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Just over three decades ago, a new outbreak of opportunistic infections and Kaposi’s sarcoma was reported in a small number of homosexual men in California and New York1,2. This universally fatal disease was eventually called the acquired immunodeficiency syndrome (AIDS) due to complete loss of CD4+ T-lymphocytes. Within the first year of its description, the disease was also identified in hemophiliacs, injecting drug users, blood transfusion recipients and infants born to affected mothers. Soon thereafter a heterosexual epidemic of AIDS was revealed in Central Africa, preferentially affecting women3,4. Little did we know at that time that this small number of cases would eventually mushroom into tens of millions of affected individuals, becoming one of the greatest pandemics of modern times.
Within two years of the initial reports of AIDS, a retrovirus, later called the human immunodeficiency virus (HIV), was identified as the cause of AIDS5. Diagnostic tests were developed to protect the blood supply and to identify those infected. Additional prevention measures were implemented including risk reducing programs, counseling and testing, condom distribution, and needle exchange programs. However, HIV continued to spread, infecting 10 million individuals within the first decade of its recognition.
The second decade of AIDS was marked by further intensification of the epidemic in other areas of the world. The southern cone of Africa experienced an explosive HIV epidemic. Asia and the former Soviet Union, also noted a marked increase in the spread of HIV. However, by the mid-1990s with the discovery of highly active antiretroviral therapy, fatalities in the developed world started to decline. Use of antiretroviral drugs (ARVs) during pregnancy also resulted in a significant decline in mother to child transmission of HIV in high-income countries. However, without access to ARVs, MTCT and mortality in low and middle-income countries continued to increase to 2.4 million deaths, with over 3 million new infections in 2001, with two thirds occurring in sub-Saharan Africa6.
It was not until the third decade of the epidemic that the world’s public health officials, community leaders, and politicians united to combat AIDS. In 2001 the UN General Assembly endorsed a historic Declaration of Commitment on HIV/AIDS and renewed this commitment in 20117. These actions resulted in the formation of a Global Fund to fight AIDS, Tuberculosis, and Malaria to finance AIDS activities in developing countries. In 2003 President G.W. Bush announced the President’s Emergency Plan for AIDS Relief (PEPFAR), which allocated billions of dollars to countries hardest hit by AIDS.
This unprecedented global response to the AIDS pandemic can serve as a paradigm for the response to other global health threats. For example the global AIDS response incorporated a multi-sectoral approach involving public health officials, clinicians, civil society, business and labor, armed forces, law, and politicians working in concert and with financial resources in excess of $15 billion per year8 to achieve a decline in HIV incidence and mortality. As a pandemic, it required a coordinated global response led by UNAIDS since 1996. This transformational response helped redefine what is meant by health diplomacy and a led to a new culture of accountability in international development. Tiered pricing of medicines became commonplace and renewed optimism provided a boost for research on other neglected global health issues. This response to AIDS highlighted the shortage in health care workers, and the weaknesses in availability of essential medications, in primary health care and in our public health systems. Stigma and inequities in care for those affected by HIV focused attention on social and medical equity and human rights.
Whereas it has been argued that health care provision for patients with other conditions may have suffered from “vertical” AIDS programs, in particular because of their recruitment of scarce health care workers9, there is also evidence that the AIDS response eventually had multiple collateral benefits including a major increase in attention and funding for global health, particularly for malaria and tuberculosis, and a strengthening of services for maternal and child health in some countries 10-12 Although not perfect, this type of unified and integrated response to AIDS can serve as a model for society’s future response to the growing epidemic of chronic diseases, obesity, injuries, and for maternal and child health13.
UNAIDS estimates that in 2011, 34.2 million people were living with HIV, as compared to 29.1 million in 2001; 2.5 million had become newly infected, a 24% decline as compared to 2001, and 1.7 million died, a decline of 11% as compared to 20018,14. Similarly, new infections among neonates and infants have decreased from a peak of 570,000 in 2003 to 330,000 in 2011 as a result of interventions to prevent MTCT.
However, these global figures hide a wide diversity. Figure 1 shows adult HIV prevalence levels by country, with sub-Saharan Africa continuing to be the most affected continent, followed by Eastern Europe and the Caribbean15. A special case is southern Africa, where HIV has become hyper-endemic with adult HIV prevalence rates as high as 31% in Swaziland, 25% in Botswana, and 17% in South Africa, reaching an astonishing 54% among women between 30 and 34 years in Swaziland 7. Even within a country, differences in HIV prevalence can vary widely by region and risk group. Thus, in 2010 within South Africa, provincial antenatal HIV prevalence ranged from 18.4% in the Northern Cape to 39.5 % in Kwazulu Natal16. Men who have sex with men (MSM), female sex workers, injecting drug users, truck drivers, fishermen, and military are disproportionally affected around the world17-22 .
There is also heterogeneity in epidemiologic trends. Whereas HIV spread is slowing in most regions, HIV incidence continues to increase in Eastern Europe, and several Asian countries14. There is also a resurgence of HIV infection due to increased risk behaviour among MSM in several European cities, such as a 68% increase in sexual risk behaviour among MSM in Amsterdam23 in spite of high rates of HIV testing and access to ART. At the same time HIV is spreading to previously unaffected populations, such as IDUs in parts of Africa, and MSM across Asia and Africa, where widespread homophobia drives these men underground.
With 25 licensed antiretroviral drugs available for HIV treatment, there is a wide choice of effective drugs for treating HIV. With reductions in ARV price, availability of generic ARVs, and international financial aid, the number of people receiving ART has risen from < 200,000 in 2001 to 8 million individuals in low and middle-income countries14 (Figure 2). As a result of the marked increase in availability of ARVs, the death rate in some of the hardest hit countries has started to decline following mortality reductions in the late nineties in the U.S. and Europe24.
With the life expectancy of an HIV-infected individual under treatment approaching an uninfected individual25,26, there has been an increased emphasis on starting ARV therapy much earlier in the course of infection. The revised 2012 DHHS guidelines recommend ART for all HIV-infected individuals27 (Table 1). These recommendations are based on evidence of ongoing HIV replication on disease progression. Additionally because ART use prevents transmission of HIV in discordant couples28, the guidelines recommend that ART be offered to all HIV infected individuals to reduce the risk for their sexual partners.
In variance with the US and European guidelines29, WHO guidelines continue to recommend treating all individuals with CD4 counts ≤ 350 recognizing the limitations of cost and availability in many countries30,31. However, all guidelines strongly recommend ART for individuals regardless of CD4 count with pregnancy, history of an AIDS-defining illness, tuberculosis, and HIV/hepatitis B co-infection, and more recently for HIV-discordant couples31 (Table 1).
Despite advances in the accessibility to ARVs, many challenges remain in the provision of HIV care. In the U.S., the CDC estimates that 1.2 million persons are living with HIV, of whom only 28% ultimately had suppressed viral levels32-34 (Figure 3). In one study in Mozambique, of 7,005 identified HIV-infected individuals, only half enrolled in care and only a small percent ultimately started ARVs and maintained adherence rates >90%for more than 180 days35 (Figure 3). This declining cascade in access to treatment is mostly due to an inconsistent pattern of diagnosis, linkage to care, differences in levels of CD4 cell count for initiation, and retention in care. In sub-Saharan Africa the percent of individuals being tested for HIV remains low. The average CD4 cell count at time of ART initiation in low and middle-income countries remains low with a median cell count of 124 cells/mm3,36. Intensified efforts are needed to identify those infected, initiate therapy, use standardized effective regimens, and encourage adherence and retention. Only with success at each stage in the continuum of care can the ultimate goals of improving health, extending lives, and preventing further HIV transmission be achieved.
Reducing incidence has been a top priority for AIDS control. The initial prevention strategy was based on behavioral change: abstinence, be faithful, and use of a condom. This strategy met with only limited success, with Thailand’s 100% condom campaign and Uganda’s initial AIDS response being exceptions37,38. There is growing evidence that a relative decline of HIV incidence rates of over 25% between 2000 and 2010 in numerous African countries are the result of behavioural change39. Condom use continues to increase, with several countries including South Africa, India and Botswana, reporting over 75% condom use during last high risk sexual intercourse6. However, condom use is still low in many other countries. A cause of concern is that in several African countries such as Uganda, South Africa and Botswana, more men reported multiple partners in 2009 than ten years ago7.
Access to sterile injection equipment and substitution therapy, referred to as harm reduction, is highly effective in reducing HIV spread among IDUs40. Yet, several countries in Eastern Europe and Asia whose HIV epidemics are driven by injecting drug use continue to use ineffective, punitive approaches, with sustained high HIV incidence as a consequence, also feeding the sexual spread of HIV41. Structural approaches42 such as programs to reduce violence against women43 and cash transfers, i.e., cash payments that can be used for food purchases, transportation, education, health care and other expenses in adolescent school girls in Malawi44, should be integrated more in HIV prevention agendas. In addition, laws that drive MSM underground or prohibit harm reduction for IDUs, can be major obstacles to effective HIV prevention17. That such laws can be reversed was illustrated by India, which decriminalised same sex relations in 2009.
The first major biomedical breakthrough in prevention was the finding of reduced susceptibility to HIV in circumcised men with an efficacy rate of 50 to 60% in three clinical trials45-47. Five years after the completion of these studies, high rates of community effectiveness (70%) in decreasing HIV incidence have been reported48. With an estimated cost per infection averted in the range of $150 to $900 over a ten-year period depending on local HIV incidence, male circumcision appears to be one of the most cost-effective prevention interventions, requiring only a one-time intervention49.
Use of ARVs prior to sex is referred to as pre-exposure prophylaxis. Pre-coital use of 1% Tenofovir gel reduced HIV acquisition by 39% in women and daily oral Tenofovir/Emtricitabine among MSM reduced HIV acquisition by 44%, with greater efficacy observed among individuals who achieved high levels of adherence in both trials50,51. Daily Tenofovir and Tenofovir/Emtricitabine reduced HIV acquisition by 66% and 73%, respectively, among uninfected partners in HIV serodiscordant partnerships, and in young heterosexuals in Botswana52. While these studies are encouraging, two studies produced conflicting results finding no efficacy with either oral or gel Tenofovir53,54. The explanation for these discrepant studies may be due to low adherence to the drug regimens, or differences in mucosal penetration. Recently, the FDA approved daily oral Truvada (emtricitabine and tenofovir disoproxil fumarate) for PrEP in combination with safer sex practices to reduce the risk of sexually-acquired HIV infection in adults at high risk.
Viral load is the single greatest risk factor for all transmission modes55, and treatment as prevention is based on the fact that ART can reduce plasma and genital HIV viral load to undetectable levels, thereby reducing infectiousness28. This principle was first proved for prevention of MTCT56 and subsequently in preventing sexual transmission by 96% within couples 28. This shift from a focus on downstream therapeutic application of ART to a more upstream preventive benefit of eliminating HIV transmission has inspired optimism for the creation of an “AIDS-free generation”..
There is consensus that no single intervention can stop the spread of HIV, and that “combination prevention” is the best approach57. Effective biomedical interventions coupled with behavioral and structural approaches may now successfully reduce HIV incidence to very low levels and ultimately control the epidemic. There is also a need to test in community randomized trials how effective treatment as prevention works at the population level; what the optimum program design would be, and in combination with which prevention interventions, and equally important, to ensure good treatment coverage for those in immediate need of clinical treatment.
From both an impact and a cost-effectiveness perspective, HIV prevention efforts should focus more on populations at highest risk for transmission, and should be customized to a wider range of realities than is presently the case. It should be stressed that all components of combination prevention require some form of behaviour intervention, be it to ensure adherence to condom use or ARV-based prevention, or to prevent increased risk behaviour. However, even when optimally applying the most effective HIV interventions, most mathematical models suggest that by 2031 – 50 years after the discovery of AIDS – there may still be as many as one million new infections annually globally58,59. While desperately needed, the search for a vaccine still eludes investigators, although one recent trial in Thailand with a 31% efficacy provided a much needed boost to vaccine research60.
After thirty years in the AIDS epidemic, there are over 34 million people living with HIV, and still 2.5 million new infections and 1.7 million deaths each year, emphasizing that the global response will have to be sustained for at least several decades. There is now an impressive array of evidence-based interventions that can be implemented to treat established infections and prevent new ones. Studies among high-risk populations have shown that HIV prevention can work even in the most challenging settings. Yet, despite this, UNAIDS reports that only 60% of sex workers, 46% of IDUs, and 40% of MSM were reached with HIV prevention programs in 2008, and HIV incidence is rising again in several populations, including in Uganda8,14 .
In 2011, less than 25% of all HIV infected individuals had access to, or were virologically suppressed with ARV treatment14. To ensure ART access, many lower-income countries are still dependent almost entirely on international aid, which has declined in recent years. As we witness the increase in chronic care and chronic diseases in people with HIV as a result of treatment and increased life expectancy, innovative solutions of care delivery must be developed, including task shifting and integrated service delivery in the community.
In conclusion, enormous progress has been made in the global AIDS response, but these achievements are fragile because of the enormous challenge of sustaining political, programmatic and technical commitment, and national and international funding. A certain level of AIDS “fatigue” coincides with the unprecedented opportunities of new tools to control AIDS. In this new era prevention and care will need to be targeted strategically and creative combinations of behavioral, biomedical, and structural interventions implemented widely58,59. These programs will require universal access, wide scale implementation, careful monitoring and evaluation, financial and technical resources, and robust commitment. Only then may we begin to see a substantial impact on the spread of HIV globally.
Note – See changes in Ref 27 and 29
27. Panel on Antiretroviral Guidelines for Adutls and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Updated 2013. Department of Health and Human Services. (Accessed at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf)
29. European Guidelines for treatment of HIV infected adults in Europe: Version 6.1 2012. (Accessed at http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf)
WHO clinical staging for HIV consists of stage 1--asymptomatic patients and persistent generalized lymphadenopathy; Stage 2--moderate unexplained weight loss, recurrent respiratory infections, herpes zoster, recurrent oral lesions, etc.; Stage 3--severe weight loss (>10% body weight), chronic diarrhea > one month, thrush, severe bacterial infections, tuberculosis within the last 2 years, etc; Stage 4--opportunistic infections consistent with AIDS, HIV wasting syndrome, HIV encephalopathy, etc.