ONE DISEASE, TWO EPIDEMICS -- AIDS AT 25

Twenty-five years have passed since the first cases of AIDS were
recognized. During the first two decades, the epidemiology and
clinical presentation of the disease were established, and potent
antiviral therapies were developed -- for use in patients who could
afford them. The progress of the past five years has been less
dramatic. Indeed, the most salient change was a widening of the gap
between the haves and the have-nots, so that today a single virus is
responsible for two distinct public health calamities.

Placed against the backdrop of the global AIDS epidemic, the
AIDS-related problems in developed countries seem tame. Much current
activity in high-income countries involves managing the predictable
effects of any potent therapy -- toxic effects and drug resistance --
rather than scrambling to provide basic care. Of course, these
problems are not trivial. After a decade of highly active
antiretroviral therapy, the group of common side effects loosely
called body-fat or metabolic abnormalities -- lipodystrophy and
lipoatrophy, diabetes, glucose intolerance and insulin resistance,
and dyslipidemia -- still have no established remedy. Adjustment of
the antiretroviral regimen, improvements in diet and exercise, and
additional medications help some of the people some of the time. Yet
management of the disease often remains inadequate, a limitation that
chills enthusiasm for the early initiation of therapy. Current
guidelines recommend that no treatment be given to an asymptomatic
person with a plasma human immunodeficiency virus (HIV) RNA
concentration of less than 100,000 copies per milliliter, unless the
CD4 cell count is below 200 per cubic millimeter.1

At the same time, the rate of drug resistance among circulating HIV
strains continues to increase: from approximately 5 percent in
samples gathered before 1996 to at least 15 percent in isolates
obtained between 1999 and 2003.2 Patients should therefore undergo
resistance testing before therapy is begun.

In the United States, approximately 1 million persons are living with
HIV infection or AIDS, and 164,000 to 312,000 of them remain unaware
of their infection.3 Experts hypothesize that most of the 40,000 new
infections that occur annually in this country arise from contact
with these undiagnosed persons. Given this likelihood, investigators
have examined the potential benefit of routine screening, rather than
testing of only those perceived to be at increased risk. This
strategy appears to be as cost-effective as screening for colon,
breast, or prostate cancer, and the availability of a rapid oral test
has simplified broadscale testing.

Some worry, however, that routine testing could erode patient
confidentiality by circumventing safeguards that were erected in the
1980s, when HIV infection seemed to be untreatable and universally
fatal. Current debate focuses on whether these once-crucial laws
paradoxically now impede the public health response to the epidemic
by encumbering the testing process.

For those who have already tested positive, treatment has become more
convenient but not more potent in the past five years, with the
introduction of numerous once-daily dosing regimens. Enfuvirtide, the
first fusion inhibitor, is effective in many persons with highly
resistant virus, but twice-daily injections are difficult for some to
sustain.1 The possibility that tenofovir, with or without
emtricitabine, may be effective as prophylaxis has received attention
on two different fronts. The first was a description of its frequent
use as a "party" pill by uninfected persons who planned to engage in
high-risk activity. The second was more recent studies showing that
its use in high-risk populations reduces the infection rate. This
approach, however, may accelerate the emergence of drug resistance
and thereby compromise the effectiveness of the prophylactic or
therapeutic use of these medications.

Meanwhile, the second epidemic -- in low- and middle-income countries
- -- has grown far vaster than that in the United States, as HIV
continues its nightmarish expansion (see table). Only one fifth of
people in developing countries who need treatment are receiving
antiretroviral therapy.4

View this table: [in this window] [in a new window]

Worldwide Prevalence and Incidence of HIV Infection and AIDS and
Related Mortality in 1995, 2000, and 2005.

The establishment of cheap, effective approaches to prevention has
been similarly elusive. Until a vaccine is developed, prevention must
continue to rely on more complicated and probably less useful
options. The effect of male circumcision on HIV transmission remains
controversial, despite a report from South Africa, where more than
3000 men were randomly assigned to undergo either circumcision or
observation.5 The trial was stopped early because of a 61 percent
reduction in the rate of new infections in the circumcision group
that persisted after researchers had controlled for differences in
sexual behavior, condom use, and health care-seeking behavior. The
response to this study, however, remains wary and even dismissive, a
hesitance that seems misplaced, given the role of HIV in forcing
frank discussions of sexual activity.

Two long-considered prevention strategies appear to be ready for
definitive clinical trials. Although monthly azithromycin given to
prevent genital ulcer disease did not reduce the risk of HIV
transmission, long-term antiviral therapy for genital herpes simplex
- -- a tactic that may have a better biologic foundation -- is now
being examined. Similarly, studies of microbicides are finally advancing.

The provision of clean disposable needles for health care and the
maintenance of a safe blood supply were high priorities for the
United States in the 1980s. The cost of establishing similar programs
in resource-poor countries is daunting, yet the risk of HIV
transmission by either route is substantial -- perhaps higher than
the risk from sexual contact. Currently, because of its cost, only 30
percent of countries routinely screen blood. Screening potential
donors is a cheaper approach, yet it may rely on the race-based
exclusion of donors, creating a different dilemma.

Another concern has been the powerful reciprocal interactions between
HIV and Mycobacterium tuberculosis. Although these interactions were
demonstrated by outbreaks of multidrug-resistant tuberculosis in the
United States 15 years ago, the devastation caused by these
intertwined epidemics continues to startle. Tuberculosis kills as
many as one of every seven people with AIDS worldwide, and one third
of the increase in cases of tuberculosis over the past five years can
be attributed to the HIV epidemic.

Control of tuberculosis in areas where HIV is endemic is complicated
by several factors, including a growing fear of acquiring
tuberculosis that makes some health care workers reluctant to care
for those infected with HIV. A lone optimistic note has been the
increasing interest in applying a tool that helped to tame
tuberculosis in some countries -- directly observed therapy -- to the
treatment of HIV infection. If effective, this tactic may preserve
both individual health and the drug susceptibility of circulating virus.

It is unfortunate that for the past 25 years, the lessons learned
about HIV prevention and control in one country have failed to inform
decisions in others. As a result, the world has witnessed a
slow-motion domino effect, as the disease overwhelms country after
country. Typically, locals place the blame on foreigners and foreign
behavior -- just as the French once called syphilis "the Italian
disease" and the Italians considered it "the French disease." This
sort of buck passing has delayed the control of AIDS in every
country. By the time the scale of the problem is finally appreciated,
a mature epidemic is in place, and the cost in lives and money has
increased exponentially.

We can only hope that the years ahead will be characterized not just
by better drugs, new vaccines, and improved prevention methods, but
also by the adoption of the humility necessary to control a disease
that is transmitted through sexual activity and drug use -- two of
proper society's least favorite topics. The prime mover of the
epidemic is not inadequate antiretroviral medications, poverty, or
bad luck, but our inability to accept the gothic dimensions of a
disease that is transmitted sexually. Only when we cease to dodge
this fact will effective HIV-control programs be established. Until
then, it is no exaggeration to say that our polite behavior is killing us.

Source Information

Dr. Sepkowitz is an infectious-disease specialist at Memorial
Sloan-Kettering Cancer Center, New York.

An interactive AIDS timeline is available with the full text of this
article at www.nejm.org.

References

Guidelines for the use of antiretroviral agents in HIV-1-infected
adults and adolescents. Bethesda, Md.: Department of Health and Human
Services, 2005. Masquelier B, Bhaskaran K, Pillay D, et al.

Prevalence of transmitted HIV-1 drug resistance and the role of
resistance algorithms: data from seroconverters in the CASCADE
collaboration from 1987 to 2003. J Acquir Immune Defic Syndr
2005;40:505-511. Glynn M, Rhodes P.

Estimated HIV prevalence in the United States at the end of 2003.
Presented at the National HIV Prevention Conference, Atlanta, June
12-15, 2005. (Accessed May 18, 2006, at
http://www.aegis.com/conferences/nhivpc/2005/T1-B1101.html.) AVERT.

World estimates of the HIV & AIDS epidemics at the end of 2005.
(Accessed May 18, 2006, at http://www.avert.org/worldstats.htm.)
Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambejou J, Sitta R, Puren A.

Randomized, controlled intervention trial of male circumcision for
reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med 2005;2:e298-e298.