1. PrEP and PEP for HIV: Before and After Prevention
Fourth annual USC college of nursing clinical practice conference
Sabra S. Custer, DNP, MS, FNP-BC
Clinical associate Professor, College of Nursing
PrEP slides originally by Divya Ahuja, MD
Associate professor, school of medicine

2. Annual HIV Incidence
There are approximately 50,000 new infections in the US each year
Homosexual men (MSMs), particularly young, African-American MSMs are disproportionately affected
African-Americans in general are disproportionately affected

3. HIV Prevention Efforts
Abstain, Be faithful, Condoms, Counseling & testing
ABC
Immunization I C
Circumcision
HSV-2 suppressive treatment H
From plenary session titled “Microbicides and Other Prevention Technologies” by Gita Ramjee, PhD. D
Diaphragms
Genital tract
infection control G E F
Exposure prophylaxis (MTCT, PEP, PrEP)
Female-controlled microbicides
Ramjee G. XVI IAC, Toronto 2006, #TUPL02

4. Pre-exposure prophylaxis
PrEP
Pre-exposure prophylaxis

5. PrEP Timeline Clinical Practice Guideline for PrEP August 2012 TDF2
Partners PrEP
June 2013
Bangkok TDF Study
November 2010
iPrEx
July 2012
FEM-PrEP
March 2013
VOICE
June 2013
CDC Interim Guidance:
PrEP for IDU
July 2012
FDA Approval
TDF/FTC PrEP
This is a timeline for selected PrEP research, shown with green arrows above the timeline, and approval and guidance documents for PrEP, shown with blue arrows below the line.
iPrEx studied TDF/FTC as PrEP in MSM and male-to-female transgender women. Those who took PrEP were less likely to be infected with HIV.
FEM-PrEP, a study testing TDF/FTC oral daily as PrEP in females was stopped due to inability to determine effectiveness: there were equal numbers of infections in the TDF/FTC and the placebo arms. These results were thought to be related to adherence, and were published in July 2012.
VOICE, a study testing 3 regimens for PrEP in females: oral TDF, intravaginal TDF, and oral TDF/FTC found that none of the approaches were effective, and this result is believed to be related to poor adherence in the treatment arms. The oral TDF arm was halted in September, 2011, the vaginal TDF arm halted in November, 2011, and the TDF/FTC arm continued until the planned completion date in August, 2012.
TDF2 and Partners PrEP tested daily TDF/FTC oral formulation as PrEP in high risk heterosexual men and women and found that those who took PrEP were less likely to become infected with HIV.
The Bangkok TDF Study tested daily TDF in injection drug users, and found that the participants who used TDF were less likely to become infected with HIV.
Reference:
PrEP was FDA approved in July CDC has released interim guidance in line with major PrEP studies, and in 2014 both the NYS AIDS Institute and the CDC released guidelines for PrEP. These guidelines are referenced extensively in this set of slides.
January 2011
CDC Interim Guidance:
PrEP for MSM
August 2012
CDC Interim Guidance:
PrEP for
heterosexuals
May 2014
US Public Health Service
Clinical Practice
Guideline for PrEP

7. Barriers to Use of PrEP Eligibility Adherence
Increased risky sexual practices
Side effects
Reimbursement
Patient accountability
Provider knowledge, comfort, and willingness to prescribe

8. PrEP Candidates Men who have sex with men (MSM) who:
Have an HIV-positive sexual partner
Have a recent bacterial STI
Have a high number of sex partners
Have a history of inconsistent/no condom use
Engage in commercial sex work
Transgender individuals who:
Engage in high-risk sexual behaviors
Candidates for PrEP are people at ongoing, substantial risk of acquiring HIV infection. The next few slides will show several groups to consider as candidates for PrEP.

9. PrEP Candidates Heterosexual women and men who:
Have an HIV-positive sexual partner
Have a recent bacterial STI
Have a high number of sex partners
Have a history of inconsistent/no condom use
Engage in commercial sex work
Live in a high-prevalence area or network
Injection drug users (IDU) who:
Have an HIV-positive injecting partner
Share injection equipment
Have been through recent drug treatment (but currently injecting)
PrEP is appropriate to discuss with an HIV-negative female attempting conception with an HIV-infected male. It is recommended that the HIV-infected male partner should also be on treatment as prevention with undetectable viral load, in order to lower risk of HIV transmission.
nPEP is an alternative to PrEP if the risk is one-time or over.

10. iPrEx Study Randomized, controlled study
High-risk (MSM) assigned to Truvada vs placebo
44% reduction in the incidence of HIV
Secondary analysis of individuals on PrEP
Acquisition reduced by 92% in those with detectable drug levels
Grant RM, Lama JR, Anderson PL, et al; iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010;363(27):

11. The PROUD Study
The PROUD study enrolled MSMs from 13 sexual health clinics in England between 2012 and 2014
Eligibility criteria :
negative HIV test
condomless anal intercourse in the previous 90 days
545 MSM randomized 1:1 to daily TDF/FTC
Either immediately (IMM)
Or after a deferral (DEF) period of 12 months
Relative reduction in HIV acquisition of 86% in the Immediate arm (62-96%; P=0.0002).
Confirmed STI (rectal chlamydia/gonorrhea) in
Immediate arm-29%
Deferred arm -27%
McCormack S, Dunn D, Desai M. (2016) Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD)… The Lancet 387(10013),53-60.

12. PrEP Studies: HIV transmission risk lowest when participants took PrEP consistently
STUDY
OVERALL
Reduction in risk of HIV infection
Detectable level of medication in the blood
iPrEx
44%
>90%
TDF2
62%
---
Partners PrEP
75%
90%
PROUD
86%
BTS
49%
74%
Summary of the PrEP trials from the 2014 CDC guideline:
Adherence is very important for efficacy: compare the overall reduction in risk of HIV infection for participants on PrEP with the subgroup on PrEP who had detectable medication in their blood. The reduction in risk was much higher for the group with detectable levels of medication, which indicates they were taking the medication regularly. TDF2 reported on adherence and efficacy in a slightly different way: of the people in the study who became infected, only half of those had detectable levels of medication in their blood. Those who became infected and did have detectable levels of medication had very low levels of medication present. All had lower levels than matched participants who did not become infected during the trial.
Self-assessment of risk may be important for motivation and adherence. The Fem-PREP and VOICE trials had low levels of adherence measured by level of medication in the blood. One thought about this is that women did not assess themselves to be at high risk of HIV, although the researchers had targeted a group they defined as high risk.
References: and
Adapted from summary of research at

13. Rule out Acute HIV Infection before PrEP
Symptoms of Acute HIV
Fever
Fatigue
Myalgia
Skin rash
Headache
Pharyngitis
Cervical Lymphadenopathy
Arthralgia
Night sweats
Diarrhea
These are the most common symptoms of acute HIV, with fever being the most common (75%), and diarrhea the least common on the list (27%).
Daar ES, Pilcher CD, Hecht FM. Curr Opin HIV AIDS. 2008;3(1):10-15.

14. Case Study
32 year old black female seeks pregnancy. Tested six months ago and is HIV-negative. Her male partner is HIV-positive and not currently on antiretroviral treatment. What do you recommend?
Risk reduction could include PrEP plus:
Partner treatment as prevention
nPEP if appropriate prior to PrEP
Testing and treatment of STIs in both partners
Assess for substance use and impact on sexual decision-making and risk
Timing unprotected intercourse with ovulation
High-tech approaches: sperm washing + IVF/ IUI

15. PrEP for Safe Conception
Mother takes PrEP to prevent her from acquiring HIV from male partner
Limited data
In the small studies, no HIV transmission to the woman
Among women in Antiretroviral Pregnancy Registry: no birth defects with Truvada

16. PrEP for Serodiscordant Partners
54 year male
Monogamous with HIV-positive partner
The HIV positive partner has had a undetectable viral load for > 1 year.
Would you give PrEP to the HIV negative partner?

17. CDC guidelines support PrEP even when the HIV positive partner is undetectable
Likelihood of acquiring HIV is very low from a virally-suppressed HIV-positive partner
However:
Partner may have virological blips
Partner may become non adherent
Patient may not be monogamous

18. 2014 PrEP Prescribing Guidelines
Determine eligibility: negative HIV test, high risk of infection and creatinine clearance > 60ml/min
Assess for Hepatitis B sAg and pregnancy (female patients)
Prescribe : Tenofovir-emtricitabine (Truvada) one pill once daily (90 day supply)
Monitor: creatinine clearance, HIV status, and pregnancy every 3 months and STI screen every 6 months; counsel on adherence and risk reduction

19. Providing PrEP Before starting PrEP: Clinical eligibility Educate
Side effects
Limitations
Daily adherence
Symptoms of seroconversion
Monitoring schedule
Safety
Criteria for discontinuation
Partner information
Social history: housing, substance use, mental health, domestic violence
NYS AIDS Institute guidelines have useful checklists for pre-prescription assessment and education.
The most common side effects of TDF are nausea and flatulence. The most common side effects of emtricitabine are rash and headache. Side effects are more common in the first month of treatment and often subside after a few weeks, which is known as the “start-up syndrome.”
If a patient considering PrEP has an HIV infected partner, ask about whether they are on antiretrovirals and if there is resistance information available.
a patient’s social history can identify potential barriers to adherence to PrEP and indications for referral for services.

20. Providing PrEP After confirmation of clinical eligibility:
Prescribe no more than 90-day supply of PrEP
Truvada 1 tablet PO daily
(tenofovir 300mg + emtricitabine 200mg)
Insurance prior approval
Truvada for PrEP Medication Assistance Program
CDC guidance recommends prescribing no more than a 90-day supply at the first prescription.
TDF 300mg daily is an acceptable alternative only for IDU and heterosexually active adults.
The CDC does not recommend:
Alternate medications in place of or in addition to TDF/FTC or TDF
Intermittent or episodic dosing
Expedited partner treatment for PrEP

21. Providing PrEP 3-month visit: HIV test Assess for acute infection
Check for side effects
Pregnancy testing
Prescribe 90-day supply of medication
CDC guidelines recommend visits every 3 months after the first prescription for PrEP. Consider the NYS AIDS Institute guidelines recommendation for closer follow up, especially for adherence-related concerns: check in with patients at 2-weeks to assess for medication toleration and side effects. Visit at 30-days to check for side effects, assess renal function in those at increased risk of kidney disease and for risk reduction, adherence and condom provision. The AIDS Institute guideline recommends continuation of visits every 30 days if adherence is an issue. (
Every visit:
Assess adherence
Risk reduction counseling
Provide condoms

22. Providing PrEP Every visit: Assess adherence Risk reduction counseling
6-month
9-month
12-month
HIV test
STI test
STI tests
Pregnancy test
Renal function
90 day prescription
Assess the need to continue PrEP
Continue seeing patients every 3 months.
Renal function is monitored with estimated creatinine clearance.
Consider the NYS AIDS Institute recommendation of a urinalysis for proteinuria and rechecking hepatitis status at the 12 month mark.
Every visit:
Assess adherence
Risk reduction counseling
Provide condoms

23. Discontinuing PrEP Positive HIV result Acute HIV signs or symptoms
Non-adherence
Renal disease
Changed life situation: lower HIV risk
If a patient seroconverts on PrEP, check CD4 and VL, send genotype and link to HIV care. Counsel on HIV transmission prevention and offer partner notification services.
Upon discontinuation, document: HIV status, reason for discontinuation, and recent adherence and reported sexual risk behavior.

24. On-Demand PrEP IPERGAY: randomized trial, 400 high-risk MSM
peri-coital PrEP:
Truvada 4 tablets or placebo two 2 to 24 hours before sex, a second dose 24 hours later, and a last one 24 hours later
86% reduction in HIV acquisition with on-demand PrEP

25. Future of PrEP Nano-formulations or long acting meds
Cabotegravir: investigational HIV integrase inhibitor
Can be administered orally or as long-acting subcutaneous or intramuscular injection
Single injection of long-acting version could be effective for up to 3 months

26. Financial Issues Coverage for PrEP varies in US
Most private insurers are providing coverage, with prior authorization requirements
Potential issue of economic disparity for uninsured/low-income patients

27. Reimbursement for PrEP
Follow the CDC Clinical Guidelines for PrEP
Common ICD-10 codes for PrEP counseling:
Z20.2 “Contact with and (suspected) exposure to infections with a predominantly sexual mode of transmission”
Z11.4 “Encounter for screening for HIV”
Z11.3 “Encounter for screening for infections with a predominantly sexual mode of transmission”
Use the usual E/M charge based on length/complexity of visit

28. Reimbursement for PrEP
Although regular HIV screening labs are rated “A” by USPSTF and should be covered without a “patient due balance”, the greater frequency of labs needed while on PrEP may generate charges
Broad coverage by Medicaid for PrEP – prior authorizations may be necessary
-SC Medicaid does provide Truvada for PrEP with NO prior authorization necessary
Broad coverage for Truvada by private insurers as well, prior authorizations also likely necessary

29. Truvada Costs Out-of-pocket estimated expense: $1,300 a month
The manufacturer of Truvada offers assistance to uninsured individuals:
The manufacturer of Truvada also has a co-pay assistance program applicable to some insured individuals:

30. Payment Assistance Information
Project Inform:
-explains payment assistance for insured and un-insured
Assessment of Medicaid Coverage of HIV/AIDS Prevention, Screening, and Care Services: A Ten State Review:

32. PrEP works.
Lets use it appropriately and responsibly

33. Post-exposure prophylaxis
PEP
Post-exposure prophylaxis

34. PEP Categories oPEP –for occupational exposures
HCWs who may experience a cut, needle stick, or other potentially infectious body fluid exposure “on the job”
nPEP –for non-occupational exposures
Persons who are potentially exposed to HIV through consensual or forced intercourse, accidental puncture wounds, or IVDU

35. Occupational HIV Exposures
Definition of exposure: percutaneous injury or contact of mucous membrane or non-intact skin with blood, tissue, or other potentially infectious body fluids
-potentially infectious body fluids: semen, vaginal secretions, CSF, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, amniotic fluid
-only potentially infectious if visibly bloody: feces, nasal secretions, saliva, sputum, sweat, tears, urine, vomitus

36. Risk of Occupational HIV Transmission
Average risk after percutaneous exposure to HIV-infected blood: 0.3%
Average risk after mucous membrane exposure to HIV-infected blood: 0.09%
Factors that increase risk of HIV transmission:
-device (needle, etc) is visibly contaminated with blood
-needle had been placed directly into a vein or artery
-deeper injuries
-amount of HIV present in the source patient’s blood

37. Non-Occupational HIV Exposures
Sexual contact, consensual or forced
Accidental cuts or punctures with sharp objects
Intentional use of contaminated or shared needles for IVDU

38. Evaluation of Non-Occupational Exposures
HIV status of the potentially exposed person
-baseline rapid testing should be conducted to ensure they are not already HIV-positive
Timing and frequency of exposure
-nPEP should be initiated within 72 hours of exposure
Risk of HIV acquisition based on type of exposure
HIV status of the exposure source
-often difficult to obtain for non-occupational exposures

39. Risk of Non-Occupational HIV Transmission
Receptive anal intercourse = 1.38%
Receptive penile-vaginal intercourse = 0.08%
Needle sharing for IVDU = 0.63%
Needlesticks = 0.23%
As with occupational exposures, increased amount of HIV present in the source patient’s blood or body fluids increases risk of transmission
For sexual exposures, non-intact mucous membranes increases risk of transmission

40. Other Considerations for Possible Sexual Exposures
Prophylaxis for bacterial STIs, trichomoniasis
Testing for Hepatitis B and C
Pregnancy prevention for female patients
Counseling and other support for survivors of sexual assault

41. Shared Principles for All Types of PEP
Importance of quick initiation of PEP following possible HIV exposure
Importance of HIV tests for the potentially exposed patient
Use of a “complete” three-drug regimen for PEP
Duration of treatment is 28 days
Follow-up testing required at 6 weeks and 4 months (with newest, 4th-generation Ag/Ab tests)

42. Time is of the Essence!
PEP should be initiated as quickly as possible for all types of exposures
nPEP guidelines state effectiveness is unlikely >72 hours after exposure
For frequent possible exposures, discuss PrEP with the patient

43. Baseline Testing for Exposed Person
Gold standard is the 4th generation Ag/Ab test to establish that exposed person is currently HIV-negative
-decreased window period compared to older tests
Familiarity with common manifestations of acute HIV infection could be helpful for rare instances of very acute HIV exposed person
-can proceed based on 4th generation test results, but consult to ID would be prudent

44. raltegravir (Isentress) 400 mg twice daily
What to Prescribe?
oPEP and nPEP guidelines recommend the same regimen:
emtricitabine/tenofovir DF (Truvada)200/300 mg daily +
raltegravir (Isentress) 400 mg twice daily
~For 28 days~

45. Alternative Choices
Dolutegravir (Tivicay) 50 mg can be substituted for raltegravir (Isentress), advantage is once-daily dosing
For renal dysfunction (creatinine clearance < 59 mL/min), can substitute zidovudine/lamivudine 300/150 (Combivir) or dose-adjust the individual components
nPEP guidelines include recommendations for weight-adjustment for children

46. Additional Items
Guidelines recommend checking serum creatinine at 4-6 weeks after exposure (along with first follow-up HIV test) for patients prescribed Truvada
Provision of ‘starter packs’ in the emergency department setting is recommended for survivors of sexual assault who need PEP
Consider follow-up and broader support needs for survivors of sexual assault

47. References
US Public Health Service (2014). Preexposure Prophylaxis for the Prevention of HIV Infection in the United States – Retrieved from:
Kuhar, D, et al (2013, Sept). Updated US Public Health Service Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis. Infection Control and Hospital Epidemiology, (34,9), pp
CDC, US DHHS (2016). Updated Guidelines for Antiretroviral Postexposure Prophylaxis After Sexual, Injection Drug Use, or Other Nonoccupational Exposure to HIV – United States, Retrieved from: