The n e w e ng l a n d j o u r na l of m e dic i n e

edi t or i a l s

Antiretroviral Treatment as Prevention

Scott M. Hammer, M.D.

The numbers that define the scope of the HIV–
AIDS pandemic are staggering: 30 years, 60 mil-
lion infections, 30 million deaths. We have not
been defenseless in this fight, however. The in-
troduction of potent combination antiretroviral
therapy in 1996 and the public health approach
to HIV treatment in resource-limited settings in
2002 have changed the course of the epidemic.1,2
In parallel with treatment, the use of antiretro-
viral drugs as a prevention tool has been a focus
from the beginning of the antiretroviral-therapy
era, with the hallmark achievement being the pre-
vention of mother-to-child transmission of the vi-
rus. The result has been the virtual elimination
of neonatal HIV-1 infection in resource-rich set-
tings. Sadly, this intervention in its most effective
form reaches only a minority of HIV-infected
pregnant women in resource-limited settings.3,4
In this issue of the Journal, Cohen et al.5 de-
scribe the results of the HIV Prevention Trials Net-
work (HPTN) 052 study, which has now provided
definitive proof that (as suggested by the findings
of previous cohort studies6) antiretroviral treat-
ment reduces the rate of sexual transmission of
HIV-1. This multinational study enrolled 1763 dis-
cordant couples, in whom the HIV-1–infected part-
ner had a CD4 count between 350 and 550 cells per
cubic millimeter. The HIV-1–positive partners were
randomly assigned to receive early antiretroviral
therapy (in which therapy was started at enroll-
ment) or delayed antiretroviral therapy, in which
therapy was initiated when the CD4 count dropped
below 250 cells per cubic millimeter or an HIV-1–
related event occurred. The study posed two ques-
tions: Would antiretroviral treatment of the HIV-1–
positive partner reduce the rate of transmission
to the negative partner, and would immediate
therapy slow disease progression in the HIV-1–
infected index patient, as compared with delayed
therapy?
The answer to the first question was a resound-
ing yes. Of a total of 39 HIV-1 transmission events,
28 were genetically linked, as determined by viral
sequence analysis. Of the 28 linked transmissions,
only 1 occurred in the early-therapy group, where-
as 27 occurred in the delayed-therapy group, result-
ing in a 96% reduction in the rate of transmission.
Of these 27 transmissions, 9 were man-to-woman,
18 were woman-to-man, and all occurred when
the infected partner was not receiving antiretro-
viral therapy.
The answer to the second question, whether
early therapy would reduce the rate of disease
progression in the HIV-1–infected index cases, was
a more muted, but still definite, yes. A total of
105 participants had at least one clinical end
point: 40 in the early-therapy group and 65 in the
delayed-therapy group, for a reduction of nearly
40% in the progression of HIV-1–related disease.
Extrapulmonary tuberculosis dominated the clin-
ical events and drove the between-group difference
(3 cases vs. 17 cases).
As with any initial report of a major clinical
trial, questions remain. Will the pending data
with respect to viral genotyping shed light on the
one transmission that had not yet been analyzed
or on the three transmissions that were indeter-
minately linked? What are the viral and host
factors that explain why transmission events oc-
curred largely in Africa? Would isoniazid treat-
ment of latent tuberculosis have eliminated the
statistical difference in the treatment end point
that was driven by extrapulmonary tuberculosis?
How generalizable are these results? Answers to

n engl j med 365;6  nejm.org  august 11, 2011 561

The New England Journal of Medicine
Downloaded from nejm.org on August 13, 2015. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

these questions and others will emerge through designed clinical trials have the potential to pre-
further analyses of the data from the HPTN 052 serve health and control the epidemic until a safe
study and subsequent trials. and effective HIV vaccine is a reality.
Drugs to prevent HIV-1 transmission are being Disclosure forms provided by the author are available with the
investigated in both infected and uninfected per- full text of this article at NEJM.org.
sons. In HIV-1–negative persons, drugs can be
From the Division of Infectious Diseases, Columbia University
used before or after high-risk exposure (or both). Medical Center, New York–Presbyterian Hospital, New York.
The use of 1% tenofovir topical gel as a microbi-
cide in women7 and of oral combination therapy This article (10.1056/NEJMe1107487) was published on July 18,
with tenofovir and emtricitabine in men who have 2011, at NEJM.org.
sex with men8 has reduced rates of HIV-1 acquisi- 1. Dieffenbach CW, Fauci AS. Thirty years of HIV and AIDS:
tion by 39% and 44%, respectively, findings that future challenges and opportunities. Ann Intern Med 2011;154:
have provided strong encouragement for these 766-71.
2. Gilks CF, Crowley S, Ekpini R, et al. The WHO public-health
approaches. approach to antiretroviral treatment against HIV in resource-
In HIV-1–positive persons, the use of antiretro- limited settings. Lancet 2006;368:505-10.
viral agents to prevent secondary transmission has 3. Panel on Treatment of HIV-Infected Pregnant Women and
Prevention of Perinatal Transmission. Recommendations for use
led to a variety of proposed test-and-treat strate- of antiretroviral drugs in pregnant HIV-1-infected women for ma-
1,9
gies. The dovetailing of individual and public ternal health and interventions to reduce perinatal HIV transmis-
health benefits that are suggested by the findings sion in the United States. May 24, 2010. (http://aidsinfo.nih.gov/
ContentFiles/PerinatalGL.pdf.)
of the HPTN 052 study provides a major impetus 4. World Health Organization. PMTCT strategic vision 2010-
for these initiatives to move forward. 2015: preventing mother-to-child transmission of HIV to reach
Antiretroviral therapy is by no means perfect the UNGASS and Millennium Development Goals. (http://www
.who.int/hiv/pub/mtct/strategic_vision.pdf.)
and is not the ultimate answer to controlling and 5. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1
ending the HIV epidemic. Adverse events, emer- infection with early antiretroviral therapy. N Engl J Med 2011;
gence of drug-resistant viral strains, maintenance 365:493-505.
6. Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1
of adherence, sustainability, and cost are just some transmission after initiation of antiretroviral therapy: a prospec-
of the concerns. However, this is precisely the tive cohort analysis. Lancet 2010;375:2092-8.
wrong time to limit access to antiretroviral thera- 7. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Ef-
fectiveness and safety of tenofovir gel, an antiretroviral microbi-
py in resource-limited settings, since we have the cide, for the prevention of HIV infection in women. Science
tools in hand to maintain or restore health in in- 2010;329:1168-74.
fected persons and reduce transmission to their 8. Grant RM, Lama JR, Anderson PL, et al. Pre-exposure chemo­
prophylaxis for HIV prevention in men who have sex with men.
­
sexual partners. N Engl J Med 2010;363:2587-99.
Aggressive programs to diagnose and treat 9. Granich RM, Gilks CF, Dye C, De Cock KM, Williams BG.
HIV infection as part of a comprehensive care Universal voluntary HIV testing with immediate antiretroviral
therapy as a strategy for elimination of HIV transmission:
package and multiple approaches to the preven- a mathematical model. Lancet 2009;373:48-57.
tion of transmission that have been tested in well- Copyright © 2011 Massachusetts Medical Society.

Nutrition Support in Critical Illness — Bridging the Evidence Gap

Thomas R. Ziegler, M.D.
The modern field of specialized nutrition sup-
port began with seminal studies showing that
parenteral nutrition could stimulate growth and
development in infants, as well as wound healing
and convalescence in adults with the severe short
bowel syndrome, who until that time had been
unable to survive with enteral nutrition alone.1,2
Later, technical developments and recognition
that malnutrition among hospitalized patients
was common3 led to growth in nutrition support
services. By the 1980s, the use of specialized
regimens of enteral and parenteral nutrition were
routine in intensive care units (ICUs) worldwide,
despite little evidence from rigorous, controlled
clinical trials supporting the efficacy of these
interventions.4,5
With time, there has been improved aware-
ness about complications related to the use of

562 n engl j med 365;6  nejm.org  august 11, 2011

The New England Journal of Medicine

Downloaded from nejm.org on August 13, 2015. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.