Lessons learned from past passive immunization trials to prevent HIV MTCT Laura Guay MD EGPAF Vice President for Research Research Professor, George Washington University SPH
PACTG 185 Outline HIVIGLOB Phase I/II HIVIGLOB Phase III Community/Participant trial preparation
PACTG 185 Design Multicenter, randomized controlled HIV Hyperimmune Immunoglobulin (HIVIG) trial in US and Puerto Rico 1993-1997 HIVIG (North American Biologicals, Boca Raton, FL) plus zidovudine (ZDV) compared with intravenous immunoglobulin (IVIG) plus ZDV in HIV-positive pregnant women with CD4 counts < 500 cells/µl receiving standard ZDV regimen at the time HIVIG or IVIG 200 mg/kg IV to women every 4 weeks from 20-30 weeks gestation to delivery Infant IV infusion of HIVIG or IVIG (arm same as mother) 200 mg/kg within 12 hours of birth Target- 400 pairs per arm; stopped for futility after 501 enrolled
PACTG 185 PK and Safety Results Pharmacokinetics: Maternal mean half-life after 1 and 3 infusions was 15 and 32 days respectively Newborn half-life was 30 days HIVIG rapidly cleared p24 antigenemia with no change in RNA levels The HIVIG was safe and well tolerated by the pregnant women and their neonates. Side effects seen were common to immunoglobulin infusions 6 women and no infants discontinued infusion due to side effects No difference between arms
PACTG 185 Efficacy Results Kaplan-Meier estimated transmission rate by treatment arm was 4.1% (95% CI, 1.5% 6.7%) in HIVIG and 6.0% (95% CI, 2.8% 9.1%) in IVIG recipients (P=.36) There was a difference between treatment arms in the distribution of infants who had a positive HIV culture at birth (none in HIVIG vs. 5 in IVIG recipients; P 5.05). Trend toward lower transmission among women receiving HIVIG who started ZDV before pregnancy (1.9% in HIVIG vs. 9.2% in IVIG recipients; P=.09 ) or who had baseline CD4 cell count <200 µl (5.6% in HIVIG vs. 14.9% in IVIG recipients; P =.12).
HIVIGLOB Phase I/II Design Safety, tolerance, PK, and virologic and immunologic changes associated with Ugandan HIV hyperimmune globulin (HIVIGLOB) in HIV infected pregnant Ugandan women and their infants HIVIGLOB prepared from Ugandan discarded units of HIV infected blood (CD4 cells>500, p24 ag neg) at the Swedish Institute for Infectious Disease Control 10-35 fold reduction in infectivity against primary subtype isolates (B,C,E, A, but not D) contained 98% monomeric IgG. IgG subclass enzyme immuno-assays on the 16% HIVIGLOB solution: titer of IgG1 antibody to rgp160= 1:3 200 000; rp24 =1:10 000 000; LP2-V3/MN-peptide =1:100 000. A prospective, phase I/II, three-arm dose escalation trial of 50, 200, and 400 mg/kg HIVIGLOB in 31 women at 37 weeks gestation and infants within 16 hrs of birth (1996-1997).
HIVIGLOB Phase I/II Results All three dosing levels were well tolerated by women and infants Common side effects associated with immunoglobulin infusions 2 neonatal deaths prior to HIVIGLOB infant infusion High pre-infusion p24 antibody titers in pregnant women 1:18 282 (range, 1:25 to 1: 6 576 925) Maternal p24 antibody t1/2 in three dosing groups (50, 200, 400 mg/kg) were 27, 15, and 29 days respectively Cord blood median p24 antibody titer= 1:14 191 (range, 1:1437 to 1:2 348 010) Infant p24 antibody t1/2 in three dosing groups were 30 days, 32 days, and 29 days
HIVIGLOB Phase I/II Results Significant increases in p24 antibody postinfusion only in 400 mg/kg dose No significant changes in HIV RNA or CD4 cell counts post-infusion in any arm No women had p24 antigenemia prior to infusion Lowest transmission in 400 mg/kg group but numbers too small to make transmission conclusions
HIVIGLOB Phase III design Phase III, randomized, clinical trial of single-dose nevirapine (sdnvp) plus HIVIGLOB compared with sdnvp for PMTCT in HIV positive pregnant women and their infants in Kampala. 2 out of 3 arms of a multi-country trial including extended NVP to 6 weeks arm, not included in analysis Single intravenous 240-mL dose (~200 mg/kg) of HIVIGLOB to women at 36-38 weeks gestation Single intravenous 24-mL (~400 mg/kg) dose to newborns within 18 hours of birth Study recruitment 2004-2006
HIVIGLOB Phase III Results 204 pairs in HIVIGLOB arm + 290 in sdnvp arm Only 173 (85%) of women received infusion mostly due to delivery prior to infusion 4 infants did not get HIVIGLOB (2 neonatal deaths, 2 refusals) HIVIGLOB was safe and well tolerated No difference in AE between arms Common side effects for IV immunoglobulins 14 infants had possibly related SAEs: 8 during the infusion (1 discontinuation, 2 temporarily held, and 5 no change in infusion); 6 after completion of the infusion. 2 infant deaths at home within 1 and 3 days of birth where some contribution of HIVIGLOB could not be ruled out. Women asked for more - felt much better after getting infusion
HIVIGLOB Phase III Efficacy Results Interpretation of the HIVIGLOB efficacy was complicated by the unanticipated low rate of HIV infection at birth in the sdnvp control arm (4.1%), significantly lower than the HIVIGLOB/sdNVP arm (9.1%) and the rates seen with the same sdnvp regimen in the third arm of this trial (9.6%) The difference persisted throughout the study period; however, it was no longer statistically significant by the 6- week time point. The difference in the proportion of HIV infected children at 6 months, the primary endpoint, was not statistically significant between the HIVIGLOB/sdNVP arm and the sdnvp arm (18.7% vs. 15.0%, RR = 1.240, 95% CI: 0.833 to 1.846, P = 0.290).
Community sensitization Multiple stakeholder meetings, but primarily scientific: MOH, IRBs, other HIV researchers, health facility staff Better community sensitization with later HIV Vaccine trial (HPTN 027 infant ALVAC) than with the early passive immunization studies. Added UNEPI to technical meetings due to concern re effect of HIV vaccine on standard infant immunizations CAB engagement including adult HIV vaccine participants Media training on trial and general vaccine information Study summary, key messages, and Q&A information provided to leaders (HIV and others) in country
Participant Study Preparation Multiple step process of providing information and obtaining informed consent Consent form pictorial flip chart (English and Luganda) Provided tool for counselors to use Attempt to convey key messages to women Provide explanation about what antibodies are, why product is from HIV infected donors but does not contain HIV Assessment of understanding conducted by person other than one obtaining consent
GROUP 2, 200 women Mother Baby NVP + Syringe used to give baby syrup by mouth HIVIGLOB + NVP HIVIGLOB + NVP
HIV infected cell HIV antibody Cell with HIV + HIV antibody HIV antibodies are taken out of the blood and made into HIVIGLOB
Practical considerations Acceptability of IV infusions- need to establish smooth system for IV infusion that will minimize obstacles to participation Separate room in postnatal ward for HIVIGLOB infusions for women; infused babies in the special care unit (more skilled nurses, proximity to emergency equipment/care, privacy) Need to address confidentiality for non-disclosed partners/family members Delay in clinic/maternity Background neonatal sepsis and death rates have to be considered in study populations due to temporal association with infusion.
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