Pediatric HIV Infection and the Medical Management of Pregnant Women infected with HIV. Ernesto Parra, M.D., M.P.H.

Pediatric HIV Infection and the Medical Management of Pregnant Women infected with HIV Ernesto Parra, M.D., M.P.H. Adjunct Associate Professor UTHSCSA Department of Pediatrics and Family and Community Medicine

Learning Objectives Identify the various risk factors associated with HIV perinatal infection List the prophylactic interventions used to prevent transmission of HIV to newborns Understand the diagnostic screening procedure for determining infection among infants born to mothers with HIV Appreciate the therapeutic challenges in treating infants, children, and adolescents infected with HIV

Presentation Outline Scope of Problem Pregnancy and Transmission of HIV Treatment of Newborn Exposed to HIV Dx of HIV in Perinatally Exposed Infant Pediatric Treatment Guidelines Immunization Guidelines Adolescents: Special Consideration

Children (<15 years) estimated to be living with HIV 2013 North America and Western and Central Europe 2800 Eastern Europe & Central Asia 14 000 Caribbean 17 000 Latin America 35 000 Middle East & North Africa 16 000 Sub-Saharan Africa 2.9 million Asia and the Pacific 210 000 3.2 Million UNAIDS

Estimated number of children (<15 years) newly infected with HIV 2013 North America and Western and Central Europe <500 Eastern Europe & Central Asia <1000 Caribbean <1000 Latin America 1800 Middle East & North Africa 2300 Sub-Saharan Africa 210 000 Asia and the Pacific 22 000 Total: 240 000 UNAIDS

Modes of HIV Infection Among Children Intrauterine Birthing (Vaginal or C-Section) Breast Feeding Contaminated Medical Equipment or Therapies Injecting Drug Use Sexual

Modes of HIV Infection Among Children Intrauterine Birthing (Vaginal or C-Section) Perinatal Breast Feeding Contaminated Medical Equipment or Therapies Injecting Drug Use Sexual

Estimated Numbers of Perinatally Acquired AIDS Cases by Year of Diagnosis, 1985 2010 United States and Dependent Areas 1,000 800 No. of cases 600 400 200 0 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 Year of diagnosis

Screening and Care of 93 Patients Seen at FFACTS by Age (Yrs) in Past 2 years Age NB 0-5 6-9 10-12 13-17 Number 73 1 3 4 12

Screening and Care of 93 Patients Seen at FFACTS by Age (Yrs) in Past 2 years Age NB 0-5 6-9 10-12 13-17 Number 73 1 3 4 12 2

Screening and Care of 93 Patients Seen at FFACTS by Age (Yrs) in Past 2 years Age NB 0-5 6-9 10-12 13-17 Number 73 1 3 4 12 2 1 Perinatally exposed infant screened for HIV every 1.4 wks

Screening and Care of 93 Patients Seen at FFACTS by Age (Yrs) in Past 2 years Age NB 0-5 6-9 10-12 13-17 Number 73 1 3 4 12 2 1 Perinatally exposed infant screened for HIV every 1.4 wks 3% of infants screened are positive for HIV

Diagnoses of HIV Infection among Adults and Adolescents, by Sex, 2009 2013 United States and 6 Dependent Areas 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, but not for incomplete reporting.

77%

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.

Rates of Diagnoses of HIV Infection among Adult and Adolescent Females, 2013 United States and 6 Dependent Areas N = 9,479 Total rate = 6.9 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, but not for incomplete reporting.

Increasing Number of Women of Childbearing Age with HIV Infection in U.S. Near-constant number of women newly infected every year Most of newly infected women are of childbearing age Increasing survival of women infected with HIV Overall, increasing number of infected women of childbearing age in U.S.

Prevention of MTCT In Pregnancy When do you start cart? What cart do you use? What about a C-Section?

Worldwide Timing of MTCT of HIV if No Intervention Pregnancy Labor & Delivery Breast Feeding 10-25% 35-40% 35-40% JAMA 2001; 289;709-712

Risk Factors for MTCT of HIV High Maternal Viral Load (HIV-RNA) Low Maternal CD4 Cell Count Primary HIV infection in Pregnancy Duration of Rupture of Membranes Mode of Delivery Genital Tract Infections Low Birth Weight Substance Abuse Cigarette Smoking

Risk of HIV Perinatal Transmission in U.S. 25% mother-to-child transmission in untreated mother

United States Timing of MTCT of HIV if No Intervention 25% Newborns Infected with HIV Pregnancy Labor & Delivery X Breast Feeding

Timing of Perinatal Transmission During Pregnancy 1% Risk 33% Risk 66% Risk 1 st Trimester 2 nd Trimester 3 rd Trimester Conception Delivery

Of infants born HIV-positive and go untreated: 30% advance to AIDS and die < 5 years 70% advance to AIDS and die in < 10 years

Clinical Course of Untreated Infants Born with HIV Infection Birth 2-5 Years 8-10 Years In Utero 34% Labor & Delivery 66%

Clinical Course of Untreated Infants Born with HIV Infection In Utero 34% Birth 2-5 Years 8-10 Years VL CD4 Labor & Delivery 66% VL<20 or VL CD4

Clinical Course of Untreated Infants Born with HIV Infection In Utero 34% Birth 2-5 Years 8-10 Years VL CD4 Thrush FTT PCP Diarrhea Regressive Milestone AIDS Death Labor & Delivery 66% VL<20 or VL CD4 Clinically Healthy

Viral Load Primary Independent Predictor of Perinatal Transmission Viral Load c/ml Transmission Risk >100,000 40.6% 50,001-100,000 30.9% 10,001-50,000 21.3% 1,000-10,000 16.6% <1,000 <1% Garcia PM, et. al, NEJM Mofenson LM, et. al, NEJM

When to Start HIV Therapy Among Pregnant Women who are HIV-Positive If Antiretroviral-Naïve: Start cart ASAP + Genotype If Currently on Antiretroviral Therapy Continue cart (even Efavirenz) + Genotype If Previously Received Antiretroviral Therapy Restart cart + Genotype DHHS Guidelines, 2015

Prevention of MTCT In Pregnancy When do you start cart? What cart do you use? What about a C-Section?

Preferred cart Regimens for ARV-Naïve HIV-infected Pregnant Women NRTI PI NNRTI ISTI ABC/3TC ATV/r EFV after RAL TDF/FTC or 3TC DRV/r 8 weeks ZDV/3TC gestation DHHS Guidelines, 2015

Preferred cart Regimens for ARV-Naïve HIV-infected Pregnant Women NRTI PI NNRTI ISTI ABC/3TC ATV/r EFV after RAL TDF/FTC or 3TC DRV/r 8 weeks ZDV/3TC gestation Preferred Combo=Dual NRTI + PI or NNRTI or ISTI DHHS Guidelines, 2015

Prevention of MTCT In Pregnancy When do you start cart? What cart do you use? What about a C-Section?

Risk of Perinatal HIV Transmission by Method of Delivery and Viral Load PACTG 367 Cohort, 72 US Sites, single or multi-agent, 2875 births Vaginal Cesarean Viral Load Delivery Section No RNA 22.4% 8.3% 10,000 + 7.3% 4.1% 1,000-9,999 1.9% 2.8% <1,000 0.7% 0.8% Shapiro, CROI, 2004

Perinatal ACTG Protocol 076: 1991-1993 Timing Intervention Antipartum: >1 st Trimester ZDV PO: 100 mg x 5/day + Intrapartum: Delivery ZDV IV: 1 mg/kg/hr + Postparum: Newborn ZDV PO: 2 mg/kg x 6/day x 6 wks

Trends in Perinatal Transmission w/antiretroviral Use The Women & Infant Study: 1990-1999 Year Intervention MTCT < 1993 No Treatment 20.0% 1994 ZDV only 10.4% 1995 ZDV + NRTI 3.8% > 1996 ZDV + NRTI + PI 1.2% NRTI = Nucleoside Reverse Transcriptase Inhibitor Class, e.g., AZT, DDI, 3TC PI = Protease Inhibitor Class Cooper ER, JAIDS 2002

Treatment of Newborns Whose Mother Receive No Antiretroviral Therapy During Pregnancy Intervention MTCT ZDV 6 wk 4.8% ZDV 6 wk + NVP 3 dose 2.2% ZDV 6 wk + NVP 3 dose + 3TC 2 wk 2.4% Nielsen-Saines K, NEJM 2012

Treatment of Newborns Whose Mother Receive No Antiretroviral Therapy During Pregnancy Intervention MTCT ZDV 6 wk 4.8% ZDV 6 wk + NVP 3 dose 2.2% (p=0.03) ZDV 6 wk + NVP 3 dose + 3TC 2 wk 2.4% Nielsen-Saines K, NEJM 2012

Treatment of Newborn Exposed to HIV Mother HIV-positive Newborn HIV Tx During Pregnancy - ZDV 4 mg/kg/dose/q12 po Start Day 1 x 6 weeks No Tx During Pregnancy - ZDV 4 mg/kg/dose/q12 po Start Day 1 x 6 weeks + - Nevirapine on Days 1, 3, & 6 12 mg daily po if >2 kg wt 8 mg daily po if < 2 kg wt

Peripartum Strategies to Prevent MTCT of HIV Pregnancy MOC use of antiretrovirals Labor & Delivery IV ZDV C-Section if MOC VL > 1,000 copies/ml Infant 4 wks ZDV if Mom VL <1,000 6 wks ZDV + NVP x 3, if MOC VL >1,000 or unknown No breast feeding

Timeline for Diagnosing HIV in Exposed Infant Birth 2 Weeks 2 months 6 months HIV-RNA CBC HIV-RNA CBC HIV-RNA CBC* HIV-RNA DHHS Guidelines 2015

Timeline for Diagnosing HIV in Exposed Infant Birth 2 Weeks 2 months 6 months HIV-RNA CBC HIV-RNA CBC HIV-RNA CBC HIV-RNA HIV Negative: 2 or more HIV-RNA<20 One after 1 st month & one after 4 th month, or 2 after 6 months DHHS Guidelines 2015

Timeline for Diagnosing HIV in Exposed Infant Birth 2 Weeks 2 months 6 months 18 months HIV-RNA CBC HIV-RNA CBC HIV-RNA CBC HIV-RNA HIV Ab- Assay HIV Negative: 2 or more HIV-RNA<20 One after 1 st month & one after 4 th month, or 2 after 6 months HIV Positive: 2 or more HIV-RNA >20 On separate sample lab draws DHHS Guidelines 2015

Current Antiretroviral Medications NRTI Zidovudine ZDV Lamivudine 3TC Tenofovir TDF Abacavir ABC Emtricitabine FTC Didanosine DDI Stavudine D4T 2 NRTI Combo Pills ZDV/3TC TDF/FTC ABC/3TC ZDV/3TC/ABC NNRTI Efavirenz EFV Etravirine ETR Nevirapine NVP Rilpivirine RPV Delavirdine DLV Protease Inhibitor (PI) Loprinavir LPV Atazanavir ATV Darunavir DRV Fosamprenavir FPV Ritonavir RTV Nelfinavir NFV Tipranavir TPV Saquinavir SQV Amprenavir APV Indinavir IDV Integrase Inhibitor Raltegravir RAL Elvitegravir EVG Dolutegravir DTG CCR5 Antagonist Maraviroc MVC Fusion Inhibitor Enfuvirtide ENF 3 Drug Combo Pills TDF/FTC/EFV TDF/FTC/RPV TDF/FTC/COBI/EVG ABC/3TC/DTG 2 Drug PI Combo Pills LPV/r ATV/COBI DRV/COBI

Current Antiretroviral Medications for Age < 6 Years NRTI Zidovudine ZDV Lamivudine 3TC Tenofovir TDF Abacavir ABC Emtricitabine FTC Didanosine DDI Stavudine D4T Protease Inhibitor Loprinavir LPV Atazanavir ATV Darunavir DRV Fosamprenavir FPV Rtionavir RTV Nelfinavir NFV Tipranavir TPV NNRTI Efavirenz EFV Etravirine ETR Nevirapine NVP Fusion Inhibitor Enfuvirtide ENF

Age at Which Antriretroviral Agents Can Be Used Birth ZDV 3TC FTC NVP D4T 2 Wks LPV/r DDI 1 Mo FPV/r RTV 3 Mo ABC ATV/r 2 Yr TDF NFV TPV/r RAL 3 Yr EFV DRV/r 6 Yr ETR ENF 12 Yr DTG EVG 18 Yr RPV IDV/r SQV DLV MVC DHHS Guidelines 2015

Age and Practical Feasibility At Which Antriretroviral Agents Can Be Used Birth ZDV 3TC FTC NVP D4T 2 Wks LPV/r DDI 1 Mo FPV/r 3 Mo ABC ATV/r 2 Yr TDF NFV 3 Yr EFV 6 Yr ETR 12 Yr DTG EVG DHHS Guidelines 2015

Preferred Regimens > Newborn ZDV ZDV DHHS Guidelines 2015

Preferred Regimens > Newborn ZDV/3TC ZDV/FTC DHHS Guidelines 2015

Preferred Regimens > Newborn ZDV/3TC ZDV/FTC LPV/r DHHS Guidelines 2015

Preferred Regimens > Newborn ZDV/3TC ZDV/FTC LPV/r (ABC/3TC)(ABC/FTC) DHHS Guidelines 2015

Preferred Regimens > Newborn >3 Years Old ZDV/3TC ZDV/FTC ABC/3TC ABC/FTC LPV/r (ABC/3TC)(ABC/FTC) AZT/3TC AZT/FTC DHHS Guidelines 2015

Preferred Regimens > Newborn >3 Years Old ZDV/3TC ZDV/FTC ABC/3TC ABC/FTC LPV/r (ABC/3TC)(ABC/FTC) AZT/3TC EFV AZT/FTC DHHS Guidelines 2015

Preferred Regimens > Newborn >3 Years Old >6 Years Old ZDV/3TC ZDV/FTC ABC/3TC ABC/FTC ABC/3TC ABV/FTC LPV/r EFV (ABC/3TC)(ABC/FTC) AZT/3TC AZT/FTC AZT/3TC AZT/FTC DHHS Guidelines 2015

Preferred Regimens > Newborn >3 Years Old >6 Years Old ZDV/3TC ZDV/FTC ABC/3TC ABC/FTC ABC/3TC ABV/FTC LPV/r (ABC/3TC)(ABC/FTC) AZT/3TC EFV AZT/FTC AZT/3TC ATV/r AZT/FTC DHHS Guidelines 2015

Preferred Regimens > Newborn >3 Years Old >6 Years Old ZDV/3TC ZDV/FTC ABC/3TC ABC/FTC ABC/3TC ABV/FTC LPV/r (ABC/3TC)(ABC/FTC) AZT/3TC EFV AZT/FTC AZT/3TC ATV/r AZT/FTC > 10 Years Old TDF/3TC TDF/FTC LPV/r EFV ATV/r DHHS Guidelines 2015

Problems with Agents of Preferred Regimen Palatability (spit up) Tolerability (vomit) Side effects (e.g., diarrhea, sedation w/lpvr) Dosing frequency Limited formulations available Dosing calculations based on TBSA vs. Weight Contraindicated due to young age

Therapy Goals (< 3 months) Viral load = Undetectable CD4 cell count Clinical improvement

Frequency of Clinic Follow-up Visits Every 3-4 months, if on cart Every 6 months, if VL<20 & CD4, >2 years DHHS Guidelines 2015

Recommendation for Routine Pediatric Immunizations of Children Infected with HIV At any CD4%; Routine inactivated immunizations are recommended, but more effective when CD4% >15% (CD4 >200) If CD4% <15%; live attenuated vaccines, e.g., MMR and varicella not recommended If CD4% >15%; MMR and varicella can be given Current Opinion in HIV and AIDS, 2007

HIV Among Youth (Age 13-24) U.S. Incidence of HIV 25.7% of people newly infected (1-in-4 are youth) 75% are men having sex with men (MSM) 57% African American, 20% Latino, 20% White U.S. Prevalence of HIV 6.7% of all people living with HIV 59.5% are unaware of their infection MMWR 61(47) 2012

Rates of Diagnoses of HIV Infection Among Adolescents Aged 13 19 Years, 2013 United States and 6 Dependent Areas N = 1,931 Total Rate = 6.5 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, but not for incomplete reporting.

Prevalence of diagnosed HIV Infection Among Adolescents Aged 13 19, Yearend 2012 United States and Dependent Areas N = 7,300 Total Rate = 24.3 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, but not for incomplete reporting.

Risk Factors for HIV Among Adolescents Concerns regarding sexual identity Sexually transmitted infections Substance abuse Sexual abuse Survival sex Lack of housing or homelessness Concerns for safety

Barriers to HIV Testing and Care for Adolescents Concrete Thinking Present Orientation Denial Disorganized lifestyle Autonomy and Trust issues Secrecy and Confidentiality Concerns Isolation lack of parental support Funding Transportation Housing

Modes of HIV Infection Among Children Intrauterine Birthing (Vaginal or C-Section) Perinatal Breast Feeding Contaminated Medical Equipment or Therapies Injecting Drug Use Sexual

Review of Learning Objectives Identify the various risk factors associated with HIV perinatal infection List the prophylactic interventions used to prevent transmission of HIV to newborns Understand the diagnostic screening procedure for determining infection among infants born to mothers with HIV Appreciate the therapeutic challenges in treating infants, children, and adolescents infected with HIV

Known HIV Unknown