College Call Girls Pune Mira 9907093804 Short 1500 Night 6000 Best call girls...
Weekly HIV Research Presentations and Clinical Practices
1. The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease clinicians, physicians and
researchers. The goal of these presentations is to provide the most
current research, clinical practices and trends in HIV, HBV, HCV, TB
and other infectious diseases of global significance.
The slides from the AIDS Clinical Rounds presentation that you are
about to view are intended for the educational purposes of our
audience. They may not be used for other purposes without the
presenter’s express permission.
AIDS CLINICAL ROUNDS
3. I have no commercial interests or financial
relationships associated with topics discussed.
I will be not be discussing off-label use of
medications
4. 27 year old HIV+ female
(diagnosed 2005 CD4
878/39%, undetectable) on
FTC/TDF/RAL presents with
planned pregnancy 7w2d
following Intrauterine
insemination (IUI)
5. 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
6. 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
7. Some morning sickness & minor constipation
No fevers, chills, new lymphadenopathy or
respiratory complaints
8. 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
9. 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
10.
11. 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
12. 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)
13.
14. 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
15. 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
16. 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
17. 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
18. 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
19. 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
21. 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)
24. 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
25. *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.
26. *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
27. 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
29. 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).
30. 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).
31. 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)
32.
33.
34.
35.
36. 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%
37. 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)
38. 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
39. 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
40. 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
41. 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
42.
43. 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
44. 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
45. 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)
46. 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
47.
48. 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
49. 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
50. 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)
51. 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%)
52. 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
53. 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
54. 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
55. 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
56. 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
59. 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.
60. 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.
61. 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