Pubdate: Thu, 08 Jun 2006
Source: New England Journal of Medicine (MA)
Section: Volume 354:2411-2414  June 8, 2006  Number 23
Copyright: 2006 Massachusetts Medical Society
Author: Kent A. Sepkowitz, M.D.


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


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 AVERT.

World estimates of the HIV & AIDS epidemics at the end of 2005. 
(Accessed May 18, 2006, at 
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.
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MAP posted-by: Beth Wehrman