Rapid Testing at L

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Rapid Testing at LD

• Alice Stek, MD
• Department of Obstetrics and Gynecology
• Division of Maternal-Fetal Medicine
• University of Southern California
• Los Angeles, California
• July 2006

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Rapid Testing in Labor and Delivery

• Goal Eradicate perinatal (mom-to-baby) HIV
  transmission in California.
• Objective In California, to have every pregnant
  woman, and her obstetric health care provider,
  know her HIV status as early as possible during
  her pregnancy and no later than when she begins
  delivery.

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Adults and children estimated to be living with
HIV as of end 2004
Eastern Europe Central Asia 1.4 million
Western Central Europe 610 000
North America 1.0 million
East Asia 1.1 million
North Africa Middle East 540 000
Caribbean 440 000
South South-East Asia 7.1 million
Sub-Saharan Africa 25.4 million
Latin America 1.7 million
Oceania 35 000
Total 39.4 million 4.9 million new
infections/yr 3.1 million deaths/yr
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Estimated number of children lt15 years newly
infected during 2004
Western Central Europe lt 100
Eastern Europe Central Asia 1 800
North America lt 100
East Asia 4 100
North Africa Middle East 9 100
Caribbean 6 100
South South-East Asia 51 000
Sub-Saharan Africa 560 000
Latin America 6 800
Oceania lt 300
Total 640 000 (570 000 750 000)
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Perinatal HIV Transmission In Absence of
Antiretrovirals
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How have we been able to decrease MTCT?

• identification of HIV-infected women
• antiretroviral medications
• good obstetric care
• cesarean delivery (in selected situations)
• formula feeding

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• Timing of Perinatal HIV Transmission

• Cases documented intrauterine, intrapartum, and
  postpartum by breastfeeding
• In utero 2540 of cases
• Intrapartum 6075 of cases
• Additional risk with breastfeeding
• 14 ? risk with established infection
• 29 ? risk with primary infection

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• MTCT rates of under 1 are feasible and are
  currently achieved with state-of-the-art care in
  settings with adequate resources.
• Most cases of MTCT in USA now occur in women with
  no HIV care/women with unknown HIV status.
• Interventions in peripartum period can reduce
  MTCT.

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Neonatal diagnosis

• maternal IgG antibodies
• present in all neonates of HIV mothers, up to
  12-18 months
• test mothers, identify infants at risk
• HIV DNA PCR (some include RNA PCR)

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ACTG protocol 076ZDV for prevention of perinatal
transmission

• Started 1991, closed to accrual 1994 after
  interim review
• ZDV (AZT) vs placebo
• antiretroviral naïve women, CD4 gt200, 14-34 weeks
  gestation
• ZDV during pregnancy, iv during labor, syrup to
  baby for 6 wks
• no breastfeeding
• transmission to infant
• ZDV arm 7.6
• placebo arm 22.6

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Neonatal Prophylaxis Proportion of HIV Infected
Infants by Timing of AZT Receipt
Infected Infants
Wade et al, NEJM, 1998
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HIVNET 012nevirapine vs ZDV in Uganda

• NVP single dose intrapartum
• single dose infant 1st 72 hrs
• ZDV oral intrapartum
• infant 7 days
• 6 wks 18 mo.
• transmission NVP 12 16 ZDV 20 26
• gt95 breastfeeding
• minimal adverse events
• n618

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Reducing Intrapartum HIV Transmission Studies
of Short Course ARV Therapy
ZDV
Placebo
Placebo
NVP
ZDV/3TC
ZDV
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Cesarean SectionIPD meta-analysis

• meta-analysis of individual patient data
• 15 prospective cohorts
• 5 European, 10 North American
• gt7000 pregnancies
• before 1997 (rarely combination therapy)
• adjusted for antiretroviral therapy, maternal
  disease stage, birthweight
• Read, J. for International Perinatal HIV Group
• 12th World AIDS Conference, Geneva, 1998 NEJM
  April, 1999

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Meta-Analysis of Mode of Delivery and Perinatal
Transmission, N. America and Europe (n8533)
elective cesarean
vaginal
Source The International Perinatal HIV Group,
NEJM, 1 April 1999
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Transmission According to Mode of Delivery
(N2,075) PACTG 367
Vaginal vs. ECS P .12
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Peripartum Transmission According to Last
Antenatal Plasma HIV-1 RNA Level and Mode of
Delivery (P367)
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Cesarean delivery and MTCT

• Most US studies VL, ART most important, addition
  of cesarean to successful medical therapy - no
  added benefit
• European cohorts some demonstrate benefit of
  cesarean in all groups

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Breastfeeding vs formula Nairobi, Kenya

• randomized breastfeeding vs formula
• mean duration breastfeeding 17 months
• cumulative infection 24 mo 37 vs 21
• HIV-free survival 24 mo 58 vs 70
• 75 of risk difference in 1st 6 months
• breast milk transmission 16
• 44 of vertical transmission attributable to
  breastfeeding
• n401 Nduati, JAMA 2000

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• Breastfeeding and HIV Infection

• Women with HIV infection in the U.S. should not
  breastfeed
• Women considering breastfeeding should know their
  HIV status

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Neonatal diagnosis

• maternal IgG antibodies
• present in all neonates of HIV mothers, up to
  12-18 months
• test mothers, identify infants at risk
• HIV DNA PCR (some include RNA PCR)

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CDC November 2001

• Voluntary HIV testing as routine part of PNC
• Simplification of counseling consent
• HIV testing and treatment at time of LD for
  women with unknown or undocumented HIV status,
  using rapid test or expedited testing
• Test neonates, with consent, if mother not tested

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ACOG (Am. College of Obstetricians and
Gynecologists) Committee Opinion 304, Nov. 2004

• universal HIV testing of pregnant women
• routine PNC test preferably opt-out approach
• repeat test in third trimester if high risk
• rapid HIV test in labor for women with
  undocumented HIV status
• initiate treatment to prevent MTCT if rapid test
  positive
• postpone breastfeeding until confirmation
  obtained

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California Assembly Bill 1676effective Jan 2004

• Test for HIV as early as possible during prenatal
  care prenatal care provider to
• counsel all pregnant patients re HIV present as
  routine
• inform patients of intent to test for HIV
• obtain consent, patient to accept or refuse
• consent/refusal form in chart
• refer to specialist in PNC for HIV women
• If no HIV result in chart at LD, test then, with
  consent
• LD test by a method that will ensure the
  earliest possible results
• testing is not mandatory, but should be presented
  as routine

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Confidentiality and Reporting HIV Test Results

• Health and Safety Code Section 121010
• Patients health care provider can disclose HIV
  results via medical record or in other ways to
  licensed health care professionals or any agent
  or employee of the patients health care provider
  who provides direct patient care

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Rapid Testing in Labor and DeliveryThe
Technology

• Four rapid HIV tests available (Oraquick here)
• All tests provide an HIV negative OR a
  PRELIMINARY HIV positive result that requires a
  confirmatory HIV test.
• In general, HIV treatment does not begin until
  confirmation.
• In Labor and Delivery, treatment to inhibit HIV
  transmission begins immediately.

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Developing Solution
Reusable Stand
Specimen Collection Loop
Test Paddle
OraQuick
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Rapid Testing in LD Meaning of the Results

• Predictive value (PV) of the rapid assay varies
  with the prevalence of HIV infection among the
  population in the area
• Negative predictive value of a single rapid test
  is high
• The predictive value of a positive rapid test is
  higher among persons with risk and in areas with
  high HIV prevalence

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Performance of Oraquick rapid HIV test

• HIV prevalence positive predictive value
• 10 99
• 2 98
• 1 91
• 0.5 83
• 0.3 75
• 0.1 50

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Prenatal HIV Testing

• Pre-test counseling should include
• A discussion of
• The nature of HIV and AIDS
• Benefits of early diagnosis and medical
  intervention
• HIV transmission and risk reduction behaviors
• HIV Testing is confidential
• The nature and meaning of the HIV Test

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Prenatal HIV Testing

• Prenatal pre- and post- HIV test counseling
  should include information about
• Possibility of HIV testing of infant in the
  maternity setting if mother status is unknown
• the provision of the results of the test to the
  mother
• use of antiretroviral therapy to help reduce
  transmission to newborn

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Post test counseling recommendations for women
who test HIV-

• Should include a discussion about
• The meaning of the test result
• Possibility of exposure during past three months
  (risk determines need for re-testing)
• Negative test result does not imply immunity
• Reinforce personal risk reduction strategies

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Post test counseling recommendations for women
who test HIV

• Should include a discussion about
• The meaning of test result
• The availability of medical care
• Risks and benefits of ART to prevent mother-child
  transmission
• Risk of transmission through breastfeeding
• Document the test results and provision of post
  test counseling in patient record

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Perinatal HotlineNational HIV Perinatal
Consultation and Referral Service (UCSF)

• For clinicians questions about rapid and
  standard HIV testing during pregnancy, care of
  HIV-infected pregnant women and their exposed
  infants

888/448-8765 24 hours/day 7 days/week
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• USPHS guidelines for HIV-infected woman in labor
  with no prior treatment

• These treatment options based on published
  studies
• Intrapartum IV ZDV followed by 6 weeks ZDV for
  the newborn (many consider this below standard of
  care)
• Oral ZDV/3TC for mother at onset and during labor
  followed by 1 week oral ZDV/3TC for the newborn
• Single dose NVP for mother at onset of labor
  followed by single dose of NVP for the newborn at
  4872 hrs of age
• The 2-dose NVP regimen as above combined with
  intrapartum IV ZDV and 6 week ZDV for the newborn
• not studied, but probably most effective and
  recommended by many expert clinicians ZDV 3TC
  NVP

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USPHS guidelines for infants whose mothers
received no antiretroviral therapy during
pregnancy or intrapartum

• The 6-week neonatal ZDV component of the ZDV
  chemoprophylactic regimen should be encouraged
  for the newborn.
• ZDV should be initiated as soon as possible after
  delivery within 1-2 hours, at most within 12
  hrs.
• Note Most experienced pediatricians choose to
  use ZDV in combination with other antiretroviral
  drugs in this high-risk setting many
  experts recommend ZDV3TCNVP.

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After single-dose nevirapine interventions to
decrease risk of NVP resistance

• Significant NVP levels for 2-3 weeks after SD NVP
• Risk of NVP resistance mutations after SD NVP
• at least 15
• compromises maternal treatment options
• consider 3 weeks additional antiretroviral meds
• Combivir (ZDV 3TC) 1 bid x 3 weeks should be
  effective
• This and other regimens currently being studied
  in PACTG and AACTG and in South African studies

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postpartum management of newly identified HIV
woman (rapid testing)

• post-test counseling
• confirmatory testing
• basic HIV education
• no breastfeeding
• confidentiality, disclosure, notification
• evaluation of patient and infant safety
• depression, domestic violence, substance abuse,
  housing, ability to provide prophylaxis to infant
  and keep clinic appointments

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Referrals treatment for newly identified HIV
woman postpartum

• ensure referral to clinic providing comprehensive
  HIV care for mom and baby
• family-centered with adult and pediatric HIV
  services
• initial contact with clinic staff before
  discharge, if possible
• involve hospital and clinic social workers
• consider baseline labs while hospitalized
• generally preferable to start antiretroviral
  treatment as outpatient, however may need to
  cover NVP tail
• prophylaxis for opportunistic infections if CD4
  lt200, especially trimethoprim -sulfamethoxazole
  for pcp pneumonia

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Baseline labsobtain before discharge if possible

• CBC
• full chemistry panel
• Hepatitis B C
• CD4
• viral load
• CMV, toxoplasmosis titers
• RPR

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Rapid HIV testing on LD serviceLA County USC
Medical Center experience

• 2003 no MTCT in our Maternal-Child-Adolescent
  HIV Clinic patients in 7 years (now gt9 yrs with
  no transmission)
• Several recent MTCT cases in women with unknown
  HIV status in which gt6-day lab turn-around time
  for HIV test prevented effective intervention (6
  days after birth is too late)
• No rapid HIV testing available at LACUSC
• MCA pediatricians and obstetrician (AS) took
  initiative for rapid testing and convinced
  clinical lab director of its importance
• Lab directors personal investment was critical
  to success
• Started RHIV program January 2004

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Rapid HIV testing on LD serviceLACUSC
experience Jan 2004 Jan 2006

• Indications for rapid HIV test
• Women expected to deliver in 2 days, or
  postpartum, or their neonates
• No HIV results during current pregnancy
  available, or negative HIV results gt2 mo ago, but
  continued high risk
• Rapid HIV test service extended to employee
  health (exposed worker source), sexual assault
  clinic, limited cases in ER
• RHIV ordered by resident or faculty MDs, CNMs,
  NPs, PAs

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Rapid HIV testing on LD serviceLACUSC
experience Jan 2004 Jan 2006

• Standard hospital HIV test consent form
• Stat test in clinical lab, Reveal (MedMira) blood
  test results telephoned to ordering MD or RN
• Clinical lab in main hospital building, ¼ mile
  away
• Our maternity patients
• majority have complicated pregnancies
• 4 no prenatal care
• 78 Latina, 12 Black, 59 Spanish-speaking
• Almost 100 Medi-Cal insured

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Rapid HIV testing on LD serviceLACUSC
experience Jan 2004 Jan 2006

• 2940 women delivered
• 964 RHIV tests done
• 3 of all HIV tests at LACUSC
• 671 (71) done on OB/neonatal service patients
• approx 1 per day

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Rapid HIV testing on LD serviceLACUSC
experience Jan 2004 Jan 2006

• Median time from blood draw to results in
  computer 87 minutes
• 45 min. blood draw arrival in lab, 42 minutes
  in lab
• 4/671 RHIV , 2 WB , 2 false-positive
• PPV .5
• HIV prevalence in women who had RHIV test 0.3

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Rapid HIV testing on LD serviceTrue positives
(5 positives to date 3 true, 2 false)

• 29 wks, psychotic, poor historian, but states
  HIV. RHIV , started HAART for PMTCT. Left
  hospital when psych hold not continued, failed
  F/U at MCA
• Term, in labor. Declined Cesarean. ZDV, 3TC, NVP
  to mom intrapartum neonate. Bottlefed. Infant
  HIV neg
• Term, prodromal labor. Homeless, psych disorder.
  Cesarean, ZDV, 3TC, NVP to mom intrapartum
  neonate. Bottlefed. Infant HIV neg.

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Rapid HIV testing on LD serviceFalse positives
(5 positives to date 3 true, 2 false)

• Term, prodromal labor. Twin Towers, substance
  abuse. No PNC records available. Cesarean, ZDV,
  3TC, NVP to mom intrapartum neonate. Bottlefed.
  Repeat RHIV , Western Blot neg, HIV RNA PCR neg.
• Term, delivered in parking lot of another
  hospital. No PNC records available. Preliminary
  positive RHIV misinterpreted by OB intern and
  pediatricians. Breastfed until next shift. Later
  neonatal ZDV, 3TC, NVP. Repeat RHIV , WB neg,
  HIV RNA PCR neg.

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Rapid HIV testing on LD serviceLACUSC
experience conclusions

• While HIV prevalence of 0.3 was lower than we
  expected among pregnant women with no documented
  HIV results at time of delivery admission, it was
  still higher than the 0.07 overall
  seroprevalence among childbearing women in LA
  County.
• We expected to identify more HIV women with our
  rapid testing protocol. One interpretation of
  these findings is that local prenatal care
  providers are identifying most HIV women during
  PNC.
• Our testing protocol the RevealTM RHIV test
  performed well in this setting. RHIV performed at
  the hospital clinical lab provided excellent
  turn-around time, acceptable positive predictive
  value and acceptable lab workload.

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Issues/Rapid HIV

• Number of women who will require test
• Where test completed (lab vs. LD)
• Consent/acceptance of test
• Timing issues goal lt40 minutes -waiting
  around/timers
• Reporting results who, how
• Interventions if result positive

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• MTCT rates of under 1 are feasible and are
  currently achieved with state-of-the-art care in
  settings with adequate resources.
• Most cases of MTCT in USA now occur in women with
  no HIV care/women with unknown HIV status.
• Interventions in peripartum period can reduce
  MTCT.

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NVP

• Resistance issues

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Duration of circulating nevirapine postpartum

• After single dose NVP 200 mg intrapartum
• NVP detectable (gt50 ng/ml)
• 8-14 days pp 77
• 15-21 days 56
• 21-45 days 0
• T. Cressey, Chiang Mai, Thailand
• 15th International AIDS Conference, Bangkok, July
  2004

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NVP resistance mutations

• HIVNET 012
• intrapartum NVP, no other HIV meds, Uganda
• 19 new resistance mutations at 6-8 wks
• high VL or low CD4 increased risk
• PACTG 316
• intrapartum NVP, standard HIV treatment, USA
• 14/95 (15) new resistance mutations at 6 wk pp
• no correlation with antiretroviral meds, VL, CD4

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Minority Variants with NNRTI Resistance Frequent
After Maternal SD NVPPalmer S et al. Retrovirus
Conf, Boston 2005 (Abs 101)
S. Africa - subtype C infection Real-time assay
detection limit 0.1
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Impact of single-dose NVP on virologic response
to later treatment Thai study follow-upG.
Jourdain, 11th Retrovirus Conf., Feb 2004. NEJM
July 2004

• All received ZDV, randomized to SD NVP vs placebo
  intrapartum
• 18 of women with intrapartum SD NVP had NVP
  resistance mutations at 10 d postpartum
• In women who later started NNRTI regimen for
  maternal indication, at 6 months VL was lt50 (
  good response to therapy) in
• 74 if no intrapartum NVP
• 50 if intrapartum NVP, no mutations at 10 days
• 38 if intrapartum NVP, mutations at 10 days

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After single-dose nevirapine interventions to
decrease risk of NVP resistance

• Significant NVP levels for 2-3 weeks after SD NVP
• Risk of NVP resistance mutations after SD NVP
• at least 15
• compromises maternal treatment options
• consider 3 weeks additional antiretroviral meds
• Combivir (ZDV 3TC) 1 bid x 3 weeks should be
  effective
• This and other regimens currently being studied
  in PACTG and AACTG and in South African studies