09.P.PM07: Mullens - PHE: Infant Morbidity and Mortality Survey

ACTIVITY CONTINUING UNDER PERFORMANCE PASS

ACTIVITY UNCHANGED FROM FY2008

From COP08:

Title: Risk factors for adverse pregnancy outcomes among HIV-infected and HIV-uninfected women in

Botswana

Time and Money: 2 years are required to collect and analyze the data. The Year 1 budget for the project is

$216,000. ($200,000 approved).

Local Co-investigator: Local co-investigators will include Dr. William Jimbo, CDC, Dr. Anthony Ogwu

(Botswana-Harvard School of Public Health Partnership [BHP]), Dr. Joseph Makhema (BHP), Dr. Petr Svab

(Princess Marina Hospital), Dr. Tracy Creek (CDC), Dr. Roger Shapiro (BHP), Dr. Shahin Lockman (BHP)

and Jennifer Chen (Harvard Medical School and BHP.)

Project Description: This project will document the rates and etiologies of stillbirth and early neonatal

mortality, and the rates of premature delivery among HIV-infected and HIV-uninfected women in Botswana.

All births occurring at Princess Marina Hospital (PMH) and Scottish Livingstone Hospital (SLH) during a two

year period will be reviewed by chart abstraction. Risk factors for these three adverse pregnancy outcomes

will be explored, including HIV status, CD4 count, ARV use, medications, medical conditions, and

demographics. Mothers with stillbirths and early neonatal deaths will be consented for "verbal autopsies" to

determine the cause of these events; for HIV PCR testing of the stillbirth or infant (if mother HIV-infected);

and for maternal HIV-1 RNA and CD4 cell count testing (if mother is HIV-infected).

Hypotheses:

--Rates of stillbirth, premature delivery, and early neonatal mortality, are increased among HIV-infected

women.

-- Rates of stillbirth, premature delivery, and early neonatal mortality, are increased among HIV-infected

women with advanced disease.

-- The cause of stillbirths, and possibly early neonatal deaths, differs between HIV-infected and HIV-

uninfected women. Early stillbirths may be related to HIV infection in utero. ART may modify the risk of

stillbirths from HIV-infection.

Primary Objectives:

--To determine rates of stillbirth, premature delivery, and early neonatal mortality by maternal HIV status.

--Among HIV-infected women, to determine rates of stillbirth, premature delivery, and early neonatal

mortality by CD4 cell count and by receipt of different ART regimens in pregnancy.

--To determine the causes of stillbirth and early neonatal mortality through verbal autopsies and laboratory

testing, and to determine whether maternal antenatal ART modify the risk for these events.

Secondary Objectives:

--To ascertain the number/proportion of women with known HIV status by the time of delivery (and the

timing of HIV testing) among women who deliver at PMH and SLH.

--To ascertain the total number of HIV-infected women who have CD4 counts measured during pregnancy

(and the timing of CD4 testing).

-- To ascertain the total number of HIV-infected women who have CD4 counts measured during pregnancy

and begin ART ante partum and/or intra partum.

--To determine the total number of HIV-infected women who received CTX during pregnancy.

--To compare infant birth weight by HIV status.

Programmatic Importance/Anticipated Outcomes:

HIV-infection has been associated with adverse pregnancy outcomes, including higher risk of stillbirth.

Stillbirth rates as high as 13% have been reported among HIV-infected women in Africa who were followed

from conception. It remains unknown whether the cause of excess stillbirths is related to HIV infection of the

fetus, or whether maternal ARV use affects the risk of stillbirths among HIV-infected women. Three-drug

ART is recommended during pregnancy for women in Botswana with CD4 cell count greater than 200 and

may be offered to women with higher CD4 cell counts in the future. It is therefore critical to understand the

background rate and cause of stillbirths in Botswana, and whether ART influences the stillbirth rate. These

data may also guide the decision for when to start ART during pregnancy.

The anticipated outcomes of this study are: 1) To create a large database that provides information about

stillbirth, prematurity, and early neonatal mortality rates in Molepolole and Gaborone, Botswana, and to

provide information about risk factors for these events.

2) To provide detailed information about the causes of stillbirth and early neonatal mortality to the Botswana

government and the scientific community, and determine whether differences exist by HIV status and ART

receipt. 3) To determine whether stillbirths in Botswana are related to fetal HIV infection, and if so, whether

the timing of infection (and other risk factors) affect the likelihood of stillbirth. 4) To understand whether

ART, and the duration of ART exposure, might modify the risk for stillbirth related to HIV-infection.

Methods:

This study will be carried out at PMH and SLH. There are approximately 5,000 births per year at PMH, and

approximately 2,500 births per year at SLH. Therefore, data will be collected from up to 15,000 births over 2

years. If it is feasible to perform the study at the Gaborone City Council maternities, several thousand

additional deliveries may also be available from Gaborone.

Activity Narrative: On a daily basis for up to 24 months, study researchers will assess the obstetrical records and other

available medical records of all women admitted to the maternity ward of the participating sites. Attempts

will also be made to identify and document stillbirths in cases where women are seen at either antenatal

clinics or on the female medical ward.

Study researchers will work with maternity nurses to anonymously extract data from the obstetrical records

of women who deliver at these sites. The information likely to be available from the obstetric and medical

records includes maternal age, the clinic where obstetrical care was provided, HIV status (if known), CD4

cell count if HIV-infected (and if performed), drugs taken during pregnancy, gestational age at delivery,

pregnancy outcome (live birth versus stillbirth), and birth weight. Information will also be obtained regarding

early neonatal mortality, recording all infant deaths that occur in the hospital within 72 hours of delivery. The

information will be entered anonymously into a database.

When stillbirths or early neonatal deaths (greater than72 hrs) are identified, study staff will be informed by

maternity nurses at PMH and SLH. Mothers will be contacted by study staff, and asked for consent for

further evaluation of the cause of stillbirth/death. Verbal autopsies will be performed to provide details of the

pregnancy, maternal medical history, and information about the fetus or infant (including feeding history).

Stillborn fetuses / deceased infants will be examined by the study physician to rule out gross congenital or

other abnormality. When women are HIV-infected, consent for HIV PCR testing of stillbirths and infants, and

maternal HIV-1 RNA and CD4 cell count testing, will be obtained. HIV PCR testing of stillbirths will be

obtained by cardiac puncture.

Budget justification for Year 1 Budget:

Salaries; $206,000

Supplies: $ 1,000

Travel: $ 5,000

Laboratory: $ 4,000

Total: $216,000

New/Continuing Activity: Continuing Activity

Continuing Activity: 17319

Continued Associated Activity Information

Activity Activity ID USG Agency Prime Partner Mechanism Mechanism ID Mechanism Planned Funds

System ID System ID

17319 17319.08 HHS/Centers for Mullens & 8742 8742.08 CoAg (5444.08) $216,000

Disease Control & Associates

Prevention

Emphasis Areas

Human Capacity Development

Public Health Evaluation

Estimated amount of funding that is planned for Public Health Evaluation $200,000

Food and Nutrition: Policy, Tools, and Service Delivery

Food and Nutrition: Commodities

Economic Strengthening

Education

Water

Table 3.3.01:

09.P.MC03: PHE - Infant Male Circumcision

CONTINUING ACTIVITY UNDER PERFORMANCE PASS

From COP08:

note: April 08 Reprogramming- +$40,000 due to additional administrative costs while awaiting clearance.

This activity supports the Botswana-Harvard Partnership (BHP) to conduct a pilot test of an expanded infant

male circumcision program in 4 hospitals. The evaluation will identify medical, cultural,

programmatic/economic and ethical issues to consider in scaling up infant male circumcision for HIV

prevention in Botswana. Two letters of support for this activity from the Ministry of Health are in the

appendix of this Operational Plan.

Many studies have shown a protective effect of male circumcision on acquisition of HIV. Circumcision of

infants is easier and safer than that of adolescent or adult men. Previous work has shown that women and

men in Botswana find male circumcision to be an acceptable HIV prevention strategy.

In this activity, Harvard will ascertain 1) parental acceptance/uptake in the face of actual, expanded service

delivery options; 2) feasibility and safety of modern male circumcision techniques in existing service delivery

sites; and 3) satisfaction with results by parents of infants. Secondary objectives include 1) determining

factors associated with the uptake of infant circumcision, 2) evaluate safety and outcomes of Mogen vs.

Plastibell techniques in the Botswana setting, and 3) evaluate the cost of the intervention. The population to

be studied will be mothers (and their partners and male infants) at least 21 years of age who deliver in one

of four district hospitals: Scottish Livingstone Hospital in Molepolole; Athlone Hospital in Lobatse; Deborah

Retief Memorial Hospital in Mochudi; and Princess Marina Hospital in Gaborone.

In the proposed study protocol, an experienced urologist will train 2 physicians to conduct circumcisions for

the study. Four nurses will support the study, one in each hospital. Harvard will also train additional

physicians in the techniques as requested by the MOH. Harvard will administer a questionnaire to collect

socio-demographic data and assess knowledge and attitudes about male circumcision from consenting

postpartum mothers of infant boys. Second, these new mothers/parents will be offered circumcision for

their sons, who will be randomized to circumcision using one of two standard techniques (Mogen Clamp vs.

Plastibell) at 1-4 weeks of age. The investigators will monitor complications (e.g. bleeding, infection) and

follow-up infants and parents at 4 weeks and 6 months to ascertain surgical outcomes and parental

satisfaction with results. Investigators plan to accrue approximately 600 mothers in the questionnaire

portion and 300 infants in the circumcision portion over 12-18 months from among the approximately 9,000

births/year in the four hospitals.

The study team will also develop or adapt family education materials that could be used in future expansion

of infant male circumcision in Botswana. These materials may include hand-outs for parents and family

members of the infants and visual aids to assist with parent education in the clinic setting. Throughout the

pilot and after, Harvard will share progress, achievements, and challenges with the MOH and other key

stakeholders.

Local co-investigators include Dr. J. Makhema, Botswana-Harvard Partnership; Dr. P. Kebaabetswe, CDC;

and Dr. C. Lesetedi, Ministry of Health. Dr. R. Plank of Harvard University will be the primary international

co-investigator and based in Botswana. Approximately $186,000 of the budget is for staff costs in

Botswana, about $5,000 for supplies, $8,000 for participant compensation, $5,000 for travel, and $10,000

for miscellaneous supplies and communication.

New/Continuing Activity: Continuing Activity

Continuing Activity: 17648

Continued Associated Activity Information

Activity Activity ID USG Agency Prime Partner Mechanism Mechanism ID Mechanism Planned Funds

System ID System ID

17648 17648.08 HHS/Centers for Mullens & 8742 8742.08 CoAg (5444.08) $254,000

Disease Control & Associates

Prevention

Emphasis Areas

Human Capacity Development

Public Health Evaluation

Estimated amount of funding that is planned for Public Health Evaluation $250,000

Food and Nutrition: Policy, Tools, and Service Delivery

Food and Nutrition: Commodities

Economic Strengthening

Education

Water

Program Budget Code: 08 - HBHC Care: Adult Care and Support

Total Planned Funding for Program Budget Code: $4,936,715

Total Planned Funding for Program Budget Code: $0

Program Area Narrative:

In response to the challenges that HIV and AIDS present to Botswana, efforts continue to be made to diversify approaches, fine

tune technical support, and plan for future program sustainability with the support of the Presidents' Emergency Plan for AIDS

Relief (PEPFAR). The national HIV prevalence rate is 23.9% among adults ages 15 to 49, according to recent UNAIDS data, and

an estimated 300,000 are living with HIV/AIDS. About 53.2% of Batswana know their HIV status up from 25% in 2004, 95% of

pregnant mothers gaining that information through the Prevention of Mother to Child Transmission program. The Botswana 2007

Sentinel Survey indicated that HIV prevalence among pregnant women (15-49 years) is 33.7%, though the overall trend appears

to be decreasing from 37.4% in 2003. Challenges remain, however, with prevention, particularly the issue of multiple concurrent

partnerships, alcohol abuse, nascent civil society, and human capacity development.

Infrastructure in the medical and public health systems is strong and support from the Gates Foundation and industry sponsors

allowed the Ministry of Health (MOH) and the Ministry of Local Government (MLG) to roll out a national anti-retroviral therapy

(ART) program, the Masa Program, in 2002 which, as of July 2008, is treating a total of 109,991 patients with ART, including

almost 19,000 patients outsourced to registered private practitioners, which is estimated to be 97% of those Batswana in need of

ART (113,000) and recent outcome data give a cumulative program mortality of 9,323, since 2002. At the current time,

approximately 4% of adult patients are on second-line ART due to first-line failure for differing reasons, although there is limited

national data on HIV drug resistance.

The United States Government (USG) assistance over the period of the President's Emergency Plan for AIDS Relief (PEPFAR) in

Botswana has focused on strengthening the national Masa Program. No partners who directly provide care and support or ART

have been supported from the inception of PEPFAR in Botswana. Despite the exemplary response Botswana has pioneered,

there have been significant challenges and USG assistance has and will continue to assist the Government of Botswana (GOB) to

focus on these challenges. One of the principal clinical challenges has been the resurgence of TB in Botswana, which is

described in more detail in the TB/HIV program narrative.

A prolonged challenge within the GOB has been the mechanisms responsible for procurement and logistics of drugs, including

anti-retrovirals (ARV), other care and support medications and supplies, such as laboratory reagents. In FY2007 and FY2008,

Supply Chain Management Systems (SCMS) began to work with Central Medical Stores, the Drug Registration Unit and other

relevant GOB organizations to improve the quality of these services. This will continue with FY2009 funding (described in the ARV

Drugs Program Area Description), with added support for a national patient data management system to include pharmacy data.

This strengthening of systems will be accomplished at the same time that the USG support for ARV purchases decreases. The

GOB currently funds 70% of the Masa Program costs. In addition to the support for logistics and procurement, PEPFAR funds will

continue to support the data management section of the MASA Program to produce valuable outcome measures from one of

Africa's most mature treatment programs through secondment of epidemiologists and statisticians to the Monitoring and

Evaluation (M&E) Section of the MOH and through technical assistance (TA) (see the Strategic Information Program Description).

Another major threat to the continued success of Botswana's response to the HIV epidemic is the availability of technical

personnel, a need on which the USG support has focused over the past five years. The GOB has undertaken the development of

a Medical School at the University of Botswana to train students and junior doctors within Botswana for the first time and PEPFAR

support will integrate with this long-term capacity building initiative. For the current year, there will be direct support for faculty

positions in the Laboratory Sciences (described in Laboratory Program Area Description section) at the allied Institutes of Health

Sciences. USG-funded training partners will be expected to develop plans for integration of their services with the nascent medical

school beginning this year. These partners include Harvard University who have developed a national curriculum for HIV/AIDS

care providers known as KITSO, a Master Trainer Program, and who are involved in task shifting initiatives to train personnel for

the planned decentralization of ART to the primary level. Principal activities with Harvard this year will focus on the transition of

this Track 1.0 partner to a local USG prime partner, as well as its integration into the GOB strategic framework along with other

USG-funded training partners in country. Other training partners who will continue to be supported in FY2009 are the University of

Pennsylvania who will continue to provide mentoring and didactics at the tertiary and secondary levels of HIV/AIDS care,

expanding their services from Gaborone and Francistown to other principal sites in Botswana through outreach, particularly in the

area of TB/HIV co-management (described in the TB/HIV Program Area Description) and I-TECH/University of Washington, who

will continue to develop curricula, organize Continuing Medical Education (CME) activities for both GOB and private providers,

and promote decentralized "cascade" training to the primary level. All three principal training partners will be expected and

assisted to improve the integration of their activities with each other and with the GOB's strategic plan for long-term capacity over

the coming year.

While services at the facility level have developed admirably, the community involvement in care and support has been slower, in

large part due to the underdeveloped role of civil society in Botswana. A number of programs that started in FY2007 and FY2008

will be continued and strengthened in FY2009, including local non-governmental organization (NGO) capacity in Francistown

through Project Concern International (PCI) and NGO-strengthening activities to deliver community-based care in other parts of

Botswana by a new prime partner not yet identified. All of these activities are designed to improve community linkage for care and

support services provided in facilities with particular emphasis on pre-ART care, in other words, care and support for HIV-infected

individuals prior to qualification for ART, in order to improve retention of patients and long-term follow-up. A specific package of

care is available, which includes cotrimoxazole and nutritional education, but safe water treatment and bed nets are not included

most likely because the publicly-supplied water is safe to drink and malaria, the incidence of which is low, is endemic only in

sparsely populated northern areas of Botswana. These community linkages are expected to reduce transmission of HIV and

increase timely initiation of ART for improved morbidity and mortality. The new partner will specifically work with Prevention with

Positives (PwP) initiatives in the community and at Tebelopele counseling and testing centers to achieve these goals.

Programs in end-of-life care have been initiated and are supported by a collaboration of the Botswana Nurses Association and the

African Palliative Care Association through the American International Health Alliance's (AIHA) Twinning Center to promote

effective comfort care and opioid use.

Initiatives in women's health this year will focus on promoting screening for cervical cancer. The national policy of Pap smear

based screening will be piloted along with the provision of treatment services and a resource-limited strategy of "see and treat" will

be introduced for women in primary care settings. The small, but underserved, population of registered refugees with HIV/AIDS in

the United Nations High Commission for Refugees (UNHCR) camp in Dukwe is not eligible for GOB-funded ART and so will

receive USG-funded ART through the Masa Program in FY2009.

Table 3.3.08: