Antiretrovirals to prevent HIV infection: Pre-and postexposure prophylaxis

Article (PDF Available)inCurrent Infectious Disease Reports 10(4):323-31 · August 2008with139 Reads
DOI: 10.1007/s11908-008-0052-5 · Source: PubMed
  • 32.76 · University of North Carolina at Chapel Hill
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Abstract
More than 3 million people are now receiving antiretroviral therapy (ART) worldwide. Currently, the indications for ART depend primarily on CD4 count, blood viral burden, and clinical signs and symptoms suggesting advanced HIV disease. However, interest is increasing in ART's preventive potential. Postexposure prophylaxis following both occupational and nonoccupational exposure to HIV is the standard-of-care in many settings. Observational and ecologic studies suggest that ART administered to HIV-infected people reduces transmission within serodiscordant couples. Pre-exposure prophylaxis to prevent HIV infection is a potentially safe and intermittent intervention for very high-risk people, and clinical trials to evaluate this preventive strategy are underway. The prevention benefits of ART may begin to affect the decision of when to start therapy and add a much-needed strategy to current HIV prevention efforts.
Antiretrovirals to Prevent HIV Infection:
Pre- and Postexposure Prophylaxis
Cynthia L. Gay, MD, MPH, and Myron S. Cohen, MD
Corresponding author
Cynthia L. Gay, MD, MPH
Division of Infectious Disease, University of North Carolina at
Chapel Hill, 130 Mason Farm Road, CB #7030, Chapel Hill, NC
27599, USA.
E-mail: Cynthia_gay@med.unc.edu
Current Infectious Disease Reports 2008, 10:323331
Current Medicine Group LLC ISSN 1523-3847
Copyright © 2008 by Current Medicine Group LLC
More than 3 million people are now receiving antiretro-
viral therapy (ART) worldwide. Currently, the indications
for ART depend primarily on CD4 count, blood viral
burden, and clinical signs and symptoms suggesting
advanced HIV disease. However, interest is increasing in
ARTs preventive potential. Postexposure prophylaxis fol-
lowing both occupational and nonoccupational exposure
to HIV is the standard-of-care in many settings. Observa-
tional and ecologic studies suggest that ART administered
to HIV-infected people reduces transmission within
serodiscordant couples. Pre-exposure prophylaxis to pre-
vent HIV infection is a potentially safe and intermittent
intervention for very high-risk people, and clinical trials
to evaluate this preventive strategy are underway. The
prevention benefits of ART may begin to affect the deci-
sion of when to start therapy and add a much-needed
strategy to current HIV prevention efforts.
Introduction
The public health impact of using antiretroviral therapy
(ART) has been largely ignored as a strategy for HIV pre-
vention. ART can be used to prevent HIV transmission
through three mechanisms: 1) reduction of HIV viral load
in individuals aware of their status; 2) postexposure pro-
phylaxis following risk exposures; and 3) as pre-exposure
prophylaxis with oral and/or topical microbicides. The
concept of using ART to decrease infectiousness in an
HIV-infected individual stems from the strong asso-
ciation between risk of HIV transmission by all exposure
routes and HIV viral levels in the blood [1–3]. The use of
postexposure prophylaxis following occupational expo-
sures is now the standard of care in many settings, and
accumulating evidence from large registries will further
inform this practice. Postexposure prophylaxis following
nonoccupational exposure and studies on its feasibility
and acceptability are expanding, as is the development of
guidelines for its use based on exposure risk. To date, ART
as pre-exposure prophylaxis to prevent HIV infection has
primarily been studied in animals, but human studies of its
safety and efcacy are ongoing.
Sexual Transmission of HIV
To date, a Ugandan study of serodiscordant couples
provides the strongest evidence for a direct correlation
between the probability of HIV sexual transmission and
increasing blood viral load [1]. This association was con-
rmed in subsequent studies of serodiscordant couples in
Zambia and Thailand [4,5]. In the Ugandan and Thailand
studies, no transmission events occurred when HIV RNA
was less than 1500 copies/mL [1] and 1094 copies/mL [5],
respectively. The association between peripheral HIV viral
load and sexual transmission likely reects the correlation
between HIV concentrations in blood and in genital [6]
and rectal [7] secretions. However, importantly, the cor-
relation between HIV concentrations in blood and genital
secretions is inconsistent, as demonstrated by signicantly
increased HIV shedding in the genital tract in the setting
of sexually transmitted diseases (STDs) [8,9].
The wider implementation of methods to detect acute
HIV infection (AHI) has led to several insights into viral
and transmission dynamics following HIV acquisition.
In a prospective study in Malawi, HIV shedding was
signicantly increased in semen during AHI, when very
high levels of virus are detected in blood [10]. HIV con-
centrations in semen peaked 4 weeks after infection and
were contained in most subjects at 10 weeks after infec-
tion [10]. Increased viral shedding in genital secretions
during AHI supports recent data, which suggest that
a signicant proportion of sexual HIV transmission is
driven by AHI [11•,12••]. In the Rakai study, nearly half
of HIV transmission events among discordant couples
occurred during early HIV infection [11•]. Similarly, a
retrospective study using cluster analysis of viral vari-
ants in HIV-infected patients in Montreal suggested
early infections accounted for approximately half of
transmissions over a 5-year period [12••].
324 Update on AIDS
Effects of ART on Infectiousness
The greatest potential public health benet of ART lies
in preventing transmission in serodiscordant couples,
reected in the substantial number of undiagnosed indi-
viduals in serodiscordant relationships detected through
massive household screening in Uganda [13•]. Evidence of
ART’s prevention benets can be found in retrospective
analysis, prospective observational studies, and ecologic
data. A retrospective study of 436 serodiscordant couples
found that the relative risk of HIV transmission from a
man to his female partner was lower in the 15% of men
who received zidovudine monotherapy for more advanced
disease (OR, 0.5; 95% CI, 0.1–0.9) [14]. Another retro-
spective study comparing HIV transmission events among
393 discordant couples in the pre-highly active ART
(HAART), early HAART, and post-HAART periods
reported an 80% reduction in HIV transmission events
following the introduction of triple drug therapy in the
infected partner (OR, 0.14; CI, 0.030.66) [15].
In an observational study in Zambia and Rwanda, index
partners in 248 of 1034 discordant couples initiated ART if
their CD4 cell count was less than 200 cells/mL [16•]. For
susceptible partners, the risk of acquiring HIV decreased
if their HIV-infected partner received ART (OR, 0.19;
95% CI, 0.050.8), even after adjustment for self-reported
condom usage (adjusted OR, 0.21; 95% CI, 0.050.8).
Similarly, a study in Uganda reported a 98% reduction
in the estimated risk of HIV transmission following ART
initiation: a decrease from 45.7 to 0.9 transmissions per
1000 person-years in 454 of 926 participants with 2 years
of follow-up [17••]. Findings from this study are somewhat
limited due to loss to follow-up and exclusion from analysis
of almost 50% of subjects. Importantly, only individu-
als with low CD4 counts or advanced HIV disease were
started on ART in these studies, whereas earlier initiation
of ART at higher CD4 counts, especially in people at risk
for transmitting HIV, could be implemented as a preven-
tion strategy. Notably, such observational studies are
susceptible to the effects of unexpected modiers and the
inability to determine long-term benet.
The variable ndings from ecologic analyses on the
preventive benet of ART likely reect the inability
of such studies to relate HIV-infected individuals on
ART to HIV incidence or prevalence and to correlate
HIV transmission with prevalence, because many HIV-
infected individuals remain undiagnosed, and those with
high viremia may account for a disproportionate number
of incident cases. In San Francisco, a 60% reduction in
expected HIV cases among men who have sex with men
(MSM) was attributed to increased ART availability
[18]. Following the introduction of free ART in Taiwan,
a 53% reduction in anticipated HIV cases was accred-
ited to increased access to ART [19]. In contrast, another
study among MSM in San Francisco found no decline
in incident HIV infections despite increased availability
of ART [20], and increased incident HIV was reported
among MSM in STD clinics in Amsterdam following
increased ART availability [21].
To better dene the ability of ART to prevent HIV
transmission, a randomized trial comparing two treatment
strategies to prevent sexual HIV transmission among 1750
serodiscordant couples over a 5-year period is underway
(www.hptn.org). HIV-infected partners with CD4 counts
between 350 and 550 cells/mm
3
are randomized to imme-
diate ART versus delayed ART until their CD4 counts fall
below 250 cells/mm
3
or they develop an AIDS-dening
illness. In addition to the impact of ART on HIV trans-
mission, the study will assess the safety, adherence, and
development of ART resistance in the study population.
ART for Postexposure Prophylaxis
Most data on the biologic plausibility of ART to prevent
HIV infection following exposure derive from the rhesus
macaque model using simian immunodeciency virus (SIV)
infection or SIV/HIV chimeric viruses (SHIV). Although
some SIV and SHIV macaque studies have suggested that
ART could prevent transmission, subsequent studies using
different inoculum doses, ART agents, and delay to ART
administration after exposure have been less promising [22].
In efforts to more closely simulate high-risk human sexual
exposures, the macaques model has recently used repeated
rectal inoculations with lower virus titers (3.8 × 10
5
viral
particle equivalents) [23•,24]. The most recent advance
in HIV animal models is the ability to infect bone mar-
row/liver/thymus humanized mice with HIV following one
intrarectal exposure [25], with subsequent CD4 depletion
in gut-associated lymphoid tissue and the development of
AIDS-associated pathology. This new murine model shows
great potential for advancing the study of HIV prevention
strategies, including pre-exposure prophylaxis [26].
Postexposure prophylaxis following occupational and
nonoccupational exposure
The use of postexposure prophylaxis following occupational
exposure to HIV, now considered standard of care in many
countries, is based on ndings from a single, small, retro-
spective case-control study of ART prophylaxis following
needlestick exposure among US healthcare workers [27].
Findings led to the widely adapted postexposure guidelines
by the US Centers for Diseases Control and Prevention
(CDC), which were updated in 2005 [28].
A randomized, controlled trial of ART prophylaxis
following nonoccupational HIV exposure is not feasible
due to the prohibitive cost of enrolling the large sample
size required to establish preventive benet, related to
the inefciency of sexual transmission per exposure.
Regardless, the use of ART prophylaxis following
nonoccupational exposure is expanding worldwide,
as reected by the creation of the European Project
on Non-Occupational Post-Exposure Prophylaxis for
HIV (EURO-NONPEP). In 2001, the group convened
Antiretrovirals to Prevent HIV Infection: Pre- and Postexposure Prophylaxis Gay and Cohen 325
representatives from 14 countries to establish unied
guidelines for postexposure prophylaxis and a registry
of potential nonoccupational exposures [29]. The regis-
try will permit the large-scale evaluation of the uptake,
safety, efcacy, and sustainability of nonoccupational
postexposure prophylaxis. The rst US guidelines
for nonoccupational postexposure prophylaxis were
published in 2005 [30]; they recommend a three-drug
regimen for 28 days following high-risk sexual exposure
to a known or suspected HIV-infected partner.
Clinical studies of nonoccupational
postexposure prophylaxis
Several feasibility studies of nonoccupational postex-
posure prophylaxis were reviewed recently [22]. The
studies suggest that nonoccupational postexposure
ART is acceptable given 64% to 100% completion
rates for a 28-day ART course; however, nonoccupa-
tional postexposure prophylaxis failures have been
described [22]. Seven seroconversions were reported
among 702 individuals who received two or three
drugs for 28 days with 12 weeks of follow-up [31].
Four of the seven seroconverters were considered
postexposure failures given self-reported 100% adher-
ence to their ART course, and failure was associated
with anal intercourse exposure and delayed initiation
of ART. Three seroconverters started treatment more
than 55.5 hours after exposure, albeit still within
the window for which postexposure ART is recom-
mended. Failures associated with delay to treatment
are particularly concerning, because even individuals
who perceive themselves at risk for HIV infection do
not start ART promptly [32]. Interestingly, none of the
seroconverters received three drug postexposure ART,
and although the study was not designed to compare
the efficacy of dual versus triple-drug postexposure
ART, the finding lends some support to CDC recom-
mendations for triple ART for high-risk exposures.
Antiretroviral selection for nonoccupational
postexposure prophylaxis
With or without data from a randomized clinical trial,
nonoccupational postexposure prophylaxis is increas-
ingly implemented to prevent HIV infection [33], and
the selection of ART agents must incorporate expand-
ing data on the pharmacology of specic agents, the cost
of treatment, the presence or likelihood of resistance
in source partners, and tolerability. For example, ART
for nonoccupational postexposure prophylaxis has been
associated with a sixfold higher rate of ART toxicity and
an eightfold higher rate of drug discontinuation, com-
pared with ART prescribed for treatment of HIV-infected
individuals [34]. Mathematical modeling analysis sug-
gested that two-drug postexposure ART may be more
efcacious than a triple-drug regimen due to equivalent
efcacy and higher completion rates [35]. However,
despite higher rates of side effects during nonoccupa-
tional postexposure prophylaxis, associated symptoms
are usually mild and reversible, and do not necessitate
treatment discontinuation. Reports of postexposure pro-
phylaxis discontinuation due to ART toxicities have been
published for occupational [36,37] and nonoccupational
[38,39] exposures; however, a study of nonoccupational
ART prophylaxis found no difference in discontinuation
rates when comparing a triple drug regimen including a
protease inhibitor to a dual nucleoside/tide reverse tran-
scriptase inhibitor regimen [38].
More recently, two case-controlled studies evaluated
the use of tenofovir in dual nonoccupational postexposure
regimens following high-risk sexual exposures. Forty-four
subjects received tenofovir disoproxil fumarate and lami-
vudine in one study, and 68 additional subjects received
the combination of tenofovir disoproxil fumarate and
emtricitabine in a second study. Both tenofovir-based dual
regimens were associated with higher completion rates of
a 28-day postexposure course compared with historical
controls taking two- or three-drug regimens containing
zidovudine (P < 0.0001) [40]. High dropout rates during
nonoccupational postexposure prophylaxis treatment
have been reported [41,42], particularly for postexposure
prophylaxis following sexual assaults [43].
ART Pharmacology in the Genital Tract
Because the risk of sexual HIV transmission corre-
lates with peripheral viral load, it seems logical that
ART—which predictably decreases HIV RNA in blood
to undetectable levels and decreases HIV concentrations
in seminal plasma [44], female genital tract secretions
[45], and rectal secretions [46]would decrease infec-
tiousness in those taking effective ART. Indeed, HIV-1
RNA levels in plasma and genital secretions declined
rapidly and in parallel following ART initiation with a
nonnucleoside reverse transcriptase inhibitor in a recent
study among Kenyan female sex workers [47••]. Nota-
bly, in half the subjects, HIV RNA remained detectable
in cervical and vaginal secretions after 28 days of treat-
ment, suggesting persistent infectiousness.
The pharmacology of ART in the genital tract suggests
that certain antiretroviral agents may be preferable for
the prevention of HIV following sexual exposure (Fig. 1)
[48,49••,50]. Previous data found that the genital tract
concentrations of most protease inhibitors are less than
10% of plasma levels, and the genital tract concentrations
of most nucleoside/tide analogue reverse transcriptase
inhibitors are two- to sixfold higher than in blood [22].
Two recent studies found that genital tract concentrations
of lamivudine, emtricitabine, zidovudine, tenofovir, and
maraviroc were higher than in blood plasma; lopinavir and
atazanavir achieved low to moderate concentrations in the
genital tract, and efavirenz concentrations were less than
1% of levels in blood [49••,51•].
326 Update on AIDS
A
Current Infectious Disease Reports IR10-4-3-01 fig. 1A
324 pts. W/ 312 pts. D (27 x 26)
Author: Cohen Editor: Theresa Artist: TE
FI
Genital
tract
exposures
blood
plasma
Genital tract
exposures =
blood plasma
Genital
tract
exposures
blood
plasma
Male genital tract
PI
3TC (600%)
TDF (500%)
ZDV (200%)
ABC (150%)
IDV (100%)
NVP (70%)
APV (20%)
LPV, NFV (5%)
RTV, SQV (3%)
EFV (3%)
d4T (2%)
ENF (ND)
NNRTI
500%
400%
300%
200%
100%
80%
60%
40%
20%
0%
600%
NRTI
Figure 1. Antiretroviral drug levels in the
male (A) and female (B) genital tracts relative
to blood plasma levels (ratio of genital to
blood plasma levels). 3TC—lamivudine;
ABC—abacavir; APV—amprenavir; ATV—
atazanavir; d4T—stavudine; ddI—didanosine;
DLV—delavirdine; EFV—efavirenz; EI—entry
inhibitor; ENF—enfuvirtide; FI—fusion
inhibitor; FTCemtricitabine; IDV—indinavir;
LPV—lopinavir, MRV—maraviroc, NFV—nel-
finavir; NNRTInonnucleoside reverse
transcriptase inhibitor; NRTI—nucleoside
reverse transcriptase inhibitor; NVP—nevirap-
ine; PI—protease inhibitor; RTV—ritonavir;
SQVsaquinavir; TDF—tenofovir; ZDV—zid-
ovudine. (Adapted from Cohen et al. [22] and
Dumond et al. [51].)
B
Current Infectious Disease Reports IR10-4-3-01 fig. 1B
324 pts. W/ 312 pts. D (27 x 26)
Author: Cohen Editor: Theresa Artist: TE
Genital
tract
exposures
blood
plasma
Genital tract
exposures =
blood plasma
Genital
tract
exposures
blood
plasma
Female genital tract
FTC (450%)
MRV (500%)
TDF, 3TC (400%)
ZDV (200%)
IDV (200%)
ddl (100%)
NVP (80%)
DLV (20%)
EFV (0.6%)
APV (50%)
LPV, ATV (30%)
RTV (20%)
SQV (ND)
ABC (40%)
d4T (4%)
500%
400%
300%
200%
100%
80%
60%
40%
20%
0%
600%
NRTI NNRTI PI EI
Antiretrovirals to Prevent HIV Infection: Pre- and Postexposure Prophylaxis Gay and Cohen 327
First-dose genital tract drug-exposure data are par-
ticularly relevant to pre- and postexposure ART, and
they are available for tenofovir in men [52] and for 12
antiretroviral agents in women [49••,52]. Many antiret-
rovirals are detected in genital secretions within 1 to 2
hours of the initial ART dose; abacavir, tenofovir, and
didanosine achieve higher genital tract concentrations
after a single dose than during steady-state conditions
[49••]. Most recently, maraviroc demonstrated the high-
est concentration in cervicovaginal secretions relative to
blood plasma compared with all currently available ART
agents within 8 hours of a single dose [51•], and shows
promise as an effective pre- or postexposure oral agent.
In sum, the available pharmacologic data suggest that
the prompt initiation of ART with some combination of
lamivudine or emtricitabine, zidovudine, tenofovir, mara-
viroc, and possibly lopinavir or atazanavir, would result
in their rapid accumulation in tissues exposed to HIV.
Efavirenz is a less attractive candidate for pre- or postex-
posure prophylaxis given poor penetration into the genital
compartment. Additional pharmacology data on other new
antiretrovirals including integrase inhibitors are expected.
Pre-Exposure ART Prophylaxis to Prevent
HIV Transmission
Animal models of pre-exposure prophylaxis
The strategy of preemptive ART as oral therapy or a topical
microbicide to prevent HIV infection derives from rhesus
macaques studies [53,54]. In a series of studies using the
rectal mucosal challenge model, oral tenofovir delayed
but did not prevent SHIV
SF162P3
in three of four macaques
after repeated exposures [55]. In a follow-up study using
a single high-dose intrarectal inoculum, two of ve teno-
fovir-treated macaques were protected [24]. High doses of
tenofovir combined with emtricitabine, both given once
daily subcutaneously, protected six of six macaques from
SHIV despite repeated rectal exposures [56]; however, it
should be noted that such ndings cannot be translated to
protection in humans given the supratherapeutic doses of
tenofovir. Furthermore, because ART was given daily, it
is unclear if ART given before exposure to SHIV actually
prevented infection or if ART given after exposure elimi-
nated early infection and halted seroconversion. Finally,
in the absence of autopsy evaluation, there is no proof
that the animals remained uninfected.
More applicable results were reported in a study using
intermittent dosing of ART before and after intrarectal
exposure. Subcutaneous emtricitabine, 20 mg/kg, given
with a supratherapeutic dose of tenofovir, 22 mg/kg, 2
hours before and 24 hours following intrarectal exposure
prevented infection in all six exposed macaques [23•]. This
approach more closely simulates true pre-exposure pro-
phylaxis than other models; however, it also incorporated
supratherapeutic doses of tenofovir with twofold higher
concentrations in the macaques compared with humans.
Pre-exposure clinical trials
The rst clinical trials of pre-exposure prophylaxis in HIV
uninfected individuals were abandoned following commu-
nity protests regarding trial design, the perceived lack of
community input, and the risk versus benet for the study
populations. In particular, objections arose regarding the
risk of resistance with the use of a single ART agent, based
on data from animal studies [55,57]. Mathematical model-
ing analysis of the Botswana tenofovir trial determined that
less than 1% of the anticipated 45 seroconverters among
600 participants would acquire or develop a tenofovir
resistance [58]. However, the preventive advantages of com-
bination tenofovir–emtricitabine in the rhesus macaques
model [56] resulted in a switch to combination tenofovir
and emtricitabine in some studies.
Clinical trials of either tenofovir or combination
tenofoviremtricitabine as oral pre-exposure prophylaxis
in HIV uninfected high-risk individuals are under way
in Botswana, Thailand, Peru, Ecuador, and the United
States [5961]. The only available data in humans come
from a safety trial of pre-exposure tenofovir in 936 high-
risk women in Ghana, Cameroon, and Nigeria. The study
reported no difference in adverse events or grade 3 or 4
laboratory abnormalities in subjects receiving tenofovir
versus those receiving placebo [62]. Fewer seroconver-
sions occurred in the tenofovir arm versus those receiving
placebo (2 vs 6); however, neither sample size nor study
duration were sufcient to determine efcacy. In addition,
no tenofovir resistance was detected in seroconverters.
Newspaper reports on the black market sale of anti-
retrovirals at clubs for self-administered use prior to
high-risk sex [63,64] indicate that individuals are using
ART as intermittent pre-exposure prophylaxis, even with-
out proof of efcacy. In addition, in 2004, 7% of attendees
at minority gay pride events in four cities reported prior
use of ART as pre-exposure prophylaxis [65].
Topical ART as pre-exposure prophylaxis
Trials of topical microbicides for the prevention of HIV
infection in women have been disappointing; however,
topical antiretroviral agents still hold promise for HIV
prevention. Tenofovir vaginal gel was well tolerated in
HIV-infected and uninfected women with twice daily
application [66•]. Although systemic low levels of tenofovir
were detected in some subjects, no mutations conferring
tenofovir resistance were detected in the HIV-infected
women with detectible plasma or cervicovaginal HIV RNA
[66•]. A recent study measured tenofovir concentrations
in cervicovaginal uid, vaginal tissue, and blood plasma
obtained over 24 hours following a single 4-mL dose of
1% tenofovir gel in 21 healthy female volunteers, with an
assay sensitivity of 1 ng/mL [67]. Tenofovir was detected
in the blood plasma of all subjects; concentrations in most
were less than 5 ng/mL, although concentrations up to
19.5 ng/mL were measured in 20% of subjects. After 24
hours, tenofovir levels in vaginal uid and tissue measured
328 Update on AIDS
up to 4.5 to 47.1 × 10
4
ng/mL and 15 × 10
3
ng/mL, respec-
tively, which is similar to concentrations protective in prior
macaques studies using subcutaneous dosing of tenofovir.
ART as a Public Health Measure for Prevention
The public health benet of ART for prevention will
depend on several factors: 1) the proportion of HIV-
infected individuals treated; 2) targeting ART to
those most likely to transmit HIV; 3) ART efcacy
in reducing viral load in the genital tract; 4) persis-
tent infectiousness of treated participants and the
emergence and transmission of drug-resistant strains;
and 5) behavioral disinhibition. Several mathematical
modeling studies suggest that ART could substantially
reduce HIV-associated mortality and transmission with
widespread implementation. However, the preventive
benet could be undermined if ART leads to behavioral
disinhibition [68–70]. A recent modeling analysis con-
cluded that pre-exposure prophylaxis could prevent 2.7
to 3.2 million new cases of HIV in sub-Saharan Africa
over 10 years if it is targeted to the highest risk groups,
and disinhibition could be prevented [71]. Notably, the
model assumed a 90% efcacy of ART to prevent HIV
transmission, and ART efcacy was the most important
determinant of preventive benet.
ART and Sexual Behaviors
Nonoccupational postexposure prophylaxis
Previous studies on the impact of nonoccupational
postexposure ART on sexual behavior have found low
rates of repeat postexposure requests and decreases in
self-reported high-risk sexual exposures. Almost half
of participants receiving nonoccupational postexposure
prophylaxis from a community-based program and
remaining on study at week 26 reported a decrease in
the number of sexual partners [72]. Despite widespread
availability of postexposure prophylaxis in all hospital
emergency departments and the Municipal Health Ser-
vice in Amsterdam, requests for postexposure following
sexual exposure increased very minimally between
2000 and 2004 [39].
In contrast, MSM in Australia who received nonoc-
cupational postexposure prophylaxis reported more
unprotected anal intercourse 1 year later than MSM who
had not received postexposure prophylaxis (50% vs 36%;
P = 0.009), and they were at increased risk for acquir-
ing HIV (incidence, 2.37 cases per 100 person-years; RR,
2.3; 95% CI, 1.05–5.06) [73]. Even more concerning,
21% of 89 subjects in another study reported unprotected
sex during their course of ART postexposure prophylaxis
[74]. A postexposure program in San Francisco found
that the addition of ve risk-reduction counseling sessions
decreased self-reporting of unprotected intercourse [75].
In another study evaluating attitudes toward postexposure
ART among MSM [76], subjects expressing future intent
to use postexposure prophylaxis were more likely to state
that ART could prevent HIV infection and that advances
in ART decreased their concern regarding unprotected
sex and acquiring HIV infection. Those intending to use
ART prophylaxis were also more likely to report high-risk
sexual behaviors and substance abuse.
In summary, most data from several prospective stud-
ies of postexposure prophylaxis after sexual exposure fail
to demonstrate an association between postexposure pro-
phylaxis and sexual disinhibition. Furthermore, reports
of repeat requests for nonoccupational postexposure
prophylaxis and subsequent high-risk behavior in stud-
ies of postexposure prophylaxis cannot be interpreted as
an increase or change in behavior, but may simply reect
ongoing pre-existing high-risk behaviors.
The only available data on the impact of pre-exposure
ART on sexual behavior comes from the pre-exposure study
of tenofovir in West Africa, in which the average condom
use increased from 52% at last coital act prior to screening
to 95% at 12 months (for coitus in the previous 7 days) [62].
However, reports of self-administered black market ART in
uninfected individuals prior to high-risk sex necessitate dia-
logue on whether pre-exposure prophylaxis could propagate
or lead to high-risk sexual behavior [6365].
Future Strategies for ART as Prevention
Given expanding data supporting the association between
incident HIV and sexual transmission from acutely infected
index partners [11,12••] and strong evidence that ART
decreases infectiousness [11], targeted ART for acutely
infected individuals could prevent a substantial number
of new infections in high-incident areas. No established
guidelines exist for ART initiation for treatment during
AHI due to an inability to demonstrate clinical benet;
however, the ability of ART to prevent ongoing transmis-
sion from acutely infected individuals has not been studied.
The preventive benet of providing ART to individuals
acutely infected with HIV clearly depends on the ability to
diagnose AHI, which currently depends on detecting HIV
RNA in seronegative individuals. Although this technology
is costly and currently unavailable in most resource-poor
settings, screening of HIV antibody–negative specimens
via HIV RNA pooling is feasible, less expensive than indi-
vidual HIV RNA testing, and effective in detecting AHI
[77,78]. Nevertheless, targeted testing for AHI in high-risk
settings, such as STD clinics in sub-Saharan Africa, could
decrease missed opportunities to diagnose HIV and prevent
ongoing transmission in those with high viremia.
The ongoing pre-exposure prophylaxis trials include daily
dosing of tenofovir or combination tenofovir–emtricitabine;
however, intermittent ART prior to unprotected or high-risk
sex represents a more practical and cost-effective strategy,
particularly in resource-poor settings. Accordingly, the Cen-
tre for the AIDS Programme of Research in South Africa
Antiretrovirals to Prevent HIV Infection: Pre- and Postexposure Prophylaxis Gay and Cohen 329
(CAPRISA) 004 trial is investigating the topical administra-
tion of tenofovir gel 12 hours before and 12 hours following
coitus. Additional studies using exposure-associated and/or
scheduled tenofovir–emtricitabine in macaques and the new
HIV-infected bone marrow/liver/thymus humanized murine
model are anticipated to further elucidate pre-exposure dos-
ing strategies. To date, studies of pre- and postexposure
prophylaxis in humans have focused on only one strategy,
whereas strategies combining oral and vaginal ART in high-
risk individuals may provide the greatest efcacy of ART
for prevention.
Conclusions
ART represents the most powerful available biologic inter-
vention for HIV prevention. As indicated in this review,
postexposure prophylaxis is widely accepted and topical
and systemic ART pre-exposure prophylaxis will almost
certainly be developed. Belief in the benets of ART for dis-
cordant couples is so strong that the Swiss Federation has
already released a supportive policy statement, although
this has been controversial [79]. We believe ART represents
the very best marriage of treatment and prevention, and
that this realization will continue to grow rapidly. Perhaps
most important, with increased attention, the public health
benets of ART can reach their full potential.
Acknowledgment
This work was supported by the University of North
Carolina Center for AIDS Research (P30HD-37260 and
R01AI041935). Dr. Gay has been supported by a US Cen-
ters for Disease Control and Prevention Association of
Teachers of Preventive Medicine Fellowship and National
Institutes of Health Training Grant (T32AI07151).
Disclosures
The authors have reported no potential conicts of interest relevant
to this article.
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    • "In silico elucidation of the inclusion phenomenon and permeation behavior of a zidovudine–cyclodextrin complex via static lattice atomistic simulation Pradeep Kumar @BULLET Yahya E. Choonara @BULLET Lisa C. du Toit @BULLET Viness Pillay Introduction Anti-retrovirals (ARVs), especially nucleoside analog reverse-transcriptase inhibitors (NRTI), are widely used in the pre-and post-exposure prophylaxis of HIV [1] . Zidovudine (AZT), alone or in combination with other ARVs, is one of the most widely used NRTI for the treatment and prevention of HIV preferentially for inhibiting and managing HIV transmission from mother-to-child in the case of pregnancy and delivery [2, 3]. "
    [Show abstract] [Hide abstract] ABSTRACT: This study explored the molecular arrangement of the drug molecule zidovudine (AZT) within an inclusion complex of β-cyclodextrin (βCD). The intrinsic mechanistic profiling of the AZT–βCD inclusion complex was investigated using molecular modeling and structurally designed docking studies via molecular mechanics Force-Field simulations. The energetically and geometrically optimized molecular conformations revealed that the AZT molecule was preferentially oriented toward the primary rim of the βCD cavity with the azido group positioned within the cyclodextrin ring. In the second phase of this study, the mechanism of AZT permeability across the transmucosal membrane after inclusion into βCD was elucidated via interaction between βCD and the transmucosal lipid, glycosylceramide (GLC). Interestingly, βCD formed H-bonds with the lipid head groups of GLC via the secondary rim. A systematic merge of these findings elucidated a novel “tunnel model” designated to the trimolecular complex: AZT-1°ring–βCD-2°ring–GLC. The energetic parameters, grid surface area, molecular volume, surface-to-volume-ratio, Log-P, refractivity, and polarizability were computed for the molecular complexes. Computationally, the Molecular Mechanics Assisted Model Building and Energy Refinements (AMBER) algorithm was used to develop a molecular mechanics energy relationship (MMER). The MMER elucidated the role of destabilized bond stretching, angle modification and torsional strain in ionic stabilization of the geometrical complexes through hydrophobic H-bonding and electrostatic interactions. These results provided a novel bonding and non-bonding correlation for the formation and performance of βCD in terms of its role in the prospective permeation modification of the AZT molecule through the transmucosal membrane with an optimum hydrophilic–lipophilic-permeation balance.
    Article · Apr 2014
    • "HIV viral load is the key determinant of viral transmission, as demonstrated clearly in observational studies of sexual transmission among HIV-discordant couples; in those studies, no transmission was seen when the index case had a plasma viral load below 1,000 copies HIV ribonucleic acid (RNA)/mL [25,26]. By reducing plasma viral load to undetectable levels (<50 copies HIV RNA/mL), it is assumed that ART will also suppress viral burden in the genital tract to levels at which transmission is unlikely to occur [27,28], although genital shedding of HIV can sometimes occur even when plasma viraemia is sup- pressed [29]. While vertical HIV transmission occurs via a different route, proof of concept is provided by trials of PMTCT, which have demonstrated that HIV transmission from mother to child before, during, or after delivery is largely prevented by ART101112. "
    [Show abstract] [Hide abstract] ABSTRACT: Effective interventions to reduce HIV incidence in sub-Saharan Africa are urgently needed. Mathematical modelling and the HIV Prevention Trials Network (HPTN) 052 trial results suggest that universal HIV testing combined with immediate antiretroviral treatment (ART) should substantially reduce incidence and may eliminate HIV as a public health problem. We describe the rationale and design of a trial to evaluate this hypothesis. A rigorously-designed trial of universal testing and treatment (UTT) interventions is needed because: i) it is unknown whether these interventions can be delivered to scale with adequate uptake; ii) there are many uncertainties in the models such that the population-level impact of these interventions is unknown; and ii) there are potential adverse effects including sexual risk disinhibition, HIV-related stigma, over-burdening of health systems, poor adherence, toxicity, and drug resistance.In the HPTN 071 (PopART) trial, 21 communities in Zambia and South Africa (total population 1.2 m) will be randomly allocated to three arms. Arm A will receive the full PopART combination HIV prevention package including annual home-based HIV testing, promotion of medical male circumcision for HIV-negative men, and offer of immediate ART for those testing HIV-positive; Arm B will receive the full package except that ART initiation will follow current national guidelines; Arm C will receive standard of care. A Population Cohort of 2,500 adults will be randomly selected in each community and followed for 3 years to measure the primary outcome of HIV incidence. Based on model projections, the trial will be well-powered to detect predicted effects on HIV incidence and secondary outcomes. Trial results, combined with modelling and cost data, will provide short-term and long-term estimates of cost-effectiveness of UTT interventions. Importantly, the three-arm design will enable assessment of how much could be achieved by optimal delivery of current policies and the costs and benefits of extending this to UTT.Trial registration: ClinicalTrials.gov NCT01900977.
    Full-text · Article · Feb 2014
    • "After this trial was launched, several [25– 28], but not all [29], individual-level observational studies reported a protective effect of ART against HIV transmission in serodiscordant couples. In addition, many modeling exercises suggested varying degreesofpopulation-levelpreventionbenefitfrombroaderuseofART [30], the most widely discussed of which predicted elimination of HIV withinfiveyearsunderidealconditions[31].Thesemodelsarediscussed in a review by Eaton et al. [32] in the July 2012 PLoS Medicine Collection, ''Investigating the Impact of Treatment on New HIV Infections.'' A third group of eight ecological studies examined the population-level effectsofwidespreadARTonHIVincidenceusingecologicalmeasures, and reported significant effects333435363738 in all but two cases [39,40]. "
    [Show abstract] [Hide abstract] ABSTRACT: Results from several observational studies of HIV-discordant couples and a randomized controlled trial (HIV Prevention Trials Network 052) show that antiretroviral therapy (ART) can greatly reduce heterosexual HIV transmission in stable HIV-discordant couples. However, such data do not prove that ART will reduce HIV incidence at the population level. Observational investigations using ecological measures have been used to support the implementation of HIV treatment for the specific purpose of preventing transmission at the population level. Many of these studies note ecological associations between measures of increased ART uptake and decreased HIV transmission. Given the urgency of implementing HIV prevention measures, ecological studies must de facto be used to inform current strategies. However, the hypothesis that widespread ART can eliminate HIV infection may have raised expectations beyond what we may be able to achieve. Here we review and discuss the construct of the exposure and outcome measures and analysis methods used in ecological studies. By examining the strengths and weaknesses of ecological analyses, we aim to aid understanding of the findings from these studies to inform future policy decisions regarding the use of ART for HIV prevention.
    Full-text · Article · Jul 2012
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