HIV-1 treatment as prevention: the good, the bad, and the
challenges
Kumi Smith
a
, Kimberly A. Powers
a,b
, Angela D.M. Kashuba
c
, and Myron S. Cohen
a,b,d
a
Department of Epidemiology, University of North Carolina
b
Department of Medicine, University of North Carolina
c
Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
d
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North
Carolina, USA
Abstract
Purpose of review—This work focuses on the use of antiretroviral agents to prevent the sexual
transmission of HIV-1.
Recent findings—Two randomized clinical trials demonstrated that antiretroviral agents
provided before exposure to HIV-1 offer substantial protection, ostensibly directly proportional to
the concentration of antiretroviral therapy (ART) in the genital secretions. Intense focus on the use
of HIV treatment as prevention has led to publication of modeling exercises, ecological studies,
and observational studies, most of which support the potential benefits of ART. However, the
logistical requirements for successful use of ART for prevention are considerable.
Summary—ART will serve as a cornerstone of combination prevention of HIV-1. Continued
research will be essential to measure anticipated benefits and to detect implementation barriers and
untoward consequences of such a program, especially increases in primary ART resistance.
Keywords
antiretroviral therapy; pre-exposure prophylaxis; prevention
Introduction
Literally days after the activity of the first antiretroviral agent, azidothymidine (AZT), was
announced, investigators began to explore the idea of treatment as prevention [1]. The
promise of this approach is based on the idea that treatment of HIV index cases with
antiretroviral therapy (ART) will reduce their viral loads and render them less infectious to
their sexual partners. Several obvious challenges to this approach soon surfaced: would the
preventive potential of AZT and other drugs be limited by low concentrations in the genital
tract or by the development of drug resistance?
This article offers both a historical perspective and a more in-depth, contemporaneous view
of the role of HIV-1 treatment as part of secondary HIV prevention. Current evidence
suggests that this strategy holds great promise, but considerable research efforts will be
© 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
Correspondence to Myron S. Cohen, MD, University of North Carolina at Chapel Hill, CB# 7030, 130 Mason Farm Road, 2115
Bioinformatics Building, Chapel Hill, NC 27599-7030, USA, Tel: +1 919 966 2536; mscohen@med.unc.edu.
NIH Public Access
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Curr Opin HIV AIDS
. 2011 July ; 6(4): 315–325. doi:10.1097/COH.0b013e32834788e7.
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required to employ the right antiretroviral agents at the right times – and perhaps to just the
right people – to ensure maximal benefit both for individual ‘couples’ and at the population
level.
The clinical pharmacology of HIV prevention
Two studies published in 2010 demonstrate the ability of ART to prevent HIV acquisition.
In the Center for the AIDS Program of Research in South Africa (CAPRISA) 004 study,
women at risk of acquiring HIV were randomly assigned to receive either a tenofovir (TFV)
containing vaginal gel or a placebo using coitally dependent dosing [2•]. In the Pre-
Exposure Prophylaxis Initiative (iPREX) study, at-risk MSM were randomly assigned to
receive either a tablet containing tenofovir disoproxil fumarate (TDF) with emtricitabine
(TDF + FTC) or placebo dosed daily [3•]. In both trials, rates of HIV acquisition were lower
in those receiving the antiretrovirals. In CAPRISA 004, an inverse relationship was noted
between drug exposure in the vaginal lumen and risk of infection. As the CAPRISA 004
study measured drug exposure at the site of infection, and as the half-life of topically applied
TFV in the genital tract is more than 2 days, these investigators are conducting subsequent
analyses to determine whether critical exposures for protection of mucosal tissue in the
genital tract can be identified. As iPREX study only measured plasma drug exposure, it is
less likely that concentration surrogates can be estimated for rectal mucosal protection from
these data. However, both types of concentration measures may be used as surrogates for
adherence behavior, which is critical to the success of prevention interventions [4].
For treatment of the index case, the relative ability of different antiviral agents to penetrate
mucosal surfaces at the site of transmission is critical for full suppression of HIV replication
[5,6]. Drugs both within and between therapeutic classes of antiretrovirals have different
potential to concentrate in male and female genital tract secretions and in rectal tissue (Table
1) [5].
The female genital tract
The female genital tract exposure to 20 antiretrovirals has been studied in cervicovaginal
fluid. Although the female genital tract contains upper and lower compartments, analyzing
this fluid (a combination of cervical mucus and vaginal fluid) is a noninvasive approach to
understanding genital tract pharmacology. As can be seen in Table 1, there is significant
variability in drug exposure both within and between antiretroviral classes. To date, no
physicochemical properties accurately predict drug penetration into cervicovaginal fluid. Of
the nucleoside/ tide analog reverse transcriptase inhibitors (NRTIs), TDF zidovudine (ZDV),
FTC, and lamivudine (3TC) achieve concentrations of approximately 100–400% higher than
that of blood plasma. Of the non-NRTIs (NNRTIs), only etravirine (ETR) demonstrates
concentrations similar to, or higher than, that of blood plasma. For the protease inhibitors,
indinavir (IDV) and darunavir (DRV) penetrate cervicovaginal fluid at exposures of
approximately 150–200% higher than that of blood plasma. Finally, both drugs in the latest
Food and Drug Administration (FDA)-approved therapeutic classes of antiretrovirals
(coreceptor antagonists and integrase inhibitors) concentrate in cervicovaginal fluid:
raltegravir (RAL) exposure is approximately 200% higher than that of blood plasma, and
maraviroc (MVC) exposure is approximately 400% higher than that of blood plasma.
Investigators also measured the protein binding of MVC in cervicovaginal fluid and
determined that it had 10-fold less protein binding than in plasma (7.5 versus 75%) [7]. As
less protein binding results in more amount of drug available for antiviral activity, this
phenomenon must be considered in pharmacokinetic-pharmacodynamic analysis of
antiretroviral prevention strategies.
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Finally, tissue concentrations of TFV, FTC, and MVC have been measured in the vagina and
cervix [7,8]. Exposures for all of these drugs fall between those concentrations measured in
blood plasma and those in cervicovaginal fluid. This information creates insight into drug
distribution in the genital tract and demonstrates that noninvasive sampling of
cervicovaginal fluid may be a reasonable surrogate for these concentrations, which can only
be measured through invasive sampling methods.
The male genital tract
Although the male genital tract contains a number of subcompartments (testes, prostate, and
seminal vesicles), drug concentrations are typically measured in seminal plasma as an
overall marker of drug exposure. Data generated, to date, reveal that drug binding to plasma
proteins dictates drug exposure in semen: lower semen concentrations are found with drugs
that have higher protein binding [5].
NRTIs, which are generally less than 50% protein bound, achieve exposures in semen
ranging from approximately 100 to 600% of those observed in blood plasma [6]. However,
these drugs must be phosphorylated intracellularly in order to be active. After oral
administration of TDF, intracellular mononuclear tenofovir diphosphate (TFV-DP)
concentrations in the semen are at least 800% higher than that in peripheral blood
mononuclear cells [9]. This increased extracellular-intracellular relationship in semen does
not hold for the two other nucleosides investigated to date: ZDV and 3TC. Despite four-fold
to six-fold higher concentrations in seminal plasma, intracellular mononuclear cell
concentrations of ZDV triphosphate (ZDV-TP) in semen are 40% of those in peripheral
blood mononuclear cells, and mononuclear cell concentrations of 3TC-TP in semen are
approximately 100% of those in peripheral blood mononuclear cells [10]. These data
illustrate the importance of quantifying intra-cellular drug exposure to develop accurate
pharmacokinetic–pharmacodynamic models for HIV prevention. Exposure of the NNRTIs
in semen ranges from undetectable to 40% lower than plasma exposure, whereas the
majority of protease inhibitor concentrations are more than 80% lower than the blood
plasma concentration (the exception is IDV, which is 60% protein bound). RAL
concentrations are approximately 150–600% higher in semen than that in blood plasma [11].
MVC semen exposure was recently determined to be 40% lower than that in blood plasma.
However, due to low protein binding in the semen, protein-unbound (active) MVC
concentrations were still 28-fold higher than the protein-free IC
90
for HIV wild-type virus
[8].
Rectal mucosal tissue
The extent of penetration of drugs into rectal tissues also has implications for HIV
transmission. Exposures (area under the concentration time curve from 0 to tau, or
AUC
0-tau
) of MVC are approximately 30 times higher in rectal tissues than in plasma [12],
whereas exposures of DRV, ritonavir, and ETR are approximately 3, 13, and 7 times higher,
respectively, in rectal tissue than in plasma [13]. Some drugs, such as the nucleoside/tide
analogs, require cellular uptake and phosphorylation in order to be active. Intracellular and
extracellular concentrations of TFV and FTC have been recently measured in plasma and in
rectal tissues 1–14 days after a single dose [14]. TFV and FTC exposures (AUC
day 1–14
)
were 34 and four times higher in rectal tissues, respectively, than in blood plasma.
Intracellular concentrations of TFV-DP were detected for 14 days in rectal tissue, whereas
FTC triphosphate (FTC-TP) was detected for only 2 days after dosing. These data
demonstrate that, as with genital tract exposure, antiretroviral rectal tissue exposure varies
between and within drug class. Selecting those antiretrovirals with favorable extracellular
and intracellular pharmacokinetics may eliminate viral shedding from mucosal surfaces
implicated in HIV transmission.
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Viral shedding
However, even when the blood viral burden is suppressed, HIV can be recovered from the
male and female genital tract [15–19]. In an unpublished review of 51 identified studies of
HIV shedding in the female genital tract, all 31 studies that measured shedding in
individuals receiving ART found that suppression in the female genital tract was incomplete
[15]. In the most careful study to date, Cu-Uvin
et al.
[20•] found that among women with
completely suppressed plasma and genital tract viral loads at baseline, 54% had detectable
genital tract viral loads during at least 1 monthly visit over the 1-year follow-up period. In
32% of these women, the genital tract viral loads were detectable at a visit when viremia
was suppressed, suggesting that some women with undetectable blood viral loads may
maintain a high risk of onward transmission.
Two reviews of viral shedding in the male genital tract collectively identified 22 studies of
HIV-RNA persistence in the semen of men receiving ART, despite undetectable blood
plasma viral load [15,16]. The most notable among them, by Sheth
et al.
[21], involved
longitudinal assessments of paired blood plasma and seminal plasma samples from HIV-
infected men starting first-line ART. Among the 13 men who were on prolonged
combination ART (cART) with fully sustained viral suppression in blood plasma, four were
found to have detectable viral load in seminal plasma. Moreover, the investigators did not
find a significant association between isolated semen HIV-RNA shedding and local level of
any drug.
In addition to concerns about continued transmission from individuals with suppressed
viremia, a substantial number of new (untreated) patients present with HIV resistance to one
or more classes of antiretroviral agents [22•,23–25]. Transmitted drug resistance (primary
resistance) must reflect transmission from people who are partially treated, people who
stopped their treatment, or resistant variants in the genital tract. Patterns of resistance in the
genital tract correspond with observed antiretroviral drug exposure in genital excretions. For
example, the presence of protease-resistant viral isolates in seminal plasma and vaginal fluid
may be related to the poor penetration of protease inhibitors into the genital tract [5]. As
antiretrovirals achieving higher exposure in the genital tract are likely to have a greater
ability to reduce viral loads in genital compartments, improved understanding of drug
penetration into the genital tract could help guide therapy choices.
Translation of these results into public health considerations is more complex. Viral
replication in both the female and male genital tract can be independent of the blood [26•],
so different variants can be recovered, regardless of the treatment. The transmission
potential of these variants, or variants shed in spite of treatment, is unknown. However,
virologic comparisons in HIV transmission pairs suggest considerable selection during the
HIV transmission event [27]. Careful studies of transmitted drug resistance suggest that
some mutations may render viral variants less fit for transmission. For example, multiple
resistant variants are less likely to occur than single variants, and among single resistant
variants [28•,29–31].
Antiretroviral therapy, public health, and observational studies
Two kinds of observational studies have been used to support the ability of ART to reduce
transmission of HIV: studies of HIV-serodiscordant couples and ecological studies of
community populations.
Serodiscordant couples studies
Observational studies of seroconcordant and discordant couples provide a critical window
into the details of HIV-1 transmission. Eyawo
et al.
[32•] have provided an exhaustive
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review of discordant couples studies in South Africa, designed to understand whether the
male or female partner is more likely to remain uninfected. The complexity of this team’s
research helps us identify barriers to valid estimations of transmission probabilities. First,
not all partners are equally susceptible to HIV; therefore, some partners can remain HIV-
negative regardless of the infectivity of their sexual partner. Second, the infectivity of the
index case at the time of sexual contact depends primarily on the viral load, which is
generally not known and can be highly variable. Third, using the tools of molecular
virology, it has become clear that transmission events in 10–30% of couples likely involve a
third partner [33,34], with only a minority of new HIV infections taking place within
identifiable stable relationships [35•].
These concerns notwithstanding, observational studies offer the most compelling evidence
that ART can be expected to prevent HIV-1 transmission. More than a decade ago, a series
of reports linked the blood viral load of untreated index cases with the probability of HIV
transmission to their partners [36,37]. Obviously, in these studies the blood viral load must
serve as a surrogate for the genital tract HIV-1 concentration. In the most widely cited study,
from Rakai, Uganda, index case viral load was the chief predictor of heterosexual HIV
transmission risk [36]. The authors found that the mean viral load of infected individuals
who transmitted the virus to their partners was significantly higher than that of
nontransmitters (90 254 versus 38 029 copies/ml) and that no transmissions occurred in
couples in whom the infected partner’s viral load was under 1500 copies/ml. Observational
studies of HIV-discordant couples in Zambia, Spain, Thailand, and the USA uphold these
findings [38–40].
Other observational studies have demonstrated reduced HIV transmission when ART in the
index case reduced the patient’s viral load (at least theoretically); those with information on
ART distribution in the index cases are shown in Table 2 [41,42•,43–48,49•]. Bunnell
et al.
[50] estimated that ART was associated with a 98% reduction in the incidence of HIV in
heterosexuals, from 43.5 to 0.8 cases per 1000 person-years, and Donnell
et al.
[43] found
that only one of 103 genetically linked HIV transmission events in their cohort of 3381
couples occurred in a couple in which the index case was receiving ART, corresponding to a
92% reduction. A similar study of 424 couples in Spain found that none of the partners of
treated HIV-infected individuals seroconverted, whereas five of those whose index case was
not treated did [42•].
Several other studies, however, suggest that the protective effects of ART on sexual HIV
transmission may not be as consistent or absolute. Out of the 26 seroconversions in
nonindex partners of 436 HIV-discordant couples in Italy, for example, six took place in
couples in whom the HIV-infected partner was receiving AZT at the time [46]. More
recently, Sullivan
et al.
[48] found that ART in the index case of cohorts in Rwanda and
Zambia was associated with a 94% reduction in HIV transmission, but noted that ART failed
to completely eliminate risk, as four seroconversions took place when the index partner was
on ART. Finally, investigators in China recently documented 84 transmission events in a
cohort of 1927 discordant couples in which over 70% of index cases were receiving ART.
Interestingly, the authors found no statistical difference in the seroconversion rates between
those whose HIV-positive partner was receiving ART (66 of 1369 or 4.8%) and those whose
spouse was not (18 of 558 or 3.2%,
P
= 0.12). Participants in the study reported extremely
low rates of extramarital sex and drug use, and those who reported irregular condom use in
the past month were 12.64 times as likely to seroconvert (95% confidence interval 8.18–
19.75). Findings from the Chinese cohort suggest that heterosexual transmission of HIV
may persist even in populations with high treatment coverage [49•].
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