The Past, Present, and Future of AIDS

Once upon a time, there was a world without AIDS—it seems so long ago. In the past 3 decades since first recognition of the new virus and syndrome, millions of lives have been lost or thwarted by debilitating illness or by orphanhood, and there is a sure promise of many millions of damaged lives to come. Looking back, it is astonishing how much progress has been made. What had been a devastating lethal disease caused by the new human retrovirus human immunodeficiency virus 1 (HIV-1) yielded to intense efforts to devise therapies that prolonged the lives of young people in their prime. With the advent of highly active antiretroviral therapies (HAART) in 1996,¹ it was tempting to hope that science was close to vanquishing the new foe: AIDS had been converted into a manageable chronic disease.

But the advent of the new pathogen coincided with times of turbulent social change, vast disparities in well-being among groups in developed countries, and between relatively affluent nations and developing countries. It was quickly learned that transmission of HIV was entirely dependent on the transfer of blood, drug injection, semen, vaginal fluid, or breast milk. That made the new virus potentially avoidable. But even when confirmed, that knowledge was met with disbelief. In the developed world, the gay community took the first brunt of the epidemic along with injection drug users; in developing countries, it was commercial sex workers. The fact that sexual issues were involved, combined with the pervasive stigma attached to the so-called “high-risk groups,” beclouded insights into the sharply limited modes of HIV transmission and impeded efforts at behavioral intervention that were—and remain—the most powerful strategies in the struggle to curtail the HIV pandemic.

Those individuals who lived through the early years will never forget the decimation of marginalized communities, the inexorable loss of young lives and creative talent, and the rapid emergence of a generation of orphans with only grandparents to care for them. But those memories may have been rejected as hyperbole by new generations that followed.

Efforts to mobilize responses collided with harsh facts of life: health care inequities, categorical rejection of populations at high risk, and above all, fear. The caregivers who stepped up to help the first desperately ill patients with AIDS were truly heroic as they faced the unknown, but even after the facts evolved about how to protect oneself, many recoiled. Food trays were left outside hospital room doors. Tenants who were perceived to be at risk were evicted. Employees who were suspected of same-sex orientation were fired for vague cause. It was almost unbelievable that a democratic, altruistic society could turn so nasty and hostile to individuals with a lethal disease.

Despite that dismal background, the danger inherent in the crisis gave impetus to opportunity. Now, more than 25 years later, there is much progress to celebrate. Fortunately, basic biomedical science was ready just in the nick of time. Monoclonal antibody techniques facilitated identification of subclasses of T cells, which, as it turned out, existed in manifold array. Their differentiation, in turn, allowed an increased understanding of the pathogenesis of the immune deficiency that underlay opportunistic infections and rare tumors that characterized the new syndrome. The dynamics of T-cell decline facilitated the insight that the mean interval between HIV infection and the diseases emblematic of AIDS was more than 10 years—truly a “slow virus infection.”

Pharmacology also rose to the occasion. Little effort had gone into development of antiviral agents in earlier years, partly because of the almost certain rapid occurrence of antiviral resistance. The drug known as azidothymidine was the first out of the gate in 1987.² It was welcomed for the brief reprieve it gave to severely immunocompromised individuals, but it was almost intolerably toxic. Then, in the mid-1990s came an array of drugs of several classes—collectively called HAART. However, not all patients could tolerate these regimens, and each of the new drugs was ferociously expensive. Compounding that, it was soon learned that these drugs needed to be taken in combination to stave off antiviral resistance. Nevertheless, HAART was a major milestone: HIV infection and AIDS was converted from a near universal death sentence to a survivable chronic disease. Where the new drugs could be accessed, afforded, and delivered, both hope and the chance for productive years of life was restored for great numbers of patients with HIV.

Clinical medicine also responded. The acumen needed to diagnose and manage HIV/AIDS catapulted to a rarified level of clinical skill. That was not entirely a good thing. At a time when individuals most at risk were marginalized and lacked access even to basic health care, it became evident that management of patients with AIDS required highly specific expertise.

Public health had much to contribute, which revitalized its appreciation within the biomedical community. After all, it was the painstaking epidemiologic analysis of risk behaviors that provided reassurance to the larger society; change in risk behaviors was the only available strategy at the outset. The potential devastating effects of threatened quarantine measures was averted, and as blood tests for HIV antibodies became available in 1985,³ it was possible not only to restore safety to the blood supply but also to validate the efficacy of reducing risk behaviors. Nevertheless, the stigmatization of populations at risk loomed large and created divisions within both the public health and medical communities about how to proceed.

In addition, inherent strengths and weaknesses of international health agencies and scientific collaboration were tested. The global commonality of threat prompted the initiation of an annual series of international AIDS conferences that were unlike any that had happened before. A broad range of scientists—from social, behavioral, and biomedical disciplines—not only got to know each other but also got “up close and personal” with activist communities battling the epidemic on their own terms with life-and-death fervor.

At the World Health Organization, then Director General Halfden Mahler decided in 1986 to initiate a comprehensive response and recruited the late Dr Jonathan Mann to lead it. Much could be said about what happened next, but surely one of the most important effects of Mann's inspiring leadership was the vivid assertion that issues of human rights were inextricably linked with effective societal responses to the global HIV epidemic, and that political will on the part of governments was a necessary prerequisite to success.

Those brief brush strokes color the background. It is important to assess where the HIV/AIDS epidemic is today and what lies ahead. First, the scale of the epidemic worldwide increases ever more substantially. It is estimated that 25 million individuals have already died of AIDS,⁴ more than 30 million are currently infected with HIV,⁵ and vast populations are newly at risk, particularly in Asia. Horrifyingly, just as South Africa was emerging from its long nightmare of apartheid, HIV struck with such fury that life expectancy has been drastically reduced and an estimated 2.5 million individuals newly infected in the past years.⁶ For more than a decade in the United States, a “steady state” of 40 000 new HIV infections a year had been quietly acknowledged, but recent estimates indicate that more than 50 000 incident cases occurred in 2006.⁷

Strategies to prevent pediatric AIDS through the use of antiviral treatment regimens initiated at the time of delivery have been remarkably effective in developed countries, but failure to treat infected mothers beyond the perinatal period has allowed breast milk transmission to continue in vast areas in which alternatives to breastfeeding are unavailable, unsafe, or both.

Mercifully, many of the hallmark infections of HIV/AIDS have not proved capable of enhancing their virulence, but some have. Most notably, tuberculosis has been fanned from a smoldering ember to a raging fire in areas in which HIV is prevalent, and a frightening new problem has arisen—that of extremely drug-resistant tuberculosis, which reintroduces the issue of health care worker safety.

Thus, despite remarkable successes, the stage is set for trouble far into the future. The intervention of foundations and, belatedly, governments has been heartening and may indeed impede the pace of HIV spread, but the fact that sexual activity and illicit drug use are integral drivers of the epidemic makes it exceedingly problematic to take full advantage of public health insights.

The effectiveness of HAART (and probable successor drugs) has contributed hopefulness to clinical management of the complex disease, but issues of antiviral resistance cannot be solved easily and the costs of such a medicalized approach are almost unthinkable where populations are most in need. Furthermore, newly recognized syndromes such as lipodystrophy and cardiovascular disease in patients with HIV/AIDS add further complexity to the clinical challenge of their care.

Virologic worries remain. The potential for mutability within the HIV genome has been evident from the outset. But beyond that, it is now clear that HIV-1 has multiple subtypes,⁸ and while several of them can be traced back to the beginning of the epidemic, others have unquestionably arisen since then. It is likely that these subtypes represent “hybrid” viruses, arising when a single individual is co-infected with 2 subtypes, and then the viral progeny express recombined genomic information. Early in the epidemic, it was commonly assumed that individuals infected with HIV posed no additional risk to each other in the context of risky behavior. That no longer can be relied on, which makes the challenge of prevention more complex and more acutely important.

The matter of HIV vaccines has always been problematic. With no clear evidence of an innate protective immune response to HIV in humans, it is disappointing but not surprising that the most promising vaccine trials to date have failed. Indeed, it is widely accepted that, although efforts at vaccine development must continue, current scientific efforts essentially are “back to the drawing board.”

Although the list of worries for the future is extensive, 2 matters need emphasis: those of sex inequity and of stigma. These issues have always been massive impediments in the approach to all facets of the epidemic, and that will continue. As the virus encroaches inexorably on communities and populations that are marginalized, and on women and (increasingly) girls who are powerless to control their sexual vulnerability, the dismal shadow of HIV/AIDS will continue to spread across the global landscape.

There was a wishful tendency in the early years to frame efforts against HIV/AIDS as a battle that could be won. But the battlefield is now global and the enemy, in a certain poignant sense, is us. The hard lessons of prevention remain the most effective but also the most difficult. Clearly, like the day after Hiroshima, it is evident now that a new primal force has durably altered the world. HIV can be managed, dealt with, confronted in many effective ways, but will never be gone. The medical and scientific communities must not be blinded by hubris or future generations be allowed to minimize or deny the threat—for there will not ever again be a world without AIDS.