C.W. Shafer, MD HIV Specialist, AAHIVM Sioux Falls Family Medicine Residency Falls Community Health

Objectives 1. Discuss the current status of the statewide, nationwide and worldwide HIV/AIDS epidemics. 2. Describe the impact of HIV on the management of the pregnant patient. 3. Discuss Pre- and Post-Exposure Prophylaxis for HIV.

HIV in the U.S.A. 658,000 deaths 1,200,000 HIV- infected ~50,000 new cases per year 12.8% remain undiagnosed (~156,300 individuals)

South Dakota HIV Statistics Through 2014 761 cumulative HIV/AIDS cases since 1985 550 people living with HIV in SD 31 new cases in 2014; 19 males, 12 females African Americans comprise 23% of living cases, <1% of gen l population Native Americans: 16% of living cases, 9 % of gen l population

South Dakota Residents Reported Infected with HIV/AIDS: Cumulative Cases by County, 1985-2014 Harding Perkins Corson 6 Campbell Walworth < 5 McPherson Edmunds Brown 12 Marshall < 5 Day < 5 Roberts < 5 Butte 6 Custer < 5 Pennington 160 Meade 14 Ziebach Dewey < 5 Lawrence Stanley Hughes 15 12 Haakon < 5 Fall River < 5 Shannon 30 Jackson < 5 Bennett < 5 Jones < 5 Mellette < 5 Todd 8 Sully Potter < 5 Lyman < 5 Tripp < 5 0 Cases 1-5 Cases 6-30 Cases 31 310 Cases Hyde Faulk Buffalo < 5 Hand Brule < 5 Jerauld Aurora Spink < 5 Beadle 13 Douglas Charles Mix Gregory < 5 < 5 Clark < 5 Kingsbury < 5 Hamlin Grant < 5 Deuel < 5 Sanborn Miner Lake Moody < 5 < 5 6 Davison Hanson McCook 8 < 5 Hutchinson < 5 Bon Homme 7 Codington 9 Turner < 5 Yankton 30 Brookings 10 Minnehaha 310 Clay 16 Lincoln 6 Union 7 8

South Dakota HIV as of 12-31-14 Exposure Category Heterosexual - 30% MSM - 35% Injection Drug Use - 15% MSM and IDU - 4% Perinatal/Peds - 2% Transfusion - 2% Unspecified - 8%

South Dakota Residents Infected by HIV, by Gender, 1985-2014 Cases reported 40 35 30 25 20 22 35 37 32 26 25 21 22 35 22 21 16 24 33 34 25 25 20 22 19 19 36 34 35 29 21 21 31 15 11 10 8 5 0 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 HIV (female) 0 0 2 4 5 3 3 6 6 3 8 1 4 4 5 9 7 12 4 6 14 12 11 8 6 13 8 9 12 12 HIV (male) 8 11 20 31 32 23 29 15 19 19 27 20 18 12 19 11 15 7 21 13 19 22 14 26 15 22 13 20 24 19 Total 8 11 22 35 37 26 32 21 25 22 35 21 22 16 24 20 22 19 25 19 33 34 25 34 21 35 21 29 36 31 AIDS 3 3 4 10 4 16 14 20 18 24 22 19 20 13 13 15 18 13 16 13 14 22 12 12 7 12 9 12 13 8

HIV trends in the USA Mortality Mode of transmission Race Gender

Percentages of Stage 3 (AIDS) Classifications among Adults and Adolescents with HIV Infection, by Transmission Category and Year of Diagnosis, 1985 2013 United States and 6 Dependent Areas Note. 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, perinatal exposure, and risk factor not reported or not identified.

Adults and Adolescents Living with Diagnosed HIV Infection Ever Classified as Stage 3 (AIDS), by Sex, 1993 2012 United States and 6 Dependent Areas Note. All displayed data have been statistically adjusted to account for reporting delays, but not for incomplete reporting.

Stage 3 (AIDS) Classifications among Adults and Adolescents with Diagnosed HIV Infection, by Race/Ethnicity, 1985 2013 United States and 6 Dependent Areas Note. All displayed data have been statistically adjusted to account for reporting delays, but not for incomplete reporting. a Hispanics/Latinos can be of any race. b Includes Asian/Pacific Islander legacy cases.

Survival after Classification of Stage 3 (AIDS) during 1998 2009, by Months Survived and Race/Ethnicity United States and 6 Dependent Areas Note. Data exclude persons whose month of diagnosis or month of death is unknown. a Includes Asian/Pacific Islander legacy cases. b Hispanics/Latinos can be of any race.

Trends in the Percentage Distribution of Deaths due to HIV Infection by Sex, United States, 1987 2009 Note: For comparison with data for 1999 and later years, data for 1987 1998 were modified to account for ICD-10 rules instead of ICD-9 rules.

What Should I Know About HIV? 1. Relevance 2. Risk Behaviors 3. Testing 4. Medications

How is This Even Relevant to Me? Whether you realize it or not, HIV is here in SD Some of your patients are involved in high-risk behaviors Patients you are seeing may not mention their HIV If you don t ask, they won t tell

HIV: A Quick Review of the Basics The current HIV paradigm: just another chronic disease Essentially no impact on life expectancy in a significant subset of patients HIV transmission is behavior-based Tremendous progress has been made in HIV treatment, but neither a cure or a vaccine is practical Patients with HIV are just like you and me

HIV High-Risk Behaviors Engaging in anal, oral or vaginal sex with MSM, multiple or anonymous partners Injecting drugs with a shared needle Being diagnosed with an STD Exchanging sex for drugs or money Having rec d blood products 78 to 85 in US

Who Should Be Tested for HIV? All pregnant women Anyone diagnosed with any STD Everyone age 13-64 (2006 CDC recommendation for opt-out testing ) At least one time and more often based on risk Up to every 3 months based on ongoing risk Understand the possibility of false positives

Opt-Out Testing for HIV

Available HIV tests Enzyme Immunoassay (EIA) Detects HIV Antibody Rapid EIA Blood Urine Saliva HIV-1 Multispot New confirmatory test Western Blot Old confirmatory test HIV-1 RNA (Quantitative) use only when acute retroviral syndrome is suspected 4 th Generation combined Ab/Ag test

HIV Testing at Avera and Sanford Generation 4 HIV: HIV 1 and 2 antibody PLUS a p24 antigen Turnaround time: Within 1 hour Confirmatory test still required

HIV Testing in Pregnancy All women should be tested at 1 st visit Higher risk of false positive EIA s in pregnancy Repeat testing in 3 rd trimester for women at increased risk of HIV: HIV prevalence in pregnant women is > 1 per 1,000 Incarcerated women Jurisdictions with elevated HIV incidence Individuals (OR THEIR PARTNERS) involved in highrisk behaviors

Anti-Retroviral Medication Issues Take all or take none (suboptimal adherence leads to development of resistance) Potentially-serious adverse events Marrow suppression: zidovudine Pancreatitis: didanosine, stavudine and others Hepatotoxicity: multiple, esp. nevirapine and PI s CNS side effects: efavirenz Hyperglycemia and Hyperlipidemia: PI s Bone and renal toxicity: Tenofovir

What do I need to know about HAART? (Highly Active Anti-Retroviral Therapy) DRUG INTERACTIONS DRUG INTERACTIONS DRUG INTERACTIONS Be aware of side effects

HIV Medication Timeline 1987 Zidovudine (AZT/Retrovir) 1988 1989 1990 1991 Didanosine (DdI or Videx) 1992 Zalcitabine (DdC or Hivid) 1993 1994 Stavudine (D4T or Zerit) 1995 Lamivudine (3TC or Epivir), Saquinavir (Invirase, Fortovase) 1996 Ritonavir (Norvir), Indinavir (Crixivan), Nevirapine (Viramune)

HIV Medication Timeline 1997 Nelfinavir (Viracept), Delavirdine (Rescriptor) 1998 Efavirenz (Sustiva), Abacavir (Ziagen) 1999 Amprenavir (Agenerase) 2000 Lopinavir/ Ritonavir (Kaletra) 2001 Tenofovir (Viread) 2003 Emtricitabine (Emtriva), Fosamprenavir (Lexiva), Enfuvertide (Fuzeon) 2004 2005 Tipranavir (Aptivus) 2006 Darunavir (Prezista), Efavirenz/emtracitabine/tenofovir (Atripla)

HIV Medication Timeline 2007 Maraviroc (Selzentry), Raltegravir (Isentress) 2008 2011 2012 2013 Etravirine (Intelence) Rilpivirine (Edurant), Emtricitabine/rilpivirine/tenofovir (Complera) Elvitegravir/cobicistat/emtricitabine/ tenofovir disproxil (Stribild) Dolutegravir (Tivicay)

HIV Medication Timeline 2014 2015 Dolutegravir/abacavir/lamivudine (Triumeq), Elvitegravir (Vitekta), Cobicistat (Tybost) Darunavir/cobicistat (Prezcobix), Atazanavir/cobicistat (Evotaz), Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya)

Common Lab Abnormalities Neutropenia is common Elevated protein is common Atazanavir (Reyataz) causes high bilirubin Zidovudine (Retrovir) causes a high MCV Cobicistat (Tybost, Prezcobix, Evotaz, Stribild, Genvoya) can cause a false elevation in Cr

Perinatal HIV Transmission Risk Untreated: Approx. 25-28% AZT Monotherapy: 8% Prophylactic C/S: 3-5% Combination ART: <1%

ACTG 076 Trial (U.S. and France) ZDV vs. placebo ZDV mono-therapy starting at 14-34 weeks, IV ZDV intrapartum, and neonatal ZDV for 6 weeks Mother-to-Child-Transmission (MCTC) at 18 months: 8.3% in the ZDV arm 25.5% in the placebo arm

CDC Short-course ZDV Trial (Thailand) ZDV vs. placebo ZDV mono-therapy starting at 36 weeks (No IV ZDV, no neonatal ZDV) MTCT at 6 months: 9.4% in the ZDV arm 18.9% in the placebo arm

The Ditrame Trial (Cote d Ivoire, Burkina Faso) ZDV vs. placebo, Breastfeeding ZDV mono-therapy at 36 weeks, plus 1 week postpartum for mom MCTC at 6 months: 18% in the ZDV arm 27.5% in the placebo arm MCTC at 15 months: 21.5% in the ZDV arm 30.6% in the placebo arm

Case 1: B.P. 34 y/o Sudanese female Arrived in 2007 with known HIV diagnosis Had a 2 y/o HIV-negative son Initial labs: CD4: 14 Viral load: 195,000 Numerous striking skin lesions on her face Genital lesions positive for HSV ART started but poor adherence led to multi-class resistance

Case 1, Con t. Became pregnant in late 2007; G9P8 Already on lopinavir/ritonavir (Kaletra), emtracitabine/tenofovir (Truvada), and zidovudine Viral loads repeatedly < 50 copies. CD4: ~200 HGSIL Pap NSVD at 39 6/7 weeks (ART plus 076 ZDV protocol) Infant shown to be HIV negative Persistent HGSIL cervical conization scheduled, IUD to be placed at the same time

Case 1, Con t. 3 months later, pregnancy test positive ART: darunavir/ritonavir, emtracitabine/tenofovir (Truvada) and zidovudine CD4 s now in the 200 s-300 s EGA Details 25 weeks Viral load 155 31 weeks Viral load 81 36 weeks Viral load: QNS 37 weeks No show 37 ½ wks Presents to L&D with heavy bleeding

Case 1, Con t. Emergent classical C/S for near-complete abruption Transverse lie, difficult extraction, needle stick during closure of the wound Mom, infant, and surgeon did fine Current status: ART: darunavir, ritonavir, tenofovir and dolutegravir CD4: 651 Viral load: 48 copies ASCUS (s/p LEEP) with HPV typing negative for hi risk

Case 2A: S.Z. 35 y/o male Ethiopian immigrant, in the U.S. >15 years, graduated from high school in MD Presents to clinic in July 2012 with persistent cough, dysphagia, and oral thrush Rapid HIV test is positive CXR: bilat. Infiltrates subsequently dx d with PCP CD4 count: 6, HIV RNA Quant: 433,000

Case 2B: S.I. 34 y/o wife of S.Z. (who was diagnosed July, 2012) Delivered her second child in Sep, 2011 In December, 2011 presented to clinic and was diagnosed with pharyngitis. Fever, HA, ST, rash, and adenopathy In August, 2012 was found to be HIV positive CD4: 1191, HIV RNA: 3,400 Infant was HIV negative

ART: Who Gets Treated in Pregnancy? Everybody Those who require ART for their own health Those who need it only to reduce MTCT Especially Patients with acute sero-conversion Women diagnosed late in pregnancy

ART-Naïve Women Start immediately or as soon as possible Factors to consider Genotype CD4 count N/V related to pregnancy Patient readiness/ability to adhere NRTI backbone with one or more NRTI s that have high transplacental levels: ZDV, 3TC, FTC, TDF, ABC Nevirapine can be used is CD4 < 250

Women on ART Who Become Pregnant If the regimen is working, keep taking it Efavirenz: Okay to continue despite known risk of neural tube defects Nevirapine: Okay regardless of CD4 ARV resistance testing for anyone with detectable viremia (HIV RNA of > 500 copies)

Pre-conception Counseling in HIV Basic pre-conception issues The good old days of HIV care Risk/benefit Turkey basters and other creative options Sperm-washing Current practice: PrEP Tenofovir/emtracitabinedaily for the uninfected partner Timed intercourse; use condoms all the rest of the time

Mode of Delivery Scheduled C/S at 38 weeks if HIV RNA>1,000 (or unknown) Scheduled C/S not recommended if HIV RNA<1,000. (No additional risk reduction is conferred)

What About SROM/Labor in Patients Scheduled for C/S? Duration of ROM/labor 1996 study showed 4 hours of ROM was a significant cut-off 2001 study showed 2% increase in MTCT/hour of ROM HIV RNA level Current ART regimen

Intrapartum Prophylaxis Continue antepartum ART regardless of mode of delivery IV Zidovudine? Yes, if HIV RNA >1,000 (or unknown) near delivery Not required if HIV RNA <1,000 near delivery (and patient is on ART with no concerns of poor adherence) Zidovudine dose: 2 mg/kg IV over the first hour, then 1 mg/kg/hruntil cord clamp

OB Procedures in HIV: Avoid if Possible Antepartum: Amniocentesis Intrapartum: AROM Routine use of fetal scalp leads IUPC placement? Operative delivery Forceps Vacuum Episiotomy

No-Prenatal-Care Patients Presenting in Labor Rapid HIV test ASAP If positive, treat as if infected (don t wait for confirmatory test) Continue to treat infant as if mom has HIV until confirmatory test proves negative

What do I need to know about HAART? (Highly Active Anti-Retroviral Therapy) DRUG INTERACTIONS DRUG INTERACTIONS DRUG INTERACTIONS DRUG INTERACTIONS DRUG INTERACTIONS DRUG INTERACTIONS Be aware of side effects

OB Drug Interactions Methergine levels increased by Protease Inhibitors and Cobicistat-containing ARV s (CYP3A4 Inhibitors) Norvir (ritonavir) Reyataz (atazanavir) Prezista (darunavir) Kaletra (lopinavir/ritonavir) Stribild, Tybost, Prezcobix, Evotaz, Genvoya Risk of ergot toxicity, severe vasospasm, increased BP, and ischemia

OB Drug Interactions, Con t Methergine levels decreased by CYP3A4 inducers, leading to lack of effectiveness of methergine Sustiva, Atripla (efavirenz) Intelence (etravirine) Viramune (nevirapine) Oxytocin, misoprostol (Cytotec) and Hemabate (carboprost tromethamine) do not interact with HIV medications and may be used in women taking ART

Hormonal Contraception? Efavirenz, most protease inhibitors, Stribild, and to a lesser extent, nevirapine all decrease hormonal contraception levels. Raltegravir, dolutegravir and etravirine: no impact Maraviroc: serum levels increased when combined with estrogens

OCP s and Atazanavir Atazanavir/ritonavir: Decreases ethinyl estradiol, increases norgestimate. Need to use an OCP containing no less than 35 mcg ethinyl estradiol Atazanavir alone: Increases ethinyl estradiol 48% and increases norethindrone 110%. Need to use an OCP containing no more than 30 mcg ethinyl estradiol.

Drug Interactions Resources Epocrates Arv.ucsf.edu www.hiv-druginteractions.org Call your clinical pharmacist

What About the Baby? Bathe before any injections No breastfeeding (in the developed world) Initial lab: CBC for a baseline ZDV 8 mg/kg/day divided q 12 hours Continue for 4-6 weeks (per ACTG 076), depending on risk Dosage adjustment for pre-term infants PCP prophylaxis following discontinuation of ZDV, based on risk Follow-up labs: HIV-1 RNA (Quant): At 14-21 days, 1-2 months and 4-6 months of age. CBC at 1 month Standard HIV EIA at 12-18 months of age to ensure serodeconversion

Case 3: D.T. 26 y/o female refugee from Liberia Arrived in SF in 2008 Found to be HIV positive Initial numbers: CD4: 1,020 HIV RNA: 229,000 Patient essentially in denial about HIV dx

Case 3, (Con t) Date CD4 11-08 1,020 9-09 525 7-10 617 12-10 365 7-11 26 5-12 24 9-12 6 1-13 5

Case 3 (Con t) G1Po presented for OB care in early 2 nd trimester, EDC of 12-22-12 Oral thrush, ill-appearing, perineal ulcer: HSV Briefly took Atripla Genotype showed NNRTI resistance Refused to take any more ARV s Did take prophylactic meds for PCP and MAC Primary C/S scheduled at 38 weeks (pt declines) Presented in labor at 38 3/7, intact membranes, 5 cm

Case 3 (Con t) Received ZDV 2 mg/kg bolus over 1 hour Primary C/S performed without difficulty Apgars 8 and 9 Medically unremarkable postpartum and neonatal course. Baby confirmed to be HIV negative at 4 months of age

Perinatal Guidelines https://aidsinfo.nih.gov/guidelines/html/3/perinatalguidelines/0

Post-Exposure Prophylaxis What do I tell my patient? What do I tell my spouse? What do I tell my self?

Reported Blood and Body Fluid Exposures by Profession Nurses: 48.6% Residents and fellows: 7.7% Attendings: 7.7% Non-lab techs: 4.5% Resp. therapists: 3.6% CNA s: 3.2%

Occupational Exposure: Risk of HIV Transmission Percutaneous: 20/6,135 (0.33%) Mucosal: 1/1,143 (0.09%) Intact Skin: 0/2,712

Fear the Fluids? Implicated fluids: blood, semen, vaginal secretions and fluids with visible blood. Potentially infectious: CSF, synovial, pleural, peritoneal, pericardial, and amniotic fluid. Considered safe: feces, nasal secretions, saliva, gastric secretions, sputum, sweat, tears, urine, and vomitus.

Estimated Per Act Risk of HIV Acquisition by Exposure Route (per 10,000 exposures) Blood transfusion: 9,000 Needle sharing (IVDU): 67 Receptive/insertive anal IC: 50/6.5 Needle stick: 30 Receptive/insertive penile/vaginal IC: 10/5 Receptive/insertive penile/oral IC: 1/0.5

Sexual Assault Risks and benefits of HIV prophylaxis should be discussed with every sexual assault patient No good data, but case reports of HIV seroconversion from sexual assault exist

HIV in Sexual Assault: A Little Perspective Risk of transmission from single episode of consensual vaginal intercourse with HIV positive man: 0.1% Risk of transmission from single episode of consensual anal intercourse with HIV positive man: 2%

High Risk Sexual Assault Male on male rapists Location in a high-prevalence region or country Multiple assailants Anal sexual assault Sexual assaults where either the assailant or the victim has trauma, bleeding or genital lesions

Post-Exposure Prophylaxis (PEP) Usually NOT indicated Rapid HIV test for source patient, if possible Initiation: sooner is better Goal is within 1-2 hours Benefit decreased after 24-36 hours Not recommended after 72 hours Duration: 4 weeks (arbitrary) PEPline: 888-448-4911

Pre-Exposure Prophylaxis (PrEP) Tenofovir/emtracitabine (Truvada) approved in 2012 for use in HIV-uninfected individuals at substantial risk of HIV acquisition. HIV sero-disconcordant couples HIV negative partner in a couple wishing to conceive Criteria for PrEP Proven to be HIV-negative Must be able to strictly adhere to a daily med regimen Must be tested for HIV at least every 3 months

Resources -HIV Telephone Consultation Service: 1-800-933-3413 (Mon-Fri, 0800 1900 Central Time) -Perinatal HIV Hotline: 1-888-448-8765 -PEPline: 1-888-448-4911 (7 days/week, 0800-0100 Central Time) -PrEPline: 1-855-448-7737 (855-HIV-PReP) (Mon-Fri, 1000-1700 Central Time) -http://nccc.ucsf.edu