Clinical Considerations: Medical Menstrual History & Exam Overview

1. MTN-003 Study-Specific Training Selected Clinical Considerations

2. Overview of Presentation • Medical/menstrual history • Concomitant medications • Vital signs and physical exams • Pelvic exams • Genital bleeding assessment • STI/RTI management • Urinary tract infections • Pregnancy management • HIV management

3. Medical/Menstrual History • Baseline • Purpose is to establish eligibility AND document baseline medical condition, for comparison with condition during follow-up • “Focused”  history since participant became sexually active (lifetime history not required) • Probe for most accurate information possible on current health status vis-à-vis the reported history

4. Medical/Menstrual History • Baseline • Use listing of body systems on the Baseline Medical and Menstrual History form (recommended source document) to probe for history related to each system • Record symptoms, illnesses, allergies, surgeries • Record chronic and acute conditions • Record resolved and ongoing conditions • Details on gastrointestinal and urinary symptoms will be especially important

5. Medical/Menstrual History • Baseline • For genital symptoms, probe for and record as much detail as possible • Genital sores • Genital/vaginal itching • Genital/vaginal burning • Genital/vaginal pain • Pain during sex • Abnormal genital/vaginal discharge • Unusual genital/vaginal odor • Other genital symptoms (specify)

6. Medical/Menstrual History • Baseline • For menstrual history • Age at menarche • First and last day of last period • Usual menstrual cycle • If amenorrheic  expected or unexpected • Usual menstrual flow • Usual menstrual symptoms • Usual non-menstrual bleeding • Any other menstrual problems

7. Medical/Menstrual History • Baseline • For reproductive history • Contraceptive history • Pregnancies and outcomes • Obstetric, gynecologic, and/or other reproductive problems, procedures, surgeries • Sexual assault

8. Medical/Menstrual History • Baseline • Complete Concomitant Medications Log form (recommended source document) in tandem with medical/menstrual history: • Prescription medications/preparations • Non-prescription medications/preparations • All routes of administration, including topical and intravaginal • Vitamins, other nutritional supplements, herbal, naturopathic, and traditional preparations • Similarly complete Contraceptives Log form

9. Medical/Menstrual History • Baseline • Cross-reference concomitant medication information with medical/menstrual history • Probe for any medications taken for all ongoing symptoms/illnesses/conditions • Pay special attention to symptoms likely to recur during study participation (e.g., dysmenorrhea, intermenstrual spotting)

10. Medical/Menstrual History • Follow-up • Performed at all scheduled visits and at interim visits if participant presents with symptoms • “Interval”  since last visit • Follow-up Medical and Menstrual History form is recommended source document • Refer to previously completed history forms and update from there • Cross-reference Monthly Symptoms form which is administered before history taking

11. Medical/Menstrual History • Follow-up • Not necessary to actively review and ask about each body system • For most systems • Ask about current status of previously-reported conditions • Ask about symptoms reported on the Monthly Symptoms form (make sure details match) • Then ask open-ended question such as “have you had any other symptoms or problems since your last visit?” to complete the history

12. Medical/Menstrual History • Follow-up • For genital symptoms • Actively ask about each symptom listed on the Follow-up Medical and Menstrual History form • For menstrual information • Record dates of last menstrual period • If no menses since last visit  expected or unexpected • For other reproductive history information • Record any updates / changes since last visit

13. Medical/Menstrual History • Follow-up • Update Concomitant Medications Log form (recommended source document) in tandem with interval history • Specifically ask if each prior medication still being taken • Specifically ask if medications taken for any new symptoms or illnesses reported in interval history • Generally ask if any new medications taken since last visit • Similarly update Contraceptives Log form when applicable

14. Physical Exam • Required at • Screening Part 2 ● Product Use End Visit (PUEV) • Month 1 ● When clinically indicated • Quarterly • Physical Exam form is recommended source document • For any observed abnormalities, cross reference with medical history and concomitant medications and probe for additional information as needed

15. Vital signs Height Weight Oral temperature Blood pressure Pulse Respirations Clinical assessments of Head and eyes Ears, nose, and throat Neck Lymph nodes Heart Lungs Abdomen Extremities Neurological Skin Breasts Physical Exam • Other assessments at discretion of examining clinician

16. Weight • Measured as part of all physical exams and whenever blood is drawn for creatinine testing • Needed to calculate CrCl rate • Measure in kilograms and round to nearest whole number • Calibrate scale twice per year (more frequently if required by local standards)

17. Weight • Consistent weighing procedures should be followed for all participants at all time points • Each site may choose to consistently weigh participants fully clothed or wearing clinic gowns • Sites with seasonal weather variations should consider using gowns or adopting other procedures to ensure that accurate weights are measured throughout the year • Monitor for unintended weight loss and grade severity per DAIDS Toxicity Table

18. Height • Measured as part of physical exams at Screening Part 2, Semi-Annually, and at PUEV • Measure in centimeters • Do not use device on weight scale • Use wall chart • Use consistent procedures across participants and over time (e.g., remove shoes)

19. Height • If decrease of 3.8 cm is detected, repeat measurement for confirmation • If confirmed, order x-ray to assess for vertebral compression fracture

20. Some Challenges?

21. Solution

22. Blood Pressure • Measured as part of all physical exams • Should also be measured at other visits to monitor participants with abnormal pressures • Hypertension (>140 systolic, >90 diastolic) should be confirmed with repeat measurement at the same visit • Grade severity per DAIDS Toxicity Table

23. Blood Pressure • VOICE sites should ideally provide antihypertensive treatment for study participants when clinically indicated • Participants with grade 3 and higher hypertension should be counseled and treated • Participants with grade 1 and 2 hypertension should be counseled and may be treated at IoR discretion • Also consider hypertension in the context of contraceptive choice

24. Blood Pressure • Potential participants with significantuncontrolled hypertension during screening may not be immediately enrolled but may be enrolled after control is established and documented • May require a second screening attempt • Antihypertensives, including thiazide diuretics and ACE inhibitors, are not contraindicated in VOICE • PSRT available for consultation • Consider re-checking creatinine for confirmation of eligibility if antihypertensives started during screening • Otherwise follow local standard of care for monitoring and treatment

25. Hepatitis B • All participants undergo testing for Hepatitis B surface antigen (HBsAg) and surface antibody (HBsAb) at Screening Part 1 • HBsAg+  not eligible  counsel and refer • HBsAg- and HBsAb-  Hep B susceptible • HBsAg- and HBsAb+  not Hep B susceptible • If susceptible and enroll, offer vaccine • If not susceptible, vaccine not indicated

26. Hepatitis B • If susceptible and enroll and accept vaccine, ideally administer first vaccination at enrollment and second and third vaccinations at study Months 1 and 6 • If susceptible and enroll and decline vaccine • Continue to offer vaccination throughout follow-up • Perform HBsAg testing annually • (All participants have HBsAg testing at PUEV) • If assigned to oral study product, additionally perform HBsAg testing six months after PUEV

27. Pelvic Exam • WHO/CONRAD Manual • MTN-003 SSP Manual  checklists • Pelvic exam training video • Pay careful attention to which evaluations are required at all exams, which are required at some but not all exams, and which are required only when clinically indicated • Performed at Screening Part 2, Semi-Annually, and at PUEV, per

28. Ideally use two-person team: examining clinician and assistant Ensure all possibly-required supplies and paperwork are easily accessible in exam room Review specimen collection requirements for each visit in preparation for each exam Pay careful attention to the required sequence of swab collection and required handling of each swab Especially important to use the correct swab for the BV rapid test (cotton swab from kit) Pelvic Exam

29. Vaginal fluid specimen collection requirements For rapid tests and wet mount – lateral vaginal wall and posterior fornix are acceptable For archive – posterior fornix only For pH assessment – lateral vaginal wall only Swab fluids then apply to pH strip Pelvic Exam

30. To document findings, use terms from the FGGT and the pelvic exam case report forms When the term from the case report form is more specific than the term from the FGGT, use the term from the case report form Use routine QC/QA opportunities to help ensure consistency of terminology across staff and exams Pelvic Exam Terminology

31. Perform at Screening Part 2, at PUEV, and when clinically indicated and/or per local standard of care Note: Women with a documented normal result within the 12 months prior to enrollment need not have Pap smear during the screening period. Manage results per 2006 Consensus Guidelines for the Management of Women with Abnormal Cervical Cancer Screening Tests and local guidelines Pap Smear Management

32. During screening, Grade 2 (HSIL) and higher grade results are exclusionary For all abnormal results during screening, note exclusion for gynecologic procedures within 42 days of enrollment Note: Women with abnormal Pap smears can be enrolled upon completion of the initial phase of evaluation if no treatment is indicated … need for a repeat Pap within 6 months does not preclude enrollment prior to result becoming available. Pap Smear Management

33. During follow-up, HSIL and more severe abnormalities require Temporary hold of vaginal study product No change for oral study product See protocol Section 9.8 Pap Smear Management

34. Non-menstrual genital bleeding is common, especially in the context of recent uptake of hormonal contraception Refer to SSP Section 10 for procedures, algorithms, and terminology to standardize assessment of genital bleeding across sites All genital bleeding must be assessed and documented as: Menstrual or non-menstrual Expected or unexpected Genital Bleeding Assessment

35. Genital Bleeding Assessment • Expected bleeding is considered normal • Menses • Early menses • Intermenstrual bleeding explained by contraceptive method • Expected / explained absence of menses is also considered normal

36. Genital Bleeding Assessment • Unexpected bleeding is considered abnormal • Metrorrhagia = intermenstrual bleeding • Menorrhagia = regularly timed but prolonged and/or heavy menstrual bleeding • Menometrorrhagia = prolonged menstrual bleeding occurring at irregular intervals • Bleeding during pregnancy • Unexpected / unexplained infrequent bleeding (missed menses, oligomenorrhea, amenorrhea) is also considered abnormal

37. Genital Bleeding Assessment Instruct participants to report all episodes of genital bleeding Document all reported and observed bleeding Complete Genital Bleeding Assessment form and/or pelvic exam as needed to assess all unexpected bleeding

38. STI/RTI Management • Sexually transmitted infections (STI) and other reproductive tract infections (RTI) will be assessed during screening and throughout follow-up • Bacterial vaginosis • Vaginal candidiasis • Chlamydia infection • Gonorrhea infection • Syphilis infection • Vaginal trichomoniasis • [Genital herpes]

39. STI/RTI Management • STIs/RTIs should be treated per WHO guidelines, except that asymptomatic candidiasis should not routinely be treated • WHO guidelines are minimum standard, if local guidelines set higher standard, follow local guidelines • Day-to-day, consult WHO and local guidelines as needed • Provide directly observed single dose regimens whenever possible

40. Clarification for BV • WHO guidelines include both single and multi-dose regimens of metronidazole for treatment of symptomatic BV • Multi-dose = recommended • Single-dose = alternate • Multi-dose regimen is more effective and should be used in most cases • Single-dose regimen may be used on a case-by-case basis if considered more appropriate for a given participant (e.g., for participant known to have difficulty adhering to longer course regimens)

41. STI/RTI Management • STI/RTI are considered resolved when treatment has been completed and symptoms, if any, have resolved • No test of cure is required • NB: For infections diagnosed during screening, treatment must be completed, and symptoms must resolve, before enrollment

42. Clarification for Syphilis • Clinical management of syphilis should include repeat serology (RPR) at six-month intervals to confirm treatment effectiveness • If RPR titre does not decrease four-fold or revert to seronegative within six months after treatment, treatment should be repeated • NB: For syphilis infections diagnosed during screening, four-fold decrease not required before enrollment

43. Urinary Tract Infections • Diagnosed in VOICE based on the presence of symptoms and dipstick urinalysis positive for both nitrites and leukocyte esterase (LE) • Symptoms include • Frequent urge to urinate • Passage of only a small volume of urine • Pain and/or burning during urination • Lower abdominal pain and/or uncomfortable pressure above the pubic bone • Milky/cloudy, reddish or bloody urine

44. Urinary Tract Infections • At Screening Part 1, dipstick for nitrites and LE is done regardless of symptoms • After Screening Part 1, dipstick for nitrites and LE is done only among symptomatic participants • Asymptomatic participants should not be treated, regardless of dipstick results

45. Urinary Tract Infections • Symptomatic participants with dipstick positive for both nitrites and LE should be treated • During screening, treatment must be completed and symptoms must resolve before enrollment • Symptomatic participants with dipstick negative for either nitrites or LE may be treated according to clinical judgment; however this would not be diagnosed as a UTI for VOICE

46. Urinary Tract Infections • Operational note • Dipstick strips for nitrites and LE also test for protein and glucose • Even if testing for protein and glucose is not required or indicated when testing for nitrites and LE, results for protein and glucose must be documented, assessed for clinical significance, and acted upon per protocol

47. Pregnancy Management • Follow protocol Sections 7.6.3 and 9.12 and SSP Section 6.8 • Hold study product, retrieve within 5 working days • Refer to antenatal care (PMTCT) and MTN-016 • Obtain medical records related to pregnancy outcome whenever possible

48. Pregnancy Management • Provide counseling on infant feeding per WHO and local guidelines • Provide contraceptive counseling • Resume study product after pregnancy outcome provided participant is not breast feeding • At least six months breast feeding expected • Negative pregnancy test performed by study staff • For gel participants pelvic exam confirming no findings to contraindicate gel use

49. HIV Management • Follow protocol Sections 7.6.1 and 9.10 • Hold study product at first positive rapid test, retrieve within 24 hours • If infection not confirmed per algorithm, resume • If infection confirmed, permanently discontinue

50. HIV Management • Provide post-test counseling and ongoing supportive counseling • Offer continued participation in VOICE • Refer to MTN-015 • Refer to available sources of medical and psychosocial care and support