Rates of HIV in the United States have remained stable since 2008, with an estimated incidence of 50,000 new infections per year. Men who have sex with men (MSM), particularly ethnic minority MSM, are disproportionally affected by HIV. Black and Hispanic MSM had a 12% increase in new HIV infections between 2008 and 2010, and represent the only group with an increasing incidence.1 Young, black MSM (ages 13 to 24 years) in particular account for 55% of new HIV infections among young MSM (defined as ages 13 to 24 years).1 Rates of HIV among heterosexual women have decreased 21% since 2008, but still account for nearly 10,000 infections annually; black women are disproportionally affected.1 Without an HIV cure or vaccine candidate in the foreseeable future, efforts toward effective and available prevention strategies are urgently needed.
Condom use and behavior modification counseling have had a limited effect in curbing the HIV epidemic. Condom use cannot always be negotiated, and when condoms are not used consistently and correctly during every sexual act, they serve no benefit for HIV prevention.2 Recently, the AWARE trial randomized participants presenting to a sexually transmitted infection (STI) clinic for HIV testing to receive information only or risk-reduction counseling. Six months after study entry, participants who received risk-reduction counseling had no significant reduction in STIs or HIV incidence compared with those who received information only.3
The concept of using antiretroviral drugs to prevent HIV infection is not new. Prevention of maternal-to-child HIV transmission occurred in the ACTG-076 trial, in which pregnant HIV-positive women were randomized to receive zidovudine (also called AZT) or placebo antepartum and intrapartum. After birth, zidovudine or placebo was administered to the newborn for 6 weeks postpartum. The study demonstrated a 67% reduction in transmission from HIV-infected mothers to their children.4
Other methods of antiretroviral administration also have been used to reduce HIV infection. For example, HIV-negative patients can take antiretroviral drugs as postexposure prophylaxis (PEP) after a potential HIV exposure.5 Treatment as prevention (TasP) is the use of antiretroviral drugs by HIV-positive patients to reduce HIV transmission. The HPTN-052 trial randomized HIV-positive patients with HIV-negative partners to receive antiretroviral drugs immediately or delay initiation until the drugs were clinically indicated as defined by local standard of care at the time. Initiating antiretroviral drugs immediately reduced sexual transmission by 96%.6 Antiretroviral drugs for preventing maternal-to-child transmission, PEP, and TasP have been previously described.7
Preexposure prophylaxis (PrEP) is the use of oral antiretroviral drugs by HIV-negative patients to reduce the risk of becoming infected with HIV. In 2012, the FDA approved the combined use of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) as HIV PrEP for use among HIV-negative heterosexual men and women and MSM. This article reviews the clinical application of PrEP and discusses the ethical and public health concerns associated with its use.
Four randomized, placebo-controlled clinical trials have demonstrated that TDF, with or without FTC, is effective for HIV prevention in different patient groups and in variable settings (Table 1).
- The iPrEx trial enrolled 2,499 HIV-negative MSM and transgender women who have sex with men at sites in the United States and internationally. Participants were randomized to receive FTC/TDF or placebo once daily alongside a standard prevention package including condoms, treatment of STIs, and risk-reduction counseling. Thirty-six participants in the FTC/TDF arm became infected with HIV during the study, and 64 participants in the placebo arm became infected, demonstrating a 44% reduction in new HIV infections among those in the FTC/TDF study arm. Among participants taking FTC/TDF, the only significantly increased adverse reactions were unintentional weight loss and nausea. Among participants who were uninfected at enrollment and who became infected during the study, no viral resistance was detected in participants taking FTC/TDF.8
- The Partners PrEP trial enrolled the HIV-negative partner of a serodiscordant relationship (a relationship in which one partner is HIV-positive and one partner is HIV-negative) in Africa to receive FTC/TDF, TDF alone, or placebo. Among a subgroup of 198 participants who did not become HIV-positive, 82% of plasma samples contained detectable levels of TDF, indicating adherence to the regimen. TDF alone was 62% effective and FTC/TDF was 73% effective. No statistically significant difference was found between the efficacy of TDF alone compared with FTC/TDF.9
- The TDF2 Trial in Botswana enrolled heterosexual men and women and demonstrated 62% efficacy among those randomized to FTC/TDF.10
- The Bangkok Tenofovir Study randomized IV drug users to daily TDF or placebo. Participants were on directly observed therapy 86.9% of the time. The study demonstrated that TDF was 49% effective in preventing HIV acquisition in this population.11
Not all PrEP studies have demonstrated efficacy. The Fem-PrEP trial randomized 2,120 HIV-negative women in Africa to FTC/TDF or placebo and was stopped early because of lack of efficacy. Among women who became infected in the FTC/TDF study arm, 15% had detected drug levels at beginning and end of the infection window. Only 40% of matched women who remained uninfected in the study arm had detectable drug levels.12
The VOICE trial randomized 3,013 HIV-negative women in Africa to FTC/TDF, TDF alone, or placebo within the context of a larger study. This trial also stopped early due to lack of efficacy. Fewer than 30% of participants had detectable drug levels.13 Low adherence reduced the ability of these trials to demonstrate efficacy of FTC/TDF, and additional factors also may have contributed.
EFFICACY AND ADHERENCE
Each study showed significantly higher efficacy among the most adherent participants and those with detectable levels of the study drug. Among iPrEx participants with drug detected in their blood (through the same method as the Partners PrEP Study), a 95% reduction was seen in post hoc analyses.8 Partners PrEP, TDF2, and the Bangkok Tenofovir Study, respectively, demonstrated 86% to 90%, 78%, and 70% efficacy among participants with detected drug levels (Table 1).9-11 In the iPrEx study, pill use of 90% or more was recorded at only half of participants' visits.8
The iPrEx study explored who will use PrEP, how patients will use it, and the relationship between adherence and efficacy. The study offered the HIV-negative participants of three randomized preexposure prophylaxis clinical trials the option to continue tenofovir disoproxil fumarate and FTC, or to continue follow-up without antiretroviral therapy. The 1,603 participants mostly originated from the iPrEx study and participated in a study design affording the investigators a more realistic picture of PrEP use among MSM and transgender women. In this study, those choosing to receive PrEP were more likely to have condomless receptive anal intercourse and serologic evidence of herpes simplex virus. Adherence and efficacy were assessed through the more accurate concentration of tenofovir diphosphate measured in a dried blood spot alongside HIV serologic screening. No study participants whose tenofovir diphosphate concentration suggested more than 4 tablets a week acquired HIV, translating to a statistical efficacy of about 85%. Younger age and the experience of stigma associated with PrEP use from peers and healthcare professionals threatened adherence to PrEP among participants.14
INDICATIONS FOR PREEXPOSURE PROPHYLAXIS
FTC/TDF tablet by mouth once daily is indicated for the prevention of sexual HIV acquisition among heterosexual men and women and MSM at substantial, ongoing, high risk for acquiring HIV infection (Table 2). Providers and patients should be aware that PrEP is a significant undertaking requiring frequent visits with HIV and STI screening, laboratory testing, and adherence and risk-reduction counseling.
Appropriate screening for HIV, hepatitis B and C, and other STIs is required before starting patients on PrEP. Patients with known recent exposure or signs and symptoms of acute HIV syndrome should be screened by viral load (HIV RNA) testing and/or have PrEP initiation delayed. Signs and symptoms of acute HIV syndrome (Table 3) are common and often mistaken for other viral illness. Viral load testing detects HIV 1 to 3 weeks earlier than recombinant enzyme-linked immunosorbent assays (ELISAs), which are typically negative during acute infection. HIV RNA has a relatively high cost and is not typically used for screening for HIV.15 In high-risk groups, a fourth-generation HIV screening test that detects HIV Ab and HIV p24 antigen should be used within 7 days before starting PrEP.16
PREP INITIATION AND FOLLOW-UP
A 90-day prescription without refills encourages patients to return for appropriate follow-up. Follow-up every 3 months is important to ensure that the patient remains HIV-negative, as well as to monitor use of PrEP, monitor renal function, screen for STIs, and provide condoms and counseling. The CDC's guidance on prescribing PrEP is summarized in Table 4.17,18 The CDC recommends using FTC/TDF rather than TDF alone because trials have not shown any increase in toxicity with the addition of FTC.17,18 FTC/TDF for HIV PrEP among IV drug users is off-label.
Among PrEP trial participants, no increased frequency of serious adverse reactions was reported among those randomized to FTC/TDF. Mild-to-moderate nausea was seen among participants in each PrEP trial. Other significant adverse reactions include unintentional weight loss (5% or more of total body weight), dizziness, fatigue, neutropenia, mild ALT elevations, vomiting, and other gastrointestinal adverse reactions such as gas and abdominal pain. These adverse reactions generally lessened or resolved after the first month of therapy.8-11 TDF has been associated with proximal renal tubular dysfunction and decreased bone mineral density.19 A small decrease in bone mineral density was seen with FTC/TDF use in the PrEP randomized controlled trials; however, no clinical manifestation (such as increased risk of fracture) was seen among study participants. A trend toward increased creatinine was seen in the iPrEx study, but was not statistically significant.8 Adverse reactions in the randomized controlled trials are limited to those identified within a limited time span (iPrEx participants were enrolled a mean of 1.2 years with a maximum of 2.8 years); on the other hand, adverse reactions such as bone fractures may take many years to manifest.8
PHARMACOLOGY AND DRUG INTERACTIONS
TDF and FTC are nucleotide/nucleoside reverse transcriptase inhibitors, which interfere in the reverse transcriptase step of HIV viral replication. TDF and FTC are excreted by the kidneys. Coadministration with acyclovir, adefovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides, and high-dose or multiple NSAIDs can increase concentrations of TDF, FTC, or the coadministered drug. Consider alternates to these drugs in patients with risk of renal dysfunction.20 TDF does not interact with or alter the pharmacokinetics or pharmacodynamics of methadone.21
PREP AND HEPATITIS B VIRUS
TDF and FTC have antihepatitis B virus activity. TDF is about 70% effective in virally suppressing hepatitis B and causing histologic improvement, defined as a reduction of 2 or more points in the Knodell necroinflammatory score without an increase in fibrosis.22 Tenofovir 300 mg daily (the same dose indicated for PrEP) is approved for use in chronic hepatitis B infection. FTC is used off-label to treat chronic hepatitis B. If PrEP is discontinued in a patient with hepatitis B, appropriate hepatitis B therapy should strongly be considered to prevent viral resurgence.22 In some patients, viral resurgence may progress to fulminant liver failure, especially if the patient has underlying cirrhosis and HIV coinfection.23 Neither TDF nor FTC has activity against hepatitis C virus.
HIV has poor replication fidelity, meaning that in an untreated patient, viral mutations are present in high numbers. Because these mutations are less fit, they do not become the predominant viral type. However, if viral replication continues in the presence of an antiretroviral drug, mutations resistant to that drug may become the dominant type. For this reason, three or more drugs from separate drug classes are used to treat patients with HIV.
FTC/TDF is two drugs of the same class, so a patient using PrEP who becomes infected with HIV could develop a viral strain resistant to FTC and/or TDF. Drug resistance limits patients' future antiretroviral treatment options, leading to more complicated regimens with a greater pill burden and increased potential for adverse reactions.
The potential for resistance developing from PrEP has been observed in animal studies; however, viral resistance was not shown in HIV-negative participants assigned to the study drug arm of each randomized controlled trial who acquired HIV during the study period.24 In the iPrEx study, 36 men in the FTC/TDF study arm became infected with HIV (only three had detectable drug levels, indicating that most patients who became infected on the study drug were nonadherent, limiting the potential for development of resistance). Among study participants who were found to have undetected HIV at enrollment (that is, participants who were seroconverting at trial entry, and whose tests did not identify early infection), resistance to the study drugs was identified. Both iPrEx participants found to have HIV at enrollment developed resistance to FTC; none developed resistance to TDF.8 Of eight Partners PrEP study participants found to have HIV at baseline, one participant developed resistance to FTC and another resistance to TDF.9 One participant in the TDF2 trial was found to have previously undetected HIV at baseline, and developed resistance to FTC and TDF.10 No Bangkok TDF study participants had undetected HIV at enrollment.11 Mathematical modeling has determined that PrEP use would likely result in a modest increase of HIV resistance prevalence (less than 10%), and that this increase is most dependent on the amount of inadvertent PrEP use among HIV-infected patients.25 Adequate and frequent screening for HIV (as previously discussed) and strict adherence are essential for patients to avoid development of resistant HIV. Additionally, FTC/TDF efficacy could be reduced if a patient is exposed to a virus resistant to these drugs.26
TREATMENT AS PREVENTION AND PREP
Antiretroviral therapy offers HIV-positive patients a life expectancy approaching that of the general population, and also may reduce HIV transmission up to 96% in heterosexual serodiscordant couples.6,27 Provision of PrEP should include an assessment of the patient's sexual partner(s), and if any partners are known to be HIV-positive, referral into care when appropriate. Although TasP is extremely effective, only a quarter of HIV-positive patients are maintaining viral suppression on antiretroviral therapy, and 20% of HIV-infected patients are unaware of their status.1 Although reduction of HIV transmission risk is a consideration, antiretroviral therapy should only be initiated when HIV-positive patients and their healthcare providers determine that therapy is appropriate and that patients are ready, willing, and able to adhere to treatment. Treatment as prevention data reflects mostly heterosexual couples, with limited information on the role of treatment as prevention for anal intercourse and among MSM. Recent data from an early analysis of the PARTNER study, which followed 282 MSM in serodiscordant couples for a median of 1.5 years of condomless sex, found zero HIV transmissions occurred when the HIV-infected partner was on antiretroviral therapy.28 Epidemiologic and biologic plausibility research shows that antiretroviral therapy reduces rectal HIV transmission, although it may not be as robust as the reduction in patients who have vaginal sex, and could be offset by increased risk taking due to decreased perceived risk.29
PUBLIC HEALTH ANALYSIS
FTC/TDF (Truvada) is under patent until 2017 and has an annual wholesale cost listed at over $13,000. PrEP also incurs costs related to laboratory work, office visits, and management of complications. Whether the high cost of PrEP is unreasonable is a source of debate. Several models have attempted to provide insight into how the economics and epidemiology of HIV will be affected by PrEP.
The wide range of estimates reflects varied methodology that includes factoring different indirect costs, PrEP efficacy, and participants' level of HIV risk. Most models use quality adjusted life years (QALYs), which define a dollar value for each quality life year gained. A value of $50,000 to 100,000 per QALY is generally accepted as cost-effective; a value of more than $300,000 per QALY is generally accepted in the United States as exceeding the cost-benefit threshold.30 Paltiel and colleagues simulated a group of MSM, mean age of 34 years, with 1.6% mean annual incidence of HIV infection, and showed that a 50% efficacy of PrEP reduced lifetime risk of HIV from 44% to 25% and increased life expectancy from 39.9 to 40.7 years, with an incremental cost-effectiveness ratio of $298,000 per QALY gained.31 Juusola and colleagues found that initiating PrEP in 20% of MSM in the United States would reduce infections by 13% and cost $550,166 per QALY over a 20-year period. The cost per QALY improves only if its use is limited to the most high-risk MSM at $172,091. These studies did not account for indirect effects secondary to reduced HIV incidence among those not taking PrEP, which would produce a more favorable QALY.32
Desai and colleagues developed a model that considers secondary and tertiary HIV prevention. Twenty-five percent of MSM using a 50% effective PrEP regimen with 50% adherence could achieve an incremental cost of $31,972 per QALY. Widespread use of PrEP reduced HIV infections, which also benefitted MSM not taking PrEP. If 15,000 MSM use PrEP for a 5-year period, the cost could reach $900 million.33
A review of these three trials show PrEP to be more cost-effective among highest-risk MSM, characterized as those of younger age, having five or more annual sexual partners, and not regularly screened for HIV. However, even a small increase in risk taking could offset the cost efficacy. Among the general MSM population, PrEP is consistently found to exceed what many in public health would consider cost-effective.34 Models of cost-efficacy among heterosexual men and women are limited to an African setting with significantly higher HIV prevalence and lower drug cost than the United States.
PrEP cost efficacy is most dependent on the population using the strategy and the manner in which it is used. The strongest indication for PrEP is for patients having unprotected sex with persons living with or at high risk for HIV, especially if an HIV-positive partner is not using TasP. Two scenarios pose a major threat to the cost-benefit analysis of PrEP:
- Low-risk patients (those who consistently use other methods of HIV protection, including condoms) who desire PrEP for an added layer of protection. Risk assessment and HIV transmission counseling can help ensure that PrEP is reserved for high-risk patients.
- Risky sexual behavior or minimal adherence to antiretroviral therapy by patients using PrEP. This concern is explored in greater detail in the next section.
Risk and responsibility
The theory of risk compensation posits that patients maintain an average level of risk that they find acceptable, and when an intervention such as PrEP reduces their risk of acquiring HIV, they will take increased risks in other aspects of their behavior.35 For example, patients may increase their number of sexual partners or use condoms less frequently. This behavioral phenomenon is not unique to sexual settings; for example, when people wear bicycle helmets and seat belts, speed and accident risk may increase.36
Risk compensation could offset the benefits of PrEP in certain contexts. Desai and colleagues suggested that a 4.1% increase in the annual number of new sexual partners in an MSM population could fully offset the population-level benefit of PrEP.33 Additionally, if patients using PrEP increase risky sexual behavior, rates of other STIs such as syphilis, gonorrhea, Chlamydia, and viral hepatitis could increase.
The concerns of risk compensation have not been realized within the placebo-controlled randomized clinical trials of PrEP. Participants in the iPrEx study reported increased condom use and decreased number of sexual partners after enrollment and showed no increased rates of STIs.8 Social desirability and recall bias may have influenced participants' reported sexual experiences. Additionally, the study design itself could have created an experience that brought about safer sexual practices, due to the possibility of placebo drug and a level of HIV counseling unlikely to be practiced outside the study. Interestingly, iPrEx study participants who believed they were randomized to FTC/TDF showed no increased rates of receptive anal intercourse without condoms compared with baseline through follow-up, and did not decrease their rates of receptive anal intercourse after stopping the study drug. Researchers hypothesize that PrEP could serve as a daily reminder of imminent HIV risk and result in a reduction of risky behavior as demonstrated among these participants.37
Several investigators have attempted to quantify the change in risk behavior that PrEP might engender. A study interviewing 25 serodiscordant MSM couples (50 total participants), mostly of low socioeconomic class and high recreational drug use, sought their possible behavioral response to PrEP if it were 90% effective. Most men (64%) described ways that their sexual behaviors would likely change with the adoption of PrEP. Many of these changes were in the direction of greater risk taking. Additionally, 60% of participants would decrease or abandon condom use.38 In another survey of 180 MSM, 69% of participants reported that they would use PrEP known to be 80% effective, and 35% of participants who reported being likely to use PrEP responded that they would be less likely to use a condom.39 These small survey-based studies have limitations, including that participants might not represent the population for which PrEP is targeted.
Patients have a responsibility to use less-costly safer-sex methods, including condoms, and the community should not have to use valuable HIV treatment resources and healthcare dollars on persons not living with HIV.40 This understanding of practicing safer sex and responsibility ignores the powerful social and cultural forces influencing patients' ability to act safely. These influential forces, beyond the scope of this review, include structural violence, coercion, cultural and biological desires for sexual intimacy, addiction, and substance abuse. The idea of responsibility in PrEP extends well beyond the patient at risk for HIV. Also, what responsibility does the community have to offer HIV prevention services that may be more costly and aggressive than what is typically allocated toward prevention and QALY gained? The idea that risk for HIV infection is associated with socioeconomics, addiction, and discrimination is well documented.41 And the history of HIV treatment and prevention was initially lackluster in the United States. Given these circumstances, the larger community may have a responsibility to dedicate healthcare resources to prevent HIV transmission at a level above what is generally considered standard for most health conditions.
PREP AS HARM REDUCTION
Results of PrEP clinical trials alongside the aforementioned HPTN-052 and PARTNER data suggest that PrEP will mostly be used as a form of harm reduction in the United States.6,28 The goal of harm reduction is to reduce the harmful consequences of a behavior; however, it does not primarily seek to reduce the behavior itself.42 PrEP involves the dedication of public health resources toward an intervention that is not focused on eliminating condomless sex, but reducing the risk of HIV transmission during sex. This carries obvious controversy, because unlike colon or skin cancer prevention, harm reduction commits itself to a set of values that are not neutral. Also, as discussed earlier, PrEP and other harm reduction methods may lead to a complex scenario where patients feel safe and increase risky behavior, leading to overall harm through risk compensation.38-39
Trying to improve the public health through harm reduction does not necessarily reduce overall harm. The concepts of micro and macro harm help us form a utilitarian assessment of PrEP. This prevention strategy aims to reduce HIV transmission during each episode of sex (micro harm). This does not account for PrEP's influence on harms outside of the individual sex act (for example, an increase in sex frequency and the associated economic costs [macro harm]) such as increases in STIs and HIV transmission.
Another macro harm that may apply to patients not participating in PrEP is the redirection of healthcare resources toward PrEP. For example, certain regions in the United States have a shortage of healthcare providers who treat patients with HIV, who likely will need to be involved in certain aspects of PrEP management. Unfortunately, identifying and quantifying all potential harms involved can be difficult.
Oral PrEP has recently been demonstrated as an effective intervention for the prevention of HIV when used with classic prevention strategies including condoms. MSM, heterosexual men and women, and IV drug users may benefit from PrEP. Clinicians must recognize the limitations imposed by cost, adverse reactions, and need for routine monitoring. Strategies should be used so that PrEP is not prescribed for patients in low-risk serodiscordant relationships or those seeking to satisfy sexual anxieties. These groups can address their prevention concerns in a manner that offers fewer economic and health consequences.
This analysis suggests that PrEP may primarily be used as a form of harm reduction for people engaged in high-risk condomless sex in the United States. We must keep in mind that, “PrEP, unlike treatment as prevention and condoms, uniquely empowers the receptive partner.”43 For PrEP to be effective, the potential long-term and costly antiretroviral drug toxicities and increases in risky behavior must not be realized. Clinicians prescribing PrEP must actively pursue additional methods to reduce risk factors for HIV alongside PrEP. The results of this inquiry will hopefully engender policy that safeguards the vulnerable communities affected by HIV, while creating a sustainable, equitable, and successful prevention campaign.
1. Centers for Disease Control and Prevention. HIV
in the United States: at a glance. November 2013. http://www.cdc.gov/hiv/pdf/statistics_basics_factsheet.pdf
. Accessed August 26, 2014.
2. Smith D, Herbst J, Zhang X, et al. Condom efficacy by consistency of use among MSM: US. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, abstract 32, 2013.
3. Metsch LR, Feaster DJ, Gooden L, et al. Effect of risk-reduction counseling with rapid HIV
testing on risk of acquiring sexually transmitted infections: the AWARE randomized clinical trial. JAMA
4. Connor EM, Mofenson LM. Zidovudine for the reduction of perinatal human immunodeficiency virus transmission: pediatric AIDS Clinical Trials Group Protocol 076—results and treatment recommendations. Pediatr Infect Dis J
5. Smith DK, Grohskopf LA, Black RJ, et al. Antiretroviral
postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational exposure to HIV
in the United States: recommendations from the U.S. Department of Health and Human Services. MMWR Recomm Rep
6. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV
-1 infection with early antiretroviral
therapy. N Engl J Med
7. Baker J. Stay current with options for HIV
8. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV
prevention in men who have sex with men. N Engl J Med
9. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral
prophylaxis for HIV
prevention in heterosexual men and women. N Engl J Med
10. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral
preexposure prophylaxis for heterosexual HIV
transmission in Botswana. N Engl J Med
11. Choopanya K, Martin M, Suntharasamai P, et al. Antiretroviral
prophylaxis for HIV
infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir
Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet
12. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV
infection among African women. N Engl J Med
13. Marrazzo J, Ramjee G, Nai G, et al. Pre-exposure prophylaxis for HIV
in women: daily oral tenofovir
, oral tenofovir
/emtricitabine, or vaginal tenofovir
gel in the VOICE study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, GA, 2013.
14. Grant RM, Anderson PL, McMahan V, et al. Uptake of pre-exposure prophylaxis, sexual practices, and HIV
incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect Dis
15. Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med
16. Pandori MW, Hackett J Jr, Louie B, et al. Assessment of the ability of a fourth-generation immunoassay for human immunodeficiency virus (HIV
) antibody and p24 antigen to detect both acute and recent HIV
infections in a high-risk setting. J Clin Microbiol
17. US Public Health Service. Centers for Disease Control and Prevention. Preexposure prophylaxis for the prevention of HIV
infection in the US—2014: a clinical practice guideline. http://www.cdc.gov/hiv/prevention/research/prep
. Accessed September 24, 2014.
18. US Public Health Service. Centers for Disease Control and Prevention. Preexposure prophylaxis for the prevention of HIV
infection in the US—2014: a clinical providers supplement. http://www.cdc.gov/hiv/prevention/research/prep
. Accessed September 24, 2014.
19. Calmy A, Fux CA, Norris R, et al. Low bone mineral density, renal dysfunction, and fracture risk in HIV
infection: a cross-sectional study. J Infect Dis
20. Gilead Sciences. Truvada (emtricitabine and tenofovir
disoproxil fumarate) prescribing information. December 2013.
21. Smith PF, Kearney BP, Liaw S, et al. Effect of tenofovir
disoproxil fumarate on the pharmacokinetics and pharmacodynamics of total, R-, and S-methadone. Pharmacotherapy
22. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir
disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med
23. Bessesen M, Ives D, Condreay L, et al. Chronic active hepatitis B exacerbations in human immunodeficiency virus-infected patients following development of resistance to or withdrawal of lamivudine. Clin Infect Dis
24. García-Lerma JG, Otten RA, Qari SH, et al. Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir
. PLoS Med
25. Abbas UL, Hood G, Wetzel AW, Mellors JW. Factors influencing the emergence and spread of HIV
drug resistance arising from rollout of antiretroviral
pre-exposure prophylaxis (PrEP). PLoS One
26. Cong ME, Mitchell J, Sweeney E, et al. Prophylactic efficacy of oral emtricitabine and tenofovir
disoproxil fumarate combination therapy against a tenofovir
-resistant simian/human immunodeficiency virus containing the K65R mutation in macaques. J Infect Dis
27. Samji H, Cescon A, Hogg RS, et al. Closing the gap: Increases in life expectancy among treated HIV
-positive individuals in the United States and Canada. PloS One
28. Rodger A, Bruun T, Cambiano V, et al.HIV
transmission risk through condomless sex if HIV
+ partner on suppressive ART: PARTNER study. 21st Conference on Retroviruses and Opportunistic Infections. Abstract 153 LB. Boston, MA, March 4, 2014.
29. Muessig KE, Smith MK, Powers KA, et al. Does ART prevent HIV
transmission among MSM. AIDS
30. Braithwaite RS, Meltzer DO, King JT Jr, et al. What does the value of modern medicine say about the $50,000 per quality-adjusted life-year decision rule. Med Care
31. Paltiel AD, Freedberg KA, Scott CA, et al. HIV
preexposure prophylaxis in the United States: impact on lifetime infection risk, clinical outcomes, and cost-effectiveness. Clin Infect Dis
32. Juusola JL, Brandeau ML, Owens DK, Bendavid E. The cost-effectiveness of preexposure prophylaxis for HIV
prevention in the United States in men who have sex with men. Ann Intern Med
33. Desai K, Sansom SL, Ackers ML, et al. Modeling the impact of HIV
chemoprophylaxis strategies among men who have sex with men in the United States: HIV
infections prevented and cost-effectiveness. AIDS
34. Schackman BR, Eggman AA. Cost-effectiveness of pre-exposure prophylaxis for HIV
: a review. Curr Opin HIV AIDS
35. Wilde GJ. Beyond the concept of risk homeostasis: suggestions for research and application towards the prevention of accidents and lifestyle-related disease. Accid Anal Prev
36. Richens J, Imrie J, Copas A. Condoms and seat belts: the parallels and the lessons. Lancet
37. Marcus JL, Glidden DV, Mayer KH, et al. No evidence of sexual risk compensation in the iPrEx trial of daily oral HIV
preexposure prophylaxis. PloS One
38. Brooks RA, Landovitz RJ, Kaplan RL, et al. Sexual risk behaviors and acceptability of HIV
pre-exposure prophylaxis among HIV
-negative gay and bisexual men in serodiscordant relationships: a mixed methods study. AIDS Patient Care STDS
39. Golub SA, Kowalczyk W, Weinberger CL, Parsons JT. Preexposure prophylaxis and predicted condom use among high-risk men who have sex with men. J Acquir Immune Defic Syndr
40. O'Hara KM. Pre-exposure prophylaxis: where HIV
prevention and responsibility intersect. JAAPA
41. Stall R, Mills TC, Williamson J, et al. Association of co-occurring psychosocial health problems and increased vulnerability to HIV
/AIDS among urban men who have sex with men. Am J Public Health
42. MacCoun RJ. Toward a psychology of harm reduction
. Am Psychol
43. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir
gel, an antiretroviral
microbicide, for the prevention of HIV
infection in women. Science