Youth and HIV PEP Pr EP Tas P

Youth and HIV PEP, Pr. EP, Tas. P Peter L. Havens, MD Winter 2019

Patient Background • • • 16 y. o. female History of depression Prior suicide attempts Diabetes mellitus type 2 Mild asthma Lives in a group home

• • • Medications Valproate (recently added to psych meds) Ziprasidone Mirtazapine Clonidine Prazosin (for PTSD) Benztropine (for drug-induced extrapyramidal symptoms including eyes tonically looking upward Depo-provera Metformin Nicotine patch

Symptoms began Sept 2 • • Drowsiness: falling asleep frequently Dizzy-blurry vision-headache Sore throat—so severe it limited eating Generalized body aches Vomiting-rare Diarrhea—infrequent No fevers No rash

ED Hospital Admission Sept 9 (Day 7) Lethargy and Weakness • Non-focal exam. No fever • Excessively sleepy/lethargic. • Diagnosis: Altered mental status from drug use and diarrhea with dehydration • Treatment: IV fluids [and no more drugs except those prescribed] • Check some labs

Hospital Labs 9/9 (Illness Day 7) • WBC=2. 9: PMN 43%; Lymphs 44%; reactive lymphs 4% • Hemoglobin 11. 2 • Platelets 43, 000 • ALT=55; albumin=3. 0 • CT head, CXR, ECG all normal • Drug screen positive cannabinoids and cocaine

Diagnostic considerations • Valproate-induced marrow suppression? – stopped the valproate • Viral infection? – EBV serology: prior infection • Urine chlamydia positive so consider STI even though in group home

Further Laboratory Evaluation 9/11= Illness Day 9 • 9/11 --HIV DNA PCR was positive (state lab) • 9/11 --HIV RNA PCR >10, 000 copies/m. L (Focus--Roche) • 9/11 --HIV Ag/Ab screen negative (Determine --CHW) • 9/14 --HIV Ag/Ab reactive (WDL) but HIV-1 Ab differentiation assay indeterminate. HIV-2 Ab differentiation assay negative • 9/14 --HIV RNA PCR 1, 664, 578 (WDL-Roche) • 9/14 -CBC normal; ALT ↑ 162;

More Labs • 9/14 --CD 4 cell count 420 (29%); CD 8=594 (normal 230 -1090); CD 4/CD 8 ratio = 0. 71 (normal 0. 66 -3. 52) • 9/14— – HIV genotype: no drug resistance. – HLA B 57*01 negative

Diagnosis • Acute symptomatic HIV Infection Braun DL. CID 2015; 61: 1013. Frequency and Spectrum of Unexpected Clinical Manifestations of Primary HIV-1 Infection

• • • Diagnosis = Symptomatic HIV Infection Initiate antiretroviral therapy Anticipate lifelong treatment (70 years) Combination antiretroviral therapy (c. ART) 3 drugs (one or two pills, once daily): – 2 nucleoside reverse transcriptase inhibitors (NRTI) plus • protease inhibitor (PI) or • non-nucleoside reverse transcriptase inhibitor (NNRTI) or • integrase inhibitor (INSTI) Balance benefit and toxicity

Treatment: One Pill Once Daily Fixed Dose Combination Tablets FDC by FDC Components class Brand name Atripla Complera Odefsey Symfli LO Biktarvy Triumeq Genvoya Minimum body weight (kg) EFV 600 mg + FTC 200 mg + TDF 300 mg 40 FTC 200 mg + RPV 25 mg + TDF 300 mg 35 FTC 200 mg + RPV 25 mg + TAF 25 mg 35 EFV 400 mg + 3 TC 300 mg + TDF 300 mg 35 BTG 50 mg+ FTC 200 mg +TAF 10 mg 25 ABC 600 mg + DTG 50 mg + 3 TC 300 mg 25 EVG 150 mg + cobi 150 mg + FTC 200 mg + TAF 10 mg 25 Stribild EVG 150 mg + cobi 150 mg + FTC 200 mg + TDF 10 mg 35

• • What I say to an adolescent at our first visit You are not going to die from this. Life expectancy is good for those with HIV. – A person with HIV who takes one pill once daily and has viral load suppression Lives longer than a person who – Is Overweight / does not exercise /smokes Try to keep HIV in perspective in your life – Taking your medicine takes less time than brushing your teeth Undetectable = Untransmittable U=U

Objectives • • • How to call the HIV program How to test Whom to test Treatment of persons exposed to HIV (PEP) Treatment of those who test negative (Pr. EP) Treatment of those who test positive (Tas. P)

CHW HIV Program: Always on Call

HIV Testing at CHW

CDC HIV Testing Recommendations-June, 2014 Day after HIV Acquisition HIV Test Then what happens Day 0 HIV Infection Day 10 HIV RNA or DNA PCR (NAAT test) Day 22 Peaks about day 30 after infection. Plateaus around day 40. The antigen marker, p 24 peaks about 4 th generation immunoassay 30 days after infection, rapidly (HIV antibody/antigen test) decreases & may become undetectable ** Detects antigen (p 24) about 45 days after infection The test marker, Ig. M, peaks at about 35 3 rd generation immunoassay days then decreases until about 38 days (HIV antibody screen) when Ig. G antibodies are detectable **Detects Ig. M & Ig. G using a 2 nd generation test Day 38 2 nd generation immunoassay (HIV antibody screen and antibody differentiation tests such as the multispot) **Detects Ig. G Day 15 The test marker, Ig. G continues to increase until they are detectable by first generation tests and the western blot by day 45 -50 Bernard Branson et al (CDC). Laboratory testing for HIV Infection: Updated Recommendations June 27, 2014. http: //stacks. cdc. gov/view/cdc/23447 Thanks to Barb Cuene

CDC HIV Testing Recommendations-June, 2014 Antigen negative Antibody positive Antigen positive Antibody negative NAT Day 10 Antigen Day 15 Ig. M Antibody Day 22 Ig. G Antibody Day 38 Ig. M Ig. G Bernard Branson et al (CDC). Laboratory testing for HIV Infection: Updated Recommendations June 27, 2014. http: //stacks. cdc. gov/view/cdc/23447 Thanks to Barb Cuene

CDC HIV Testing Recommendations-June, 2014 Tests for Ig. G, Ig. M Antibody, P 24 Antigen. Positive by Day 15 Tests for Ig. G alone. Positive by Day 38 NAT Positive by Day 10 Bernard Branson et al (CDC). Laboratory testing for HIV Infection: Updated Recommendations June 27, 2014. http: //stacks. cdc. gov/view/cdc/23447

CDC HIV Testing Recommendations-June, 2014 Screen positive Second test Positive or Negative or Indeterminate Perform HIV NAT (HIV DNA or RNA assay) Bernard Branson et al (CDC). Laboratory testing for HIV Infection: Updated Recommendations June 27, 2014. http: //stacks. cdc. gov/view/cdc/23447

HIV NAT • • “HIV 1 RNA Quant PCR” Viral load Plasma viral load HIV RNA Measures amount of virus in plasma Positive if untreated Goal of therapy is undetectable plasma viral load Most readily available and rapid turnaround • • • “HIV DNA PCR” Measures presence of cellassociated proviral DNA Positive if untreated Positive if plasma viral load undetectable Not readily available Slower to result

Considerations • Mono-like illness in the appropriate setting: think of HIV • Low platelets suggest pathology • HIV RNA may be positive when antibody is still negative – If you are really considering HIV send it to WDL for a 24 hour result • Acute HIV can present as fever, rash, adenopathy, throat pain (FRAT) or with primary neurologic syndromes

Who to test? • Depends on the epidemiology of HIV in your location

Availability of HIV testing should be discussed with all adolescents, and should be encouraged with consent for those who are sexually active or substance users. Pediatrics 2001; 107: 188

HIV in USA Youth: 2008 -16 Rate of HIV Diagnosis, USA, 2016 overall race Black Latino White N (x 1, 000) Rate per 100, 000 40 17 10 10 12. 3 26 5. 1 1. 4 Total cases 2008 -2016: MSM Only (Total N=236, 150; numbers x 1, 000) Age (years) 13 -29 30 -49 >=50 overall 106 100 29 Black 52 28 7 race Latino 26 28 5 White 20 37 15 HIV Surveillance Supplemental Report 2018; 23(3) Mitsch A. MMWR 2018 Sept 21 67(37): 1025 Rate of HIV Diagnosis 2016: All risk groups (per 100, 000) Age (years) 13 -19 20 -24 overall 5. 8 30. 5 Black 26 108. 7 race Latino 5. 1 34 White 1. 4 10 Annual Percent Change 2008 -2016: MSM Only (Percent) Age (years) 13 -29 30 -49 >=50 overall 2. 9 -3. 5 0. 1 Black 2. 8 -3. 6 -1. 8 race Latino 4. 5 0. 6 4. 1 White 1. 5 -6. 4 0. 1 HIV is increasing in young Black and Latino MSM

HIV infections in Youth, USA • The US youth HIV epidemic is driven by – Black/African American – Men who have sex with men (MSM) • Compared to white YMSM – Black YMSM do NOT have • higher rates of unsafe sex • more partners – DO have sex with other black YMSM • Racial disparities in HIV acquisition are driven by epidemiology, not behavior

In the USA, HIV Prevalence is 6. 7 times higher in Black Americans Persons Living with HIV USA White 2014 USA Black 2014 Rate % 0. 152 1. 025 Haiti 2015 Kenya 2015 1. 21 3. 26 https: //www. cdc. gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2015 -vol-27. pdf http: //www. unaids. org/sites/default/files/media_asset/2016 -AIDS-data_en. pdf http: //data. worldbank. org/

WI HIV Epidemiology Not just Milwaukee County ALL counties have at least one case [except Florence] WI Integrated HIV Prevention and Care Plan 2017 -2021—Sept, 2016

Wisconsin HIV Epidemiology 1982 -2016 Rising in ages 15 -19 since 2000 Overall new cases ≈ 224 per year since 2000

1982: 80% white 2016: 65% people of color 1992 2016: 35% white 13 x Rate higher in Black males than White males WI DHS 2017 Annual Surveillance report through Dec 31, 2016 WI HIV Epidemiology by Race and Sex 24 x Rate higher in Black females than White females

MSM WI HIV Epidemiology by Risk Group and Age Male 13 -29 WI DHS 2016 Annual Surveillance report through Dec 31, 2015 (top graph) WI DHS 2017 Annual Surveillance report through Dec 31, 2016 (bottom graph)

WI HIV Epidemiology MSM ages 13 -29 years by Race/Ethnicity 2006 -2015: rising number of young black MSM with HIV WI DHS 2016 Annual Surveillance report through Dec 31, 2015 New Cases: Young Black MSM

HIV in the World: Selected Numbers, 2017 • Every week, 7000 young women aged 15– 24 years become infected with HIV. • In sub-Saharan Africa, three in four new infections in youth aged 15– 19 years are in girls. • Young women aged 15– 24 years are twice as likely to be living with HIV as men http: //www. unaids. org/sites/default/files/media_asset/UNAIDS_Fact. Sheet_en. pdf

For Adolescents in Kenya and Uganda, HIV is More Common in Females Wisconsin: 36% HIV Prevalence in BMSM age 15 -59 Kadede K, Ruel, et al AIDS 2016. 30: 2221

Ways to prevent HIV • • • Abstain from sex or injection drugs Always use a condom or clean works Post-exposure prophylaxis (PEP) Treatment as prevention (Tas. P) Pre-exposure prophylaxis (Pr. EP)

Post-Exposure Prophylaxis (PEP) is Routine after Sexual Assault Most PEP only requires a single dose Single Dose Only • • • Gonorrhea Chlamydia Trichomonas [Hepatitis B] [Contraception] Multiple Doses / 28 Days • HIV

HIV Post-exposure prophylaxis HIV PEP See Schilling S. Pediatrics 2015; 136: e 1495 DOI: 10. 1542/peds. 2015 -2093 Also NY state guidelines at http: //www. hivguidelines. org/wp-content/uploads/2014/10/hiv-prophylaxis-for-victims-ofsexual-assault. pdf

Probability of acquiring HIV from an HIV-infected Source Risk per Act Blood transfusion per 10, 000 percent 9250 92. 5% No maternal ART (maternal viral load ≈15, 000 copies/m. L) 8. 5% Maternal c. ART: viral load 400 -999 copies/m. L 2. 6% Receptive anal intercourse 138 Maternal c. ART: viral load 50 -399 copies/m. L 1. 38% 1. 0% Needle sharing: injection drug use 63 0. 63% Percutaneous needlestick 23 0. 23% Insertive anal intercourse 11 0. 11% Maternal c. ART: viral load <50 copies/m. L 0. 09% Receptive penile-vaginal intercourse 8 0. 08% Insertive penile-vaginal intercourse 4 0. 04% In BLACK: From CDC 2016 n. PEP guidelines (www. AIDSINFO. NIH. gov), In BLUE: Infant transmission risk: from Townsend, and Nielsen-Saines

• • HIV PEP Start within 72 hours Three antiretroviral drugs (ARVs) 28 days Take all the pills Decreases HIV acquisition after needlestick No randomized trials for sexual exposure Routinely recommended after sexual assault – Not indicated for recurring exposures In CHW ED: ARVs delivered from Walgreen’s to the patient in the ED

Ways to prevent HIV • • • Abstain from sex or injection drugs Always use a condom or clean works Post-exposure prophylaxis (PEP) Treatment as prevention (Tas. P) Pre-exposure prophylaxis (Pr. EP)

When an HIV Test is Performed High Risk? Start F/TDF (Truvada) HIV Test Negative HIV Test Performed HIV Test Positive link Pre-Exposure Prophylaxis = Pr. EP Treat: retain One pill Once daily Start c. ART 2 NRTI + (INSTI or PI) adhere Treatment as Prevention = Tas. P

Spectrum of Engagement in HIV Care (the Care “Cascade”) • • • Diagnose [“infected” OR “at risk”] Link Retain Start c. ART or Pr. EP Continue c. ART or Pr. EP Goal = Viral load undetectable • Became undetectable with c. ART • Stayed negative with Pr. EP

Treatment as Prevention Tas. P-2011 In serodiscordant couples early initiation of c. ART reduced sexual transmission of HIV from 0. 9 to 0. 04 transmissions per 100 person-years Cohen MS, for the HPTN 052 Study Team. NEJM 2011; 365: 493

Treatment as Prevention = Tas. P - 2016 • Person with HIV – taking combination c. ART with – undetectable viral load • Transmission risk to sex partner = 0% – Upper 95% confidence interval = 0. 3% • (If we did the study again, what is the highest risk we might find? ) Rodger AJ- PARTNER Study Group. JAMA 2016; 316: 171

Tas. P: Transmission Risk by Exposure Type Partner on c. ART with Undetectable Viral Load Men who have sex with Men Rate of within-couple transmission per 100 couple-years of follow-up Exposure Category Point estimate of Transmission Risk 0 0 Any sex Receptive anal sex Rodger AJ- PARTNER Study Group. JAMA 2016; 316: 171 Upper 95% confidence limit 0. 84 2. 70

Problems with Tas. P: Treatment Adherence is Imperfect • N=10, 942 in 6 academic HIV clinics • >2 viral load tests available over 1 year • 66% suppressed on all tests in the period Age at entry N All viral load results suppressed (years) (<200 copies/m. L) 18 -39 2147 52% 40 -49 2830 65% 50 -91 5894 71% Marks G, JAIDS 2016; 73: 205

Problems with Tas. P: Treatment Adherence is Imperfect • N=238, 641 in 17 areas in National HIV Surveillance System with VL done in 2011 • >2 viral load tests available 2012 -2013 • 62% suppressed on all tests in the period Age at entry (years) 13 -24 25 -34 35 -44 45 -54 >55 N 10, 369 31, 551 62, 647 87, 506 46, 555 Crepaz N CID 2016; 63: 976 Days with viral load >200 copies/m. L during 2 years (730 days) 338 245 189 152 105

Tas. P: What is the public message? • “HIV treatment prevents transmission of HIV” (UNAIDS) • “helps prevent transmission to others” (CDC) • “much less likely to pass HIV on to others” (thewellproject. org) • “less likely to infect others” (POZ)

U = U Undetectable = Untransmittable ‘Negligible’ HIV risk from people in treatment, new campaign proclaims. Vancouver’s Health Initiative for Men New York State Be Sure, Play Sure, Stay Sure

Condoms count, even with HIV Treatment: Transmission risk over 100 sex acts in discordant male couples Garnett GP and Gazzard B. Lancet 2008; 372: 270

When an HIV Test is Performed High Risk? Start F/TDF (Truvada) HIV Test Negative HIV Test Performed HIV Test Positive link Pre-Exposure Prophylaxis = Pr. EP Treat: retain One pill Once daily Start c. ART 2 NRTI + (INSTI or PI) adhere Treatment as Prevention = Tas. P

In high risk MSM, truvada Pr. EP led to a 44% reduction in HIV incidence Grant RM, For the i. Pr. Ex study team. NEJM 2010; 363: 2587 Pre-exposure prophylaxis = Pr. EP: Tenofovir disoproxil fumarate plus emtricitabine (Truvada) for HIV prevention

i. Pr. Ex: Lower DBS RBC TFV-DP associated with ↑HIV Acquisition Risk 2 -3 tablets per week is 76% protective >4 tablets per 7 tablets week is 96% per week protective is 99% protective Grant RM, Anderson PL, …Hosek S…Mayer K i. Pr. Ex study team. Lancet ID 2014

Define participant adherence groups based on Category of [DBS RBC TFV-DP] at week 4: Poor adherers (Green) rarely improve Good adherers (Blue) worsen with time Grant RM, Anderson PL, …Hosek S…Mayer K i. Pr. Ex study team. Lancet ID 2014

Pr. EP Adherence is Difficult for Youth 55% 34% 4 or more pills per week (“protective”) • >50% weeks 4 -8 -12 • Monthly study visits • 34% at week 48 • Every 3 month study visits • 0% in African American study participants: Drug concentrations never reached 4 pills per week Hosek S. JAIDS 2017; 74: 21

International AIDS Society-USA Panel Recommendations on Pr. EP 2014: no recommendation 2016: Daily TDF/FTC is recommended 2018: Daily TDF/FTC is recommended 1 -week lead-in to ensure adequate tissue levels Continue TDF/FTC 1 week after last exposure Pericoital TDF/FTC may be considered as alternative =on-demand, event-driven, or “ 2 -1 -1” for MSM with infrequent sexual exposure. Double dose TDF/FTC 2 -24 hr before exposure Single dose at 24 and 48 hours after exposure Saag MS. JAMA July 24, 2018 doi: 10. 1001/jama. 2018. 8431

International AIDS Society-USA Panel Recommendations on Pr. EP • HIV rapid Ag/Ab assay at start • HIV RNA if acute infection suspected • Creatinine at start and every 6 months • HIV rapid Ag/Ab and STI testing every 3 months • HCV antibody annually • Visits every 1 to 3 months • Do not prescribe more Pr. EP without HIV testing Saag MS. JAMA July 24, 2018 doi: 10. 1001/jama. 2018. 8431

Summary-1 • Recommend condoms • Test and treat – negative→Pr. EP – positive→c. ART=Tas. P • Adherence is difficult • Recommend condoms

Summary-2 • We have the tools to end the epidemic. • Why does the epidemic persist?

Long-Acting Antiretrovirals: Future Hope? Gulick RM and Flexner C. Annu. Rev. Med 2019

Long-Acting Antiretrovirals: Future Hope? An Injectable that Solidifies Microneedle Patches Rzhevskiy AS. Microneedles. . . Review Journal of Controlled Release 2018 Donnelly RF. Microarray Patches. . . Drug Discovery Today 2018 Kovarova M Ultra-long-acting removable drug delivery system for HIV treatment and prevention. Nature Communications 2018 Duarah S. Microneedles. . . Paediatrics. Eur J Pharmaceutics and Biopharm 2019

Thank You.

Types of Advice about Drinking • Abstinence – Don’t Drink • Abstinence plus harm reduction – Don’t drink, but – If you do drink, don’t drive. • If you do drink, don’t have sex –You make bad choices when you cannot think straight

Types of Advice about Sex • Abstinence – Don’t have sex until you are married • Abstinence plus harm reduction – Don’t have sex until you are married, but – If you do have sex • USE A CONDOM

Condoms cause sex Like umbrellas cause rain.

Helping Adolescents with HIV Make it Across the Chasm Balance Age 8 -13 Immediate drug benefit Later Therapeutic options Terra Firma Age 18 -25 Terra Firma The potential Abyss of Adolescence

Milwaukee HIV Epidemiology MSM ages 13 -29 years by Race/Ethnicity 2006 -2015: rising number of young black MSM with HIV WI DHS 2016 Annual Surveillance report through Dec 31, 2015

WI HIV Epidemiology Median Age at HIV Diagnosis by Risk Exposure and Race/Ethnicity Youngest age at diagnosis: Black MSM WI DHS 2016 Annual Surveillance report through Dec 31, 2015

For Adolescents in Kenya and Uganda, HIV is More Common in Females Wisconsin: 36% HIV Prevalence in BMSM age 15 -59 Kadede K, Ruel, et al AIDS 2016. 30: 2221

Risk of HIV Acquisition after Sexual Exposure is Reduced by Medications • Risk of HIV acquisition after a single sexual exposure is 0. 04% to 1. 38% • Antiretrovirals “reduce the risk for acquiring HIV infection after … exposure” (CDC) – Start within 72 hours – Continue for 28 days – Take all the pills

AIDS in USA Youth: 15 years going in the wrong direction AIDS in the USA 1985 -2013 Age 13 -19 years AIDS in the USA 1985 -2013 Age 20 -24 years

Males Predominate in all age groups

Adolescents and Young Adults Aged 13– 24 Years Living with a Diagnosis of HIV Infection, by Sex and Transmission Category, Year-end 2010, United States and 6 Dependent Areas Males: MSM Perinatal Females: Heterosexual Perinatal Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays and missing transmission category, but not for incomplete reporting. a Heterosexual contact with a person known to have, or to be at high risk for, HIV infection. b Includes hemophilia, blood transfusion, and risk factor not reported or not identified.

Diagnoses of HIV Infection among Adolescents and Young Adults Aged 13– 24 Years, by Race/Ethnicity, 2009– 2013 United States and 6 Dependent Areas Black / African American Predominate