Brett-Major et al.

Tropical Diseases, Travel Medicine and Vaccines (2016) 2:25

DOI 10.1186/s40794-016-0042-9

REVIEW Open Access

Are you PEPped and PrEPped for travel?

Risk mitigation of HIV infection for travelers
D. M. Brett-Major1,2,3* , P. T. Scott2, T. A. Crowell1,2, C. S. Polyak1,2, K. Modjarrad1,2, M. L. Robb1,2 and D. L. Blazes3,4

Abstract
The HIV pandemic persists globally and travelers are at risk for infection by the Human Immunodeficiency Virus (HIV).
While HIV-focused guidelines delineate risk stratification and mitigation strategies for people in their home communities,
travel issues are not addressed. In this review, direct and indirect evidence on HIV risk among travelers is explored. The
burgeoning practice of employing pre-exposure prophylaxis (PrEP) with anti-retroviral therapy in the non-travel setting is
introduced, as well as the more established use of post-exposure prophylaxis (PEP). Challenges in applying these lessons
to travelers are discussed, and a new guidelines process is scoped and recommended.
Keywords: Pre-exposure, Post-exposure, Prophylaxis, Travel, Human Immunodeficiency Virus, Review

Background acute HIV infection. A patient with an antiretroviral syn-

Pre-exposure prophylaxis (PrEP) against the Human drome might be induced to present disproportionately to
Immunodeficiency Virus (HIV) has been recommended their travel medicine provider because of undifferentiated
in several guidelines for persons at risk within their fever. Also, for pathogens like HIV which can infect people
home communities [1–3]. However, these guidelines globally, GeoSentinel cannot exclude that patients
have ignored the use of PrEP in travelers, despite the contracted their STI after returning home. Nonetheless,
high frequency of travel both within the US and to even across their cohort, STI morbidity was 6.6 per 1000 ill trav-
more HIV endemic areas. According to a travel trade as- elers, more than a quarter of which was HIV infection.
sociation, in 2015, U.S. residents spent nearly 2.2 billion That rate of HIV infection is nearly ten times lower than
person-days traveling in the US more than 50 miles from the usual universal HIV testing threshold for prevalence
their homes and using paid lodging [4]. In that same among presenting patients of one per cent. However, this
year, more than 350,000 U.S. residents went to Africa, network demonstrates that travel-associated HIV infection
4.8 million to Asia, 7.7 million to the Caribbean and occurs. Passive, travel clinic case collection is just as likely
12.6 million to Europe [5]. As this readership appreci- to underestimate HIV infection rates as most other clinical
ates, travel affects behaviors and exposures, shaping care settings. In a large, recent study of acute HIV infection
risks. Here, we will explore the current options for PrEP in East Africa and Thailand, patients were just as likely to
against HIV infection and consider them in the context not have symptoms as have them [7].
of travel medicine. Despite awareness campaigns against supporting human
trafficking through use of commercial sex, some travelers
What is the travel associated risk for HIV? travel for sex [8]. Locations wildly differ in the degree to
The GeoSentinel international surveillance network of which such settings are regulated and in the health con-
travel clinics assessed sexually transmitted infections (STI) trols applied. Sexual tourism in particular presents a sig-
among its ill presenting returned travelers [6]. Among 299 nificant risk for HIV exposure and acquisition. Among
men and 122 women with STI, 89 and 27, respectively, had UK-born adults diagnosed with HIV infection between
2002 and 2010 in England, Wales, and Northern Ireland,
* Correspondence: [email protected] 15% were determined to have acquired infections outside
1
Henry M. Jackson Foundation for the Advancement of Military Medicine, of the U.K. These individuals most commonly traveled to
Bethesda, MD, USA
2
Military HIV Research Program, Walter Reed Army Institute of Research, Silver the Thailand, the U.S., and South Africa and were more
Spring, MD, USA likely than those who acquired HIV infections in the U.K.
Full list of author information is available at the end of the article

© The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Brett-Major et al. Tropical Diseases, Travel Medicine and Vaccines (2016) 2:25 Page 2 of 8

to have heterosexual exposures and to have reported for recent humanitarian workers identified high rates
sexual contact with a commercial sex worker [9]. of unprotected sex, high alcohol use, depression,
A number of studies have shown a positive association acute stress reaction and other HIV/ STI risk factors
between travel and risky behaviors. Historical rates of [15, 16].
casual sex exposure among travelers range as high as A specialized population that may have travel associated
50% [10]. In a survey of over 2,000 backpackers in sexual health risks is that of military personnel around the
Thailand, 2 in 3 were single and young—two thirds of time of deployment. In a retrospective assessment of the
respondents were under the age of 25—and mostly from U.S. Navy and Marine Corps HIV epidemic, nearly 1 in 10
Europe [11]. Of those who were single, more than a HIV infected Sailors and Marines reported that an
third reported having sex with a new partner. This was impending deployment contributed to their becoming in-
true more often for men and men were more likely to fected with HIV [17]. In this same study, vacation as a risk
have sex with local persons. Longer length of stay was factor for their having acquired HIV infection was cited by
associated with more risk behavior. Condom use was 1 in 5, and traveling for temporary assignment by 1 in 6.
variable. A survey of over 1,000 travelers from the U.K. Peri-deployment samples captured incident cases [18].
visiting a wide variety of locales obtained similar results, This also was observed in an investigation of U.S. Army
though as might be expected the general travel popula- soldiers who had deployed to Afghanistan and Iraq [19].
tion was older than the backpackers [12]. However, both a subsequent study that explored HIV risk
Travelers presenting for health advice on the cusp factors in the context of U.S. Air Force airmen mobility
of or while working as emergency responders or (deployments, duty station changes) and an internal
long term stay humanitarian workers present special soldier-airman case control study determined that having
challenges. Given the numbers of persons who had increasing numbers of deployments was protective
undertake such work, STI risks and outcomes may against HIV acquisition [20].
be underreported. A cross-sectional study of HIV
risk behavior among over 1,200 globally distributed How are antiretroviral medications used for prophylaxis?
Peace Corps volunteers was undertaken in 1991 [13]. Antiretroviral therapy (ART), or highly active antiretroviral
One in three single men and one in five single therapy (HAART)
women had three or more sexual partners during Most medications used in antiretroviral therapy against
their tours. A sero-survey of 864 Dutch expatriates HIV infection target viral enzymes, in particular reverse
was conducted in the mid-1990s [14]. One in four of transcriptase, protease or integrase. Increasingly, ART med-
those surveyed reported having unprotected sex with ications that block cellular receptors needed by the virus
a local person but only two HIV infections were are being used. Figure 1 depicts the HIV life cycle in a cell
identified. A systematic review of pre-health advice and shows how ART drug classes apply to combating the

Fig. 1 Mechanisms of anti-HIV activity by drug class

Brett-Major et al. Tropical Diseases, Travel Medicine and Vaccines (2016) 2:25 Page 3 of 8

virus. Highly active antiretroviral therapy (HAART) refers TDF include renal disease (e.g., creatinine clearance below
to the combination of ART medications employed together 60 mL/min), osteopenia and osteoporosis. In the United
for treatment of HIV in infected persons. The nomencla- States, in single formulations for 30 tablets (one tablet per
ture reflects the evolution of therapy from single agent in day), FTC currently costs $643.82 and TDF $1,197.32.
the early years of the HIV pandemic to use of three and Their co-formulation is similarly priced at $1,759.73 [27].
four drug combinations as the ease with which HIV de- Research is underway for a variety of alternative PrEP
velops resistance came to be understood. Both international strategies that use both established HIV treatment medica-
and country-level guidelines exist for HAART [21]. tions and other approaches. The CCR5 receptor antagonist
Careful review of side effects and use characteristics is maraviroc and the non-nucleoside reverse transcriptase in-
important, particularly when these medications are not hibitor (NNRTI) dapirivine are being explored as a PrEP
part of a provider’s usual practice. Comorbid conditions option, both as the sole regimen and also in combination
such as renal disease and viral hepatitis influence the with non-HIV medications delivered in a vaginal ring or va-
choice of antiretroviral regimens. Many ART medications ginally applied tablets [28–30]. Vaginal delivery of FTC and
have significant interactions with other drugs through the TDF also are being assessed [31, 32]. An injectable, depot
induction and inhibition of metabolic pathways. Several formulation of the integrase strand transfer inhibitor cabo-
ART:anti-malarial medication interactions are cited in the tegravir has a 40 day elimination half life. A comparison is
Yellow Book [22]. For instance, efavirenz decreases serum planned between it and TDF + FTC as PrEP [33, 34]. A
concentration of atovaquone, co-formulated with progua- similar trial is in progress for a high dose, every 8 week ad-
nil in the anti-malarial medication Malarone®. A variety of ministration of the injectable rilpirivine, a NNRTI [35, 36].
fee-based and open resources for assessing drug inter- Biologic agents such as broadly neutralizing monoclonal
action risks also are available to help guide a provider’s antibodies and small molecule inhibitors also may find a
choice of treatments [23–25]. niche for this indication [37].

Pre-exposure prophylaxis (PrEP)

Post-exposure prophylaxis (PEP)
PrEP is pre-exposure prophylaxis for individuals who are
Post-exposure prophylaxis (PEP) is taken following a po-
not HIV infected but carry above average risk for be-
tential HIV exposure. Guidelines for its use are divided
coming infected with HIV. The most discussed and
into two categories, occupational PEP (oPEP) and non-
available form of PrEP is oral antiretroviral therapy.
occupational PEP (nPEP) [38–40]. Experience with PEP
The first medication for which the Food and Drug
is much more robust than that with PrEP. Uncertainty
Administration (FDA) approved an indication for PrEP was
regarding its effectiveness under ideal circumstances as
TRUVADA® [26]. It is a combination therapy of emtricita-
well as how long after an exposure initiating PEP still
bine (a nucleoside analog, FTC) and tenofovir disoproxil
brings benefit leaves it an incomplete solution [3, 41].
fumarate (a nucleotide analog, TDF) that inhibits the viral
Early guidelines advocated a risk tiered approach where
enzyme reverse transcriptase. It is taken once daily as a sin-
low risk exposures employed two NRTI, higher risk ex-
gle tablet. While the mutability of HIV and, consequently,
posures were an indication for the addition of a PI. Now,
increasing drug resistance rates have driven recommended
at least three-drug therapy is recommended (Table 1)
treatment courses to triple drug therapies, recommenda-
[42]. Certain scenarios trigger a recommendation for ex-
tions for prophylaxis have remained simple and narrow.
pert consultation. These include when use is delayed,
Table 1 compares the different guideline recommendations.
unknown sources of infection, pregnancy, breast-feeding,
While the guidelines do not focus on the travel clinic
suspected viral resistance, toxicity of the initial regimen,
setting, they provide representative sexual health question-
serious comorbidities [42]. Suspicion or confirmation of
naires and suggested criteria for both men who have sex
viral hepatitis is another setting where expert consult-
with men (MSM) and heterosexually active men and
ation is prudent for PrEP, nPEP and oPEP. nPEP and
women for determining who merits PrEP. These focus on
oPEP are taken for 28 days.
identifying patients at increased risk because of lack of
condom use, multiple sexual partners, history of sexually
transmitted infections or relationships with known HIV Who is using PrEP in their communities and to what effect?
positive partners. As recommendations on use of PrEP become increasingly
Both FTC and TDF are globally distributed and consti- liberal, impact on patient and community risks is a matter
tute the backbone of some first line HIV treatment for prospective study. However, success has been demon-
regimens. Should contraindications to these medications strated in several key high-risk populations. A 2012
exist, there are no recommended pharmacologic alterna- Cochrane review assessed four completed, randomized,
tives in the setting of pre-exposure prophylaxis. Rather, controlled clinical trials that tested TDF + FTC in high-
risk modifying behavior is indicated. Contraindications to risk groups [43]. Among nearly 9,000 pooled participants,
 Brett-Major et al. Tropical Diseases, Travel Medicine and Vaccines (2016) 2:25
Table 1 Current options for pharmacologic prophylaxis against HIVa,b
Medication Dose (mg) Frequency Comments Guidelines
Pre-Exposure Prophylaxis (PrEP) CDC WHO IAS
TDF + FTC 300/ 200 Daily TDF- Nausea, flatulence FTC- rash, headache; distinguish from the X X X
treatment co-formulation with efavirenz
TDF 300 Daily Not recommended alone in the US; whether in combination X
or alone, avoid in patients with renal injury or bone disease
non-occupational Post-Exposure CDC WHO
Prophylaxis (nPEP)
TDF + FTC 300/ 200 Daily RAL- Mild hepatitis is common, and hypersensitivity, severe skin X
+ RAL 400 Twice daily reactions have been reported though more common side effects
include fatigue, headache, dizziness, nausea and insomnia
Alternative recommendation for health adults and adolescents is
TDF + FTC + DRV. In renal dysfunction, ZDV + 3TC + either RAL or
DTG is recommended
TDF + FTC 300/ 200 Daily Alternatives for the 3rd drug on the TDF + FTC backbone include X
+ either LPV/r or ATV/r Varies RAL, DRV/r, EFV
occupational Post-Exposure PHS WHO
Prophylaxis (oPEP)
TDF + FTC 300/ 200 Daily The core recommendation is to take 3 or more tolerable drugs; X
+ RAL 400 Twice daily listed alternatives for TDF + FTC include ZDV + 3TC; listed alternatives
for RAL include DRV/r, ETR, RPV, ATZ/r, LPV/r; listed alternative for
all is a single co-formulation of four ART medications (TDF, FTC,
EVG, cobicistat)
TDF + FTC 300/ 200 Daily Alternatives for the 3rd drug on the TDF + FTC backbone include X
+ either LPV/r or ATV/r Varies RAL, DRV/r, EFV
WHO guidelines do not distinguish nPEP and oPEP
ATV Atazanavir, DRV Darunavir, DTG Dolutegravir, EVG Elvitegravir, ETR Etravirine, FTC Emtricitabine, 3TC Lamivudine, LPV Lopinivir, RAL Raltegravir, RPV Rilpivirine, RTV Ritonavir, /r boosting with ritonavir, TDF Tenofovir
disoproxil fumarate, TDF + FTC available taken together as separate tablets or in co-formulation, ZDV Zidovudine
For post-exposure prophylaxis, IAS defers to CDC. The CDC produces the nPEP recommendations, while the United States Public Health Service (PHS) generated the oPEP recommendations
a
Individual patient contraindications including drug:drug interactions, pregnancy, infections, chronic diseases such as renal or hepatic disease. They must be considered with each use. Providers should use
applicable guidelines
b
Recommendations for children differ in the guidelines with regard to age thresholds, drug selection and dosing approach

Page 4 of 8
Brett-Major et al. Tropical Diseases, Travel Medicine and Vaccines (2016) 2:25 Page 5 of 8

the relative risk (RR) of HIV infection for those on PrEP examining use among heterosexual women in Africa
was 0.51 (95%CI 0.3-0.86). TDF alone also attenuated risk [47]. Studies among commercial sex workers for PrEP
among 4,000 participants yielding a greater risk reduction, have focused on willingness to adopt surveys [48, 49].
RR 0.38 (95%CI 0.23-0.63). Although, some clinical care site-based cohorts such as
The results of practical application of PrEP in public The Combine! Study in Brazil may incorporate more
health programs for some populations have been pub- commercial sex workers than had previous studies [50].
lished. In a demonstration project on PrEP linked to sexu- The emergence and consequences of resistant HIV as-
ally transmitted infection (STI) clinics in San Francisco sociated with long term PrEP remain unclear and an
and Miami, and a community health center in Washing- area for study [51].
ton DC, 557 men who have sex with men (MSM) and
transgender women were followed for 48 weeks [44]. On Counseling the traveler on HIV risk and PrEP
study entry, almost 1 in 4 participants reported that their The most secure methods to prevent HIV acquisition are
primary partner was HIV infected—typically on antiretro- risk modifying behaviors—abstinence, appropriate con-
viral therapy—but most had additional partners. Adher- dom use, knowledge of HIV status in self and partners
ence was almost 90% in San Francisco and Washington and clean needle use. These should be reinforced in the
DC, but 65% in Miami. In addition to location, risk factors course of travel counseling even if opting to use PrEP.
for poor adherence based upon dried blood spot TDF Travel clinics should routinely assess sexual health risks in
levels were being African American, and not renting or their patient assessments and counseling. Travel-related
owning their own dwelling. Those with 2 or more risks associated with HIV infection should be elicited in
episodes of unprotected receptive anal intercourse in the the pre-travel evaluation in order to identify anticipated
previous 3 months had higher rates of adherence. STI exposures and risks associated with travel in addition to
prevalence was high at time of screening, declined at baseline, non-travel risk. For those who might benefit
24 weeks but then increased again by 48 weeks. Nonethe- from long term PrEP use, the travel medicine visit should
less, only 2 HIV incident infections were observed. As be used as an opportunity to encourage patients to discuss
these communities were selected because of an annual PrEP with their primary physician. For those with short-
HIV incidence of 2% or higher, this suggests a substantial term risks, consider provision of non-occupational post-
protective effect despite inevitable enrollment biases. exposure prophylaxis (nPEP) medications and instructions
Whether that protection is attributable only to reductions on their use after a high-risk, non-occupational exposure
of risk at the individual level, or the presence of a collect- in accordance with guidelines.
ive effect because of decreased transmission within social Currently, consensus guidelines do not exist to guide the
networks is not clear. unique decisions about offering PrEP to travelers who are
Another open label, STI clinic-linked PrEP imple- not already taking it for pre-existing risk factors in their
mentation project across 13 sites in England random- home communities. For the long-term stay travelers (i.e.,
ized 544 MSM participants to immediate or 1 year months to years) the guidelines can be used to discuss
deferred treatment groups [45]. As in the project by Liu established risk profiles in the context of the impending liv-
et al, TDF + FTC was used. The immediate PrEP group ing environment. Per country HIV prevalence rates for
experienced 3 incident HIV infections, in contrast to 20 some at risk areas are listed in the WHO Global Health
in the deferred PrEP group. Of these 20, 17 had been Observatory data repository [52]. For short-term stay trav-
infected prior to the onset of PrEP, and the other 3 may elers (i.e., days to weeks), their usual risk and contexts can
have been. Post-exposure prophylaxis of TDF + FTC + be reassessed in order to determine if baseline PrEP use
lopinavir, a protease inhibitor (PI), was administered to ought to be considered. Studies have not tested the
85 participants in the deferred group, 22 of which pharmacodynamics, adherence and efficacy of short term
received three or more courses. Of the 20 deferred PrEP. If attempting to use PrEP for travel-related risk, a
PrEP incident cases, 6 of the patients had received traveler may have to initiate it one to two weeks prior to
post-exposure prophylaxis in 12 courses of treatment. travel. Pre-prescription assessments of renal function, HIV
The authors estimated a number need to treat of 13—1 and viral hepatitis status would be prudent, as well as re-
year of PrEP in 13 men of this population would view of the medical history for renal disease and osteopenia.
prevent one incident case of HIV infection. As in the Insofar as possible, current guidelines for PrEP manage-
U.S. PrEP implementation project, STI rates were high ment should be followed. Monitoring issues will exist. For
and unperturbed. long-term travelers, in country support would have to be
Trials to assess PrEP adoption and use, patient and considered. To what degree insurance would cover episodic
social network protective efficacy are underway now in PrEP use for travel is not clear. Ideally, short-term travelers
developing areas that have particular stigma against will incorporate their primary care providers in these dis-
some high-risk groups [46]. Cohorts also exist cussions also as their risk may need to be reassessed.
Brett-Major et al. Tropical Diseases, Travel Medicine and Vaccines (2016) 2:25 Page 6 of 8

Conclusions and ways ahead mitigation strategies depending on specific travel related
Key summary points are listed below. sexual risk exposures such as insertive penile sex and re-
ceptive vaginal and anal sexual exposures and the incom-
 HIV infection is a threat to travelers plete knowledge of the estimated time to achieve
 Travelers have both long term and travel-associated HIV-related risks protection in relevant tissues. Specific practical guidance
 General and tailored HIV risk prevention counseling applies to for the travel medicine provider should include recom-
travelers mendations for consideration of PrEP initiation for last
 Neither PEP nor PrEP guidelines address risks and use of these in minute travelers with imminent travel and for transition-
travelers
ing travelers from PrEP to nPEP for those travelers in
 Stakeholder professional societies should cooperatively pursue travel whom pre-travel PrEP duration may have been inadequate
related guidelines and a research agenda on PrEP and other risk
prevention and mitigation approaches against HIV infection in to achieve maximum protection. Additionally, some trav-
travelers elers may be healthcare workers for who occupational
post-exposure prophylaxis (oPEP) needs may be present.
These considerations add to the need for and complexity
As technologies for PrEP improve, its application in of a guidelines process.
the traveler may become simpler. Depot injections that
Acknowledgements
can be applied regardless of baseline health status, for The authors thank Dr. Shilpa Hakre of the Henry M. Jackson Foundation for
instance, would be welcome. Regardless, PrEP use in the technical advice.
traveler, as PrEP use in communities, carries manage-
Funding
ment and policy issues that merit attention. Travel and This work was supported by a cooperative agreement (W81XWH-07-2-0067)
HIV interested professional societies and bodies should between the Henry M. Jackson Foundation for the Advancement of Military
Medicine, Inc., and the U.S. Department of Defense (DOD).
consider convening a dedicated review and guidelines
process for this issue. Some travelers that may not be Availability of data and supporting materials
good candidates for long term PrEP could benefit from Data sharing is not applicable to this article as no datasets were generated
or analyzed for this review.
episodic, short-term PrEP associated with travel, should
safe and effective approaches for this use be agreed. Authors’ contributions
Should such a guidelines effort be undertaken, several DMB and DLB conceived the paper concept. All authors participated in
considerations useful to travel medicine providers require content design, writing and editing. All authors read and approved the final
manuscript.
focused attention. These include PrEP evaluation for eligi-
bility, minimum screening labs, PrEP initiation, toxicity Competing interests
monitoring, discontinuation/transition to nPEP, HIV epi- The authors declare that they have no competing interest.

demiology and resistance, and impacts upon risk reduc- Consent for publication
tion counseling. Both the way level of HIV risk is Not applicable.
addressed in PrEP guidelines and the potential different
Ethics approval and consent to participate
sexual health risks present among varying types of travel Not applicable.
and traveler also need to be considered. Travel medicine
services are provided in a variety of settings and by a range Disclaimer
The views expressed are those of the authors and should not be construed
of providers. This includes primary care providers, infec- to represent the positions of the Henry M. Jackson Foundation, Bill and
tious diseases specialists, stand-alone travel medicine Melinda Gates Foundation, U.S. Army, Uniformed Services University, or the
clinics and comprehensive travel medicine clinics inte- Department of Defense.

grated in infectious diseases and preventive medicine Author details

1
clinics. Knowledge regarding PrEP is associated with clin- Henry M. Jackson Foundation for the Advancement of Military Medicine,
ical experience using PrEP and ART prescribing experi- Bethesda, MD, USA. 2Military HIV Research Program, Walter Reed Army
Institute of Research, Silver Spring, MD, USA. 3Division of Tropical Public
ence [53–55]. Ideally, patients present 4–6 weeks prior to Health, Department of Preventive Medicine and Biostatistics, F. Edward
travel for evaluation by a travel medicine provider. How- Hébert School of Medicine, Uniformed Services University, Bethesda, MD,
ever, patients often present much more proximal to antici- USA. 4Bill and Melinda Gates Foundation, Seattle, WA, USA.

pated departure and require expedited evaluation, Received: 15 September 2016 Accepted: 15 November 2016
couseling, and interventions. The lead time required to
achieve protective drug levels in serum, rectal, and vaginal
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