IMPAACT 2010 Eligibility Criteria

Protocol References Section Title 4.1 Inclusion Criteria 4.2 Exclusion Criteria

VESTED Design: Phase III, three-arm, randomized, open-label study Population: HIV-1-infected pregnant women initiating antiretroviral therapy at 14-28 weeks gestation and their infants Sample Size: 549 mother-infant pairs (approximately 183 per arm) This covers 4.1.1 4.1.2 4.1.3 4.1.6

Mothers must be … At least 18 years of age Willing and able to provide written informed consent for maternal and infant study participation In second trimester of pregnancy (14-28 weeks at study entry) HIV-infected ART-naïve This covers 4.1.1 4.1.2 4.1.3 4.1.6

Inclusion Criterion 4.1.3 At screening, mother is ART-naïve, defined as having not received prior antiretroviral therapy other than ARVs received during prior pregnancies or prior periods of breastfeeding Receipt of any single, dual, or triple ARV regimen during prior time-limited periods of pregnancy and breastfeeding is permitted Receipt of up to 14 days of ARVs during the current pregnancy is permitted prior to study entry so that initiation of ARVs during the current pregnancy is not delayed during the study screening period

Exclusion Criterion 4.2.4 Mother has a history of … Receipt of any antiretroviral medication within six months prior to study entry, with the exception of receipt of up 14 days of ARVs during the current pregnancy Note that we have jumped here to one of the study EXCLUSION criteria so that we can highlight all of the criteria involving maternal use of ART. For mothers who may have received ARVs during prior pregnancies or prior periods of breastfeeding, in order to be eligible for this study, they must not have received any ARVs within six months prior to study entry (other than the 14 days of ART allowed in the current pregnancy).

Do you have any questions about maternal ARV use in relation to eligibility?

Do you have any questions about confirmation of maternal HIV infection?

Confirmation of Maternal Infection Sample #1 Sample #2 Two different rapid antibody tests One EIA or WB or immunofluorescence or chemiluminescence test One HIV DNA PCR One quantitative HIV RNA PCR (result above LOD) One qualitative HIV RNA PCR One total nucleic acid test Rapid antibody test for a total of three different rapid tests These same requirements were specified for PROMISE and P1078 (Version 2.0). Although standard of care testing will vary across sites, it is commonly expected that two rapid tests may be performed in standard of care settings. In this case, and assuming the two rapid tests are adequately documented, it may only be necessary to perform one additional rapid test for study purposes, to confirm infection prior to enrolment. Having said that, all sites will need to establish maternal HIV testing algorithms for this study in consultation with the IMPAACT Laboratory Center, and will need to follow these algorithms consistently throughout the study.

Confirmation of Maternal Infection If both samples are tested using antibody tests, at least one must be tested in a laboratory setting that operates according to GCLP guidelines and participates in an appropriate EQA program If nucleic acid testing is used, at least one test must be performed in a CLIA-certified (US sites) or VQA-certified (non-US sites) laboratory For tests performed in other settings, adequate source documentation including the date of specimen collection, date of testing, test performed, and test result must be available FDA-approved methods should be used when possible, and when a combination of three rapid tests are performed, at least one must be FDA approved

How much blood will you need to collect for this testing? At your site, which HIV tests do you expect to perform to confirm maternal HIV infection per protocol Section 4.1.2? Follow-up Question: How much blood will you need to collect for this testing?

Consider a mother whose antenatal records indicate that she was booked at 16 weeks gestation three days prior to screening for the study. Will you perform a pregnancy test as part of the study screening process for this mother? Yes No Section 6.1 and SoE footnote 4

What about pregnancy testing? Protocol Section 6.1 and Antepartum SoE footnote 4 Maternal pregnancy testing may or may not be required to meet the eligibility criteria in protocol Section 4.1.6. If available maternal medical records document a positive pregnancy test result, or if pregnancy is confirmed by ultrasound scan prior to enrolment, no pregnancy testing is required. Otherwise, a blood or urine pregnancy test should be performed, with results available for eligibility determination prior to enrolment.

Which of the following ALT and AST values are acceptable for inclusion? Normal only Normal and grade 1 Normal, grade1, and grade 2 Something else 4.1.4 4.2.2 4.2.3 4.2.4

Which of the following creatinine values are acceptable for inclusion? Normal only Normal and grade 1 Normal, grade1, and grade 2 Something else 4.1.4 4.2.2 4.2.3 4.2.4

Which of the following creatinine clearance (CrCl) values are acceptable for inclusion? Normal only Normal and grade 1 Normal, grade 1, and grade 2 Something else 4.1.4 4.2.2 4.2.3 4.2.4

Maternal CrCl Evaluation Grade 1 Grade 2 Grade 3 Grade 4

Which of the following hemoglobin values are acceptable for inclusion? Normal only Normal and grade 1 Normal, grade1, and grade 2 Something else 4.1.4 4.2.2 4.2.3 4.2.4

Mothers with Hepatitis B or Hepatitis C infection should be excluded from the study. True False Maybe 4.1.4 4.2.2 4.2.3 4.2.4

VESTED FAQ The eligibility criteria seem to allow for women with hepatitis B or hepatitis C to take part in the study. Are there any clinical management issues or concerns that we should be aware of for these women, particularly with respect to initiation of DTG or TAF? The protocol does not require laboratory testing for hepatitis B or hepatitis C infection as part of the study screening process, although hepatitis B testing is required at entry. You are correct that these infections are not exclusionary; however, grade 2 or higher ALT and AST values are exclusionary, as is current treatment for active hepatitis C. Unstable liver disease within 14 days prior to study entry is also exclusionary. For enrolled mothers who are not receiving treatment for active hepatitis C at study entry, but who may later receive such treatment during follow-up, the IMPAACT 2010 Clinical Management Committee should be consulted with respect to the potential use of precautionary or prohibited concomitant medications (refer to protocol Sections 5.9 and 5.10). [answer continues … ]

Consider a mother who plans to stay with her extended family after giving birth to her infant. Should this mother be excluded from the study? Yes No Maybe

Consider a mother who received EFV/3TC/TDF during a prior pregnancy 18 months ago. She reports that she had trouble sleeping and abnormal dreams while taking this regimen. Should this mother be excluded from the study? Yes No Maybe 4.1.3 4.2.4

Consider a mother who was sick with gastroenteritis on the day she first presented for antenatal care. Because of dehydration, she was hospitalized overnight and then discharged the next day. Two days later she presents to the study site for screening. Should this mother be excluded from the study? Yes No Maybe 4.2.4

At your site, what questions will you ask to determine whether a mother has a history of … Clinically significant heart disease and/or known prolonged QTc interval? Zika virus infection (diagnosed or suspected) Suicidal ideation or attempt? Receipt of a prohibited medication?

What are your questions about the study eligibility criteria?