failure and drug-resistant virus. Barriers to adherence include fear of disclosure, forgetfulness, health illiteracy, substance abuse, complicated regimens, and patients being away from their medications, financial constraints, sex, stigma, alcohol use, inadequate knowledge about the disease and ARVs, lack of social support, lack of food, transport costs and depression . Despite these challenges, best estimates demonstrate that adherence in resource-limited settings is similar to that in resource-rich settings, possibly due to focused efforts on support groups and community acceptance of adherence behaviors [52,53]. Although adherence when asymptomatic is often a concern, experience with millions of asymptomatic people on ART suggest that with the proper support people without symptoms are able to adhere to treatment. Furthermore, studies show a positive behavioral impact of being on ART and recent work suggests that people who know their HIV status [54,55] or are on ART [56,57▪,58–60] are less likely to engage in risky sexual behavior. ALthough it is difficult to generalize in regards to sexual behavior around HIV diagnosis and treatment, it is reassuring that studies have not found disinhibition to be a major problem in developing country settings.
- ART and impact on HIV transmission: good treatment will reduce viral load [61–63] by up to 10 000 times  and can be sustained for at least 7 years [61,64] and for many people probably for decades. The time from diagnosis to eligibility at less than 350 CD4 count is on average a few years [47▪], and starting treatment earlier does come with the risk of toxicity, which must be carefully weighed against the health risks of uncontrolled HIV replication [22,25,26▪]. People on ART who are fully adherent to treatment are unlikely to infect their sexual partners or their children [20,24▪▪,65]. Studies using programmatic data suggest that high ART coverage with strong adherence focus will reduce [66–68] and maintain drug resistance at manageable levels [69,70].
- Simplification in the programmatic approach and task shifting: using CD4 cell count criteria to determine ART eligibility is of limited value given the variation in CD4 counts seen across populations [71,72], for an individual  and the difficulty in determining the rate of decline . Additionally, CD4 levels are a poor predictor of viral load . Requiring a CD4 count for eligibility complicates access to ART in that it requires multiple visits, comparatively sophisticated lab equipment and waiting for laboratory – a significant factor in patient drop out in many programmes. Abandoning the use of CD4 cell counts for ART eligibility may translate into many more people starting treatment earlier, improved health outcomes, and considerable cost savings [75,76] that could be invested to pay for drugs. Starting people on ART when they are healthy may also facilitate task shifting of routine treatment from doctors to other healthcare workers and community members. It may also help people avoid the clinical management challenges posed by immune reconstitution syndrome, which is more commonly seen when starting ART later.
- Streamlining the policy environment: the policy environment is rapidly shifting and some resource-rich countries have changed their national treatment guidelines to offer earlier treatment (<500 CD4 cell count) or even immediate treatment using simpler, safer, and better tolerated regimens. Additionally, countries are also offering ART for special sub-populations irrespective of CD4 count, such as people diagnosed with TB, Hepatitis B and serodiscordant couples. WHO has recently released guidelines and documents promoting earlier access to ART with CD4 cell counts above 350 μl for special populations. It is important to continue compiling and analyzing all the clinical evidence and its application in policy around the globe to ensure that all people living with HIV have the same standards to treatment access, irrespective of whether they are rich or poor.
- Economics of expanding ART and return for investment: expanding ART access makes economic sense. The current approach will not control or eliminate HIV in most settings and costs will continue to increase as people are infected and others become ill and need care and treatment. Economic forecasting suggests that ART is cost effective and that providing more frequent testing and earlier ART could lead to cost-savings over the medium term [77,78▪,79▪]. Studies suggest the return on every dollar invested in ART is significant from a health systems perspective and there is increasing evidence of the significant economic benefits for the family, community and society [77,78▪,79▪].
- Acute phase of HIV infection and concurrency: in some settings and studies the acute phase of HIV infection with high viral load has been shown to have a significant impact on overall population incidence [80▪,81▪]. It has been argued that earlier onset of ART would not cover this factor [80▪,81▪], as those with early HIV infection will be unaware of their infection and thus not a target population for ART. However, the relative importance of the acute phase of HIV infection as well as other factors for HIV transmission in a population, such as concurrency of sexual partnerships, will gradually become less important as a factor for population incidence, if the majority of people living with HIV will know their status and be on ART, effectively reducing the pool of those being infectious.
- Research while implementing: more data and research will add to a large body of evidence, however, many of the large trials will likely take at a minimum 2–4 years for preliminary results to become available. Meanwhile earlier HIV testing and immediate offer of treatment is already in progress in many settings and for specific populations. Applying the new science that supports the impact of treatment for prevention of HIV and TB, programmes will benefit from lessons learned during implementation including practical information on how to best address long-standing challenges including human rights, drug supply, drug delivery, providing high-quality HIV testing and counseling, how to best task shift starting treatment, viral load and resistance testing, monitoring and evaluation, stigma and discrimination.
- Human rights and community engagement: communities are increasingly concerned about the need to protect the right to have access to HIV services, including voluntary HIV testing and immediate access to ART, within a human rights framework. Human rights and community support is essential for quality service delivery and is inexpensive when compared with other aspects of HIV programming [82▪]. As more people access HIV testing and ART, stigma may be reduced and people living with HIV will be better able to focus on living their lives rather than treating their illness.
- Risks of early treatment: starting treatment earlier is not without potential risks and challenges for both the individual and the healthcare system. From an individual perspective starting earlier could be associated with higher likelihood of toxicity, lack of adherence leading to drug resistance, and problems associated with disclosure to others regarding their HIV status. From a health system perspective, delivering ART for additional people could strain over-burdened human resources, supply chains and budgets. Programs expanding ART will need to continue to focus on improving retention, adherence, supply chain and the public health laboratory network to support people receiving ART. It is critical that targeted operations research, work with people living with HIV, medical staff and communities to fully understand the factors that contribute the current treatment cascade, and how the significant losses can be overcome at each step.
Public health interventions must be based on convincing evidence and may take many years to implement. Research on male circumcision culminated in three definitive randomized clinical controlled trials since 2007 show consistent efficacy [83–88], but a number of high HIV-burden countries have still not adopted circumcision as part of HIV prevention policy . We cannot afford to wait years to implement new scientifically proven interventions while the HIV/AIDS toll continues with 1.8 million annual deaths and 7000 new HIV infections a day. Business as usual that includes ‘test and wait’ is not an effective HIV control and elimination strategy. We need a conceptual shift towards a ‘test and treat’ approach that focuses on providing HIV testing and counseling with the option of starting ART for everyone living with HIV whenever they are diagnosed with HIV. However, questions remain and such approaches cannot be implemented naively. While reviewing the science regarding the question of whether or not we should start treatment earlier, we should also focus on the conditions that need to be in place to minimize potential risks, and to set up systems that allow to carefully monitor possible positive and negative effects of moving towards ‘test and treat’ in a given population. As we move towards universal access to antiretroviral therapy for everyone who is infected with HIV, we should take advantage of the opportunity of reaching people with and without HIV to promote other means of combination prevention, including the use of male and female condoms, male circumcision where prevalence is high, methadone maintenance and needle exchange programmes where the epidemic is driven by intravenous drug users, and condom promotion, and targeted behavior change programmes. In other words, although treatment is life-saving and a necessity for people living with HIV, it is also critical to not lose sight of other important elements of our response to HIV. A fully effective response will only be possible and successful through the engagement of the different sectors and specialties including public and private sectors, medical doctors and other health providers, social scientists, activists, faith-based organizations, and last but not least, people living with HIV and their communities.
Michael Bartos, Peter Godfrey-Fawcett, Joep Lange, and Bernard Schwartlander for their review and helpful insights.
Disclaimer: The opinions and statements in this article are those of the authors and do not represent the official policy, endorsement or views of UNAIDS.
Conflicts of interest
J.M. is supported by the British Columbia Ministry of Health; through an Avant-Garde Award (No. 1DP1DA026182-01) from the National Institute of Drug Abuse (NIDA), at the US National Institutes of Health (NIH); and through a KT Award from the Canadian Institutes of Health Research (CIHR). He has also received financial support from the International AIDS Society, United Nations AIDS Program, World Health Organization, National Institutes of Health Research-Office of AIDS Research, National Institute of Allergy & Infectious Diseases, The United States President's Emergency Plan for AIDS Relief (PEPfAR), Bill & Melinda Gates Foundation, French National Agency for Research on AIDS & Viral Hepatitis (ANRS), the Public Health Agency of Canada, the University of British Columbia, Simon Fraser University, Providence Healthcare and Vancouver Coastal Health Authority. He has received grants from Abbott, Biolytical, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare. R.G., and B.W. have no conflicts of interest to declare.
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