Prevention of HIV-1 Infection with Early Antiretroviral Therapy - NEJM

The New England Journal of Medicine published a study on the effect of early antiretroviral therapy on HIV-1 transmission in serodiscordant couples. The study found that early therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy.

n engl j med 365;6nejm.org august 11, 2011 493
The new england
journal of medicine
established in 1812 august 11, 2011 vol. 365 no. 6
Prevention of HIV-1 Infection with Early Antiretroviral Th
Myron S. Cohen, M.D., Ying Q. Chen, Ph.D., Marybeth McCauley, M.P.H., Theresa Gamble, Ph.D
Mina C. Hosseinipour, M.D., Nagalingeswaran Kumarasamy, M.B., B.S., James G. Hakim, M.D.,
Johnstone Kumwenda, F.R.C.P., Beatriz Grinsztejn, M.D., Jose H.S. Pilotto, M.D., Sheela V. Godbole,
Sanjay Mehendale, M.D., Suwat Chariyalertsak, M.D., Breno R. Santos, M.D., Kenneth H. Mayer, M
Irving F. Hoffman, P.A., Susan H. Eshleman, M.D., Estelle Piwowar-Manning, M.T., Lei Wang, Ph.D
Joseph Makhema, F.R.C.P., Lisa A. Mills, M.D., Guy de Bruyn, M.B., B.Ch., Ian Sanne, M.B., B.Ch
Joseph Eron, M.D., Joel Gallant, M.D., Diane Havlir, M.D., Susan Swindells, M.B., B.S., Heather Ribaud
Vanessa Elharrar, M.D., David Burns, M.D., Taha E. Taha, M.B., B.S., Karin Nielsen-Saines, M.D
David Celentano, Sc.D., Max Essex, D.V.M., and Thomas R. Fleming, Ph.D., for the HPTN 052 Study
A bs tr ac t
The authors’ affiliations are listed in the
Appendix. Address reprint requests to Dr.
Cohen at the University of North Carolina
at Chapel Hill, Institute for Global Health
and Infectious Diseases, Suite 2115, Bio-
informatics Bldg., 130 Mason Farm Rd.,
CB 7030, Chapel Hill, NC 27599, or at
[e-mail].
*Other members of the HIV Prevention
Trials Network (HPTN) 052 Study Team
are listed in the Supplementary Appen-
dix, available at NEJM.org.
This article (10.1056/NEJMoa1105243) was
published on July 18, 2011, at NEJM.org.
N Engl J Med 2011;365:493-505.
Copyright © 2011 Massachusetts Medical Society.
Background
Antiretroviral therapy that reduces viral replication could limit the transmission of
human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples.
Methods
In nine countries, we enrolled 1763 couples in which one partner was HIV-1–positive
and the other was HIV-1–negative; 54% of the subjects were from Africa, and 50%
of infected partners were men. HIV-1–infected subjects with CD4 counts between
350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive
antiretroviral therapy either immediately (early therapy) or after a decline in the CD4
count or the onset of HIV-1–related symptoms (delayed therapy). The primary preven-
tion end point was linked HIV-1 transmission in HIV-1–negative partners. The pri-
mary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe
bacterial infection, a World Health Organization stage 4 event, or death.
Results
As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence
rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were
virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years,
95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-
therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving
early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to
0.88; P = 0.01).
Conclusions
The early initiation of antiretroviral therapy reduced rates of sexual transmission of
HIV-1 and clinical events, indicating both personal and public health benefits from
such therapy. (Funded by the National Institute of Allergy and Infectious Diseases
and others; HPTN 052 ClinicalTrials.gov number, NCT00074581.)
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T h en e w e ngl a nd j o u r na lo f m e dic i n e
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Combination antiretroviral thera-
py decreases the replication of human im-
munodeficiency virus type 1 (HIV-1) and
improves the survival of infected persons.1,2 Such
therapy has been shown to reduce the amount of
HIV-1 in genital secretions.3-5 Because the sexual
transmission of HIV-1 from infected persons to
their partners is strongly correlated with concentra-
tions of HIV-1 in blood6 and in the genital tract,7 it
has been hypothesized that antiretroviral therapy
could reduce sexual transmission of the virus. Sev-
eral observational studies have reported decreased
acquisition of HIV-1 by sexual partners of patients
receiving antiretroviral therapy.8-11These results
have been extrapolated to suggest that the use of
early antiretroviral therapy could reduce the spread
of the virus in a population.12 Some ecologic stud-
ies have shown a reduction in the incidence of new
cases of HIV-1 after expanded use of antiretroviral
therapy.13,14
The effect of the timing of the initiation of
antiretroviral therapy on clinical and microbiologic
outcomes has been controversial in evaluations
of the benefit of therapy and of the associated
short- and long-term complications and costs. For
many years, antiretroviral therapy was delayed un-
til a patient’s CD4 count fell below 200 cells per
cubic millimeter, which led to frequent opportu-
nistic infections.15 Retrospective analyses of pa-
tients with HIV-1 infection who were treated in
developed countries have suggested a benefit from
early antiretroviral therapy,16-18although the abil-
ity to control for bias in these studies has limits.
To evaluate the effect of combination antiretro-
viral therapy on the prevention of HIV-1 transmis-
sion to uninfected partners and on clinical events
in infected persons, the HIV Prevention Trials Net-
work (HPTN) conducted a multicontinent, ran-
domized, controlled trial, called HPTN 052, to
compare early versus delayed antiretroviral ther-
apy for patients with HIV-1 infection who had
CD4 counts between 350 and 550 cells per cubic
millimeter and who were in a stable sexual rela-
tionship with a partner who was not infected.
Methods
Study Population
We enrolled HIV-1 serodiscordant couples at 13 sites
in 9 countries (Gaborone, Botswana; Kisumu, Ke-
nya; Lilongwe and Blantyre, Malawi; Johannesburg
and Soweto, South Africa; Harare, Zimbabwe; Rio
de Janeiro and Porto Alegre, Brazil; Pune and Chen-
nai, India; Chiang Mai, Thailand; and Boston). A
pilot phase started in April 2005, and enrollment
took place from June 2007 through May 2010. Cou-
ples were required to have had a stable relation-
ship for at least 3 months, to have reported three
or more episodes of vaginal or anal intercourse
during this time, and to be willing to disclose their
HIV-1 status to their partner. Patients with HIV-1
infection were eligible if their CD4 count was be-
tween 350 and 550 cells per cubic millimeter and
they had received no previous antiretroviral therapy
except for short-term prevention of mother-to-child
transmission of HIV-1. (Full criteria for inclusion
and exclusion are provided in the Supplementary
Appendix, available with the full text of this article
at NEJM.org.)
The study protocol, which is also available at
NEJM.org, was approved by at least one local insti-
tutional review board affiliated with each site, by
boards affiliated with collaborating organizations,
and by other local regulatory bodies when appro-
priate (for details, see the Supplementary Appen-
dix). All study participants provided written in-
formed consent in their local languages, or English,
if preferred.
Study Oversight
The study was funded by the National Institute of
Allergy and Infectious Diseases (NIAID) of the
National Institutes of Health, which assumed all
sponsor responsibilities through an investigation-
al new drug application with the Food and Drug
Administration (FDA). The antiviral agents that
were used in the study were donated by pharma-
ceutical companies, which were not involved in the
design or management of the study. All authors
vouch for the completeness and accuracy of the
data presented, as well as the fidelity of the report
to the study protocol.
Study Design
HIV-1 serodiscordant couples were randomly as-
signed in a 1:1 ratio to either an early or delayed
strategy for receipt of antiretroviral therapy. Per-
muted-block randomization was used with strat-
ification according to site. In the early-therapy
group, antiretroviral therapy was initiated in the
partner with HIV-1 infection at enrollment. In the
delayed-therapy group, therapy was initiated after
two consecutive measurements in which the CD4
count was 250 cells per cubic millimeter or less or
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Prevention of HIV-1 Infection
n engl j med 365;6nejm.org august 11, 2011 495
after the development of an illness related to the
acquired immunodeficiency syndrome (AIDS).
HIV-1–infected participants who had active tuber-
culosis were excluded, and isoniazid prophylaxis
was available, according to local guidelines and
practice standards.
After enrollment, study participants were asked
to attend three monthly visits, which were fol-
lowed by quarterly visits unless they became ill
or needed additional antiretroviral medications.
HIV-1–infected participants who were receiving
antiretroviral therapy had one additional visit
2 weeks after starting therapy. HIV-1–uninfected
partners were encouraged to return for all visits
together for counseling on risk reduction and
the use of condoms, for treatment of sexually
transmitted infections, and for management of
other medical conditions. Some HIV-1–infected
participants received trimethoprim–sulfamethoxa-
zole prophylaxis, according to local guidelines.
HIV-1–uninfected partners were tested for
HIV-1 seroconversion on a quarterly basis. Samples
from all seroconversion events were evaluated at a
central laboratory, and results were reviewed by an
independent HIV end-point committee. Partners
with seroconversion were released from the study
and referred to a prearranged local clinic for care.
After the initiation of antiretroviral therapy,
virologic failure for HIV-1–infected participants
was defined as two consecutive plasma HIV-1 RNA
measurements of more than 1000 copies per mil-
liliter at 16 weeks or later. Assessment for clinical
signs and symptoms, laboratory measurements,
interviews about sexual behavior, review of ad-
herence to the antiretroviral regimen (including
a self-reported questionnaire and pill counts), and
adherence counseling were conducted at each visit.
(Details regarding study procedures, including
guidelines for adherence counseling, are provided
in the Supplementary Appendix.)
Any woman who was pregnant at enrollment
or became pregnant was provided antiretroviral
therapy appropriate for use during pregnancy at
the start of the second trimester. On the basis of
the judgment of the site investigator, women in the
delayed-therapy group discontinued antiretrovi-
ral therapy after delivery or when breast-feeding
ended. A new partner could be enrolled with an
HIV-1–infected participant if the original partner
was released from the study and the new HIV-1–
uninfected partner met all inclusion or exclusion
criteria.
Antiretroviral Drugs
Study drugs included a combination of lamivudine
and zidovudine (Combivir), efavirenz, atazanavir,
nevirapine, tenofovir, lamivudine, zidovudine, di-
danosine, stavudine, a combination of lopinavir
and ritonavir (Kaletra and Aluvia), ritonavir, and a
combination of emtricitabine and tenofovir (Tru-
vada). A prespecified combination of these drugs
was provided to participants at monthly or quar-
terly visits. Sites could also use locally supplied,
FDA-approved drugs if they could be purchased
with nonstudy funds. For participants with viro-
logic failure, specified second-line treatment regi-
mens were provided.
Assessment of Linkage of Seroconversions
To assess whether seroconversions were linked,
HIV-1 pol gene sequences were generated by pop-
ulation sequencing for study-partner pairs and for
10 additional HIV-infected local control subjects for
each relevant site. Sequences were analyzed with
the use of phylogenetic methods. The probability
of linkage was also assessed with the use of
Bayes’ theorem to compare the genetic similarity
of HIV-1 from partner pairs with the genetic sim-
ilarity of HIV-1 from local control subjects. In some
cases, HIV-1 samples from partner pairs were ana-
lyzed with the use of ultra-deep pyrosequencing
of the gp41 region.19
Statistical Analysis
We determined that an enrollment of 1750 sero-
discordant couples would provide a power of at
least 87% to detect a 39% reduction in the inci-
dence of HIV-1 transmission to uninfected part-
ners in the early-therapy group, as compared with
the delayed-therapy group (primary prevention end
point). By the end of the trial, we anticipated a
total of 188 transmission incidences, with cumu-
lative incidence rates of 8.3% in the early-therapy
group and 13.2% in the delayed-therapy group, for
a total duration of 6.5 years, with an accrual peri-
od of 1.5 years and a 5% annual loss to follow-up.
The sample size of 1750 would also provide a pow-
er of 92% to show that early initiation of antiret-
roviral therapy provided at least a 20% reduction
in the rate of serious clinical events associated with
HIV-1 infection, which included death, a World
Health Organization (WHO) stage 4 event, or a se-
vere bacterial infection or pulmonary tuberculosis
(primary clinical end point). By the end of the trial,
we anticipated a total of 234 such clinical events,
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with cumulative incidence rates of 8.7% in the
early-therapy group and 18.0% in the delayed-
therapy group.
The study was reviewed twice each year by an
independent NIAID multinational data and safe-
ty monitoring board. To guide the board in its
recommendations regarding trial continuation, a
composite monitoring end point was developed to
include the occurrence of either death or WHO
stage 4 events (excluding esophageal candidiasis)
in HIV-1–infected participants or the transmission
of HIV-1 to uninfected partners, whichever oc-
curred first in the discordant couple. These were
the events that were considered to have the great-
est clinical effect on both the HIV-1–infected par-
ticipant and the uninfected partner. A Lan–DeMets
implementation of an O’Brien–Fleming monitor-
ing boundary was used to evaluate the interim data
with respect to this composite end point.20,21An
early termination would be indicated if there were
conclusive evidence to rule out a hazard ratio of
0.80 or more in the early-therapy group. Interim
analyses were planned when approximately 25%,
50%, 75%, and 100% of a total 340 composite
events were observed.
We used the Kaplan–Meier method to calculate
event-free probabilities and person-year analysis for
incidence rate for a given year. We also used Cox
regression to estimate relative risks, which were
expressed as hazard ratios and 95% confidence
intervals, and to provide adjustment for potential
prognostic factors, such as the infected partici-
pant’s baseline CD4 count, baseline plasma HIV-
1 RNA concentration, and sex. The same Cox
analyses were performed on linked transmis-
sions, any transmissions, clinical events, and com-
posite monitoring events. We used chi-square tests
to compare the frequencies of adverse events. A
P value of less than 0.05 was considered to indi-
cate statistical significance. The cutoff was ad-
justed for multiple comparisons in trial-monitoring
boundaries.
R esult s
Study Participants
A total of 10,838 persons were screened in order
to enroll 1763 HIV-1–serodiscordant couples; 886
couples were randomly assigned to the early-ther-
apy group and 877 to the delayed-therapy group)
(Fig. 1, and the Supplementary Appendix). Twelve
additional HIV-1–uninfected partners were enrolled
as the result of a new relationship.
The majority of couples (97%) were heterosex-
ual, and 94% were married; 50% of HIV-1–infected
participants were men. The majority of partici-
pants (61%) were between 26 and 40 years of age.
At enrollment, 1291 of HIV-1–infected participants
(73%) and 1281 of HIV-1–uninfected partners
(72%) reported having had at least one sexual
encounter during the previous week. During the
same period, 5% and 6%, respectively, reported
having unprotected sex. The median CD4 counts
for the HIV-1–infected partners were 442 cells per
cubic millimeter in the early-therapy group and
428 cells per cubic millimeter in the delayed-ther-
apy group. The median log10 plasma viral load
was 4.4 in each study group. Participants in
the two study groups were similar in educational
status, self-reported sexual behavior, and rate of
condom use (Table 1).
At enrollment, less than 5% of participants had
a sexually transmitted infection, and rates and
types of infection were similar in the two study
groups (see the Supplementary Appendix). A to-
tal of 84 of 449 HIV-uninfected male partners
(19%) in the early-therapy group and 64 of 460
(14%) in the delayed-therapy group had been cir-
cumcised (P = 0.05). New sexually transmitted in-
fections were detected with similar frequency
among participants in the early-therapy group and
the delayed-therapy group during the study, with
36 and 34 syphilis infections, 6 and 8 gonorrhea
infections, 10 and 11 chlamydia infections, and
22 and 19 trichomonas infections, respectively.
Among HIV-1–infected participants, a mean of
96% of those in the early-therapy group and 95%
of those in the delayed-therapy group reported
100% condom use during the study.
On April 28, 2011, the data and safety moni-
toring board recommended that the results of the
study be released on the basis of data collection
through February 21, 2011. At that time, 90% of
couples remained enrolled in the study, with a
median follow-up of 1.7 years; the total number of
person-years of follow-up was 1585 in the early-
therapy group and 1567 in the delayed-therapy
group. The expected effect of early versus delayed
antiretroviral therapy on log10 plasma viral load
and CD4 counts in the HIV-1–infected participants
was observed shortly after enrollment. By 3 months
after randomization, 89% of the participants in
the early-therapy group had a plasma viral load of
less than 400 copies per milliliter, as compared
with 9% in the delayed-therapy group. CD4 counts
in the early-therapy group rose after the initia-
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Prevention of HIV-1 Infection
n engl j med 365;6nejm.org august 11, 2011 497
1763 Couples underwent randomization
(including 82 couples from run-in study)
3526 Were identified as 1763 eligible
HIV-serodiscordant couples
10,838 Patients were screened
7312 Were excluded
3058 Were HIV-positive but were ineligible
owing to CD4 count
2565 Were HIV-negative but HIV-positive partner
was ineligible
308 Were HIV-positive with HIV-positive partner
155 Were ineligible owing to sexual history
1226 Had other reason
886 Couples were assigned
to early-therapy group
877 Couples were assigned
to delayed-therapy group
7 New HIV-1–uninfected
partners were enrolled
2 Partners were HIV-
positive at enrollment
5 New HIV-1–uninfected
partners were enrolled
2 Partners were HIV-
positive at enrollment
893 Partners were enrolled for HIV-1
transmission analysis
882 Partners were enrolled for HIV-1
transmission analysis
Semiannual-visit attendance
Month 6
Month 12
Month 18
Month 24
Month 30
Month 36
Month 42
809/874
720/800
509/601
340/393
230/267
113/129
43/50
93%
90%
85%
87%
86%
88%
86%
Semiannual-visit attendance
Month 6
Month 12
Month 18
Month 24
Month 30
Month 36
Month 42
803/873
727/800
535/612
346/399
231/267
122/135
49/54
92%
91%
87%
87%
87%
90%
91%
22 (2%) Partners had no follow-up
5 (1%) Died
9 (1%) Declined further participation
1 (<1%) Was unable to adhere to
visit schedule
3 (<1%) Relocated
2 (<1%) Were unable to be contacted
31 (3%) Ended relationship
4 (<1%) Had other reason
31 (4%) Partners had no follow-up
4 (<1%) Died
13 (1%) Declined further participation
3 (<1%) Were unable to adhere to
visit schedule
3 (<1%) Relocated
2 (<1%) Were unable to be contacted
42 (5%) Ended relationship
1 (<1%) Had other reason
Figure 1. Enrollment and Outcomes.
This trial profile describes recruitment of couples from the general population, randomization, HIV-1–uninfected
partner’s enrollment, seroconversion at baseline, retention, and loss-to-follow-up for assessment of the primary end
point of linked HIV-1 transmission. Enrolled partners were followed on a quarterly-visit schedule, although atten-
dance at semiannual visits is shown.
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T h en e w e ngl a nd j o u r na lo f m e dic i n e
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tion of antiretroviral therapy, from a median of
442 cells per cubic millimeter at enrollment to
603 cells per cubic millimeter by 12 months, and
the counts continued to rise throughout the follow-
up period (see the Supplementary Appendix). A
modest decline in CD4 counts was observed in the
delayed-therapy group, from a median of 428 cells
per cubic millimeter at enrollment to 399 cells per
cubic millimeter by 12 months. A total of 21% of
HIV-1–infected participants in the delayed-therapy
group began taking antiretroviral therapy after
a median of 42 months. Among all participants,
72% received a combination of zidovudine, lamivu-
dine, and efavirenz (see the Supplementary Appen-
Table 1. Baseline Characteristics of the Participants.*
Characteristic HIV-1–Infected ParticipantsHIV-1–Uninfected Participants†
Early Therapy
(N = 886)
Delayed Therapy
(N = 877)
Early Therapy
(N = 893)
Delayed Therapy
(N = 882)
Demographic
Female sex — no. (%) 432 (49) 441 (50) 441 (49) 418 (47)
Age group — no. (%)
18–25 yr 145 (16) 161 (18) 154 (17) 174 (20)
26–40 yr 556 (63) 547 (62) 537 (60) 526 (60)
>40 yr 185 (21) 169 (19) 202 (23) 182 (21)
Education level — no. (%)
No schooling 101 (11) 69 (8) 112 (13) 77 (9)
Primary schooling 360 (41) 347 (40) 317 (35) 344 (39)
Secondary schooling 346 (39) 388 (44) 373 (42) 367 (42)
Postsecondary schooling 79 (9) 72 (8) 91 (10) 93 (11)
Missing data 0 1 (<1) 0 1 (<1)
Marital status — no. (%)
Single 49 (6) 38 (4) 53 (6) 43 (5)
Married or living with partner 833 (94) 833 (95) 834 (93) 833 (94)
Widowed, separated, or divorced 4 (<1) 6 (1) 6 (1) 6 (1)
Region — no. (%)
North or South America 142 (16) 136 (16) 145 (16) 139 (16)
Asia 267 (30) 264 (30) 268 (30) 264 (30)
Africa 477 (54) 477 (54) 480 (54) 479 (54)
Sexual activity — no. (%)
Any unprotected sex in past week 37 (4) 51 (6) 49 (5) 53 (6)
No. of sex partners in past 3 mo
0–1 831 (94) 833 (95) 863 (97) 844 (96)
2–4 48 (5) 41 (5) 29 (3) 36 (4)
>4 7 (1) 2 (<1) 1 (<1) 1 (<1)
Missing data 0 1 (<1) 0 1 (<1)
No. of sexual encounters in past week
0 246 (28) 225 (26) 253 (28) 240 (27)
1–2 430 (49) 438 (50) 410 (46) 433 (49)
3–4 156 (18) 158 (18) 180 (20) 151 (17)
>4 54 (6) 55 (6) 50 (6) 57 (6)
Missing data 0 1 (<1) 0 1 (<1)
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Prevention of HIV-1 Infection
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dix). Adherence to the study regimen of at least
95% (as measured by pill count) was observed in
79% of participants in the early-therapy group and
in 74% of those in the delayed-therapy group.
Details with respect to regimens of antiretroviral
therapy and pill counts are provided in the Sup-
plementary Appendix.
Virologic failure was observed in 45 of 886
participants (5%) in the early-therapy group and
in 5 of 184 participants in the delayed-therapy
group who initiated antiretroviral therapy (3%)
(P = 0.23). Of all treated participants, 66% initiated
a second-line regimen.
Primary Prevention Outcome
A total of 39 HIV-1 transmission events were ob-
served (incidence rate, 1.2 per 100 person-years;
95% confidence interval [CI], 0.9 to 1.7), with
4 events in the early-therapy group (incidence rate,
0.3 per 100 person-years; 95% CI, 0.1 to 0.6) and
35 events in the delayed-therapy group (incidence
rate, 2.2 per 100 person-years; 95% CI, 1.6 to 3.1),
for a hazard ratio in the early-therapy group of
0.11 (95% CI, 0.04 to 0.32; P<0.001) (Table 2and
Fig. 2; also see the Supplementary Appendix for
details regarding the incidence of transmission).
Through viral genetic analysis, 28 transmissions
were linked to the HIV-1–infected participant (in-
cidence rate, 0.9 per 100 person-years; 95% CI,
0.6 to 1.3), with 1 transmission in the early-therapy
group (incidence rate, 0.1 per 100 person-years;
95% CI, 0.0 to 0.4) and 27 transmissions in the
delayed-therapy group (incidence rate, 1.7 per
100 person-years; 95% CI, 1.1 to 2.5), for a hazard
ratio in the early-therapy group of 0.04 (95% CI,
0.01 to 0.27; P<0.001). The remaining 11 trans-
missions (3 in the early-therapy group and 8 in the
delayed-therapy group) included 7 transmissions
that were unlinked (3 in the early-therapy group
and 4 in the delayed-therapy group), 3 transmis-
Table 1. (Continued.)
Characteristic HIV-1–Infected ParticipantsHIV-1–Uninfected Participants†
Early Therapy
(N = 886)
Delayed Therapy
(N = 877)
Early Therapy
(N = 893)
Delayed Therapy
(N = 882)
Clinical
CD4 count — no./mm3
Median 442 428
Interquartile range 373–522 357–522 NA NA
Plasma RNA viral load — no. (%)
<400 copies/ml 54 (6) 43 (5) NA NA
400–1000 copies/ml 24 (3) 33 (4) NA NA
1001–10,000 copies/ml 212 (24) 183 (21) NA NA
10,001–100,000 copies/ml 407 (46) 432 (49) NA NA
100,001–1 million copies/ml 186 (21) 186 (21) NA NA
Missing data 3 (<1) 4 (<1) NA NA
Women reporting previous antiretroviral
therapy during pregnancy
— no./total no. (%)
115/432 (27) 119/441 (27) NA NA
Type of serodiscordancy — no. (%)
HIV-positive man, HIV-negative woman436 (49) 417 (48) NA NA
HIV-positive woman, HIV-negative man431 (49) 441 (50) NA NA
HIV-positive man, HIV-negative man 18 (2) 19 (2) NA NA
HIV positive woman, HIV-negative
woman
1 (<1) 0 NA NA
* Data regarding the incidence of sexually transmitted infections are provided in the Supplementary Appendix. HIV denotes
human immunodeficiency virus, and NA not applicable.
† Some participants with HIV-1 infection had more than one uninfected partner during the study period.
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n engl j med 365;6nejm.org august 11, 2011500
sions that could not be classified on the basis of
available data, and 1 transmission that has not yet
been evaluated. The latter 4 transmissions were
all in the delayed-therapy group.
The rate of transmission events in the delayed-
therapy group was relatively constant across the
first 3 years of study follow-up for both linked
and any transmissions. Of the 28 HIV-1–infected
participants who had linked transmission to a
partner, 17 (61%) had a CD4 count of more than
350 cells per cubic millimeter at the study visit
before the detection of linked HIV-1 transmission.
The single linked transmission in the early-therapy
group was identified 3 months after the HIV-1–
infected participant initiated treatment; all linked
transmissions in the delayed-therapy group oc-
curred while the HIV-1–infected participant was
not receiving antiretroviral therapy. The Kaplan–
Meier curves for both linked and any transmis-
sions show immediate and sustained reduction in
the risk of HIV-1 transmission after the initiation
of antiretroviral therapy (Fig. 2).
Of the 28 linked transmissions, 23 (82%) oc-
curred at African sites. HIV-1–infected women
were the source of infection in 18 of 27 (67%)
linked transmissions in the delayed-therapy group,
Table 2. Incidence of Partner-Linked and Any HIV-1 Transmission and Clinical and Composite Events.
Variable Early Therapy Delayed Therapy
Hazard or Rate Ratio
(95% CI)*
Events Person-yr
Rate
(95% CI) Events Person-yr
Rate
(95% CI)
no. % no. %
Linked transmission
Total 1 1585.3 0.1 (0.0–0.4) 27 1567.3 1.7 (1.1–2.5) 0.04 (0.01–0.27)
1 yr 1 819.0 0.1 (0.0–0.7) 16 813.3 2.0 (1.1–3.2) 0.06 (0.00–0.40)
2–3 yr 0 686.5 0.0 (0.0–0.5) 9 682.8 1.3 (0.6–2.5) 0.00 (0.00–0.50)
>3 yr 0 79.9 0.0 (0.0–4.6) 2 71.2 2.8 (0.3–10.1)0.00 (0.00–4.75)
Any transmission†
Total 4 1585.3 0.3 (0.1–0.6) 35 1567.3 2.2 (1.6–3.1) 0.11 (0.04–0.32)
1 yr 2 819.0 0.2 (0.0–0.9) 18 813.3 2.2 (1.3–3.5) 0.11 (0.01–0.46)
2–3 yr 2 686.5 0.3 (0.0–1.1) 14 682.8 2.1 (1.1–3.4) 0.14 (0.02–0.62)
>3 yr 0 79.9 0.0 (0.0–4.6) 3 71.2 4.2 (0.9–12.3)0.00 (0.00–2.16)
Clinical events‡
Total 40 1661.9 2.4 (1.7–3.3) 65 1641.8 4.0 (3.1–5.0) 0.59 (0.40–0.88)
1 yr 29 831.0 3.5 (2.3–5.0) 39 832.6 4.7 (3.3–6.4) 0.75 (0.44–1.24)
2–3 yr 9 739.8 1.2 (0.6–2.3) 21 725.7 2.9 (1.8–4.4) 0.42 (0.17–0.96)
>3 yr 2 91.1 2.2 (0.3–7.9) 5 83.6 6.0 (1.9–14.0)0.37 (0.04–2.24)
Composite events§
Total 23 1700.1 1.4 (0.9–2.0) 79 1642.0 4.8 (3.8–6.0) 0.28 (0.18–0.45)
1 yr 13 843.7 1.5 (0.8–2.6) 47 833.9 5.6 (4.1–7.5) 0.27 (0.14–0.51)
2–3 yr 8 763.8 1.0 (0.5–2.1) 26 732.5 3.5 (2.3–5.2) 0.30 (0.12–0.67)
>3 yr 2 92.6 2.2 (0.3–7.8) 6 75.5 7.9 (2.9–17.3)0.27 (0.03–1.52)
* Hazard ratios were calculated with the use of unstratified univariate Cox regression analysis on an intention-to-trea
basis. Year-specific rate ratios were calculated on the basis of the person-year analysis. P<0.001 for the between-
comparison for linked transmission, P<0.001 for all transmission, P = 0.01 for clinical events, and P<0.001 for com
events, with all comparisons favoring early therapy.
† Any transmission includes all transmission events observed during follow-up, regardless of their linkage between p
‡ Clinical events include death, World Health Organization stage 4 events, severe bacterial infections, and pulmonar
culosis for index partners.
§ Composite events include death or World Health Organization stage 4 events (excluding esophageal candidiasis) f
the index partner or HIV transmission to the uninfected partner, whichever occurred earlier.
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Prevention of HIV-1 Infection
n engl j med 365;6nejm.org august 11, 2011 501
and a man was the source of the single transmis-
sion in the early-therapy group. Women were the
HIV-1–infected participant in 58% of African cou-
ples. A high viral load in blood plasma of infected
participants at baseline increased the risk of
HIV-1 transmission (Table 3). The median plas-
ma viral load in 27 participants at the visit most
proximal to the detection of HIV-1 transmission
was 4.9 log10 (range, 2.6 to 5.8). Conversely, self-
reported 100% condom use at baseline was associ-
ated with a reduced risk of HIV-1 transmission. In
the stratified multivariate analysis according to
Cumulative Probability
1.0
0.8
0.6
0.4
0.2
0.0
0 1 2 3 4 5
Years since Randomization
C DClinical Event
A Linked HIV Transmission
No. at Risk
Early
Delayed
893
882
658
655
298
297
79
80
31
26
24
22
0.3
0.2
0.1
0.0
0 1 2 3 4 5
Delayed
Early
Cumulative Probability
1.0
0.8
0.6
0.4
0.2
0.0
Years since Randomization
B Any HIV Transmission
No. at Risk
Early
Delayed
893
882
658
655
298
297
79
80
31
26
24
22
0.3
0.2
0.1
0.0
0 1 2 3 4 5
Delayed
Early
Cumulative Probability
1.0
0.8
0.6
0.4
0.2
0.0
Years since Randomization
No. at Risk
Early
Delayed
886
877
700
701
333
317
85
86
36
32
29
25
0.3
0.2
0.1
0.0
0 1 2 3 4 5
Delayed
Early
Cumulative Probability
1.0
0.8
0.6
0.4
0.2
0.0
Years since Randomization
Composite Event
No. at Risk
Early
Delayed
886
877
719
702
344
320
90
84
36
28
29
22
0.3
0.2
0.1
0.0
0 1 2 3 4 5
Delayed
Early
0 1 2 3 4 5
0 1 2 3 4 5 0 1 2 3 4 5
Figure 2. Kaplan–Meier Estimates for Partner-Linked and Any HIV-1 Transmission and for Clinical and Composi
Shown are Kaplan–Meier estimates for the cumulative probabilities of linked HIV-1 transmission between partners (Panel A),
transmission (Panel B), clinical events (Panel C), and composite monitoring events (Panel D) among participants in the early
and delayed-therapy groups.
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T h en e w e ngl a nd j o u r na lo f m e dic i n e
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site, the adjusted hazard ratio for linked transmis-
sion in the early-therapy group was 0.04 (95% CI,
0.01 to 0.28; P<0.001) (Table 3).
Primary Treatment Outcome
A total of 105 treatment end points, as measured
by the first serious HIV-1–related clinical event or
death, were observed in HIV-1–infected partici-
pants: 40 in the early-therapy group and 65 in the
delayed-therapy group (hazard ratio, 0.59; 95% CI,
0.40 to 0.88; P = 0.01 (Table 2, and the Supplemen-
tary Appendix). Of such clinical events, 44% oc-
curred in Asia and 45% in Africa. The baseline
plasma viral load was an important predictor of
clinical events, as assessed on multivariate analy-
sis (Table 3). In the stratified multivariate model,
the adjusted hazard ratio for clinical events in the
early-therapy group was 0.59 (95% CI, 0.40 to 0.89).
The difference in the rate of clinical events ap-
peared to be driven mainly by the incidence of
extrapulmonary tuberculosis, which developed
in 3 participants in the early-therapy group and
17 in the delayed-therapy group (P = 0.002); of these
cases, 55% were observed in India. Pulmonary tu-
berculosis was observed in 13 participants in the
early-therapy group and 15 in the delayed-therapy
group; isoniazid prophylaxis was administered
to only 4% of participants in each study group.
There were 23 deaths during the course of the
study, 10 in the early-therapy group and 13 in the
delayed-therapy group (hazard ratio, 0.77; 95% CI,
0.34 to 1.76; P = 0.27) (for details regarding causes
of death, see the Supplementary Appendix).
Composite Monitoring Events
Among 102 composite monitoring events, there
were 39 transmission events in which the sexual
partner acquired HIV-1. Among HIV-1–infected
participants, 21 died and 42 had WHO stage 4 clin-
ical events. Of these monitoring events, 58 (57%)
occurred in Africa, 31 (30%) in Asia, and 13 (13%)
in the Americas. Overall, 23 monitoring events
were observed in the early-therapy group and 79
in the delayed-therapy group (hazard ratio, 0.28;
95% CI, 0.18 to 0.45; P<0.001) (Table 2). Accord-
ing to the monitoring guidelines that were based
on the Lan–DeMets implementation of O’Brien–
Fleming boundaries, the computed z statistic was
4.43, which exceeded the prespecified cutoff of
3.93 and thus ruled out the hypothesis that early
Table 3. Hazard Ratios for Prognostic Factors for Partner-Linked and Any HIV-1 Transmission and for C
and Composite Events.*
Variable
Linked
Transmission
Any
Transmission
Clinical
Events
Composite
Events
hazard ratio (95% CI)
Univariate analysis
Early therapy vs. delayed therapy 0.04 (0.01–0.26)0.11 (0.04–0.32)0.60 (0.41–0.90)0.28 (0.18–0.45)
Baseline CD4 count (per 100 CD4
i ncrement)
1.27 (1.02–1.59)1.25 (1.02–1.52)0.84 (0.70–1.00)1.06 (0.91–1.24)
Baseline viral load (per unit log10
increment)
1.96 (1.17–3.27)1.66 (1.08–2.55)1.74 (1.32–2.30)1.51 (1.15–1.97)
Male sex vs. female sex 0.69 (0.31–1. 52)0.88 (0.45–1.71)1.61 (1.05–2.48)1.18 (0.78–1.78)
Baseline condom use (100% vs. <100%)0.35 (0.14–0.88)0.47 (0.19–1.14) NA 0.68 (0.29–1.60)
Multivariate analysis
Early therapy vs. delayed therapy 0.04 (0.01–0.28)0.11 (0.04–0.33)0.59 (0.40–0.89)0.28 (0.18–0.45)
Baseline CD4 count (per 100 CD4
increment)
1.24 (1.00–1.54)1.22 (1.02–1.47)0.90 (0.75–1.08)1.11 (0.96–1.28)
Baseline viral load (per unit log10
increment)
2.85 (1.51–5.41)2.13 (1.30–3.50)1.65 (1.24–2.20)1.60 (1.21–2.11)
Male sex vs. female sex 0.73 (0.33–1.65)1.00 (0.51–1.97)1.46 (0.95–2.26)1.18 (0.78–1.80)
Baseline condom use (100% vs. <100%)0.33 (0.12–0.91)0.41 (0.16–1.08) NA 0.64 (0.27–1.52)
* Hazard ratios were calculated with the use of univariate and multivariate Cox regression analysis, stratified accord
study site. The results are similar to those calculated with the use of unstratified Cox regression analysis, which are
shown. NA denotes not applicable.
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Prevention of HIV-1 Infection
n engl j med 365;6nejm.org august 11, 2011 503
therapy would provide at most a 20% reduction in
the risk of the composite monitoring end point.
Adverse Events
After the exclusion of primary clinical end points
(death, WHO stage 4 events, pulmonary tubercu-
losis, and severe bacterial infections), 246 HIV-1–
infected participants had one or more severe or
life-threatening adverse events (grade 3 or 4): 127
of 886 (14%) were in the early-therapy group and
119 of 877 (14%) were in the delayed-therapy
group (P = 0.64). The most frequently reported ad-
verse events included infections, psychiatric and
nervous system disorders, metabolism and nutri-
tion disorders, and gastrointestinal disorders (for
details, see the Supplementary Appendix). Grade
3 or 4 laboratory abnormalities during study fol-
low-up occurred in 242 participants (27%) in the
early-therapy group and 161 participants (18%)
in the delayed-therapy group (P<0.001). The most
frequent laboratory abnormalities included neutro-
penia, abnormal phosphate level, and total biliru-
bin elevations (with bilirubin elevations observed
primarily in participants taking atazanavir as part
of their drug regimen) (see the Supplementary
Appendix).
Discussion
In this study involving 1763 serodiscordant cou-
ples in which HIV-1–infected participants had a
CD4 count of 350 to 550 cells per cubic millime-
ter, there was a relative reduction of 96% in the
number of linked HIV-1 transmissions resulting
from the early initiation of antiretroviral therapy, as
compared with delayed therapy. There was a relative
reduction of 89% in the total number of HIV-1
transmissions resulting from the early initiation
of antiretroviral therapy, regardless of viral link-
age with the infected partner. The sustained sup-
pression of HIV-1 in genital secretions resulting
from antiretroviral therapy is the most likely mech-
anism for the prevention of HIV-1 transmission that
we observed.4,5
The majority of HIV-1 transmissions (82%) were
observed in Africa. This result reflects not only the
large number of study participants who were en-
rolled in this region (54%) but also other factors
that increase the probability of HIV-1 transmission
among African couples. Several groups have re-
ported higher viral loads in patients with HIV-1
infection in sub-Saharan Africa than in patients in
developed countries.22,23Clade C HIV-1, the domi-
nant type in southern Africa, may have other trans-
mission advantages as well.24 More frequent sexual
encounters and limited condom use would also
favor increased HIV transmission among African
couples, possibilities that are being evaluated.
Although HIV-1 transmission from patients
with acute and early HIV-1 infection and advanced
HIV-1 disease and the acquired immunodeficiency
syndrome (AIDS)25 appears to be most efficient,26
the results from this and other studies9 emphasize
that HIV-1 can be transmitted from infected per-
sons who are asymptomatic or minimally symp-
tomatic and who have high CD4 counts. Since
most persons with established HIV-1 infection fall
into the latter category, such transmission, albeit
not maximally efficient, must help fuel the spread
of HIV-1.
Early antiretroviral therapy was associated with
a relative reduction of 41% in the number of HIV-
1–related clinical events, which suggests a clinical
benefit for the initiation of antiretroviral therapy
when a person has a CD4 count of 350 to 550 cells
per cubic millimeter, as compared with therapy
that is delayed until the CD4 count falls into the
range of 200 to 250 cells per cubic millimeter. In
contrast to a recent trial15 comparing the effect of
the initiation of therapy in patients with a CD4
count ranging from 200 to 350 cells per cubic mil-
limeter with those with a count below 200 cells
per cubic millimeter, we did not detect a signifi-
cant between-group difference in overall mortality.
Despite our relatively short follow-up period, the
magnitude of the clinical effect we observed was
similar to that seen in observational studies con-
ducted in the developed world.16-18The difference
between the early-therapy group and the delayed-
therapy group was driven largely by the diagnosis
of extrapulmonary tuberculosis, with the majority
of these cases occurring in India. The use of iso-
niazid prophylaxis, although recommended by the
WHO for patients with HIV-1 infection,27 was in-
frequently prescribed for participants in this study.
In addition, data from observational studies fo-
cusing on HIV-1–related and non–HIV-1–related
clinical events and CD4 counts have led to the
hypothesis that delayed antiretroviral therapy could
ultimately lead to an increased rate of clinical
events, regardless of subsequent therapy.28 How-
ever, we cannot evaluate this possibility without a
longer period of follow-up.
We noted more adverse events in the early-
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T h en e w e ngl a nd j o u r na lo f m e dic i n e
n engl j med 365;6nejm.org august 11, 2011504
therapy group than in the delayed-therapy group,
including more adverse events related to antiretro-
viral therapy. The clinical importance of the labo-
ratory abnormalities that were responsible for this
difference is unclear. Further examination of these
data and additional longitudinal follow-up will be
important to better understand the clinical and
public health benefits of early antiretroviral ther-
apy, as compared with drug costs and side effects.
Our study has several limitations. In order to
examine the effects of antiretroviral therapy on
HIV-1 transmission, we studied stable HIV-1–dis-
cordant couples, who may not be entirely repre-
sentative of the general population.29 We provided
ongoing couples counseling and condoms, which
probably contributed to the low incidence of HIV-1
infection, as previously reported.30 Some partici-
pants received trimethoprim–sulfamethoxazole
and isoniazid prophylaxis at the discretion of the
investigators, which could have reduced the de-
gree of benefit observed with early antiretroviral
therapy.31
In conclusion, the biologic plausibility of the
use of antiretroviral therapy for the prevention
of HIV-1 infection has been carefully examined
during the past two decades.32 The idea of HIV-1
treatment as prevention has garnered tremendous
interest and hope33 and inspired a series of pop-
ulation-level HIV-1 treatment-as-prevention studies
that are now in the pilot or planning stages.34,35
Such interventions are based on the hypothesis
that the use of antiretroviral therapy reliably pre-
vents HIV-1 transmission over an extended peri-
od of time. In this trial, we found that early anti-
retroviral therapy had a clinical benefit for both
HIV-1–infected persons and their uninfected
sexual partners. These results support the use
of antiretroviral treatment as a part of a public
health strategy to reduce the spread of HIV-1
infection.
Supported by the HIV Prevention Trials Network (HPTN) and
by grants (UM1-AI068619 and U01-AI068619; UM1-AI068613
and U01-AI068613, to the HPTN Network Laboratory; and UM1-
AI068617 and U01-AI068617, to the HPTN Statistical and Data
Management Center) from the National Institute of Allergy and
Infectious Diseases. Study drugs were donated by Abbott Labo-
ratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sci-
ences, GlaxoSmithKline/ViiV Healthcare, and Merck.
Dr. Hosseinipour reports receiving lecture fees from Abbott
Virology; Dr. Eshleman, consulting fees from Roche Diagnostics,
lecture fees and samples or laboratory reagents from Abbott Diag-
nostics and Celera Diagnostics, and lecture fees from Monogram
Biosciences; Dr. Mills, grant support from GlaxoSmithKline; Dr.
de Bruyn, travel support from Sanofi Pasteur; Dr. Eron, consult-
ing fees and grant support from Merck, Bristol-Myers Squibb,
GlaxoSmithKline, and ViiV Healthcare, consulting fees from
Gilead Sciences and Tibotec, and lecture fees from Bristol-Myers
Squibb and Roche; Dr. Gallant, consulting fees from Abbott Lab-
oratories, Bristol-Myers Squibb, Gilead Sciences, Merck, Tibotec
Therapeutics, ViiV Healthcare, GlaxoSmithKline, Pfizer, Sangamo
BioSciences, and Koronis, grant support and travel support from
Gilead Sciences, and lecture fees from Monogram Biosciences;
Dr. Havlir, study drug from Abbott; and Dr. Swindells, consult-
ing fees from Gilead Sciences and Abbott Diagnostics and grant
support from Pfizer, GlaxoSmithKline,and Bristol-Myers
Squibb. No other potential conflict of interest relevant to this
article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Drs. Wafaa El-Sadr, Quarraisha Abdool Karim, and
Ward Cates for their help in the preparation of the manuscript.
Appendix
The authors’ affiliations are as follows: the University of North Carolina School of Medicine, Chapel Hill (M.S.C., M.C.H., I.F.H
the Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center (Y.Q.C., L.W.), and the University of
(T.R.F.) — both in Seattle; Family Health International, Arlington, VA (M.M.), and Durham, NC (T.G.); the UNC Project, Lilong
(M.C.H.) and the College of Medicine–Johns Hopkins Project, Blantyre (J.K.) — both in Malawi; the Y.R. Gaitonade Center for
Research and Education, Chennai (N.K.), and the National AIDS Research Institute, Pune (S.M., S.V.G.) — both in India; Univ
Zimbabwe, Harare (J.G.H.); Instituto de Pesquisa Clinica Evandro Chagas, Fiocruz (B.G.), and Hospital Geral de Nova Iguacu
Laboratorio de AIDS e Imunologia Molecular-IOC/Fiocruz (J.H.S.P.) — both in Rio de Janeiro; Research Institute for Health Sc
Chiang Mai University, Chiang Mai, Thailand (S.C.); Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil (B.R.S.); Fenw
(K.H.M.) and Harvard School of Public Health (H.R., M.E.) — both in Boston; Johns Hopkins University School of Medicine (S.
E.P.-M., J.G.) and Johns Hopkins Bloomberg School of Public Health (T.E.T., D.C.) — both in Baltimore; Botswana Harvard AID
stitute, Gaborone (J.M.); Centers for Disease Control and Prevention (CDC) Division of HIV/AIDS Prevention, Kenya Medical
Institute–CDC Research and Public Health Collaboration HIV Research Branch, Kisumu (L.A.M.); Perinatal HIV Research Unit
and Department of Medicine (I.S.), University of the Witwatersrand, Johannesburg; University of California, San Francisco, S
cisco (D.H.); University of Nebraska Medical Center, Omaha (S.S.); Division of AIDS, National Institute of Allergy and Infecti
eases, National Institutes of Health, Bethesda, MD (V.E., D.B.); and David Geffen UCLA School of Medicine, Los Angeles (K.N
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