1. Pacific AIDS Education and Training Center1

2. PreExposure Prophylaxis
Catherine Diamond MD MPH

4. Objectives Know current US recommendations for PrEP
Identify candidates for PrEP
Learn about resources for providing PrEP

5. Background Basics
PrEP is indicated for individuals at high risk of HIV infection, regardless of sex or risk factor
Once daily, oral tenofovir-emtricitabine currently is the only medication FDA-approved for PrEP (July 2012), brand name Truvada
Efficacy is dependent on adherence
PrEP is indicated for individuals at high risk of HIV infection.
Once daily, oral tenofovir-emtricitabine is the only medication FDA-approved for PrEP.
Efficacy is highly dependent on adherence.
Note that when I say PrEP, I mean tenofovir-emtricitabine.

6. iPrEx Study WHO 2499 MSM/TW WHAT TDF-FTC VS PLACEBO WHEN 2007-2009
WHERE
PERU/ECUADOR/SOUTH AFRICA/BRAZIL/THAILAND/USA
RESULTS
MEDIAN ONE YEAR FUP
36 HIV CASES TDF-FTC
64 HIV CASES PLACEBO
44% REDUCTION IN HIV INCIDENCE
NEJM 2010; 363:

7. iPrEx Study Results: Cumulative Probability of HIV Infection
Placebo
(n=1248)
P=0.005
Cumulative Probability
of HIV Infection
Emtricitabine/
Tenofovir DF
(n=1251)
Slide: iPrEx Study Results: Cumulative Probability of HIV Infection
Among the 100 subjects with emergent HIV infection, 36 occurred in the emtricitabine/tenofovir DF group and 64 occurred in the placebo group. This represented a relative reduction in the cumulative probability of HIV acquisition 44% compared with placebo (P=0.005).1
Reference
Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:
Weeks
Grant RM, et al. N Engl J Med. 2010;363:

8. IPrex Initial & Extension Adherence Data
In FTC–TDF group, study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001)
In extension analysis of blood levels, 76% risk reduction with 2 doses/week, 96% with 4 doses & 99% with 7 doses
Age was strongest determinant of adherence: participants in their 30s were twice as likely to have detectable drug levels as participants under 25, and over-40s were 3 times as likely
Lancet Infectious Diseases ;9:820–829.

9. CDC PrEP Candidates MSM Heterosexual IDU HIV-positive sexual partner
Recent bacterial STI
High number of sex partners
History of inconsistent or no condom use
Commercial sex work
High-prevalence area/network e.g. methamphetamine
HIV-positive injecting partner
Sharing injection equipment
Recent drug treatment (but currently injecting)

10. Risk Behavior Assessment for MSM
In the past 6 months:
Have you had sex with men, women, or both?
(if men or both sexes) How many men have you had sex with?
How many times did you have receptive anal sex (you were the bottom) with a man who was not wearing a condom?
How many of your male sex partners were HIV-positive?
(if any positive) With these HIV-positive male partners, how many times did you have insertive anal sex (you were the top) without you wearing the condom?
Have you used methamphetamines (such as crystal or speed)?
The CDC guideline and the providers’ supplement include multiple tools for providers offering PrEP, including risk behavior assessments like this one, to help identify MSM and assess for sexual practices which are associated with increased risk of HIV infection.

11. Clinical Eligibility Criteria
Documented negative HIV test result before prescribing PrEP
No signs/symptoms of acute HIV infection
Normal renal function; no contraindicated medications
Documented hepatitis B virus infection and vaccination status
HIV serology
History +/- HIV PCR Cr
HBSag, HBVSab
Table in PrEP guidelines
HCV Antibody
I also do HAV IgG
Urine pregnancy

12. Initial Assessment Counsel Offer vaccination STD check Adherence
Safer sex e.g. condoms
Side effects
Offer vaccination
HAV
HBV
HPV
MCV4
STD check
RPR
GC/CT urine, rectal, throat

13. 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)
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

14. What would you tell him about side effects?
Nausea may occur with initiation of tenofovir-emtricitabine (~10%); it typically resolves with time
Kidney injury occurs rarely (2% in iPrex)
Periodic monitoring is obligatory
Abnormalities usually resolve with drug discontinuation
A small decrease in bone mineral density may occur, preliminary evidence shows reversible
Nausea may occur with initiation of tenofovir-emtricitabine; it typically resolves with time.
Kidney injury occurs rarely (2% in iPrex).
Periodic monitoring is obligatory.
Abnormalities usually resolve with drug discontinuation.
A small decrease in bone mineral density may occur; the clinical significance of this is unknown.
I have yet to see a patient who stopped PrEP because of nausea/vomiting.

15. How would you counsel him about…
The length of time on PrEP before he is maximally protected?
PrEP reaches maximum protection from HIV for receptive anal sex at ~7 days of daily use when maximal levels are achieved in rectal tissue
For all other activities, including insertive anal sex, vaginal sex & injection drug use, PrEP reaches maximum protection at ~20 days when there is a blood steady state ?
The length of time on PrEP before he is maximally protected?
7 days, when maximal levels are achieved in rectal tissue?
If stopping PrEP, how long he should take it beyond his last high-risk sexual encounter?
4 weeks, by analogy to PEP?

16. Providing PrEP 1-week: phone check
Every visit:
Assess adherence
Risk reduction counseling
Provide condoms
1-week: phone check
Did they get the medication, cost & are they taking it?
1-month visit (optional): HIV test, adherence +/- creatinine
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. (

17. Providing PrEP Every visit: Assess adherence Risk reduction counseling
Provide condoms
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.

18. Remember Features of Acute HIV
FREQUENCY (%)
Fever 77
Myalgia 52
Rash 51
Headache 47
Pharyngitis 43
Cervical adenopathy 41
Diarrhea 28
Daar ES, Pilcher CD, Hecht FM. Curr Opin HIV AIDS
Table with symptoms of acute HIV infection

19. ~10-15 DAYS IF SENSI <50
Diagnosis of HIV
~15-20 DAYS

20. Risk of HIV Resistance
In iPrEx trial, drug-resistant virus developed in 2 persons with unrecognized acute HIV infection at enrollment for whom TDF/FTC had been dispensed
These participants had negative antibody test results before they started taking PrEP, tested positive at a later study visit, and PCR on stored specimens from the initial visit detected presence of virus
When questioned, most of the 10 acutely infected participants (8 of whom had been randomly assigned the placebo group) reported signs and symptoms consistent with a viral syndrome
Both acutely infected patients to whom TDF/FTC had been dispensed had M184V/I mutation (emtricitabine resistance)

21. Acute HIV
While ~94% had signs or symptoms , likelihood of symptom was ~30% on any given visit*
HIV RNA high
Check HIV RNA prior to PrEP if symptoms or suspect exposure within past month
If exposure within 72 hours, PEP not PrEP
Urgent referral to HIV specialist if positive
Partner notification if positive
*Prospective Study of Acute HIV-1 Infection in Adults in East Africa and Thailand N Engl J Med 374(22): , 2016

22. When Do I Use nPEP?
Evaluate persons rapidly for nPEP when care is sought ≤ 72 hours after a nonoccupational exposure that presents a substantial risk for HIV acquisition
Preferred regimen for otherwise healthy adults is tenofovir disoproxil fumarate (tenofovir DF or TDF) (300 mg) with emtricitabine (200 mg) once daily plus raltegravir (RAL) 400 mg twice daily or dolutegravir (DTG) 50 mg daily for 28 days

23. Discontinuing PrEP Positive HIV result Acute HIV signs or symptoms
Non-adherence
Renal disease
Changed life situation: lower HIV risk
Caution with HBV flares
If stopping PrEP, how long he should take it beyond his last high-risk sexual encounter?
4 weeks, by analogy to PEP?
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. PrEP as Part of Planned Conception
No increased birth defects with tenofovir-emtricitabine among women in the Antiretroviral Pregnancy Registry
No HIV transmissions to female partners in one small study of 13 couples (Whetham, AIDS Care, 2014)
Limited data
No evidence that PrEP is unsafe with breastfeeding
No increased birth defects with tenofovir-emtricitabine among women in the Antiretroviral Pregnancy Registry
No HIV transmissions to female partners in one small study of 13 couples (Whetham, AIDS Care, 2014)
Other reproductive strategies for such couples may be limited to non-existent.
But, data are still limited.

25. Utility of PrEP on top of Treatment as Prevention is unknown.
Pros
Cons
ART adherence may be imperfect, with resulting viral rebound
Viral “blips” occur in otherwise suppressed individuals on ART
Concurrent STDS?
CDC guidelines support PrEP in the context of TasP
People may not be honest with their providers about (non-)monogamy
Any additional benefit of PrEP on top of TasP may not outweigh risks
If resources are limited, TasP seems wiser than PrEP
Pros: ART adherence may be imperfect, with resulting viral rebound.
Viral “blips” occur in otherwise suppressed individuals on ART.
CDC guidelines support PrEP in the context of TasP.
People may not be honest with their providers about (non-)monogamy
Cons: TasP is quite effective, and the additional benefit of PrEP on top of TasP may not outweigh its risks.
If resources are limited, TasP seems wiser than PrEP.

26. PrEP as Bridge to ART Study: Partners PrEP Demo Project (CROI, 2015)
Population: 1,013 heterosexual serodiscordant couples
Intervention: PrEP until seropositive partner on ART for 6 months
Results: 96% risk reduction compared to a historical control
Study: Partners PrEP Demo Project (CROI, 2015)
Population: 1,013 heterosexual serodiscordant couples
Intervention: PrEP until seropositive partner on ART for 6 months
Results: 96% risk reduction compared to a historical control

27. IPERGAY study supports “on-demand” PrEP in MSM with frequent sex
Population: 400 MSM
Intervention: Event-driven PrEP versus placebo
Results: 86% HIV risk reduction with on-demand PrEP
IPERGAY regimen: 3 doses per sex act
Two 2-24 hours before sex
One pill each 24 and 48 hours after sex
Population: 400 MSM
Intervention: Event-driven PrEP versus placebo
Results: 86% HIV risk reduction with on-demand PrEP
IPERGAY regimen: 3 doses per sex act
Two 2-24 hours before sex
One pill each 24 and 48 hours after sex
This study was also stopped early by the data safety and monitoring board. Overall, 34% of patients acquired a new sexually-transmitted infection.
CROI, 2015

28. CDC still recommends daily PrEP.
Caveats about IPERGAY
Participants had a median of 10 sex acts per month.
Most subjects took 3-4 doses of PrEP per week (median 14 pills per month).
Caution: The efficacy of on-demand PrEP for less frequent sex is unknown.
CDC still recommends daily PrEP.
Participants had a median of 10 sex acts per month.
Most subjects took 3-4 doses of PrEP per week (median 14 pills per month).
Caution: The efficacy of on-demand PrEP for less frequent sex is unknown.
CDC still recommends daily PrEP.

29. Human immunodeficiency virus preexposure prophylaxis (PrEP) referrals, intakes, and initiation by month at Kaiser Permanente San Francisco, July 2012–February 2015.
Human immunodeficiency virus preexposure prophylaxis (PrEP) referrals, intakes, and initiation by month at Kaiser Permanente San Francisco, July 2012–February The graph includes a total of 1045 referrals, 835 intakes, and 677 initiations, including 20 individuals who restarted PrEP after discontinuing during the study period.
The graph includes a total of 1045 referrals, 835 intakes, and 677 initiations, including 20 individuals who restarted PrEP after discontinuing .
Jonathan E. Volk et al. Clin Infect Dis. 2015;61:

30. PrEP at Kaiser Permanente San Francisco, July 2012–February 2015
835 (80%) of referrals were evaluated
657 (82%) of 801 patients started Prep
Median 37 years
99% MSM
8% had prior prep
84% reported multiple partners
30% had HIV-infected partner
50% had STI within one year, 33% rectal GC or CT; 6% syphilis
Non-initiators
low risk (35%), cost concern (15%), not wanting to FUP (10%), prefer post-exposure prophylaxis (6%), concern of disinhibition (1%)
3% had HIV at baseline, creatinine clearance <60 ml/minute (1%) or osteoporesis (1%)

31. Agents/Delivery in Development
Two Phase 2 injectable PrEP studies now being conducted in the U.S.—HPTN 077 and ÉCLAIR investigating the safety and tolerability of the long-acting investigational product GSK (cabotegravir) every 12 weeks
ASPIRE silicone vaginal ring contains the experimental ARV dapavirine continuously released in the vagina, replaced once every four weeks

32. Conclusion/Talking Points
PrEP efficacy and importance of adherence
Periodic HIV testing and creatinine checks are mandatory
The risk of HIV drug resistance if he/she becomes infected with HIV while on PrEP
Side effects: GI, renal, bone
What we think about time to maximal protection, time to continue after last high-risk encounter
PrEP does not protect against other STIs
PrEP efficacy and importance of adherence
Periodic HIV testing and creatinine checks are mandatory.
The risk of HIV drug resistance if he/she becomes infected with HIV while on PrEP
Side effects: GI, renal, bone
What we think about time to maximal protection, time to continue after last high-risk encounter
PrEP does not protect against other STIs, except perhaps HSV (Celum, Ann Intern Med, 2014).
In one study of heterosexual individuals in Africa, tenofovir-emtricitabine reduced HSV-2 incidence by ~30% (Celum, Ann Intern Med, 2014).
Mention that the patient in this case initiated PrEP, has not had side effects, and remains HIV negative to date.

35. Prep Guidelines www.cdc.gov
Truvada Risk Evaluation and Mitigation Strategy (REMS) website (NB: REMS due to fear of resistance)