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THE JO U R N A L O F
FAMILY PRACTICE
HIV prevention: A 3-pronged approach HIV infection may not command the headlines it once did, but the public health threat it poses is still formidable. These steps can help us get ahead of it.
Nicholas Y ago da , M D ; Richard M o o re II, M D CommUnityCare, Austin, Tex (Dr. Yagoda); Rural Health Group, Roanoke Rapids, NC (Dr. Moore)
The authors reported no potentia l conflic t o f interest relevant to this article.
PRACTICE RECOMMENDATIONS > Screen all pregnant women and individuals ages 15 to 65 for human immunodeficiency virus (HIV) infection. (A)
> Prescribe tenofovir disoproxil fumarate/ emtricitabine (Truvada) for pre-exposure prophy laxis for patients at high risk of acquiring HIV. (A)
> Offer needle and syringe exchange programs and, when appropriate, opioid substitution therapy to indi viduals who inject drugs, (a)
Strength o f recommendation (SOR)
(A) Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
( c j Consensus, usual practice, opinion, disease-oriented evidence, case series
D espite advances in human immunodeficiency virus (HIV) screening and treatment over the last 30 years, HIV remains a public health concern. In the United States, after an initial decline, total HIV incidence has failed to significantly decrease in the last 25 years. More than 1.2 mil lion people are living with HIV in the United States, and 12.8% of them (156,300) are unaware they are affected.1 Of those di agnosed with HIV, only 30% are receiving treatment and are virally suppressed.2 Due to structural inequalities and psycho social factors, African American and Latino patients remain disproportionately affected.3 The incidence of HIV infection among men who have sex with men has increased, and the in cidence of HIV infection among people who inject drugs has plateaued after years of progressive decline.4
HIV prevention strategies are highly effective, but in gener al are underutilized. This article reviews 3 prevention strategies that can be administered by family physicians: HIV screening, pre-exposure prophylaxis (PrEP), and harm reduction.
Who and how to screen for HIV Early identification of HIV infection generally leads to reduced transmission because diagnosis is associated with decreases in risky behavior.5’6 In addition, antiretroviral therapy (ART) is more effective when initiated early, before the development of advanced immunosuppression.7'9
The "window period” of acute HIV infection (AHI) is the time from when the virus is transmitted to when markers of infection can be detected. Because this window period is as sociated with high viral transmission rates, family physicians must be familiar with symptoms of AHI ( t a b l e 1 ) 1011 and as sociated risk factors (eg, recent condomless sex or sharing of drug injection equipment with someone who is HIV-positive or of unknown HIV status).
CONTINUED
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> Both the USPSTF and the CDC recommend universal opt-out HIV screening because such screening is associated with higher testing rates than opt-in screening.
TABLE 1
C lin ic a l f e a tu r e s o f a c u t e H IV i n f e c t io n 1011
Clinical feature Frequency
Fever 70%-80%
Fatigue, lethargy, malaise 66%-70%
Rash (maculopapular) 50%
Myalgias 50%
Sore throat/pharyng itis 40%-60%
Headache 45%
Lymphadenopathy 40%
Gl symptoms (nausea, vom iting, diarrhea)
30%
Gl, gastrointestinal; HIV, human immunodeficiency virus.
Screening for HIV solely based on the presence of risk factors or clinical sym ptom s is not enough, however. The U nited States Preventive Services Task Force (USPSTF) rec om m ends screening all p regnant w om en and individuals ages 15 to 65 for HIV.12 Screening based solely on risk factors or clinical sym p tom s frequently leads to m issed diagnoses and identification of HIV infection at m ore advanced stages.1314 Both the USPSTF and the Centers for D isease Control and Preven tion (CDC) recom m end universal opt-out screening (patients are inform ed tha t HIV screening will be perform ed and tha t they m ay decline testing) because such screening identifies HIV earlier and is associated with higher testing rates than opt-in screening, w hich requires explicit w ritten consent and extensive pre-test counseling.
I W h ich te s t to use. HIV screening w ith a fourth-generation an tigen /an tibody com bination im m unoassay—w hich detects bo th HIV p24 antigen and HIV an tibodies—pro vides greater diagnostic accuracy than older tests.15 These new er tests detect HIV approxi m ately 15 days after initial infection, reducing the w indow period of AHI.15,16 If you suspect a patien t has AHI, consider early repeat HIV testing w ith a fourth-generation assay, or in i tial co-testing w ith a fourth-generation assay and a nucleic acid am plification test for HIV RNA, w hich m akes it possible to detect infec tion approxim ately 5 days earlier than fourth- generation assays.15
Offer pre-exposure prophylaxis to high-risk patients PrEP is the use of ART prior to HIV expo sure to prevent transm ission of the virus. It should be used w ith conventional risk reduc tion strategies, such as providing condom s, counseling patients about reducing risky b e haviors, supporting m edication adherence, and screening for and treating o ther sexually transm itted infections.
The US Food and Drug Adm inistration (FDA) has approved only one medication, Truvada (tenofovir disoproxil fum arate/em - tricitabine; TDF/FTC), for use as PrEP. Oral tenofovir-based regim ens can effectively p re vent HIV transm ission,17 20 and strong adher ence is associated with a risk reduction of 90% to 100%.17 23 The protective effect of oral PrEP is particularly strong in high-risk populations (eg, m en who have sex w ith m en, people who inject drugs), w here the num ber needed to treat to prevent one HIV infection ranges from 12 to 100, depending on the patients' risk pro file.24'26 The CDC and D epartm ent of Health and H um an Services have issued guidelines for using PrEP in high-risk patients.27
I Barriers to im p lem en tin g PrEP. Despite being highly effective, PrEP is not routinely prescribed to high-risk patients; modeling suggests that current use of PrEP is insuffi cient to significantly im pact the incidence of HIV.28 D em and for PrEP is high am ong target groups,21,29,30 but patients have expressed con cerns about adverse effects31 and stigma re lated to ART, HIV; and being at risk for HIV.32,33 Young age, lack of social support, low percep tion of risk, and failure to show up for appoint m ents are also barriers to PrEP use.28,30,34
Some physicians have expressed concern tha t prescribing PrEP m ay prom ote high-risk sexual behavior.35 However, because PrEP is m ost beneficial in individuals w ho already engage in high-risk sexual behavior, strategic delivery of PrEP rem ains an effective risk-re ducing strategy.17,18,21,26,36,37 Even in instances w here PrEP has b een associated w ith higher- risk sexual behavior and higher rates of sexu ally transm itted infections, it still prevents as m uch as 100% of new HIV infections.38
Fear of drug resistance also contributes to slow im plem entation of PrEP. Drug resistance has been observed in clinical trials of PrEP, but
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TABLE 2
Resources for implementing pre-exposure prophylaxis for HIV Resource Contact in fo rm ation
Clinician Consultation Center PrEPline
855-448-7737 (11 am-6 pm EST)
http://nccc.ucsf.edu/2014/09/29/introducing-the-ccc-prepline/
North Carolina AIDS Training and Education Center
http://www.m ed.unc.edu/ncaidstrain ing/prep/for-providers/for- prep-prescribers
Centers fo r Disease Control and Prevention
www.cdc.gov/hiv/risk/prep/index.htm l
HIV, h u m a n im m u n o d e fic ie n c y v irus.
it has been exceedingly rare and predominantly limited to patients who had unrecognized AHI when they started PrEP.39 Furthermore, the few cases of drug resistance attributable to PrEP pale in comparison to the large number of es timated HIV infections averted—infections that would require lifelong ART with its own associ ated risks of drug resistance. By decreasing HIV transmission, PrEP is expected to decrease total drug resistance.40
I Cost is another obstacle. Truvada costs approximately $1,540 per month.41 However, analysis has demonstrated that PrEP is cost- effective when targeted to high-risk patients.42 Most insurance plans cover PrEP, but often re quire high deductibles and copays; fortunate ly, this financial burden for patients can be mitigated or eliminated by co-pay assistance programs. The manufacturer of Truvada offers assistance programs for both insured and un insured patients who are candidates for PrEP; details are available at http://www.truvada. com/truvada-patient-assistance.
I Stigma has historically burdened in dividuals who seek to protect their sexual health, including HIV-negative individuals who are candidates for PrEP. Stigma sur rounding HIV may decrease ART-based HIV prevention in men who have sex with men,43 while increasing high-risk behaviors44 and all-cause mortality.45
The resources listed in table 2 can help physicians overcome some of the barriers to implementing PrEP.
How to deliver PrEP Whether HIV specialists or primary care cli nicians are best suited to provide PrEP is a
subject of debate. HIV specialists are most familiar with ART and routine monitoring of adherence; however, they have less access to HIV-negative patients, who are the target group for PrEP.35 Family physicians tend to work in closer proximity and maintain longi tudinal relationships with PrEP target groups, but in general have less experience with ART and evaluating AHI. Some may argue that competing demands may make it impractical to take a detailed sexual history during a pri mary care visit.40 In truth, both HIV specialists and family physicians can be appropriately equipped to provide PrEP.
table 3 outlines the steps necessary to provide a patient with PrEP.47 Assessing risk is the initial step; PrEP is beneficial for patients who have one or more risk factors for HIV in fection. To be eligible for TDF/FTC, a patient must be HIV-negative, and should be tested for hepatitis B virus (HBV) infection and kid ney disease. Because TDF/FTC treats HBV in fection, candidates for PrEP who test positive for HBV should be evaluated for treatment of HBV before initiating PrEP. Candidates for PrEP who test negative for HBV infection and immunity should be vaccinated.
Candidates for PrEP should also be screened and monitored for kidney disease. TDF can cause increased serum creatinine due to tubular toxicity. A patient who has an estimated creatinine clearance <60 mL/min should not receive TDF/FTC for PrEP. If a pa tient's estimated creatinine clearance falls be low 60 mL/min or serum creatinine increases by 0.3 mg/dL above baseline after PrEP is started, TDF/FTC should be discontinued, and the patient should be evaluated for the underlying cause of the kidney disease.27
C O N T IN U E D
> Strong adherence to pre-exposure prophylaxis for HIV is associated with a risk reduction of 90% to 100%.
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TABLE 3
Step-by-step checklist for initiating pre-exposure prophylaxis for HIV1' Step 1: Assess risk
Having any one or more of the following risk factors places the individual at risk for HIV:
Risks for sexual transmission
□ Condomless sex in prior 6 mo
□ Any STI diagnosed in prior 6 mo
□ Not in a monogamous relationship w ith partner confirmed to be HIV-negative
□ Relationship w ith HIV-positive partner(s)
□ Commercial sex work
Risks for nonsexual transmission
□ Shared injection equipment (needles or "works")
□ Known HIV-positive injecting partner(s)
□ Recent drug treatment (but currently still injecting)
□ Sexually active w ith injecting partner(s)
Step 2: Determine clinical eligibility
W ithin 30 days before starting PrEP, check viral hepatitis status and renal function:
□ Hepatitis B surface antigen (sAg) Must be hepatitis B sAg negative
□ Hepatitis B surface antibody (sAb) • Truvada (tenofovir disoproxil fumarate/emtricitabine) treats hepatitis B virus; stopping can cause "flare"
□ Serum creatinine
□ eCrCI
□ Urinalysis (to establish baseline)
eCrCI must be >60 mL/min (by Cockcroft-Gault equation)
Within 7 days before starting PrEP, test fo r HIV infection
Test for HIV with ONE of the following:
□ HIV RNA (viral load)
□ Antigen/antibody combination assay (4th generation)
□ Rapid test w ith fingerstick blood
□ Traditional blood test w ith ELISA (EIA) and reflexive confirmatory testing
Must be HIV negative
• Preference for HIV RNA (viral load) or 4th generation Ag/Ab assay; both can detect early HIV infection
• Do NOT rely on oral rapid testing; sensitivity lower than w ith blood
Any of these symptoms in prior month? No symptoms of HIV infection
□ Fever • Must be free of these symptoms in the month
□ Fatigue prior to starting PrEP
□ Skin rash
□ Pharyngitis
□ Cervical adenopathy
• If ANY symptoms are present, rule out acute HIV by ordering HIV RNA (viral load)
See footnotes on facing page.
Before starting PrEP, candidates should be screened for HIV infection and symptoms of AHI. Strongly consider testing for sexually transmitted infections that may increase the risk of HIV transmission, such as syphilis, gonorrhea, or chlamydia.
Candidates who are eligible for PrEP must be counseled on medication adverse effects, adherence strategies, and symptoms of sexu ally transmitted infections. To initiate PrEP,
candidates may be given a one-month supply of TDF/FTC; adherence, adverse effects, and other risk-reduction strategies are assessed at an office visit 3 to 4 weeks later. Subsequent prescriptions are then dispensed as a 3-month supply, with office visits to monitor PrEP scheduled for at least once every 3 months. During these monitoring visits, evaluate the patient’s HIV status, pregnancy status, adher ence, adverse effects, risk-reduction behav-
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TABLE 3
Step-by-step checklist for initiating pre-exposure prophylaxis for HIV1' (cont'd) Step 3: Consider other tests
If not already done in the prior 6-12 months
□ Serum RPR for syphilis
□ NAATs for gonorrhea and chlamydia
• Cervix or urine in woman and urine/urethra in men, along with pharynx and rectum, as appropriate
□ NAAT for Trichomonas vaginalis (or wet prep), as appropriate
□ Hepatitis C antibody for anyone who injects drugs or has sex with an IDU, and MSM
Step 4: Counsel patient
"Startup syndrome"
• Some patients develop mild headaches, nausea, or flatulence; resolves within first month for most
• Patient should notify provider of any unexpected reactions—especially rashes
Adherence strategies
• Pair pill-taking with daily task (something consistent every day, even on weekends)
• Set an alarm, use a pill box, and keep an extra dose handy (in car, at work, etc)
Anticipatory guidance
• Dose can be safely taken 3-4 hours before or after a planned dosing time
• Truvada has no interactions with alcohol or recreational drugs; avoid sex under influence
Step 5: Prescribe, monitor, and support
First prescription: Truvada, one tablet by mouth daily, dispense #30, no refills
Return to clinic in 3-4 weeks to assess adherence, adverse effects, and risk-reduction behaviors
Subsequent prescriptions: Truvada, one tablet by mouth daily, dispense #30, 2 refills
At least every 3 months: At least every 6 months: Every 12 months:
□ Repeat HIV testing for ALL patients on PrEP □ Check creatinine and eCrCI □ Urinalysis
□ Assess adherence, adverse effects, and risk-reduction behaviors
□ Check for STIs if not done in interim
□ Assess ongoing need for PrEP Ag/Ab, antigen/antibody; eCrCI, estimated creatinine clearance: EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay: HIV, human immunodeficiency virus; IDU, injection drug user; MSM, men who have sex w ith men; NAAT, nucleic acid amplification test; PrEP, pre-exposure prophylaxis; RPR, rapid plasma reagin; STI, sexually transmitted infection.
Source: North Carolina AIDS Training and Education Center. For PrEP Providers. North Carolina AIDS Training and Education Center Web site. Available at: http://www.med.unc.edu/ncaidstraining/prep/for-providers/for-prep-prescribers. Accessed July 7, 2015. Used w ith the permission of Dr. Christopher Hurt o f the North Carolina AIDS Training and Education Center.
iors, and indications for continued PrEP. Every 6 months, renal function and sexually trans mitted infection status should be reassessed.
Reducing risk of harm among patients who inject drugs Nonsexual transmission of HIV is a route of high infectivity.48 It includes transfusion of infected blood, sharing of equipment during injection drug use, and percutane
ous needle sticks. Sharing of equipment dur ing injection drug use is estimated to account for 8% of new infections in the United States.4
Harm reduction is a collection of strategies meant to reduce complications of illicit drug use, including HIV transmission. These strate gies include needle and syringe programs that provide injection drug users with sterile equip ment, and opioid substitution therapy.
Needle and syringe programs decrease HIV transmission49 and risky behaviors related
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TABLE 4
H a r m r e d u c t io n t r a in in g a n d s u p p o r t r e s o u r c e s
R e s o u rc e U R L C o m m e n t
H a rm R e d u c t io n
In t e r n a t io n a l h t t p : / / w w w . ih r a . n e t / n o r t h - a m e r ic a -
h a r m - r e d u c t io n - p r o g r a m m e s
E d u c a t io n a n d a d v o c a c y r e la te d t o
h a r m r e d u c t io n
S u b s ta n c e A b u s e
a n d M e n t a l H e a lth
S e rv ic e s
A d m in is t r a t io n
h t t p : / /w w w .s a m h s a .g o v /m e d ic a t io n -
a s s is te d - t r e a tm e n t
G u id a n c e f o r t r a i n in g a n d o b t a in in g
t h e w a iv e r n e c e s s a ry t o b e a b le t o
p r e s c r ib e b u p r e n o r p h in e p r o d u c ts in
a n y s e t t in g s in w h ic h y o u a re q u a l i f ie d
t o p r a c t ic e
P ro v id e rs ' C lin ic a l
S u p p o r t S y s te m f o r
M e d ic a t io n
A s s is te d T r e a tm e n t
h t t p : / /p c s s m a t .o r g / T r a in in g a n d m e n t o r in g p r o g r a m
f o r m e d ic a t io n a s s is te d t r e a t m e n t o f
o p io id m is u s e
> In clinical trials of pre-exposure prophylaxis, drug resistance has been rare and mostly limited to those w ho had unrecognized acute HIV infection.
to injection drug use,50 but federal funding of such programs is prohibited. Opioid substitu tion therapy reduces the incidence of HIY50,51 injection drug use, sharing of drug preparation and injection equipment, and drug-related behaviors associated with a high risk of HIV transmission.50,52 However, in the United States, the quality of these programs varies; a study of opioid substitution therapy delivery found that 22.8% of programs provided doses that were too low to be effective.53
FDA-approved medications for opioid substitution therapy include sublingual bu-
prenorphine, sublingual buprenorphine/- naloxone tablets or strips (Suboxone), and oral m ethadone. Buprenorphine-based regimens can be provided by appropriately trained prim ary care clinicians; m ethadone requires a referral to a narcotic treatm ent program, table 4 provides training and sup port resources for physicians who want to integrate opioid substitution therapy into their clinical practice. 3FP
CORRESPONDENCE
Richard Moore II, MD, 250 Smith Church Road, Roanoke Rapids, NC 27870; [email protected].
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