10/10/18

HIV Update • HIV natural history review • Acute HIV infection October 10, 2018 • 2018 Top 10 List • Miscellaneous Issues relevant Jack Stapleton, MD for Primary Care

Natural History of HIV Infection No Infection Primary HIV Infection Neurologic Disease

Exposure PGL to HIV • Also called: Early Infection Asymptomatic Symptomatic AIDS – Acute Retroviral Syndrome, HIV-Mono Disease • Occurs in 40% to 70% of new HIV infections Acute Disease • 1 - 12 weeks post-exposure 0 0.2 0.7 2.2 6.1 7.3 8.1 8.2 8.1 7.4 6.7 n/100 developing AIDS diagnoses • Average duration ~ 1-8 weeks

0 1 2 3 4 5 6 7 8 9 10 years post-infection • Neuropathic and Dermatopathic presentation No Infection Exposure • Antibody test often negative during illness to HIV IRIS Infection Tx Monitor for side effects

Acute HIV Infection Fever 87.5 % Malaise 72.5 % Myalgia 60 % Rash 57.5 % Headache 55 % Night Sweats 50 % Sore Throat 42 % Lymphadenopathy 37.5 % Arthralgia 27.5 % Nasal Congestion 17.5 % Oral Ulcers 7.5% Thrush 5 % Ann. Int. Med. 134:25-29, 2001

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Kinetics of and Immune Response CD4 -Agcount NegativeHIV Ab Serology

Positive 2018 HIV/AIDS Top 10 Serology HIV RNA

HIV RNA

CD4 count

1-12 wks 8-10 yrs 2-3 yrs

Number 1 HIV – CD4 Cell Interaction • CD4 = Binding • CCR5 and CXCR4 Though not so new – this still makes Entry Corecptors • Transmitted = the Top 10 CCR5 • Polymorphism: Evidence for HIV cure by CCR5D32/ CCR5D32 • Mainly Caucasian CCR5D32 stem cell transplantation • Homozygosity = HIV resistance! Timothy Brown – the “Berlin Patient” R5 Inhibitor therapy = maraviroc CCR5 = “M” tropic Or Non-Syncytia-inducing Schneider et al., Blood epub 12/8/10 “R5” virus

Case Summary Sadly • HIV-infected man with AML • SCTx with CCR5D32 homozygous 2006 Follow up studies of • GVHD, Relapse, repeat SCTx 2007 bone marrow/SCTx and/or • 11 years follow up: early treatment of newborns CD4+ T cells reconstituted not successful CCR5D32/CCR5D32 No sign of HIV infection (RNA - DNA) Provides proof of principle • Results “strongly suggest that cure of HIV has been achieved in this patient”

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Number 2 Treatment Prevents Transmission HPTN 052 U=U

Undetectable Viral load

Untransmittable HIV

How many infectious diseases eradicated by Consequences of U=U medical intervention? • Treat as prevention: goal of HRSA One: Smallpox • Will it stop the spread of HIV? How many infectious diseases eradicated by - Should help treatment? - Other STIs as model None • Caveat’s Including infections curable by single dose therapy: – Other STIs increasing a. Syphilis – Identify all infected? b. Gonorrhea – Adherence? c. Chlamydia d. Bacterial Vaginosis – Resistance? e. Fungal vaginosis – Access?

Single pill (Truvada, combination tenofovir + emtricitabine) daily Number 3 PrEP Works (if you take it) (Pre-exposure Prophylaxis)

Preexposure chemoprophylaxis

for HIV prevention in men who Cumulative probability of HIV Infection have sex with men. Grant et al., NEJM 362:2587, 2010 Weeks since randomization Grant et al., NEJM 362:2587, 2010

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Detecting Risk Eligibility? Detecting Risk: Eligible? HIV-positive sexual parnter Recent bacterial STI Negative HIV test prior to PrEP High number of sex partners No signs of acute HIV Inconsistent or no condom Use Normal renal function Commercial sex worker Documented HBV infection status In IVDU: HBV vaccination status Sharing injection works Recent drug treatment TelePrEP programs: UI and IDPH PHS guidelines: Expansion to others https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2017.pdf

UI HIV/AIDS Clinic Trends Number 4 300 0 250 0 Total patients seen New patients/year 200 0 Changing Epidemiology Active Clinic patients 150 0

100 0

500

0 198 8 199 1 199 5 200 0 200 5 201 0 201 5

Which HIV prevalence goes with which population? U.S. Statistics • 1.12 million living with HIV, 2015 1. 30.6% 1. Nigeria • 39,800 new infections in 2016 2. 18.9% 2. S. Africa • May be decreasing? 3. 3.3% 3. Urban S. Africa 4. 1.2% 4. General US Pop. • Not reduced in young MSM 5. 0.4% 5. Washington DC • 20% to 50% unaware of infection

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New HIV Infections by ART: Numbers 5 to 10 transmission category, 2015 New Drugs (5) New HIV Infections by Race/Ethnicity, 2015 Multiple races 3% (1,100) New Combinations (6)

Asians 2% (740) Change in guidelines (7) Transmitted Resistance (8) 41% IRIS (9) New Approaches (10)

Number 5 – New Drugs More – New Drugs Tenofovir disoproxil fumarate vs Bictegravir (integrase inhibitor) Tenofovir alenfenamide fumarate Doravirine (NNRTI) (TDF vs TAF) Generics TDF, 3TC, EFV, ZDV, NVP, TAF = prodrug – lower [plasma] ABC, FosAPV, ATV Reduces renal toxicity and DDIec, D4T bone mineral loss

# 5 & 6 – New Drugs/Combos Number 7: Guideline Changes Tenofovir formulation in combo meds Many changes, some of the key Truvada = TDF Descovy = TAF ones include: Stribild = TDF Genvoya = TAF Treat all patients with HIV VL > 20 Complera = TDF Odefsy = TAF Preferred regimens include: Atripla = TDF Biktarvy = TAF 2 NNRTs + integrase inhibitor; Symfi = TDF Symfi Lo = TAF other regimens in certain patients Delstrigo = TDF Symtuza = TAF Fewer CD4 counts Jaluca (no Tenofovir – 2 drug) https://aidsinfo.nih.gov/ Slide # 43

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Number 8: Transmitted Resistance (U.S.)

• Overall prevalence: 15% ART Resistance • Race/ethnicity not associated with resistance • Lower among 4% with non-subtype B Check HIV genotype: • NNRTI (8%) > NRTI (6%) > PI (4.5%) When starting ART • NNRTIs: K103N (67%) > Y181C (14%) > G190A (9%) • NRTIs: For failing regimen before switch TAMs & T215 revertants >> M184V* (19%) >> K65R (1%) For switch, best done on meds! • PIs: L90M > M46I/L > D30N >> V82A* > I84V*

Illustrates importance of pre- treatment drug resistance testing.

# 9 = IRIS: Immune Reconstitution Natural History of HIV Infection Inflammatory Syndrome No Infection Neurologic Disease

• Paradoxical worsening of pre-existing infectious Exposure PGL diseases following initiation of antiviral therapy (ART) to HIV

• Associated with: low CD4 counts (<50), unrecognized Early OI, high microbial burden, starting ART close to the Infection Asymptomatic Symptomatic AIDS time OI therapy is started. Disease Acute Disease • Manifestations: New OI’s (VZV, HSV, PCP, M.Tb., MAI, KS, Cryptococcal disease, Toxoplasmosis). Both No Infection local and systemic inflammation may occur. Exposure to HIV IRIS • Management: If severe, may need to stop ART or Infection Tx Monitor for side effects consider use of corticosteroid therapy.

Number 10: New Approaches Miscellaneous Topics Long-acting ART and Abs Licensed: Monoclonal Abs Young women Ibalizumab. IV q 2 weeks Hepatitis B, C co-infection (combination only) Cabotegravir+RPV injectable (Phase III)

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Transmission & Maternal HIV RNA HIV Therapy & Pregnancy

• ART naïve • ARV prophylaxis to prevent perinatal transmission is – Genotype always recommended for all HIV-infected women – If late; consider 4 drug therapy pending genotype • Risk of perinatal transmission greater with higher • Timing - First trimester maternal VL. – May delay Rx if maternal CD4 count is high (>500) – However, perinatal transmission can occur even at – If CD4 350 – 500, debatable, but most would treat undetectable maternal VL, so VL should not be a – Always recommend if CD4 < 350 determining factor in starting ART for perinatal prophylaxis – Avoid teratogenic meds (Efavirenz, Delavirdine, • ARV drugs are highly effective in preventing HIV • Timing – after first trimester transmission, regardless of disease stage – Treat all • Stress adherence

NRTIs with high placental transfer Pregant, On therapy 3TC ZDV FTC HIV VL: ABC d4T TDF At least one of these drugs should be used Suppressed, continue unless contraindications EFV, other teratogenic drugs in 1st trimester – NNRTIs Change – this year – Continue EFV unless | in the first 4-6 weeks of pregnancy EFV, DLV: Teratogenic Avoid drugs with adverse potential (d4T/ddI) NVP: Should not start if CD4 >250 Continue NVP regardless of CD4 count RPV: No data HIV Not suppressed: Genotype and ARV Hx; Base change on data

Other considerations Report all cases of ARV use in pregnant women to the Antiretroviral Pregnancy Registry: HIV+HBV co-infection: http://www.APRegistry.com Need to Rx both; Vaccine

Collects observational, non-experimental data regarding HIV+HCV: ARV exposure during pregnancy to assess potential teratogenicity. No HCV Rx with current meds HBV and/or HCV infected: Vaccinate for HAV

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Anti-HIV Drugs: 2018 cART - 3 or 4-drug combinations Anti-HIV Drugs: 2018 Triumeq (ABC, 3TC, DTG) NRTI’s (Nucleoside RT Inhibitors) Biktarvy (TAF+BIC+FTC) AZT/ZDV (zidovudine, retrovir), 3TC (lamivudine, Complera (TDF, FTC, RPV) epivir); Abacavir (ABC, Ziagen); TFV (TDF/TAF) Odefsey (TAF, FTC, RPV) Tenofovir, viread); FTC (Emcitribine); Stibild (TDF, FTC, ELV, Cobi) Combination NRTIs: Truvada (TDF+FTC); Genvoya (TAF, FTC, ELV, Cobi) Cimduo (generic TDF+3TC); Descovy (TAF+FTC); ATRIPLA (TDF, FTC, EFV) Epzicom (ABC+3TC); Combivir (ZDV, 3TC); Symfi and Symfi Lo (TDF or TAF[lo], 3TC, EFV) Trizavir (ZDV, 3TC, ABC); Symtuza (TAF, FTC, DRV, Cobi) Seldom, if ever used: ddC (zalcytibine, HIVID); d4T Delstrigo (TDF, 3TC, doravirine) (stavudine, zerit); ddI (, videx); ddIEC (didanosine extended release) New 2-drug to know about: Juluca (DTG+RPV)

Anti-HIV Drugs: 2018 Anti-HIV Drugs: 2018

Integrase Inhibitors PRI’s (Protease Inhibitors) Raltegravir (isentress); dolutegravir (Tivicay); Darunavir (Prezista, DRV); Ritonavir (Norvir, RTV); Elvitegravir (Vitekta – boosted); bictegravir Atazanavir (Reyataz, ATZ) (only as combo - biktarvy) Combinations: Prezcobix (DRV+cobi); Evotaz (ATZ+CBT) NNRTI’s (Non-Nucleoside RTIs) Seldom, if ever used: Saquinavir (Invirase,SQV); Efavirenz (sustiva); Etravirine (intelence); (Crixivan, IDV); Nelfinavir (Viracept, NLV); Amprenavir Rilpivirine (Edurant); Doravirine (Pifeltro) (Angenerase, AMP); Lopinavir/rtv (Kaletra); Seldom, if ever used: Neviripine (virammune); Fosamprenavir; Tipranavir Delavirdine (rescriptor) Monoclonal Antibodies: Ibalizumab (Trogarzo) Entry inhibitors (seldom used) Fuzeon, maraviroc PK Boosting: Cobicistat (tyboost, cobi); Ritonavir

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