Prevention of HIV-1 Infection with

Early Antiretroviral Therapy

(HPTN 052)

Patrick Leonard G. Co, MD

Infectious Diseases Journal Club
 Objectives
To briefly outline the currently available
interventions for interrupting transmission of
HIV infection
To discuss the findings of the HPTN 052 study
To analyze the implications of this study for
future strategies in HIV prevention
 The Scope and Extent of the HIV
Pandemic (as of the end of 2009)
People living with HIV/AIDS: 33.3 M
Adults newly infected with HIV in 2009: 2.2 M
In South and South-East Asia:
Adults & children living with HIV/AIDS: 4.1 M
Adults & children newly infected: 270,000
Adult prevalence rate: 0.3%
AIDS-related deaths in adults & children: 260,000

UNAIDS (2010): UNAIDS report on the global AIDS epidemic

 Proven HIV Prevention Strategies
UNAIDS & WHO: Expanded access to proven
prevention strategies could prevent 50% of
the 62 million new HIV infections projected to
occur between 2005 and 2015
There is no single solutionno magic
bulletto prevent HIV.
The most effective prevention programs are
those that use a combination of strategies to
achieve maximum impact

Fact Sheet: The Global HIV Prevention Working Group

 Proven HIV Prevention
Strategies
Preventing Sexual Transmission
Preventing Blood-borne Transmission
Preventing Mother-to-Child Transmission
 Preventing Sexual Transmission
Implement Behavioral Change Programs
Promote Effective Usage of Condoms
Encourage and Facilitate HIV Testing of
Individuals at High-Risk for HIV Infection
Ensure Early Diagnosis and Offer Effective
Treatment for Other STDs
 Behavioral Change Programs
Practice Safe Sex
Need to provide people with comprehensive
information on reducing HIV risk
Effective among high-risk groups
Remaining sexually abstinent or delaying initiation
of sexual activity
Decreasing the number of sexual partners
Using condoms consistently and correctly if
sexually active

Fact Sheet: The Global HIV Prevention Working Group

 Condom Use
Consistent use of condoms can reduce an
individuals risk of HIV transmission by 85%
Also effective at preventing other STDs, such
as syphilis and gonorrhea, that have been
linked to increased risk for HIV acquisition and
transmission

U.S. National Institute of Allergy and Infectious Diseases,

Scientific Evidence on Condom Effectiveness for Sexually
Transmitted Disease Prevention, 2001.
 Encourage HIV Testing
Fewer than 1% of adults in developing
countries had access to HIV testing in 2005
People who know their HIV status are more
likely to protect themselves and others from
infection

Fact Sheet: The Global HIV Prevention Working Group

 Prompt Diagnosis and Treatment of
Other STDs
Co-infection with other Control efforts should
STDs increases the risk be initiated as early as
of HIV acquisition and possible in the course of
transmission by at least a countrys epidemic
2-5x Should be targeted
Promptly detecting and toward people at
treating STDs can help highest risk2
reduce HIV risk by up to
38%1
1. H. Grosskurth et al., Impact of improved treatment of sexually transmitted diseases
on hiv infection in rural Tanzania: randomized controlled trial, Lancet 1995;346:530-6.
2. Garnett G et al., Strategies for limiting the spread of HIV in developing countries: conclusions
based on studies of the transmission dynamics of the virus, J Acquir Immune Defic Syndr Hum
Retrovirol 1995;9:500-13.
 Issues to be addressed in Designing
HIV Containment Strategies
Health Education: must increase public
awareness of HIV through information
dissemination
Logistical: cost of any potential interventions
Political: government/NGO support needed
Socio-Cultural: continuing stigma attached to
HIV infection reluctance of pxs to be tested
Religious: opposition of religious sectors to
certain interventions (e.g. Condoms)
ART for Prevention of HIV-1 Infection?
ART reduces the amount of HIV-1 in blood and
genital secretions.
Sexual transmission of HIV-1 from infected
persons to their partners is strongly correlated
with concentrations of HIV-1 in blood and in
the genital tract.
Hypothesis: Can ART reduce sexual
transmission of HIV-1?
Graham SM, Holte SE, Peshu NM, et al. Initiation of antiretroviral therapy leads to a rapid
decline in cervical and vaginal HIV-1 shedding. AIDS 2007;21:501-7.
Baeten JM, Kahle E, Lingappa JR, et al. Genital HIV-1 RNA predicts risk of
heterosexual HIV-1 transmission. Sci Transl Med 2011;3:77ra29.
 Non-RCT studies showing benefit of
ART in preventing transmission of HIV
Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-
1 transmission after initiation of antiretroviral therapy:
a prospective cohort analysis. Lancet 2010;375: 2092-8.
Del Romero J, Castilla J, Hernando V, Rodriguez C,
Garcia S. Combined antiretroviral treatment and
heterosexual transmission of HIV-1: cross sectional and
prospective cohort study. BMJ 2010;340:c2205.
Reynolds SJ, Makumbi F, Nakigozi G, et al. HIV-1
transmission among HIV-1 discordant couples before
and after the introduction of antiretroviral therapy.
AIDS 2011;25:473-7.
 When is the best time to give ART?
Effect of timing of ART on clinical and
microbiologic outcomes still controversial
Many associated complications
High cost of treatment
Retrospective analyses of HIV-1 infected pxs:
Early (350-500 cells/mm3 ) vs. delayed (<200
cells/mm3) ART may be beneficial
Sterne JA, May M, Costagliola D, et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a
collaborative analysis of 18 HIV cohort studies. Lancet 2009;373:1352-63.
Cain LE, Logan R, Robins JM, et al. When to initiate combined ART to reduce mortality and AIDS-defining illness in HIV-
infected persons in developed countries: an observational study. Ann Intern Med 2011;154:509-15.
 Prevention of HIV-1 Infection
with Early Antiretroviral Therapy
Cohen MS, Chen YQ, McCauley M, et al.
N Engl J Med 2011; 365:493-505.
 Clinical Questions
Among HIV-1 serodiscordant couples, does
early initiation of ART decrease transmission
of HIV infection to the uninfected partner
compared with delayed treatment?
Does early initiation of ART decrease the
incidence of clinical events in the HIV-positive
partner compared with delayed treatment?
 Was the assignment of patients to
treatments randomized?
YES (p. 494, under Methods: Study Design)
HIV-1 serodiscordant couples were randomly
assigned in a 1:1 ratio to either an early or
delayed strategy for receipt of antiretroviral
therapy.
Permuted-block randomization was used with
stratification according to site.
 HPTN 052 Study Design
Stable, healthy, serodiscordant couples, sexually active
CD4 count: 350 to 550 cells/mm3

Randomization

Immediate ART Delayed ART

CD4 350-550 CD4 <250

Primary Transmission Endpoint

Virologically-linked HIV-1 transmission events

Primary Clinical Endpoints

WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial
infection and/or death
Inclusion Criteria
Exclusion Criteria
 HPTN 052 Enrollment

10,838 Individuals Screened

Major reasons for exclusion:
3058 HIV+ but CD4 count out of range
2565 HIV- but HIV+ partner ineligible
308 Seroconcordant couples
155 Ineligible due to sexual history

1763 Couples
(3526 Individuals)
Randomized

Immediate Arm Delayed Arm

886 Couples 877 Couples
 HPTN 052 Enrollment
(Total Enrollment: 1763 couples)

U.S.

Thailand
Americas India
278 Kenya

Malawi Asia
Brazil
Zimbabwe 531
Botswana
South Africa Africa
954
 HPTN 052 Enrollment
Region Site Couples
Porto Alegre, Brazil 90
Americas
Rio de Janeiro, Brazil 186
(278)
Boston, United States 2
Chennai, India 250
Asia
Pune, India 175
(531)
Chiang Mai, Thailand 106
Gaborone, Botswana 77
Kisumu, Kenya 60
Blantyre, Malawi 230
Africa
Lilongwe, Malawi 251
(954)
Johannesburg, South Africa 46
Soweto, South Africa 50
Harare, Zimbabwe 240

Total 1763
Were all patients who entered the
trial accounted for? Were they
analyzed in the groups to which
they were randomized?
YES (p. 497 [Figure 1] under Results:
Study Participants)
Enrollment and Outcomes
Enrollment and Outcomes
Were the groups similar at the
start of the trial?
YES (p. 496 and Table 1, under
Results: Study Participants)
 HPTN 052: Baseline Characteristics

Index Partner
Immediate Delayed Immediate Delayed
N = 886 N = 877 N = 893 N = 882
Female 49% 50% 49% 47%
Age (median) 33 32 32 32
Married 94% 95% 93% 94%
Any unprotected sex 6% 8% 8% 8%
442 428
CD4 (median [IQR]) --- ---
[373-522] [357-522]
HIV RNA log10 4.4 4.4
--- ---
(median [IQR]) [3.8-4.9] [3.9-4.9]
 HPTN 052: Baseline Characteristics

Index Partner
Immediate Delayed Immediate Delayed
N = 886 N = 877 N = 893 N = 882
Female 49% 50% 49% 47%
Age (median) 33 32 32 32
Married 94% 95% 93% 94%
Any unprotected sex 6% 8% 8% 8%
442 428
CD4 (median [IQR]) --- ---
[373-522] [357-522]
HIV RNA log10 4.4 4.4
--- ---
(median [IQR]) [3.8-4.9] [3.9-4.9]
Aside from the allocated treatment,
were groups treated equally?
YES (pp. 494-5 under Methods:
Study Design)
 ART Regimens Used
Combination of Didanosine
lamivudine and Stavudine
zidovudine (Combivir) Combination of
Efavirenz lopinavir and ritonavir
Atazanavir (Kaletra and Aluvia)
Nevirapine Ritonavir
Tenofovir Combination of
Lamivudine emtricitabine and
Zidovudine tenofovir (Truvada)
 Follow-up visits
All participants: Three monthly visits, followed
by quarterly visits unless they became ill or
needed additional antiretroviral medications.
HIV-1uninfected partners: encouraged to
return for all visits together for counseling on
risk reduction and the use of condoms, for
treatment of STDs, and for management of
other medical conditions.
 Counseling and testing for
seroconversion
At each visit: Assessment for clinical signs and
symptoms, laboratory measurements,
interviews about sexual behavior, review of
adherence to ART, and adherence counseling
HIV-1uninfected partners were tested for
HIV-1 seroconversion on a quarterly basis.
What were the results?
 Results
Enrollment took place from June 2007 through
May 2010 and was scheduled to run until
2015.
On April 28, 2011, the data and safety
monitoring board recommended that the
results of the study be released on the basis of
data collection through February 21, 2011.
HPTN 052: HIV-1 Transmission

Total HIV-1 Transmission Events: 39

Early Arm = 4 Delayed Arm = 35

(n=893) (n=882)

p < 0.0001
 HPTN 052: HIV-1 Transmission

Total HIV-1 Transmission Events: 39

Linked Transmissions: Unlinked or TBD

28 Transmissions: 11

18/28 (64%) transmissions from infected

participants with CD4 >350 cells/mm3
Delayed Arm:
Early Arm: 1 23/28 (82%) transmissions in sub-Saharan Africa
27
18/28 (64%) transmissions from female to male
partners
p < 0.001
 100 Early ART Effectively Suppresses VL
Proportion of participants with VL<400 at each visit

Immediate Arm
80

Delayed Arm (not on ART)

Delayed Arm (on ART)
60
40
20
0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Months
 HIV Transmission: CD4 Count and HIV-1 RNA

28 Linked Transmissions

HIV RNA (log10 copies/mm3)

CD4+ (cells/mm3)

Immediate Delayed Immediate Delayed

(1) (27) (1) (27)

Median proximal CD4 (range): 400 (229-858) Median proximal log10 VL (range): 4.9 (2.6-5.8)
Immediate arm: 584 (584-584) Immediate arm: 2.6 (2.6-2.6)
Delayed arm: 391 (229-858) Delayed arm: 4.9 (2.6-5.8)
 One Transmission Event on Early ART

Index begins ART

AZT/3TC/EFV Index VL<400 Partner HIV+ (WB)

Enrollment
Screening

Days -14 0 1 28 85

Partner VL < 400 Transmission: probably occurred >84 days

Index CD4 = 482
Index VL = 87,202
earlier (before ART could suppress genital
tract HIV)
Multivariate Analysis of Linked Transmission Events

Variable Hazard Ratio 95% Confidence Interval

Treatment
(immediate vs. delayed)
0.04 [0.01 - 0.28]

Baseline CD4
(per 100 CD4 Increment)
1.24 [1.00 - 1.54]

Baseline Viral load

(per unit log increment)
2.85 [1.51 - 5.41]

Baseline condom use

(100% vs. <100%)
0.33 [0.12 - 0.91]
 Efficacy of Early ART in Preventing
Partner-Linked HIV-1 Transmission
Relative Risk Relative Risk Absolute Risk Number
(RR or Hazard Reduction Reduction Needed to
Ratio) (RRR) (ARR) Treat
95% CI (NNT)
p-value
Risktx / 1-RR Riskcontrol 1/ARR
Riskcontrol Risktx

0.04 0.96 0.03 34 <0.001

(0.01-0.27)
 Efficacy of Early ART in Preventing Any
HIV-1 Transmission*
Relative Risk Relative Risk Absolute Risk Number
(RR or Hazard Reduction Reduction Needed to
Ratio) (RRR) (ARR) Treat
95% CI (NNT)
p-value
Risktx / 1-RR Riskcontrol 1/ARR
Riskcontrol Risktx

0.11 0.89 0.04 28 <0.001

(0.04-0.32)
*Any transmission includes all transmission events observed during follow-up,
regardless of their linkage between partners.
Efficacy of Early ART in Preventing Clinical
Events*
Relative Risk Relative Risk Absolute Risk Number
(RR or Hazard Reduction Reduction Needed to
Ratio) (RRR) (ARR) Treat
95% CI (NNT)
p-value
Risktx / 1-RR Riskcontrol 1/ARR
Riskcontrol Risktx

0.59 0.41 0.38 3 0.01

(0.40-0.88)
*Clinical events include death, World Health Organization stage 4 events,
severe bacterial infections, and pulmonary tuberculosis for index partners.
 Efficacy of Early ART in Preventing
Composite Events*
Relative Risk Relative Risk Absolute Risk Number
(RR or Hazard Reduction Reduction Needed to
Ratio) (RRR) (ARR) Treat
95% CI (NNT)
p-value
Risktx / 1-RR Riskcontrol 1/ARR
Riskcontrol Risktx

0.28 0.72 0.06 16 <0.001

(0.18-0.45)
*Composite events include 1) death, 2) WHO stage 4 events (excluding
esophageal candidiasis) for the index partner, or 3) HIV transmission to the
uninfected partner, whichever occurred earlier.
 Adverse Events
(Excluding Primary Endpoints)
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).
Most frequently reported AEs: infections,
psychiatric and nervous system disorders,
metabolism and nutrition disorders, and
gastrointestinal disorders.
 Laboratory Abnormalities
Seen in 242 participants (27%) in the early-
therapy group and 161 participants (18%) in
the delayed-therapy group (P<0.001)
Most frequent laboratory abnormalities:
neutropenia, abnormal phosphate level, and
total bilirubin elevations (esp. w/ atazanavir)
Clinical significance is unclear; longer follow-
up required
Applicability of Results to the
Local Setting
Is the study population comparable to the
local population?
Problem: Most pxs in HPTN 052 were involved
in a stable, monogamous, heterosexual
relationship, but in the Philippines, HIV is
currently predominantly a disease of high-risk
groups, particularly MSM who usually have
multiple sexual partners.
Response: It is difficult to extrapolate the
results of HPTN 052 to our local setting;
similar local studies will be needed.
 Is the treatment regimen feasible in
the local setting?
Problem: Although the price of ART for low-
and middle-income countries has continued to
fall (around P3000/yr), this is still beyond the
means of many pxs
ART coverage is also suboptimal (around 50%)
Response: Substantial support from NGOs will
be needed to finance and implement such a
program if local studies confirm the efficacy of
ART for prevention of HIV transmission.
WHO/GPRM - Global Price Reporting Mechanism (2010,
May): Transaction prices for Antiretroviral Medicines and
HIV Diagnostics from 2008 to March 2010
 Will the potential benefits of treatment
outweigh its potential harm?
Problem: There have been few studies showing
significant clinical and virologic benefits for
initiating ART at a CD4 count of >350-500
cells/mm3, as was done in this study. On the
other hand, the potential adverse events
associated with ART are well-documented.
Response: Again, more data from local studies
will be needed before any definitive
recommendation for giving ART to prevent HIV
transmission in our country can be made.
 Learning Points
90% of patients in the immediate-ART group
achieved VL <400 copies/mL within the first year
of follow-up.
Overall, only one patient on ART transmitted HIV
to his partner, compared with 27 transmissions
from persons who were not on ART (96%
reduction in transmission risk)
Multivariate analysis: high baseline VL was a
strong predictor of transmission (hazard ratio,
2.8); consistent condom use at baseline was
highly protective (HR, 0.33)
 Learning Points
Early ART also significantly reduced the risk for clinical
illness, both overall and most notably with respect to
extrapulmonary tuberculosis (3 vs. 17 cases).
Early initiation of ART prevents HIV transmission more
effectively than any other tested intervention, while
also clearly providing personal benefit to the patients
being treated.
These data provide a convincing rationale for changing
HIV treatment guidelines to recommend earlier
initiation of ART worldwide and for making the
commitment to follow through with adequate funding.
2011 Breakthrough of the Year
The HPTN 052 study
convincingly demonstrated
that antiretroviral
medications can not only
treat but also prevent the
transmission of HIV infection
among heterosexual
individuals.
Anthony S. Fauci, M.D.
Director, NIAID
Thank you!