SECTION 2: PRE-EXPOSURE PROPHYLAXIS (PrEP) FOR THE PREVENTION OF HIV INFECTION

Katherine Frasca, MD

As Dr. Goldschmidt has mentioned, about 40,000 new HIV infections were diagnosed in the United States in 2015, the most recent year for which data are available. About two-thirds of these occurred in men who have had sex with men (MSM). Blacks/African Americans are at highest risk for HIV infection.[CDC HIV surveillance 2015] A recent study based on CDC data estimated that the lifetime risk of an HIV diagnosis in MSM was 16.7%, but in black/African American MSM this risk rose to 41.1%.[Hess 2017 ]

Section 2, Graphic 1. Lifetime risk of HIV diagnosis by risk group.[Adapted from Hess 2017]

Although the total number of new HIV diagnoses in 2015 represents an overall decrease from previous years, certain segments of the population experienced increases in the rate of new diagnoses, including persons 25 to 29 years of age. A concerning trend is that patients younger than 25 years of age account for over 20% of new diagnoses every year (Section 2, Graphic 2).[CDC HIV surveillance 2015] These individuals may not yet be open about their sexual orientation or activities, potentially creating an important barrier to care.

Section 2, Graphic 2. New US HIV diagnoses by age group. [Adapted from CDC HIV surveillance 2015]

Addressing these barriers to care plays a critical role in effective HIV treatment. About 20% of the HIV-infected population is unaware of their infection.[Gardner 2011] These individuals are believed to account for a significant proportion of new transmissions. The remaining 80% of HIV-infected individuals are aware of their infection, but only about half receive ongoing medical care.[Gardner 2011] The large drop-off between awareness and treatment reflects structural barriers, such as access to care and cost, as well as social issues, including social stigma, discrimination, and denial. The majority of patients who receive medical care achieve effective viral suppression,[Gardner 2011] further highlighting the need to effectively channel patients from diagnosis to appropriate care.

Both the groups who are undiagnosed and those who are diagnosed but are not retained in medical care represent key targets for prevention. A study based on 2009 HIV infections in the United States estimated that these 2 groups were responsible for 91.5% of the HIV transmissions that occurred during that year.[Skarbinski 2015] In other words, 9 in 10 new HIV infections could have been prevented through early diagnosis of HIV and ongoing treatment.

Fast Facts

Nine in ten new HIV infections could have been prevented through early diagnosis of HIV and ongoing treatment

Screening and Prevention

The first step in detecting and preventing HIV infection is screening. It is crucial to identify individuals at risk for STI through the use of language that removes stigma or judgment. Moreover, if you pose sexual health questions as part of an overall health assessment and don’t single them out, they can seem less intimidating to the patient. You can say to the patient (with a checklist), “I am going to ask a series of routine questions right now that cover a range of topics. This is what I ask all my patients. You can answer really openly; everything is confidential.”  It is better to use open-ended questions and not make any assumptions about someone’s sexual health or sexual identity. Recommended questions for the sexual health assessment include:

  • “How many current sexual partners do you have?”
  • “Do you have sex with men, women, or both?”
  • “Do you have oral, anal, or receptive sex?”
  • “How often do you use condoms with the above types of sex?”
  • “How often do you use substances (alcohol, drugs) prior to sex?”

A related area is substance-abuse screening, as injection drug users are also at increased risk for HIV infection due to shared needles. Right now, in certain cities, the cost of using IV drugs is less than the cost of street oral narcotics. It’s really important to recognize who might be a candidate for HIV prevention just from their substance abuse profile independent of their sexual behavior. Recommended questions for substance abuse screening include:

  • “How often do you use drugs that are not prescribed by a physician?”
  • “What kinds of drugs do you use?”
  • “How often do you inject drugs?”
  • “Have you ever been in a methadone maintenance or rehab program?”

Patients with or at risk of sexually transmitted disease should receive testing for HIV and other STI. We know that 30% to 60% of the subjects in the HIV PrEP studies came on board with an STI. If their HIV test is negative, then they should enter the HIV prevention continuum. Patients should be introduced to the prevention toolbox, including circumcision, PrEP, and safe sex practices (Section 2, Graphic 3). They should also be encouraged to take advantage of available counseling, support, and outreach services. Patient support should address mental health and substance abuse disorders, 2 important barriers to care. You will note that we have identified many of these supportive services provided by the Colorado Health Network right in your own area. Finally, adherence support is critical to successful prevention. In this context, adherence refers not only to medications such as PrEP, but also to continuing safe sex practices, such as condom use and repeat HIV testing as necessary.[McNairy 2014]

Section 2, Graphic 3. The HIV prevention continuum. [McNairy 2014][McNairy ML, El-Sadr WM. A paradigm shift: focus on the HIV prevention continuum. Clin Infect Dis. 2014;59(suppl 1):S12-S15, by permission of Oxford University Press.]

Case #2

A 20-year-old male comes to your office for a routine visit. When you ask about his sexual history, he reports sexual activity with multiple women without condom use. He also reports a 1-time episode of anal sex with a man. He has had multiple prior STIs including gonorrhea and chlamydia but currently is asymptomatic. He has never had a test for HIV infection.

Clinical Considerations

Which of the following is a reason to screen this patient for HIV?

  1. This patient should be screened because he has had multiple sexual partners without a condom
  2. This patient should be screened because he has had prior anal sex with a man
  3. This patient should be screened because he is 20 years old and has not been previously screened
  4. This patient should be screened because he has had a prior STI
  5. All of the above

Analysis

The correct answer is E, all of the above, with a special focus on his age and lack of previous screening. Since 2006, the CDC has recommended that screening for HIV infection be performed routinely for all patients aged 13 to 64 years (ie, at least 1 time in a lifetime if the HIV prevalence in the area is above 0.1%). Additional specific risk factors are not required,[Branson 2006] although they may increase the urgency of the recommended screening. Previous CDC screening recommendations were based on perceived risk, but it is estimated that risk-based testing missed as many as a quarter of infections because patients do not always disclose risky behavior.[Peterman 1996] Repeat screening is recommended at least annually for individuals at high risk for HIV, including injection-drug users and their sex partners, persons who exchange sex for money or drugs, sex partners of HIV-infected persons, and individuals who have had more than 1 sex partner, or whose sex partners have had more than 1 sex partner, since their most recent HIV test.[Branson 2006]

Screening should be instituted by an opt-out approach; a formal consent process is no longer required. Patients may, of course, refuse the test. As Dr. Goldschmidt discussed, the preferred laboratory test is a 4th-generation assay that detects both HIV antibodies and the p24 antigen.

How are these screening guidelines being applied in everyday practice? A 2009 survey of 367 clinician educators who were members of the Society of General Internal Medicine found that only 53% of respondents encouraged trainees to conduct routine HIV testing. Although most of the respondents were familiar with the CDC recommendations to test patients for HIV regardless of risk, more than a third continued to rely on risk-based testing strategies. As shown in Section 2, Graphic 4, several barriers to recommending routine testing were identified, including a low perceived local HIV prevalence and disagreement with the recommendations. [Berkenblit 2012]

Section 2, Graphic 4. Barriers to routine HIV testing in clinical practice.[Berkenblit 2012]

Even among patients with a diagnosed STI, such as chlamydia or gonorrhea, screening rates are disappointingly low. A study of Medicaid patients who had been diagnosed with an STI or with pelvic inflammatory disease found that only 43% had been screened for HIV.[Adekeye 2016] Suboptimal HIV screening represents missed opportunities to improve HIV prevention.

Fast Facts

A study of Medicaid patients who had been diagnosed with an STI or with pelvic inflammatory disease found that only 43% had been screened for HIV

Which Patients Should Receive PrEP?

Case #3

A 24-year-old man comes to your clinic for routine medical care. He has a history of multiple prior STIs (gonorrhea, syphilis) and reports a 1-time episode of unprotected anal sex with a man. He also has a history of brief heroin use, during which time he shared needles but quit a few months ago. He is asymptomatic today and has come to you for routine advice on how he can reduce his risk of HIV infection.

Clinical Considerations

Which of the following is NOT an indication for PrEP?

  1. Prior unprotected anal sex with a man (MSM)
  2. Shared injection equipment
  3. Recent STI
  4. Being a young adult between the ages of 20 and 30

Analysis

The answer is D. The only characteristic listed here that is not considered an indication for PrEP is age. PrEP refers to ARV medication taken by uninfected individuals to prevent the acquisition of HIV infection.[WHO HIV/AIDS website 2017] In 2012, the FDA approved the first drug for PrEP, an oral combination pill consisting of tenofovir/emtricitabine that is taken once daily.[USPHS PrEP guidelines2014] PrEP represents 1 piece of the prevention toolkit: it is NOT a replacement for condoms or other safe sex practices.

As shown in the Section 2, Graphic 5, guidelines published by the US Public Health Service and the CDC in 2014 list a number of high-risk categories that should prompt consideration of PrEP in HIV-negative individuals. Men who have sex with men are at highest risk; other factors to consider include unprotected sex, a high number of sexual partners, and shared injection paraphernalia. Injection drug use is also an indication for PrEP regardless of sexual risk factors. PrEP should only be offered to patients with a documented negative HIV test result, no signs/symptoms of acute HIV infection, normal renal function, no contraindicated medications, and documented HBV infection and vaccination status.[USPHS PrEP guidelines 2014]

A recent study estimated that, based on 2015 data, 1,232,000 individuals in the US met the criteria for PrEP based on their risk of potentially acquiring HIV infection.[Smith 2015] However, between 2012 and 2015 only approximately 80,000 US patients began treatment with PrEP.[Mera 2016 ] The gap between eligible patients and treated patients suggests that there is a significant need for PrEP education and integration into daily clinical practice.

Section 2, Graphic 5. Risk factors associated with substantial risk of acquiring HIV infection.[USPHS 2014]

A Closer Look at PrEP: The Evidence

The effectiveness of PrEP has been demonstrated in studies involving MSM and heterosexual populations (see Section 2, Graphic 6). The iPrEX study was a randomized international trial in which 2499 HIV-negative MSM and trans-gender women received treatment with placebo or tenofovir/emtricitabine once daily. During the course of the study (median follow-up of 1.2 years), there was a 44% reduction in HIV infections in the group treated with tenofovir/emtricitabine compared with the placebo group (95% CI 15 to 63; P=.005).[Grant 2010] In an open-label extension to this study that included analysis of drug concentrations in dried blood spots, there were no infections observed in individuals who took a minimum of 4 doses per week.[Grant 2014] The PROUD study was an open-label trial of MSM randomly assigned to receive tenofovir/emtricitabine immediately or after a deferral period of 1 year during routine clinical care. The study was stopped early due to clear evidence of PrEP efficacy. At the time, the trial was stopped, HIV infection had occurred in 3 of 243 patients in the immediate group compared with 20 of 222 patients in the deferred group, even though there were 174 prescriptions for PEP in the deferred group. The risk reduction was 86% (90% CI 64 to 96; P=.001). The authors calculated that 13 individuals would need to be treated to avoid 1 HIV infection.[McCormack 2016]

In the IPERGAY study, MSM were randomized to receive PrEP with tenofovir/emtricitabine or placebo before and after sexual activity (on-demand PrEP). This study also found a risk reduction of 86% for PrEP versus placebo (95% CI 40 to 98; P=.002). Of the 2 seroconversions that occurred in the PrEP arm, neither patient had detectable drug levels in plasma samples at the time of HIV diagnosis.[Molina 2015] Although PrEP was administered on demand in this study rather than taken daily, the median number of pills per month for trial participants was 15, or approximately 4 per week, [Molina 2015] so these subjects were essentially getting the same level of coverage as subjects who took the drug on a daily basis. The CDC therefore recommends daily PrEP, rather than PrEP administration on-demand or at the time of sexual activity, to ensure that appropriate coverage is achieved.

Fast Facts

In the iPrEX open-label extension, there were no infections observed in individuals who took a minimum of 4 doses per week.

Section 2, Graphic 6. Risk reduction for PrEP with tenofovir/emtricitabine versus placebo in randomized trials of MSM and transgender women.[Grant 2010;McCormack 2016;Molina 2015]

PrEP has also been found to be highly effective in preventing heterosexual transmission of HIV. Risk reductions relative to placebo ranged from 49% with tenofovir monotherapy, in a study conducted in Bangkok, to 75% with tenofovir/emtricitabine, in a study conducted in Kenya and Uganda.[Choopanya 2013; Baeten 2012; Thigpen 2012]

In addition to the potential value PrEP offers individuals by protecting them from HIV infection, PrEP also has significant societal and economic benefits. Each case of HIV infection costs between $325,000 and $435,000 (in 2012 US dollars) depending on the level of care.[Schackman 2015] A study that modeled the potential effects of different interventions based on current effectiveness data estimated that oral PrEP coverage of 40% of at-risk HIV-negative MSM over 10 years would prevent approximately 25% of new HIV infections. Increasing PrEP coverage rates to 80% would prevent an estimated 40% of new infections.[Sullivan 2012]

Fast Facts

Increasing PrEP coverage rates to 80% would prevent an estimated 40% of new infections

PrEP:  Adherence Is the Key to Success

PrEP adherence is critical to preventing HIV infection (Section 2, Graphic 7). In subjects with detectable drug in their blood, effectiveness is about 90% across a range of studies. The effectiveness rates drop across the study population as a whole owing to poor adherence. Studies with very low rates of adherence, including 2 studies of women in Africa, have shown poor outcomes.[Van Damme 2012; Marrazzo 2015] Rates of protection may also be lower in women because it can require up to 20 days of therapy for tenofovir to reach maximum levels in vaginal tissue. For anal mucosa, only 7 days is required.[USPHS PrEP guidelines 2014] Pharmacokinetic modeling studies suggest that 6 or 7 doses of tenofovir/emtricitabine per week are required to protect female genital tract tissue from HIV, whereas only 2 doses per week are required to protect colorectal tissue.[Cottrell 2016]

Section 2, Graphic 7. Impact of adherence on PrEP effectiveness TFV, tenofovir; FTC, emtricitabine

Several tools can help improve PrEP adherence. Patients should be counseled up front about what to expect from PrEP, including possible side effects and the importance of adherence. This discussion should include a review of methods that can be used to remind patients to take their PrEP medication, such as cell phone alarms or discreet pill bottles on a key chain so that the pills are always available. It is also important to address adherence barriers, such as substance abuse, mental health, and domestic abuse. Clinicians should be sure to involve other members of the healthcare team, including pharmacists, nurses, and social workers, in supporting and assessing the patient’s adherence. For instance, refill reminders from the pharmacy or periodic text messages may help improve adherence. As mentioned, our colleagues at the Colorado Health Network can assist with many of these supportive functions.

PrEP in Real-World Clinical Practice

Randomized trials do not always reflect the wide variety of patients and management practices found in routine clinical care. However, a recent US study based on data from the Kaiser Permanente Healthcare System found that PrEP is as effective in clinical practice settings as it is in randomized trials.[Volk 2015] Between 2012 and 2015, there were 835 in-person evaluations for PrEP based on 1045 referrals. Of the 801 unique individuals with at least 1 intake visit, 82% (657 subjects) initiated PrEP, 20 restarted PrEP, and 144 did not initiate PrEP. Reasons for not initiating PrEP included low risk for HIV, not wanting to do the required follow-up, preference for PEP, and concerns about cost, side effects, or increasing sexual risk behavior. Only a few individuals were ineligible for medical reasons. During the course of the study (388 person-years of follow-up), there were no HIV diagnoses reported in patients on PrEP, although many of these patients developed STIs during this time period.

PrEP Considerations and Contraindications

No therapy is entirely without concerns, and PrEP is no exception. One concern is the development of drug-resistant HIV mutations, which appears to be an important issue for HIV-infected patients who are not recognized as infected at the time of PrEP initiation. In the PROUD study, 2 of the 3 subjects who were subsequently identified as being infected at baseline developed resistance mutations at codon 184, which may have been related to treatment with emtricitabine. None of the participants developed mutations associated with tenofovir treatment.[McCormack 2016] Similarly, in the iPrEX study, 2 of the 2 subjects who were infected at enrollment developed emtricitabine-resistant infections, but no tenofovir-resistant infections were observed.[Grant 2010 p2597] These findings highlight the need to rule out acute HIV infection before initiating PrEP in high-risk populations. It is also important to counsel patients that PrEP is not 100% effective in preventing infection from resistant HIV viruses.

Fast Facts

It is important to rule out acute HIV infection before initiating PrEP in high-risk populations

Another potential concern is the impact of treatment on bone health. Decreases in bone mineral density (BMD) have been observed in some HIV-infected persons treated with combination antiretroviral therapy, including regimens containing tenofovir.[USPHS PrEP guidelines 2014] In two PrEP trials with tenofovir/emtricitabine in uninfected individuals, an approximately 1% decline was observed in BMD during the first few months of treatment. BMD levels generally stabilized thereafter and there were no increases in fragility fractures.[Mulligan 2015; Liu 2011] Because of the apparent minimal impact on bone health, bone scans are not recommended before initiating PrEP or during therapy. However, if a person being considered for PrEP has a history of fragility fractures or significant risk factors for osteoporosis, he or she should be referred for appropriate consultation and management.[USPHS PrEP guidelines 2014]

Case #4

A 30-year-old woman who has an HIV-positive partner and is interested in PrEP comes to your office. She tells you that she may have some underlying liver disease and has a history of mild kidney disease. She would like to become pregnant and is not on oral contraceptives.

Clinical Considerations

Which of the following is a contraindication to PrEP?

  1. Liver disease
  2. Renal disease
  3. Desire for pregnancy
  4. All of the above

Analysis

The correct answer is B, Renal disease. Decreases in renal function have been observed in HIV-infected patients on tenofovir-containing regimens, and in some cases acute renal failure has occurred. A creatinine clearance ≤60 mL/min is a contraindication for PrEP initiation.[USPHS PrEP guidelines 2014] Other important contraindications are the lack of a documented HIV negative test within the past 7 days or the presence of signs/symptoms of HIV infection, as initiating PrEP in an HIV-infected individual may lead to the emergence of treatment-resistant viruses. [USPHS 2014 PrEP guidelines 2014]

There are also precautions to be considered before initiating PrEP (Section 2, Graphic 8). All individuals should have a documented HBV and HCV infection status. Unvaccinated patients who are susceptible to HBV should be vaccinated. Tenofovir/emtricitabine is active against HBV, and it is important to know whether a subject has HBV prior to starting PrEP because HBV could flare up if treatment is started and then stopped. [USPHS 2014 PrEP guidelines 2014] Caution should also be used when considering the treatment of adolescents. Although PrEP is being studied in adolescents, no trials to date have included persons younger than 18 years of age. At this point in time, there are limited data on the effectiveness of PrEP in this age group or on potential safety issues, such as effects on bone in individuals who are still growing.[USPHS PrEP 2014 ] Pregnancy is another potential issue. PrEP use may continue during periconception and pregnancy and may help prevent transmission in the absence of other protective measures. However, data directly related to the safety of PrEP in the developing fetus are limited, so it is essential that the patient be involved in the decision to continue PrEP during conception or pregnancy. [USPHS PrEP guidelines 2014] Additional important precautions are shown in the following table.

Section 2, Graphic 8. PrEP contraindications and precautions.[adapted from USPHS PrEP guidelines 2014 PrEP guidelines]

PrEP Follow-up and Counseling

Counseling is a vital component of PrEP. Some of the key points that should be covered include:

    • How it works and part of a comprehensive prevention plan (barrier protection, risk reduction, needle exchange, etc)
    • Limitations: adherence dependent, not protective against other STIs, doesn’t eliminate risk
    • Medication counseling: proper way to take, side effects, reason for limited refills
    • Time until protection is achieved: need at least 7 days of daily dosing for rectal protection, 20 days for vaginal
    • Follow-up and laboratory testing
    • Symptoms of seroconversion/acute retroviral syndrome
    • Criteria for discontinuing PrEP

The US Public Health Service/CDC guidelines recommend a number of tests that should be performed at baseline and periodically throughout PrEP, including testing for HIV and STIs, as shown below.

Section 2, Graphic 9. Clinical screening, follow-up, and monitoring during PrEP. Adapted from the US Public Health Service/CDC PrEP guidelines.[USPHS PrEP guidelines, 2014]

This rather extensive list of monitoring requirements can be quite time-consuming during a clinical visit. Tools to save time in the PrEP clinic include asking patients to perform their own triple swabs (oral, and rectal, see the Figure below), provide their urine samples;  having a nurse or support staff member assist with obtaining the patient’s required blood work before the visit, utilizing a social worker or pharmacist for support counseling (including counseling on adherence and substance abuse), and creating templates for notes/checklists using the CDC guidelines.

Section 2, Graphic 10. San Francisco City Clinic patient instructions for performing oral and rectal swabs. [Pharyngeal swab 2017; Rectal self-swab 2017][Permission on request]

There are several reasons that a patient may discontinue PrEP, including an HIV-positive test or high clinical suspicion of acute retroviral syndrome, intolerable toxicity such as development of renal disease, chronic non-adherence, or lifestyle changes resulting in reduced risk of HIV transmission. If the person wishes to resume PrEP at a later time, they should undergo all of the pre-prescription evaluations recommended for a person being considered for a new prescription.

PrEP to PEP and Vice Versa

For patients who are adherent to PrEP, there is usually no need to intensify treatment by switching to PEP in the case of a serious exposure.[Grant and Smith 2015] However, treatment intensification could be considered if the patient takes PrEP sporadically.[Grant and Smith 2015] Dr Goldschmidt also recommends considering intensified treatment if serious exposure occurs during the first month of PrEP.

But what about going from PEP to PrEP? According to Dr Goldschmidt, persons at risk for HIV infection can be transitioned from PEP to PrEP if the repeat HIV test at 4 weeks is negative. False positives are a concern; if the patient has been adherent to PEP, the virus, if present, will likely be suppressed. Accordingly, the patient should be tested with both a 4th-generation HIV test and a test for viral load (HIV RNA), the laboratory marker that appears the earliest during HIV infection (see Section 1, Graphic 4).[Grant and Smith 2015] In addition, tests for STIs, renal and hepatic function, and pregnancy should be performed as for any patient initiating PrEP (see Section 2, Graphic 9).

High-risk persons should be transitioned from PEP to PrEP immediately at the end of the 28-day treatment period.[Grant and Smith 2015; University of California, San Francisco Clinician Consultation Center 2016] Although it is possible they may have an as-yet undetected HIV infection, the enhanced protection offered by a seamless transition to PrEP likely outweighs the potential risk of beginning PrEP with an HIV-positive status, which is contraindicated. Low-risk persons can wait to initiate PrEP until absence of HIV infection is fully confirmed.[University of California, San Francisco Clinician Consultation Center 2016] PEP should be re-instituted if there is a new exposure.

Conclusions

Primary care providers have readily available tools to assess the risk of HIV transmission. It is important to make sexual history a priority during healthcare encounters and understand the key HIV risk groups, including MSM and individuals with STIs or substance abuse problems. These are your patients—discussing risk behaviors can be challenging, but it is definitely worth it given the opportunity to prevent infection. Both PEP and PrEP have been demonstrated to be highly effective, but adherence is critical. Resources are available in your community to support PrEP and help prevent HIV transmission in your high-risk patients.