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AIDS CLINICAL ROUNDS

Michael Kavanaugh 4 October 2013

I have no commercial interests or financial relationships associated with topics discussed.

I will be not be discussing off-label use of medications

27 year old HIV+ female (diagnosed 2005 CD4 878/39%, undetectable) on FTC/TDF/RAL presents with planned pregnancy 7w2d following Intrauterine insemination (IUI)

Diagnosed with HIV 2005 following sexual assault-initial CD4 299

Initially on EFV/FTC/TDF-undetectable for 7 years Changed to FTC/TDF+Raltegravir in March 2013

Pt expressed desire for pregnancy-stopped Atripla Counseled on options including Combivir/Kaletra

Had been on Depo-Provera until December 2012 Husband attempted pre-exposure prophylaxis

(Truvada) but was unable to tolerate Pursued IUI-successful on 1st attempt Obtained preliminary prenatal US-normal

HIV (as described) ADHD (as child)-previously on methylphenidate

Not currently on medications Bipolar (diagnosed age 10)

Not currently on medications HPV+, no other STDs

SH Married since 2011, College student-expected

graduation June 2014, no tobacco or alcohol Meds: FTC/TDF, Raltegravir, prenatal vitamin Allergies-None

Some morning sickness & minor constipation No fevers, chills, new lymphadenopathy or

respiratory complaints

T98.6 BP 112/79 P84 R16 Gen pleasant, healthy appearing, NAD HEENT normocephalic, pupils reactive, throat wnl CV RRR no murmur Resp cta (b) Abd +bs, soft, NT, ND (not noticeably gravid yet) Ext no edema

CD4 878/39, %Viral Load <20 HCG 777,100 from 361,100 two days prior CBC 7.3/14/42.1/362 Lytes 141/3.8/103/25/11/0.8/101 Ca 9.7 Mg 2.3 Bili 0.1 TP 6.9 Alk P 113 ALT 27 AST 22 LDH 157

Prevention of Mother to Child Transmission Teratogenicity Choice of Medication

Combivir + Kaletra Truvada, Raltegravir (Choice when discussing

options with our patient) Preterm labor Low Birth Weight Infant Prophylaxis Caesarian Section

Since 1994 New England Journal article by Connor EM et al. 477 HIV+ mothers Interventions arm-antepartum ZDV and infant AZT

for 6 weeks Transmission decreased 25.5% to 8.3% While on ZDV infants had lower Hb but normalized

1st stage I Clinical Trial 1985 FDA Approved for use March 20, 1987 Anemia-most common side effect (reversible)

Which of the following statements is TRUE about maternal to child transmission (MTCT) of HIV? The majority of MTCT occurs at or just before delivery (50%)

with an additional 25% occurring antenatally and 25% postnatally through breast-feeding

The risks of MTCT antiretroviral prophylaxis from in utero or neonatal exposure outweighs the benefits

The rate of HIV infection in infants who are breastfed is the same as in those who are not breastfed by HIV seropositive mothers

HIV has not been detected in human breast milk Caesarian section should not be considered for HIV

seropositive women in labor who are on ARVs with a viral load of >1000

Which of the following statements is TRUE about maternal to child transmission (MTCT) of HIV? The majority of MTCT occurs at or just before delivery

(50%) with an additional 25% occurring antenatally and 25% postnatally through breast-feeding

The risks of MTCT antiretroviral prophylaxis from in utero or neonatal exposure outweighs the benefits

The rate of HIV infection in infants who are breastfed is the same as in those who are not breastfed by HIV seropositive mothers

HIV has not been detected in human breast milk Caesarian section should not be considered for HIV

seropositive women in labor who are on ARVs with a viral load of >1000

Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States Last updated July 31, 2012

NNRTIs-Didanosine and stavudine removed from alternatives

PIs- Atazanavir/r is now preferred as is lopinavir/r (for treatment naïve) Previously alternative

Integrase Inhibitor-Raltegravir-moved from insufficient data to use in special circumstances

Treat mother & reduce transmission Generally-HIV+ pregnant women in 1st trimester should

continue regimen if tolerating and effective (AII) Choice of ART (childbearing)-prior to pregnancy

Effective treatment HBV status Teratogenicity of drug (should pregnancy occur)

Serodiscordant couple “treatment of infected partner may not be fully protective against sexual transmission of HIV” Recommend treating HIV infected partner (AI if CD4<550) PrEP may be offered CIII

Infant transmission study-enrolled 1542 HIV-1 women 1990-2000 in US (WITS) Prospective cohort Measured HIV RNA levels

Transmission Based on Regimen No ART (396 women) 20% ZDV alone (710 women) 10% Dual therapy (186 women) 4% 3 drugs (250 women) 1.2%

Transmission Based on Viral Load >30,000 copies/ml 23% (115 women) <400 copies/ml 1% (32 women) –undetectable at that time

Trimesters Treated

Number /Trimester

ZDV only Dual ART HAART

3rd 319 15.8 6.2 3.6 2nd & 3rd 409 8.4 4.3 0 1st, 2nd & 3rd 418 8.8 0 0

Treatment Naïve Obtain genotype prior to initiation-don’t wait for results When to start? Based on CD4 count, viral load, maternal nausea Immediate versus week 12? All should receive at least antepartum ART (regardless of CD4) Prevention of perinatal transmission

On ART at initial prenatal visit Efavirenz-concern of neural tube defects in first 5-6 weeks of pregnancy If on EFV at recognition of pregnancy (>4-6 wks), may be unnecessary to

change (affect on viral load) Recommendation-continue at that point

Pre-pregnancy counseling ARV which does not include Efavirenz should be strongly considered in

women who are planning pregnancy or not using appropriate contraception (BIII)

Zidovudine/lamivudine + lopinavir/ritonavir Zidovudine/lamivudine + atazanavir/ritonavir Tenofovir/emtricabine/efavirenz Tenofovir/lamivudine +atazanavir/ritonavir Tenofovir/lamivudine +maraviroc

Zidovudine/lamivudine + lopinavir/ritonavir Zidovudine/lamivudine + atazanavir/ritonavir Tenofovir/emtricabine/efavirenz Tenofovir/lamivudine +atazanavir/ritonavir Tenofovir/lamivudine +maraviroc

Drug Pk Concerns in pregnancy Lamivudine Recommend

No change No evidence of human teratogenicity, benefit if HBV coinfected, combined w/ ZDV (Combivir) High placental transfer

Zidovudine Recommend

Not signif (No dose Δ)

No evidence of human teratogenicity, well tolerated High placental transfer

Abacavir Alternative

Not signif (No dose Δ)

No evidence of human teratogenicity, hypersensitivity reactions (5-8%)

Emtricibine Alternative

Lower in 3rd trimester (No dose Δ)

No evidence of human teratogenicity, benefit for HBV coinfected High placental transfer

Tenofovir Alternative/ Preferred (HBV)

AUC lower in 3rd trimester

No evidence of human teratogenicity, preferred for HBV coinfected (with 3TC or FTC), monitor renal function, Monkey studies- double doses –decreased fetal growth and reduction in fetal bone porosity within 2 months of therapy Clinical Studies-bone demineralization with chronic use High placental transfer

*Preferred NNRTI-just really not preferred

Drug Pk Concerns in pregnancy Nevirapine*

(No dose Δ)

No evidence of human teratogenicity Not for CD4>250 (life-threatening hepatotoxicity) High placental transfer

Efavirenz AUC decrease 3rd trimester (No dose Δ)

Class D (anencephaly, anopthalmia, cleft palate) Monkeys with EFV 3/20 (15%) 4 case reports and 1 prospective study with neural tube defects (1st trimester exposure) Risk of NT defect only limited to 1st 5-6 weeks, Recommend-continue if pregnancy recognized at 6 weeks (CIII)

Etravirine Limited data Only 23 1st trimester exposures reported No evidence of teratogenicity in rats

Rilpivarine No Pk studies in humans

No published human data. No evidence of teratogenicity in rats or rabbits.

*ATV-package insert recommends BID dose in 2nd and 3rd trimester for treatment experienced only

Drug Pk Concerns in pregnancy Atazanavir/r Preferred

Decreased concentration *Increase dose 2nd & 3rd trimester Experienced vs. all

No evidence of human teratogenicity, question about bilirubin-not seen clinically Do not use with both TDF and H2 receptor antagonist See PI in pregnancy articles

Lopinovir/r Preferred

2nd & 3rd trimester Increase dose

No evidence of human teratogenicity Low placental transfer

Darunavir Alternative

Concentrations decreased 23-28% in 3rd trimester Recommed BID

Insufficient data to assess teratogenicity No evidence in in mice, rats or rabits

Saquinavir/r Alternative

Twice daily recommended

Insufficient data to assess teratogenicity Issues with QT prolongation

Didanosine-increased rate of birth defects compared to general population (19/409) 4.3%with 1st trimester use, (20/460) 4.3% with 2nd and third trimester

Stavudine-No evidence of human teratogenicity, lactic acidosis (occasionally fatal) in pregnanty women Do not use with ddI or ZDV

Indinavir-No evidence of teratogenicity Concern with potential for renal stones

Nelfinavir-No evidence of teratogenicity Raltegravir-Recently upgraded from insufficient data

Limited human experience Increased skeletal variants in rats, NO DEFECTS rabbits Variable levels in 3rd trimester-No dose adjustment recommended High Placental transfer

Insufficient data-No teratogenicity in rats, rabbits Fosamprenavir Tiprinavir T20 (Enfuvirtide) Maraviroc

Because clinically significant resistance to protease inhibitors (PIs) is less common than resistance to non-nucleoside reverse transcriptase inhibitors in ARV-naive individuals in general, a ritonavir-boosted PI-based regimen should be initiated (AIII).

Clinicians should be aware of a possible small increased risk of preterm birth in pregnant women receiving protease inhibitor (PI)-based combination antiretroviral regimens; however, given the clear benefits of such regimens for both a woman’s health and prevention of mother-to-child transmission, PIs should not be withheld for fear of altering pregnancy outcome (AII).

Combination Antiretroviral Use and Preterm Birth. JID. Watts H. et al. 2013.

1869 births (born of HIV+ mothers)-Cohort 18.6% (346)preterm, 7.3%(135) Small for gestational age Protease Inhibitors resulted in higher preterm birth OR 1.55

compared to NNRTI or triple NRTI regimens If exposure was 3rd trimester only-no statistical significance

Women evaluated from 22 weeks pregnancy till 1 week post-partum

Multiple racial and socioeconomic factors associated with preterm birth, also low CD4 (<200 copies/mL)

Protease inhibitor-based antiretroviral therapy and glucose tolerance in pregnancy: AIDS Clinical Trials Group A5084. Hitt J, et al. 2007 Am J Obstet Gyn. 149 HIV+ women (73 on PIs, 76 other) Abnormal Glucose Tolerance PI 26/73 versus 33/76 Not statistically significant

Gestational DM (PI 8%, other 10%-not significant) HIV+ overall, 38% 57/149-Impaired Glucose Tolerance

General population 20-25% HIV+ Gestational DM 9%

General population 2-5%

1st line for HIV+ non-pregnant and pregnant with HIV/HBV coinfection Alternative for HIV+ pregnant

Antiretroviral Pregnancy Registry-no adverse events (1219 pregnancies-1st trimester exposure)

US based cohort of 2029 children TDF 444 mothers (21%)

Evaluated Small for Gestational Age (SGA), Low Birth Weight (LBW), Weight for age-z-score (WAZ), length for age z score (LAZ), head circumference for age (HCAZ) No difference for SGA, LBW & newborn LAZ and HCAZ One year LAZ and HCAZ were smaller

Authors uncertain of clinical significance

Pregnant Rhesus macaques-received TDF (double dose)-Tarantal et al. J Acquir Immune Defic Syn 2002 TDF group (n=4)-dosed at different times (20-150 days) Lower crown-rump length Lower body weight Smaller adrenals No difference -head, arm or chest circumference or extremity bone

length vanRompay et al Antimicrob Agents Chemother 2004.

39 infant macaques-varying doses-no adverse effect on health or growth

Separate issue-High dose TDF administered to infant macaques did show growth retardation

Lower Dose TDF-effect not observed-VonRompay 2008 High dose had effect on DEXA, no effect on low dose No effect on renal failure with TDF

Multicenter Observational Study 68 enrolled TDF 33, no-TDF exposure 35

No difference between groups for low birth weight or birth length

Bone health not affected

High neonatal concentrations of raltegravir following transplacental transfer in HIV-1 positive pregnant women. Mckeown D et al. AIDS. 2010. Favorable side effect profile, no effect on CYP450,

rapid reduction in viral load, increase CD4 3 cases reported of late term use in pregnancy-goal

rapid reduction of viral load with MDR virus Patients from Uganda, Ghana, Zimbabwe Evaluated raltegravir concentrations after delivery All infants HIV negative at 12 weeks To date, no adverse events with mother

HIV/HCV coinfected Italian woman-38 weeks At time of pregnancy Truvada/RAL

CD4 543 with VL<50 coplies/mL Changed to ZDV, 3TC, LPV/r (per guidelines) Unable to obtain viral suppression-changed to DRV/r

bid at 8 weeks Poor adherence to new regimen

Wk 25, VL 189 copies/mL Wk 38 CD4 350 and VL 75,584 copies/mL Previous meds FTC, TDF, d4T, NVP, LPV/r, ATV/r,

RAL

No nevirapine (K103R mutation) & CD4>250 Added TDF and RAL to current regimen 9 days after start of RAL, pt delivered IV ZDV added at time of delivery VL decreased to 260 copies/mL at time of

delivery (2.4 log decrease in 9 days) Pt received 6 weeks post-natal ZDV/3TC and

at birth and 1 month HIV negative Cord to maternal level (RAL) 1.06 compared to

DRV levels 0.36

Per AIDS-info Addition of Raltegravir in 3rd trimester neither

endorsed nor rejected, but discussed as option

Currently being evaluated by study at UCSF & International Maternal Pediatrics Adolescent AIDS Trial (IMPAACT)

IV zidovudine is no longer required for HIV infected women on ART if HIV RNA<400 copies/ml

If HIV RNA>400 copies/ml (or unknown) IV Zidovudine

Infant ART Neonatal zidovudine (birth through 6 weeks) Dosing depends on weeks of gestation Start within 6-12 hours of birth UK-recommended for only 4 weeks (if mother on ART)

If no antepartum ART Higher dose ZDV + nevirapine (3 doses in 1st week)

Test infants at 14-21 days, 1-2 months, and 4-6 months HIV cDNA PCR

UK 4 weeks since 2005 Prospective cohort Spain 171 patients

133 received 6 weeks 33 received 4 weeks All bottle fed (exclusively)

No statistical difference in transmission No statistical difference in Hb at 6 weeks or 3 months

(12.1 vs 13.1), MCV lower in 4 week group-earlier recovery

US-Six weeks since PACTG-076 Other Post-Exposure prophylaxis is only 4 weeks

HIV RNA monitor at initial visit Repeat 2-4 weeks after starting ART Repeat monthly until undetectable Every 3 months until delivery (**34-36 weeks**) Viral Suppression should be obtained 16-24 weeks

CD4-every 3 months during pregnancy (BIII) Every 6 months on ART for >2-3 years (maybe less?)

Genotype-treatment naïve or CD4>500 to 1000 Testing for viral hepatitis Other: Toxoplasmosis, TB, STD screen, CMV? Pneumococcal HAV, HBV vaccines (if not previous) PCP prophylaxis (CD4<200)

1st Trimester inhaled pentamidine 2nd and 3rd Trimester TMP/SMX

Ultrasound both 1st and 2nd Trimester

Mother to child transmission of HIV infection in the era of highly active antiretroviral therapy. CID. European Collaborative Study. 2005. 4625 mother-child pairs in prospective cohort (97-04) In 1997-5% on HAART, by 2003 -92% on HAART Total 1147 HAART, 654 (57%) started in 1st trimester,

39% prior to pregnancy 1998 only 29% undetectable, 50% in 2003

Mother-to-child-transmission 2.87 overall From 2001-2003 0.99% (CI 0.32-2.3) 885 patients

Delivery (vaginal 410 (21%), instrument 35 (2%), elective C-section 1204 (61%) emergent C-section 306 (16%)

Entire cohort: Elective C section Adjusted OR (0.38 CI 0.24-0.61 O<0.001)

HAART era: 0.33 (0.11-0.94 p 0.40)

With undetectable viral load (560 undetectable) OR 0.52 (CI 0.14-2.03 p=0.358) Univariant Logistical Regression

Elective C section higher complication rate than vaginal

RECOMMENDATION: HIV>1000 copies/ml Assess resistance (If adequate treatment

duration) Scheduled cesarean delivery at 38 weeks Reasonable to offer elective C section-probably

benefit but grossly underpowered (suggest further reduction of transmission to 0.5-1%)

Collaboration of 7 European countries and US 1202 women with RNA<1000 at delivery 1% transmission rate 8/834 if on ART 9.8% transmission rate 36/368 untreated C section OR 0.30 p=0.022)

Vaginal delivery 37/44 transmissions Study did not factor risk of operative delivery

to mother

Cohort in France 1997-2010-received ART, not breastfeeding

IV ZDV used in 95.2% (11,538 deliveries) Lack of ZDV 4.8% (554 deliveries) If VL>1000 copies/ml-higher transmission without ZDV

(7.5% vs. 2.9% P=0.01) If VL<400, IV ZDV (0.6%, without 0%) Conclusion IV ZDV for virological failure, not if

effectively treated

Deliver vaginally, start patient on ZDV/3TC LPV/r

Perform C section, start mother on IV ZDV, provide 6 weeks of ZDV and 3 doses of NVP to the child, discourage breast feeding

Perform C section, start mother on IV ZDV, provide 6 weeks of ZDV and 6 weeks of NVP to child, encourage breast feeding

Perform C section, start mother on IV ZDV, provide 4 weeks of ZDV and 4 weeks of NVP, discourage breast feeding

Deliver vaginally, start patient on ZDV/3TC LPV/r

Perform C section, start mother on IV ZDV, provide 6 weeks of ZDV and 3 doses of NVP to the child, discourage breast feeding

Perform C section, start mother on IV ZDV, provide 6 weeks of ZDV and 6 weeks of NVP to child, encourage breast feeding

Perform C section, start mother on IV ZDV, provide 4 weeks of ZDV and 4 weeks of NVP, discourage breast feeding

If woman is on ART & viral load>400 copies/mL-provide IV ZDV (AI)

If on ART, but RNA>1000, scheduled C section recommended (AI) Scheduled C section is not recommended RNA<1000 BIII Unclear if C section is beneficial for PROM

Avoid artificial rupture of membranes, operative delivery with forceps or fetal scalp electrodes

Breast-feeding not recommended in US Different internationally

National Perinatal HIV Consultation and Referral Service at UCSF 1-888-448-8765

comparison

US British guideline WHO

39/1437 with birth defects comparable to baseline

Giles, M. HIV and pregnancy: how to manage conflicting recommendations from evidence-based guidelines. AIDS. 2013; 27: 857-862.

Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States http://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf Accessioned 27 September 2013

Lahoz R, Noguera A, Rovira N, et al. Antiretroviral-related hematologic short-term toxicity in healthy infants: implications of the new neonatal 4-week zidovudine regimen. Pediatr Infect Dis J. Apr 2010;29(4):376-379.

Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr 2002; 29:484.

Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994; 331:1173.

http://en.wikipedia.org/wiki/Zidovudine Accessioned 1 Oct 2013 Hitti J, Andersen J, McComsey G, et al. Protease inhibitor-based antiretroviral therapy and glucose

tolerance in pregnancy: AIDS Clinical Trials Group A5084. Am J Obstet Gynecol 2007; 196:331.e1. Siberry GK, Williams PL, Mendez H, et al. Safety of tenofovir use during pregnancy: early growth

outcomes in HIV-exposed uninfected infants. AIDS 2012; 26:1151. Viganò A, Mora S, Giacomet V, et al. In utero exposure to tenofovir disoproxil fumarate does not impair

growth and bone health in HIV-uninfected children born to HIV-infected mothers. Antivir Ther 2011; 16:1259.

Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 – 1 Jan 2010. Wilmington, NC: Registry coordinating center; 2010.

Tarantal A, Castillo A, Ekert J, Bischofberger N, Martin R. Fetal and Maternal Outcome After Administration of Tenofovir to Gravid Rhesus Monkeys (Macaca mulatta) J Acquir Immune Defic Syndr. 2002;29(3):207.

Van Rompay KK, Brignolo LL, Meyer DJ, Jerome C, Tarara R, Spinner A, et al. Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy) propyl]adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob Agents Chemother. 2004 May;48(5):1469–87.

Van Rompay K, Durand-Gasselin L, Brignolo L, Ray A, Abel K, Cihlar T, et al. Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics, biological and virological effects. Antimicrob Agents Chemother. 2008;52(9):3144–60.

http://www.uptodate.com/contents/prevention-of-hiv-transmission-during-breastfeeding-in-resource-limited-settings?source=see_link Accessioned 1 Oct 2013

http://www.uptodate.com/contents/antiretroviral-medications-in-pregnancy-entry-and-integrase-inhibitors?source=see_link Accessioned 1 oct 2013

McKeown D, Rosenvinge M, Donaghy S, Sharland M, Holt D, Cormack I, Hay P, SadiqS. High neonatal concentrations of raltegravir following transplacental transfer in HIV-1 positive women. AIDS. 2010: 2416-2418.

Carmela Pinnetti1*, Silvia Baroncelli2, Paola Villani3,, Massimo Fantoni1, Valerio Tozzi4, Andrea De Luca1,5,, Roberto Cauda1, Gianfranco Anzidei4, Maria Cusato3,, Mario Regazzi3, Marco Floridia2 and Enrica Tamburrini1. Rapid HIV-RNA decline following addition of raltegravir and tenofovir to ongoing highly active antiretroviral therapy in a woman presenting with high-level HIV viraemia at week 38 of pregnancy Pinnetti C. et al. J Antimicrob Chemother. 2010.. 65: 2050-52.

Briand N, Warszawski J, Mandelbrot L, Dollfus C et al. Is intrapartum IV Zidovudine for prevention of mother-to-child HIV-1 transmission still useful in the combination antiretroviral therapy era? CID. 2013: 57: 903-914.

Once daily fixed dose combinations Tenofovir, lamivudine, emtricitabine and efavirenz in breast

feeding Goal to minimimize viral load HIV transmission versus malnutrition Concerns of poor water quality and mortality

secondary to alternative causes Duration ART-at least for duration of pregnancy and

breast-feeding Generally recommend lifelong therapy

Infants of breastfeeding mothers-nevirapine for at least 6 weeks