Critical Review Preventing HIV Infection: Pre-exposure and Postexposure Prophylaxis

Susanne Doblecki-Lewis* Michael A. Kolber

Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, FL, USA

Abstract Data supporting the use of pre-exposure prophylaxis (PrEP) and nonoccupational postexposure prophylaxis (nPEP) in the prevention of HIV infection after a sexual encounter continue to grow. In this review, we describe some of the research driving the various recommendations for use of antiretrovirals in prevention. In addition, current research is described regard-

ing the establishment of viral reservoirs that argues for rethinking the timing for nPEP treatment. We discuss the variables that impact on the choice of prevention antiretrovirals, including drug distribution, drug transporters, and potential C 2014 IUBMB impact of race and ethnicity on these variables. V Life, 66(7):453–461, 2014

Keywords: human immunodeficiency virus; antiretroviral medication; prevention

Background and Need for New Prevention Strategies Progress in treatment and prevention of HIV has been remarkable. Highly effective antiretroviral therapy for HIV became available in 1996 and has dramatically changed disease survival as well as quality of life for those receiving treatment. Indeed, the number of people living with HIV/AIDS continues to increase, in part, due to the expanding availability of antiretroviral therapy and extension of lifespan (1).

Abbreviations: PrEP, pre-exposure prophylaxis; nPEP, nonoccupational postexposure prophylaxis; HIV, human immunodeficiency virus; SIV, simian immunodeficiency virus; AIDS, acquired immune deficiency syndrome; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; AZT, zidovudine; PMTCT, prevention of mother-to-child transmission; NRTI, nucleos(t)ide reverse transcriptase inhibitors; NNRTI, non-nucleoside reverse transcriptase inhibitor; Pgp, P-glycoproteins C 2014 International Union of Biochemistry and Molecular Biology V

Nevertheless, currently, more than 34 million people are living with HIV infection and more than 2.5 million people become infected with HIV annually. The number of new infections annually decreased by 33% from 2002 to 2012 globally. However, UNAIDS estimates that 2.3 million people became infected with HIV globally in 2012 (2). Regional differences in demographics of those affected by the virus are notable; in North America, focal epidemics continue to occur among men who have sex with men (MSM), and disproportionately among black and Hispanic MSM (3). Globally, transmission among MSM as well as heterosexual transmission is common, and women represent more than half of all people living with HIV/ AIDS; in sub-Saharan Africa, young women are eight times more likely than young men to be HIV infected (4). Sex workers and injection drug users, in particular, are at high risk for HIV acquisition (1). In all geographic areas, vulnerability, marginalization, and stigma have heightened risk and complicated effective prevention and treatment efforts (4, 5). The global impact of the disease remains enormous, and it is clear that there is a great need for additional highly effective prevention methods.

Volume 66, Number 7, July 2014, Pages 453–461 Address correspondence to: Susanne Doblecki-Lewis, Division of Infectious Diseases, University of Miami Miller School of Medicine, 1120 NW 14th Street, #850 (R-21), Miami, Florida 33136, USA. Tel: +305-243-4598. Fax: +305-243-4037. E-mail: [email protected] Received 21 April 2014; Accepted 15 June 2014 DOI 10.1002/iub.1286 Published online 27 June 2014 in Wiley Online Library (wileyonlinelibrary.com)

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Overview of Prevention Strategies Using Antiretroviral Medications Scientific evidence now clearly demonstrates that antiretroviral treatment has efficacy in decreasing secondary transmission (treatment as prevention) (6). Additionally, the use of antiretroviral medications by HIV-negative individuals is able to prevent infection despite exposure (pre-exposure prophylaxis

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FIG 1

Timing of different strategies using antiretroviral medications to prevent infection. Solid dark line describes usual early HIV-1 viral kinetics in the absence of antiretroviral medication. Pre-exposure prophylaxis (PrEP) is started prior to anticipated exposure (blue box) and provides antiretroviral levels at the time of exposure that prevent establishment of infection. Postexposure prophylaxis (PEP) involves antiretroviral therapy started as soon as possible after exposure, and continues for 28 days, aborting infection in the early stages before chronic infection is irreversibly established. Treatment of established infection occurs after virus or antibody to virus is detected in the blood and is life-long. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

[PrEP] and postexposure prophylaxis [PEP]; Fig. 1). Recognition of the efficacy of these interventions has created a paradigm shift in which antiretroviral therapy is implemented both for the health benefits it provides to the individual with HIV infection as well as to prevent transmission. To understand the promise and limitations of prevention using these strategies, an understanding of the biology of early infection and the pharmacological properties of candidate medications is necessary. In this review, we will summarize events occurring in early infection and how this sequence may be altered by PrEP, in which antiretroviral medication is taken before an exposure to prevent acquisition of HIV infection, and nonoccupational PEP (nPEP), in which antiretroviral medication is started soon after a sexual encounter to avert infection, as well as consider the pharmacokinetic factors that may impact drug development and utilization for this purpose. There are a number of recent reviews considering the important issues surrounding PrEP implementation in clinical settings, including economic considerations; these topics will not be considered in detail in this review (7–10).

History of Antiretroviral Use for Prevention The use of antiretrovirals for the prevention of infection after sexual exposure is based on nonhuman primate studies, stud-

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ies of maternal-to-child vertical transmission of HIV, and observational studies of individuals receiving preventative treatment after occupational exposures. Nonhuman primate studies conceptually validated the efficacy of antiretroviral medication administered prior or just following intravenous or mucosal SIV exposure in preventing infection. The nucleotide reverse transcriptase inhibitor (NRTI) tenofovir, given orally as tenofovir disoproxil fumarate (TDF), alone, or in combination with the NRTI emtricitabine (FTC), is the most extensively studied agent for this purpose. Daily or intermittent PrEP with TDF (topically or systemically administered) or combination TDF/FTC demonstrated a dosedependent reduction in infection risk, and optimized dosing provided significant (70–100%) protection following mucosal SIV exposure (11–14). Nonhuman primate studies also found that the combination of TDF and FTC may be more effective than TDF alone for PrEP (12). When used postexposure as PEP, animal studies suggest that drug administration shortly after exposure is important and that a reduction in efficacy of PEP occurs as time from exposure to drug delivery increases (15, 16). Proof of concept for antiretroviral therapy as a safe and effective preventative strategy in humans was first established in prevention of mother-to-child transmission of HIV (PMTCT). In foundational work, a randomized, placebo-controlled trial using the NRTI zidovudine (AZT) administered to HIV-infected women during pregnancy, intrapartum, and to their infants postpartum resulted in a 68% reduction in HIV perinatal transmission (17). Highly active antiretroviral therapy, typically using three medications, was used in later studies to reduce rates of transmission to less than 2% when the medications are available and administered appropriately (18). Subsequent refinement and scale-up of PMTCT has resulted in a 35% decline in pediatric HIV infections from 2009 to 2012 (2), with potential for greater impact as implementation continues to improve. Several mechanisms are involved in the protection conferred by PMTCT. Lowering of maternal viral load both in the blood and genital secretions is an important component of efficacy but does not explain the entire benefit as the use of antiretroviral medications is independently associated with reduction in the risk of transmission (19). The distribution of antiretroviral medications into fetal circulation also provides PrEP to the infant prior to exposure to maternal genital tract virus, and postnatal medication provides PEP against virus entering fetal circulation due to mixture of maternal and fetal blood during delivery or virus in blood or secretions swallowed by the infant during the birth process (18). Additionally, the success of antivirals administered to infants to prevent infection from ongoing exposure related to breastfeeding provides a basis for the efficacy of prophylaxis against repeated exposures (20, 21). In addition to the experience of PMTCT, evidence for efficacy of PEP was strengthened by the observation, documented in a case–control study, that 28 days of PEP with AZT started within 72 h of an occupational needlestick exposure was able

Prevention of HIV Infection Using PrEP and nPEP

to reduce HIV transmission events by 81% (22). Because of the observed success of PEP provision following significant exposure to HIV in the occupational setting and animal study data, PEP for 28 days became standard of care after such exposures (23, 24). Based on the difficulty of studying differences in efficacy between regimens containing two versus three or more drugs, the demonstrated superiority of three drugs in reducing HIV viral load in HIV-infected individuals, the improved safety and tolerability of recent antiretroviral medications, and guidelines for occupational exposure now recommend immediate administration of three-drug chemoprophylaxis with continuation for 28 days (25). Recent human studies have provided strong evidence that antiretroviral-based oral PrEP, as part of a prevention strategy, is safe and effective for the prevention of sexual transmission of HIV when taken regularly (Table 1). The iPrEx study demonstrated that daily oral TDF/FTC was well tolerated and reduced the risk of HIV acquisition by 44%, when compared with placebo, among MSM and transgender women (TGW) with behavioral risk for HIV (26). Adherence, measured by serum drug levels, was noted to be moderate, and the presence of detectable drug strongly correlated with protection from HIV infection, with a 92% reduction in risk of HIV acquisition among those with detectable drug levels when compared with those with no drug detected. Additionally, two large randomized, double-blinded, and placebo-controlled trials in heterosexuals have demonstrated the effectiveness of daily oral PrEP. The Partners PrEP Study (27) performed in Kenya and Uganda evaluated the efficacy of daily oral TDF, combination TDF/FTC, and placebo for the prevention of transmission in serodiscordant heterosexual couples. Efficacy of this strategy was 67% with TDF alone and 75% with combination TDF/ FTC, and not statistically different. Again, detection of drug in serum was associated with protection from HIV infection. The TDF2 Trial, comparing daily oral TDF/FTC with placebo, enrolled 1,219 heterosexual men and women in Botswana and demonstrated an efficacy of 62% (28, 29). Based on these studies, in July 2012, the US Food and Drug Administration approved oral TDF/FTC for use for the prevention of sexually transmitted HIV in adults at high risk for infection (30). The United States Centers for Disease Control and Prevention issued interim guidance for clinicians regarding the use of PrEP for heterosexuals and MSM at increased risk for HIV infection (31, 32). This guidance was expanded in June 2013 to include PrEP for injection drug users following the Bangkok Tenofovir Study, which demonstrated efficacy of PrEP for this risk group (33, 34). In May 2014, the CDC released its first clinical practice guideline for the implementation of PrEP for MSM, heterosexual men and women, and injection drug users, including tools for clinicians and patients considering PrEP use (10). Additional placebo-controlled trials in humans have demonstrated the necessity and challenge of medication adherence to allow PrEP to be effective. The FEM-PrEP study enrolled 2,021 HIV-uninfected women in Kenya, South Africa, and Tan-

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zania who were at high risk for HIV infection and randomly assigned to daily oral TDF/FTC or placebo. The study was stopped by its Data Monitoring Committee in April 2011 due to futility of the intervention. Subsequent analysis including plasma levels revealed estimated adherence of less than 40% (35). The VOICE trial, a study of 5,021 HIV-uninfected African women which randomly assigned women to receive 1% tenofovir gel, daily oral TDF, or daily oral TDF/FTC also did not demonstrate efficacy of any of the interventions, with low adherence again demonstrated by plasma drug levels (36). These clinical trials as a group have not only demonstrated the biological plausibility of achieving high levels of protection from HIV infection with oral PrEP use but also point out the challenges of achieving robust adherence to PrEP. As adherence has proven to be a major issue for PrEP interventions, additional information regarding the levels of medication and frequency of dosing that correlate with protection from HIV infection has emerged. The analysis of TDF and FTC drug levels from the iPrEx and STRAND studies approximated 76% protection for two doses of oral TDF/FTC weekly, 96% for four doses weekly, and 99% for seven doses weekly (37). Trials are underway considering the feasibility of intermittent dosing and alternative dosing strategies for PrEP. At present, only daily dosing of TDF/FTC is recommended. Additional compounds for PrEP that can be dosed less frequently are in development and may have the potential to positively impact adherence. Recently, an injectable long-acting integrase inhibitor that could be administered quarterly demonstrated efficacy in the prevention of rectal and vaginal SIV infection in macaques (38). To date, GSK1265744, an integrase inhibitor, and TMC278, an non-nucleoside reverse transcriptase inhibitor (NNRTI), have completed phase I trials, and a phase 2 trial with GSK1265744 is set to begin evaluating safety and acceptability in HIV-uninfected men (39). Additionally, vaginal rings containing the antiretrovirals dapivirine and maraviroc left in place for 28 days have demonstrated safety and acceptability in phase I human trials and are currently under evaluation in human efficacy studies (40). The possibility that the use of antiretroviral medications for PrEP could lead to resistance to these medications if HIV infection were to occur during PrEP use has not been borne out in the clinical trials performed to date (Table 1). However, resistance to medication has been reported in a number of study participants who had unrecognized HIV infection at the time oral PrEP was initiated, demonstrating the importance of adequate clinical and laboratory screening for preexisting and acute HIV infection at the time of PrEP initiation (10). Existing trials have demonstrated the scientific feasibility of PrEP and nPEP as prevention strategies as well as the importance of a combined behavioral and biomedical approach to adherence and prevention. An understanding of the underlying events that permit these interventions to succeed will allow optimization of current PrEP and nPEP strategies and innovation in pharmacological prevention.

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456

Hetero M/W (Africa)

Hetero W (Africa)

TDF2 (28)

VOICE (36)

NR, not reported.

Bangkok IDU (Thailand) Tenofovir Study (33)

Hetero W (Africa)

Hetero M/W (Africa)

Partners PrEP (27)

FemPrEP (35)

MSM (international, largely South American)

Population

TDF/FTC vs. placebo

TDF/FTC or TDF vs. placebo

TDF/FTC vs. placebo

Agent

2,411

2,120 TDF vs. placebo

TDF/FTC vs. placebo

2,977 TDF/FTC or (oral PrEP) TDF vs. placebo

1,200

4,708

2,499

Size

49

6

24 (TDF/FTC)

250 (TDF)

62

75 (TDF/FTC)

67 (TDF)

44

NR

NR

NR

2/2

3/14

3/8

0/49

5/68

NR

0/33

0/78

0/100

Resistance in participants Resistance in Efficacy participants already (reduction in infected after infected HIV infections) baseline at baseline (%)

Summary of large randomized, placebo-controlled human trials of oral PrEP

iPrEx (26)

Study

TABLE 1

Very low adherence

Very low adherence, trial stopped at interim analysis due to futility

Comments

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Prevention of HIV Infection Using PrEP and nPEP

Considerations for Drug Delivery for PrEP and nPEP For most pharmaceuticals, the goal is to reach steady-state concentrations within a therapeutic window over the dosing period. For PrEP and nPEP, pharmacological considerations are slightly different. For nPEP, rapid delivery of antivirals at effective levels is critical in preventing infection, whereas for PrEP, maintenance of intracellular levels of protective antivirals is required. To achieve these goals, interaction with the mucosal surfaces and distribution of medication into these tissues must be considered. The sequence of events for HIV infection by mucosal routes is generally similar. Initially, following inoculation, the virus must transverse host mucosal barriers, begin to expand locally, and, if successful in entering the blood, enter permissive cells and encounter a favorable environment for replication. The mucosal surface presents a significant barrier to infection, including the role of cervicomucous and the vaginal local microbiome in hindering viral translocation (41, 42). Data suggest that the cervicomucous may actively hinder viral translocation to the cervicovaginal mucosa (41). Once HIV reaches the mucosa, one virion or single-infected cell may be responsible for the ultimate infection in most cases (43). Disruption of these protections may result in increased susceptibility to viral transmission; this was demonstrated by the failure of the topical microbicide nonoxynol-9 in a clinical trial in which those participants that received nonoxynol-9 had a greater incidence of HIV infection than those receiving placebo (44). Awareness that topical pharmaceuticals must avoid chemical inflammation, mucosal disruption, or excessive alteration of the microbiome is now important part of product and study design for topical PrEP strategies. For oral PrEP, success is dependent on the pharmacology of the medications used. The NRTIs and the CCR5 antagonist, maraviroc, have demonstrated the greatest penetration into the cervicovaginal tissues as well as colorectal tissue in comparison with other antiretrovirals (45–47). Much of the work to date has involved the NRTIs TDF and FTC, both of which have favorable pharmacokinetics and concentrate in key tissues. In particular, the NRTI TDF, a prodrug, is metabolized to tenofovir (TFV), which has a plasma half-life of 17 h but undergoes two phosphorylation events to form TFV diphosphate (TFV-DP) with a half-life of 150–180 h in peripheral blood mononuclear cells. Additionally, prolonged and high concentrations of TFV and TFV-DP in rectal tissue are observed after oral dosing, with considerably lower concentrations observed in cervical and vaginal tissue. FTC and its metabolite FTC-TP in contrast have shorter plasma half-lives, much higher tissue concentrations in vaginal and cervical tissue, which is however detectable for only a short time after drug is stopped (10–14 days for FTC and up to 2 days for FTC-TP). These differences suggest that anatomical site is a strong consideration in formulation of medications and combinations of medication for PrEP (48, 49).

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Raltegravir (50), etravirine (51), and darunavir (52) also attain levels in the female genital tract and rectal mucosa greater than in the blood. Of note, drug distribution into mucosal tissues is not a class effect for any of the agents mentioned. For example, dolutegravir, a once-a-day integrase inhibitor, has a much lower female genital tract tissue penetration than raltegravir (53). Similarly, the NNRTI etravirine has considerably greater penetration in these tissue compartments when compared with another NNRTI, efavirenz (51, 52). There are many variables that affect distribution of drug to different tissues. Perfusion, molecular size, lipophilicity, intracellular partitioning, and protein binding are well known to impact tissue distribution (54, 55). Factors in the local tissue environment such as pH may modify the molecular state thereby affecting diffusion or transport potential. Once a drug reaches the site of action, it has to remain in both an active form and at a concentration sufficient to modify the HIV life cycle. For drugs that are modified intracellularly and have a long half-life, short-term variations in plasma levels may have a lesser impact on tissue concentrations. For example, the halflives of FTC and TDF are relatively long and produce significant single dose and steady-state concentration levels in the cervicovaginal fluid (56). However, many antiretrovirals move into and out of cells rapidly via transporters (57). The concentration of important drug transporter systems such as the ABC superfamily (ATP-binding cassette proteins) of which pglycoprotein (Pgp) plays a significant role, and the solute carrier proteins superfamily of transporters including the organic anion:cation transporters (OA:CT) affect movement of drug between compartments and into cells. Pgps are well-known transporters of antiretrovirals and in particular the protease inhibitors (PIs). The data are most robust for PIs and Pgp interactions (57). In particular, the PI darunavir increases the expression of surface Pgp and decreases efflux of drugs (58, 59). The data for new antiretrovirals are evolving, and transporter binding is not as well studied when compared with the PIs. In a number of studies, raltegravir did not change efflux of labeled markers or modify Pgp expression (58, 60). However, accumulation of intracellular raltegravir is increased in the presence of PIs (61), and growth inhibition assays were affected by raltegravir as were mRNA expression for ABC transporters in induction assays (62). Maraviroc, a drug that inhibits HIV binding to CCR5 and is being studied for PrEP in the Novel Exploration of TherapeuticsPrEP NIH-funded trial, increases transport function of ABCC2 (62). However, data from an early study also supported transport of maraviroc through Pgp with a decrease in cellular efflux in the presence of known inhibitors of Pgp (63), suggesting multiple egress transport paths. Many of the antiretrovirals interact with organic ion transporters that bring drug into the cell as well as with ABC transporters that move drug out of the cell. Although these interactions are critical to movement of drug through one surface and across to the contralateral surface, for example, they create a complex system when

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attempting to predict intracellular drug concentrations during nonsteady-state conditions (64, 65). In addition to the above considerations, distribution of transporter groups varies greatly in different anatomical sites (66, 67). The intestine is a site of considerable transporter activity. Although data on intestinal expression of transporters are emerging, the expression of transporters in cervicovaginal and rectal tissue critical to sexually transmitted HIV infection has not been as well studied. Available data suggest that Pgp and ABCC2 are higher in vaginal tissue when compared with colorectal tissue, and ABCC4 is higher in colorectal tissue than cervical tissue. The transporter OAT1 was not found in any tissue from the female genital tract but was present in all colorectal tissue (68). Because numerous studies monitor drug concentrations in the cervicovaginal fluid, the true cell concentrations may not be reflected in these measurements. Transporter expression varies by cell type and also varies due to single-nucleotide polymorphism (SNP) modifications. For Pgp, for example, identified SNPs modulate both expression and function of the transporter in intestinal tissue (69). However, studies of SNP linkages have not reported consistent correlations between expression and drug plasma concentrations (70). Remarkable racial differences have been observed in the MDR1 SNPs modulating transporter expression as well (71). Given the role of transporters in the distribution of antiretrovirals to key tissues, additional effort to understand the characteristics of these molecules in different tissues and populations will be important to the development of future PrEP interventions in diverse settings.

The Eclipse Phase and Viral Reservoirs Although PrEP aims to achieve steady-state intracellular concentrations of antivirals positioned to halt HIV replication in its early stages, successful nPEP depends on the ability of antivirals to intercept HIV replication before establishment of chronic infection. Thus, an understanding of the period between transit of one virion or single infected mucosal cell and seeding of critical reservoirs leading to established infection is important to understand the success and limitations of both PrEP and nPEP (43). The period of expansion and eventual entry into the blood is known as the eclipse phase, originally defined by the inability to measure virus in the blood by any of the available tests (72). During the eclipse period, the virus is relatively genetically homogeneous and has not yet established the reservoirs that prohibit pharmacologic cures. Because of the difficulties in identifying very early infection and pinpointing low levels of viral activity in tissues not easily amenable to sampling, a complete understanding of the viral seeding during the eclipse phase has been challenging to obtain. As such, information largely comes from macaque studies using defined SIV inoculum (73). Although limited, the data are instructive in terms of time frame for viral entry and spread, demonstrating that a productive local infection takes approximately 4–5 days to occur after which there seems to be almost uniformly meas-

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ureable virus in tissues distant from the site of infection. The number of animals studied and the simplicity of the drug regimen used for these experiments limit extrapolation to the exact timing needed for implementation of successful human PEP treatment. However, other studies evaluating viral hematogenous dissemination suggest that the window of time after exposure to begin PEP resulting in infection reduction is on the order of 4–5 days (73, 74). One confounding variable is that although spread to draining lymph nodes may occur within 1 day of exposure, the window of opportunity for treatment may be longer as the small founder population may not be able to produce productive infection (75). On entry into the blood, free virus will retain the ability to infect a permissive macrophage or CD4 cell expressing the coreceptor CCR5 to which it binds for 8 h (76). Cellassociated virus may survive for a significantly longer period of time (77, 78). Once a susceptible cell is infected, viral expansion occurs over a number of days and, if unchecked by antivirals, will result in a rapidly mutating viral swarm consisting of a large pool of virions with significant genetic diversity. At the early stages of hematogenous spread, the virus is still relatively homogenous and detectable in the blood stream with sensitive laboratory assays. For most infected individuals, peak viremia is typically high as is the set point established after the peak. Currently, three active antiretroviral medications are needed to adequately and reliably control viral replication in this now established infection. For patients who are considering PrEP or taking PrEP in a suboptimal manner, it is important to determine that the individual is not infected so that the possibility of developing resistance is mitigated (31). Initial variables that may influence viral establishment are proximity of a permissive cell, viral fitness, and local microenvironment that favors or inhibits transmission. Expansion depends on the virus’ ability to replicate in the T cell or macrophage and then release its prodigy to infect other cells. In addition, the virus integrates in a silent region of the host DNA, remaining latent and quiescent unless induced to activate and resume replication. It is these latent cells that contain the reservoir of virus that has not been able to be eradicated by antiretroviral therapy to date. The time it takes to establish these reservoirs is therefore critical in our understanding of prevention interventions. Although it is difficult to identify very early cases of primary HIV without frequent sampling of an uninfected population, data are accumulating that earlier treatment of an acutely infected individual results in improved virologic outcomes. For adults who are treated with combination antiretroviral therapy (cART) very early in primary HIV infection resulting in successful virological control for a prolonged period of time, data suggest that a significant proportion of individuals, estimated at 5–15%, may exhibit posttreatment control after cessation of cART (79–81). Recently, an infected newborn was started on cART 31 h after birth (82). Viral decay was followed on treatment and demonstrated a two-phase decay consistent with what is seen for treatment of infected individuals. Off therapy, the child has been negative

Prevention of HIV Infection Using PrEP and nPEP

for virus by PCR and antibody testing. In a recent abstract at the 6th International Workshop on HIV Persistence During Therapy held in Miami, it was reported that viral reservoirs were smaller in children treated early (0.5–4 m after birth) when compared with older children (83). These findings suggest that control of the HIV reservoirs is critical and best handled early after infection. The duration of therapy required to achieve post-treatment control in individuals treated early in infection is unclear, and there are no standardized markers currently available to identify patients who are likely to achieve such control after halting therapy. Furthermore, for those who do not achieve post-treatment control, interruptions in therapy have in some studies been found to be harmful to long-term immunological and virological outcomes (84). Nevertheless, the exciting possibility of post-treatment virological control after early antiretroviral therapy reveals the importance of the sequence of events occurring in acute infection and the potential for preventing this progression from viral encounter to chronic infection with antiretroviral medication. For nPEP, these data reinforce the importance of prompt initiation of antivirals after possible exposure and also support the argument that the period for potentially useful intervention, at least for some individuals, may be somewhat longer than the 3-day window period for beginning treatment suggested by the 2005 guidelines (85). Taking into consideration the length of the eclipse phase and that early treatment in infection may reduce reservoirs for those infected and produce better viral control argues for consideration of an enhanced window for initiating three-drug antiretroviral therapy as nPEP after an exposure. For individuals at high and repeated risk for sexual HIV transmission, strategies combining HIV testing and nonpharmacological strategies along with nPEP and possible transition to PrEP for appropriate candidates may be considered. Studies combining these strategies such as the PATH-PrEP study in Los Angeles are currently underway (75). Success for nPEP and PrEP interventions is defined as the inability of the virus to establish a productive long-lived infection. As described previously, establishment of infection, dissemination of the infection, and the establishment of reservoirs require a series of events to occur, and pharmaceutical strategies have been successful in interrupting this sequence to prevent infection. Building on this proof of concept, innovation to optimize the use of medications for this purpose in their biomedical properties as well as usability and feasibility will be essential to maximizing their impact on the HIV epidemic.

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