Although an outright cure and a preventive vaccine for HIV/AIDS remain elusive, the last two decades have witnessed remarkable advances in effective HIV therapeutics.1 Most significant among these has been the development of highly active antiretroviral therapy (HAART).2 With the use of HAART, the number of plasma HIV-1 RNA viral copies rapidly becomes undetectable as measured by the most sensitive commercially available assays. This allows for immune reconstitution to take place, arresting the otherwise fatal course of the disease. HIV infection can therefore be put into remission over a long-term basis.3,4 More recently, as discussed subsequently, HAART can significantly decrease HIV transmission. This article argues that an intensified expansion in the use of HAART to all those in medical need, including drug users, is essential for containing the devastation of the HIV pandemic.
Treatment of HIV/AIDS
High levels of adherence to HAART are necessary to ensure optimal virologic, immunologic, and clinical outcomes. Incomplete adherence to HAART promotes the emergence of HIV drug resistance, which can severely limit the effectiveness of currently available antiretroviral therapies. Although newer antiretroviral drugs have dramatically improved rates of response among individuals harboring HIV drug-resistant virus, the challenge of adherence will remain as long as HIV treatment requires daily use of medications on a lifelong basis.3,4
Earlier problems with HAART were related to its safety and tolerability. These have been largely ameliorated over the past decade such that modern-day HAART regimens are more effective, better tolerated, and simpler to remember and take. This is exemplified by the once-daily dosing regimen, which has become the standard of care for initial HIV therapy. Several fixed-dose combinations, including the one-pill-a-day regimen of tenofovir, emtricitabine, and efavirenz,4 have also become available and have further simplified current HIV treatment options.3,4 In parallel with these therapeutic advances are the dramatic reductions seen in HIV-related morbidity and mortality as documented by clinical trials and observational studies evaluating the efficacy of HAART.5,6 By 2006, roughly a decade after the advent of HAART, an estimated 3 million years of life or more had been saved in the United States, a direct benefit from its expanded use.7 Researchers have estimated that the average number of years of life remaining after age 20 for HIV-infected individuals who live in high-income countries and are on HAART was two thirds that of the general population.8
Treatment as Prevention
A growing body of evidence indicates that expansion of HAART coverage can help to reduce the transmission of HIV.9-15 HAART can rapidly and effectively suppress viral replication, thereby reducing an individual's plasma HIV-1 RNA viral load to an undetectable level over a sustained period of time with a corresponding decrease of HIV-1 RNA viral load in biologic fluids such as semen and vaginal secretions.16,17 The correlation between plasma viral load and viral load in other biologic fluids in the presence of successful HAART is not perfect; the exceptions that have been reported serve as cautions about the importance of secondary prevention strategies, particularly safer sex and harm reduction practices.18 From a public health perspective, however, the correlation between HIV-1 RNA viral load levels in plasma and other bodily fluids in the setting of successful HAART is sufficiently strong, particularly in the setting of long-term sustained effective HAART.
Evidence of the impact of HAART on HIV transmission has been most clearly shown in studies of vertical transmission.19 For such circumstances, the appropriate use of HAART has virtually eliminated maternal-child HIV transmission. There is now near-universal recognition of the need to expand HAART programs worldwide to improve maternal health and eliminate neonatal HIV transmission.20
Observational studies have documented the preventive role of HAART in reducing HIV transmission between HIV-discordant heterosexual couples. Attia et al conducted a systematic review and meta-analysis involving over 1000 person-years from five different cohorts of heterosexual HIV-discordant couples.21 Although there were no reports of HIV transmission in discordant heterosexual couples if the HIV-infected partner was treated with antiretroviral therapy and had a plasma HIV-1 RNA viral load below 400 copies/mL, the data were also compatible with an estimate of one transmission per 79 persons-years.21 A more recent cohort study of 3400 heterosexual discordant couples in seven African countries was reported. The couples were counseled and given access to free condoms; participants became eligible for HAART when their CD4 counts were concordant with current guidelines. Over the next 1 to 3 years of follow-up, a total of 103 new HIV infections were diagnosed within the cohort. All but one of the new HIV infections occurred between untreated couples for an estimated 92% reduction in HIV transmission by HAART.22
The effect of HAART on HIV transmission at the population level was examined in Taiwan, where, from 1996, the year HAART was introduced through 1999, there was a 53% reduction in the diagnosis of new HIV infections.23 In British Columbia (BC), Canada, the annual incidence of HIV infections decreased by approximately 50% over the same timeframe, also coinciding with the introduction of HAART.24 Of note, although the changes described in Taiwan occurred against a background stable rate of syphilis, a surrogate marker of high-risk sexual behavior in the community, the changes described in BC were of a similar magnitude despite a steady increase in syphilis rates over the same period of time. Based on BC's experience, Lima et al25,26 estimated the potential decrease on HIV incidence that would be associated with a gradual increase in HAART coverage. The model considered different scenarios of adherence and of HIV drug resistance as increased coverage engaged harder-to-reach populations who may have adherence and other health challenges. Overall, the model found that increased HAART coverage will lead to proportional decreases in HIV transmission, largely unaffected by decreases in adherence or increases in resistance rates. Of note, the latter is partially attributable to the fact that a relatively high level of adherence is required to select for and maintain resistant viral strains. Very low levels of adherence or nonadherence invariably allow the original viral strains, typically wild-type virus, to overwhelm the resistant virus. Separately, drug-resistant HIV is characterized by decreased fitness, which is most often associated with decreased plasma HIV-1 RNA viral load, an important determinant of HIV transmission.
Highly Active Antiretroviral Therapy Among HIV-Infected Drug Users
The use of HAART among HIV-infected drug users has been a subject of considerable debate. A number of reports have argued that social instability related to illicit drug use can compromise HAART-related benefits.27-29 Research has shown that drug users are often less likely to be prescribed HAART.30,31 Findings were reported in 2008 on a population-based cohort study of over 3000 antiretroviral-naive HIV-infected patients compared HAART outcomes among individuals with and without a history of injection drug use.32 A total of 915 participants had histories of injection drug users and the median duration of follow-up was over 5 years. Overall, even after 84 months after the initiation of HAART, rates of all-cause mortality were not statistically different between the two groups; the hazard ratio of mortality was 1.09 (95% confidence interval, 0.92-1.29). Similar results were found when the analysis was restricted to nonaccidental deaths. These findings suggest that HAART provides a similar survival benefit at the population level between individuals with and without a history of injection drug use.
More recently, the secondary benefit of HAART on HIV transmission was evaluated among injection drug users.33 Needle-sharing among drug users is an important determinant of HIV transmission in this setting. The issue was examined by monitoring HIV transmission, plasma viral load, and HAART use at the community level in two existing research cohorts in the downtown eastside of Vancouver. The downtown eastside represents the poorest urban neighborhood in Canada. It occupies a small geographic area but is densely populated by drug users, and it has a particularly high prevalence of injection drug use. Several prospective cohorts were established in the mid-1990s in the downtown eastside to evaluate outcomes of HIV infection among those already infected and the risk factors related to acquisition of HIV among those not yet infected. These cohorts were used to develop estimates, at semiannual intervals, of the viral load within HIV-positive individuals (ie, the “community plasma-HIV-1 RNA level”) and the HIV seroconversion rate within those who were HIV-negative (ie, the HIV incidence rate). In a multivariate model that adjusted for sharing of used syringes, unprotected sex, ethnicity, daily cocaine and heroin use, and unstable housing, the median “community plasma HIV-1 RNA level” remained associated with the time to HIV seroconversion with a hazard ratio of 3.32 (95% confidence interval, 1.82-6.08; P < 0.001) per log10 increase in plasma HIV-1 RNA viral load. Of note, the driver of the observed reduction in the community plasma HIV-1 RNA levels over time in this cohort was the use of HAART, which went from 8% in 1996 to 99% in 2007. These results provide the first-ever demonstration that a longitudinal measure of “community plasma HIV-1 RNA level” correlates with HIV incidence rate in the community and can predict HIV incidence independently of unsafe sexual behaviors and syringe-sharing in a setting of high injection drug use.
In 2010, we reported the use of centralized administrative records to evaluate the association among expansion of HAART coverage, plasma HIV-1 viral load, and new HIV diagnoses in BC, where HAART, medical services, HIV testing, and plasma HIV-1 RNA levels are available free of charge for all BC residents.34 HAART coverage increased steadily, from approximately 2500 patients on treatment in 2004 to 5000 patients in 2009. This increase was associated with a decrease in the number of new HIV infections diagnosed, however, including a 50% decrease in new HIV infections among persons with a history of drug use. Moreover, the proportion of HIV infected drug users in BC with plasma HIV-1 RNA levels above 1500 copies/mL (a surrogate for high community plasma HIV-1 viral load) decreased steadily, from approximately 50% of HIV infected drug users between 2000 and 2004 to 20% in 2009 (P < 0.001). Over the same period of time, there was a parallel increase in the number of HIV tests conducted in BC on a yearly basis.
These findings provide a strong rationale for re-examining the HIV prevention and treatment dichotomy and intensifying the public health campaign to provide HAART to HIV-infected drug users. The latter will only be feasible if structural barriers that impede access to care and support by drug users can be effectively removed and if addiction treatment and evidence-based risk reduction programs can be made available and accessible to those in need on demand.
Additional Benefits of Highly Active Antiretroviral Therapy
HAART has proven to be beneficial and cost-effective in reducing HIV/AIDS- related morbidity and mortality in both resource-rich and resource-limited settings. Appropriate use of HAART can decrease the incidence of HIV infections, as previously shown, which translates to untold savings in medical, health, and social costs for each averted infection. Similarly, the collateral benefits of HAART are realized at multiple levels, from the individual, to the family and community, to the general population, and to all of society.35 HAART has been shown to reduce the burden of tuberculosis36 among persons HIV-infected as well as the community at large.37 As noted, HAART's impact on maternal and child health has had dramatic effects, most significantly in Africa and other regions experiencing high HIV prevalence rates. A recent study in Uganda found that “motherless children” were 10 times more likely to die within 2 years of their mother's death. When HAART was provided to the cohort, there was a 95% decrease in the mortality of affected adults, an 81% reduction in mortality of uninfected children, and a 93% decrease in the number of orphans.38 Additionally, antiretroviral treatment of HIV-infected mothers after delivery allows for safe breastfeeding, which, simultaneously, can prevent HIV infection in the newborn and diarrhea secondary to formula feeding with contaminated water, a common occurrence in resource-limited settings.39 The expansion of HAART has helped to preserve the integrity of the healthcare system in high-prevalence countries where the health workforce is also affected by HIV. HIV infection is estimated to have already claimed 20% of the nursing force in South Africa,39 for example. Even greater effects of HAART are evident among South African miners, among whom the death toll from HIV is estimated to be as high as 60% in persons 30 to 44 years of age.35 HIV significantly decreases worker productivity, which can reduce opportunities for trade and destabilize local and regional economic conditions.35 Indeed, the AIDS pandemic is estimated to have reduced the average national gross domestic product growth rates across 41 African countries by 2% to 4% per year.35
It is with hope and humility that we approach the end of nearly three decades of the AIDS epidemic. An effective vaccine for the prevention of HIV continues to be elusive. Advances in HIV treatment, specifically with HAART, offer promise for managing HIV as a chronic condition for reducing AIDS-related morbidity and mortality and, in the absence of a vaccine, for preventing new infections. The rapid expansion of HAART to those in need can help to save lives.40 The evidence for this is well recognized, yet access to HAART remains suboptimal in many regions of the world. In particular, “the HIV/AIDS epidemic cannot be adequately dealt with locally or internationally without addressing the needs of HIV-infected substance users,”41 most all of whom experience stigma because of their addictions and their HIV disease. For drug users, available and accessible addiction treatment is vital for preventing the acquisition and transmission of HIV. Expanded availability and use of HAART alone is not to contain the AIDS epidemic, however, because it implicitly requires the promotion and protection of human rights, nondiscrimination, removal of stigma, and respect for every patient's privacy and autonomy.42 In addition, there is the need to improve HIV prevention, including HIV testing and counseling, behavioral risk reduction interventions, HIV outreach prevention programs, and case finding, all within an overall “combination prevention” framework.43
The full effects of expanded HAART coverage on rates of HIV transmission have yet to be characterized44,45 and will likely vary significantly among populations and settings. Treating HIV-infected individuals in the general population as a strategy to reduce HIV transmission raises important and as yet unanswered questions such as those related to voluntary and universal HIV testing, potential drug resistance, effects on behavioral disinhibition, long-term toxicities and complications that may be associated with HAART, and the overall costs and benefits for society.45 However, current treatment guidelines make it difficult, if not impossible, to conduct traditional randomized clinical trials to address these and other questions.46-49 Other approaches such as the “delayed start” design50 may be an option for evaluating the expansion of HAART in diverse settings and populations while it is underway.
A decision that all HIV medical providers, researchers, public health advocates, and policymakers must face, therefore, is do we know enough now to expand HAART to those in need or should we wait until we have more evidence on its impact and effectiveness? We argue for the former; there is a public health and humanitarian imperative to expand HAART coverage to all those in medical need according to current medical guidelines. Such an initiative will require close prospective monitoring, however, to assess the direct and secondary benefits of expanding HAART coverage and to inform the best practices for guiding global public health policy.
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