Volume 3 Issue 2Summer 2005 SPOTLIGHT

ver the past decade, the UnitedStates has seen a dramatic de-crease in the number of HIV-in-

fected children. In 2003, there were only 59pediatric AIDS diagnoses, less than a thirdof the estimated number in 1999. Much ofthis decrease is attributed to several factorsincluding enhanced voluntary HIV testingand counseling, altered social perceptions ofHIV/AIDS and readily accessible antiretro-viral treatment such as zidovudine, com-monly known as AZT, by HIV-infectedpregnant women and their newborn infants.

Yet in resource-poor countries, like thosein sub-Saharan Africa, the number of in-fants infected with HIV remains at an all-time high. Governments continue to strug-gle to overcome financial and technicalchallenges in order to make critical drugsavailable to pregnant women. In Botswana,an estimated 35.4% of pregnant women areHIV-infected, and 7,000-9,000 infants areinfected with HIV annually.

In March of 2001, HAI researchersbegan enrolling 1,200 HIV-infected preg-nant women in the Mashi Study to evaluatethe best treatment to block mother-to-childtransmission of HIV (MTCT) in Botswana.The study worked with the Botswana gov-ernment’s national program, which providesAZT free of charge to HIV-infected preg-nant women and their infants.

The first goal of the study was to deter-mine whether administering a single dose ofthe drug, nevirapine (NVP) to both moth-er and child around the time of deliverywould further reduce the transmission ofHIV from mother to child.

The word “mashi” means “milk” inSetswana and reflects the second goal of thestudy, which is to compare two different in-fant feeding techniques to prevent postnatal

transmission of HIV. Over the course of sixmonths, scientists compared exclusivebreast-feeding and six months of AZT toformula feeding and one month of AZT.

In August of 2002, data presented at theXIV International AIDS Conferencestrongly suggested that the treatment regi-men of NVP and AZT is superior to AZTalone in preventing MTCT. Subsequently,the Botswana study was redesigned so thatall babies received a single dose of NVP. Sci-entists examined the effect of giving thisnew treatment to the mothers. The studywas completed in 2004.

Drs. Roger Shapiro and Ibou Thior pre-sented the findings at a late breaker sessionat the 2005 Conference on Retroviruses andOpportunistic Infections in Boston. Theyconcluded that adding NVP to the mother’sdrug regimen was not superior to AZTalone as long as the newborn infant receivedNVP, but that the results need to be inter-preted in the context of feeding strategy andin utero infection rate. HAI researchers willcontinue to study the effect of NVP onmothers’ health through the Mashi PlusStudy, which will assess the response ofwomen to antiretroviral therapy after re-ceiving single-dose NVP.

In the breast-feeding arm of the study, re-searchers found that breast-feeding hadhigher HIV infection rates but lower mor-tality rates by seven months. High rates ofHIV-free survival through 18 months wereachieved with both infant feeding strategies.HAI researchers will also examine the effectof breast-feeding on mother and infanthealth through the Mashi Plus and InfantHealth Outcomes Studies.

HAI researchers hope that the results ofthe Mashi Study will help inform the na-tional AIDS policy in Botswana and other

sub-Saharan African countries. Dr. CarolynWester, the Mashi Study coordinator, be-lieves that studies like Mashi are making adifference on many levels. Dr. Wester said,“First, they are being designed for and im-plemented within the context and the pop-ulation they are most likely to benefit. Fur-thermore, research that is conducted along-side government programs also serves tocomplement and strengthen these services,particularly when they are first being intro-duced to the community.”

Focus: The Mashi Study

Home-based care volunteers, like these inthe village of Molepolole (one of theMashi Study sites), help care for HIV-infected mothers and their children.

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Carolyn Wester moved to Botswana in 2000to join the Botswana-Harvard School of Pub-lic Health AIDS Initiative Partnership forHIV Research and Education. In her positionas study coordinator for the Mashi Study, sheoversees daily operations including trainingand protocol adherence of study personnel atthe Mashi Study sites in Gaborone, Mole-polole, Lobatse and Mochudi.

Spotlight: How is the Prevention ofMother to Infant Transmission situationdifferent in Africa than in America? Whatare the challenges?

CW: The challenges in preventing moth-er-to-child transmission of HIV, or MTCT,are certainly unique to the context in whichone is living whether in Africa or America. Inareas of high HIV prevalence like Botswana,it is particularly important to recognize thatpreventing the spread of HIV begins with en-

abling individuals to know and protect theirHIV status and, subsequently, to make in-formed reproductive decisions.

For HIV-infected pregnant women,MTCT can occur any time during pregnan-cy, delivery or breast-feeding. Although anti-retroviral medications, or ARVs, and formu-la feeding have been shown to reduceMTCT, in order to implement these strate-gies women must have access to a number ofservices which may be taken for granted inother contexts, such as health care facilities,ARVs, personnel trained in the provision ofARVs, infant formula and clean water.

In Botswana, over 90% of pregnantwomen receive antenatal care and deliver inhealth care facilities, government-sponsoredprograms are available to citizens (includingfree ARVs and infant formula), and cleanwater is readily accessible throughout thecountry. All these services contribute to mak-ing Botswana unique, certainly within theAfrican context. However, significant chal-lenges exist in Botswana and elsewhere in get-ting these programs to the individuals whoare most likely to benefit from them.

One of the initial challenges in Botswanawas very low acceptance rates of HIV testing.Fortunately, HIV testing rates subsequentlydramatically increased for a variety of rea-sons, including wide-spread access to ARVsand the advent of “routine” HIV testing in allhealth care facilities.

Another challenge has included the com-munity’s reluctance to embrace formula feed-ing as a medically and socially acceptable wayto feed an infant. For many years communi-ty members have understood that “Breast isBest,” particularly with respect to preventingother infectious diseases that contribute toinfant illnesses in the region. As a result,

many community members were under-standably reluctant to embrace formula feed-ing – even in the context of HIV – as an ac-ceptable alternative to breast-feeding. Also, asformula feeding is advocated in the contextof HIV, women electing to formula feed riskdisclosing their HIV status and may sufferthe stigma associated with that disclosure.This continues to be a very real challenge inBotswana and elsewhere.

Spotlight: What impact will the find-ings of the Mashi Study have on the waysthat women and infants are treated aroundthe world?

CW: I believe that the findings of theMashi Study will reinforce the importance ofperforming research studies among the pop-ulations that they are most likely to benefit.The Mashi Study suggests that it is importantto consider both the HIV subtype as well asthe population affected when interpretingstudy results. I also believe that the findingsof the Mashi Study reinforce that high qual-ity data can be expected from clinical trialsconducted in the developing world.

The specific findings of the Mashi Studyare being considered carefully by policymak-ers inside and outside of Botswana. Specificareas being considered in the context ofMTCT include the optimal time to startARVs, which ARVs to recommend to bothmother and baby, and the best method of in-fant feeding. I do not want to speculate at thistime as to what policies will be adopted lo-cally as a result of the Mashi Study, but I doknow that the government of Botswana iscommitted to implementing the most effec-tive and safest strategies for preventing thespread of HIV.

VVVV iiii eeee wwww pppp oooo iiii nnnn tttt ssss An Interview with Carolyn Wester

Dr. Carolyn WesterStudy Coordinator

HIV and Breastfeeding: Mashi Plusand the Infant Health OutcomesStudy For an African mother living with HIV, thedecision to breast-feed her child is complex.If she breast-feeds, there is a 5-20% chancethat the infant will be infected with HIV

through breast milk. However, if she for-mula feeds, her child is six times more like-ly to die of an infectious disease in the firsttwo months of life. The lack of access toclean water and formula, and the societalpressures to breast-feed only make the deci-sion more difficult.

HAI scientists designed two studies tohelp shed light on the complex issues ofbreast-feeding: The Infant Health Out-comes Study and Mashi Plus. Both studieswere conducted simultaneously with the

Research & Intervention Programs

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Essential Networking in HIV/AIDS Research

As the healthy HIV-infected participantfrom the Tshepo Study leaves the clinic, Dr.Okechukwu Okezie reviews his notes fromtheir consultation. The participant hasbeen on antiretroviral therapy for only afew months and already is responding well.Dr. Okezie completes the case report form(CRF) and faxes it to the Data Manage-ment Centre (DMC) at theBotswana–Harvard School of PublicHealth AIDS Initiative for HIV Researchand Education Partnership (BHP). NowDr. Okezie is ready to see the next studyparticipant and help people stay on theirantiretroviral therapy.

While dedicated people, like Dr. Okezie,are on the front lines fighting the crisis, in-vestigators, researchers and data managershelp attack AIDS through science, analysisand technology. One integral group of cru-saders is the team that manages the datacollected from the field. This group formsthe BHP’s DMC, which was designed toservice multiple simultaneous clinical andresearch studies since 1996.

The DMC plays several key roles in eachstudy. As each study is formed, the DMChelps develop realistic project timelines fordata collection and processing, and informsstudy budgets for the resources used. Foron-going studies, the DMC enters, cleans,edits and codes data while efficiently man-aging thousands of CRFs every month.

All information gathered from the fieldmust meet stringent quality controls for ac-curacy and precision. The DMC constant-ly performs integrity checks on datatypes,patterns, inter-CRF skip logic, and cross-CRF logic throughout the data manage-ment process. Once the data is keyed, ad-ditional complex integrity checks areprocessed by the data managers using on-line query and reporting tools to further re-duce any potential errors. The paper CRFsare then filed and secured within the main

DMC room which is only accessiblethrough security clearance.

In addition to the day-to-day processingof new data, the DMC assists in producinginterim reports on study progress as well asgenerating progress reports for each studyparticipant. This reporting facilitates effi-cient follow-up for study physicians andnurses who care for and consult with studyparticipants each day.

The DMC not only serves as an impor-tant network nexus with researchers in-cluding study physicians, principal investi-gators, lab technicians, clinicians and stat-isticians in Botswana, but also has helpedseveral organizations in Africa which planto establish their own DMC.

Erik Widenfelt, the director of theDMC at BHP, has lent his expertise at a re-cent workshop held in Dakar, Senegal. Theworkshop focused on scaling up capacityand establishing information infrastructureto support clinical trials and data manage-ment. Mr. Widenfelt said, “It is importantthat study sites in Africa develop the capa-bility to efficiently manage and organizethe vital data they collect from the field.This is a good way of both maintaining crit-ical communication and sustaining re-search in fighting AIDS.”

Mashi Study, using the same data gatheredfrom mother and infant participants.

The Mashi Plus Study examines the ef-fect of breast-feeding on the health of HIV-infected women in the developing world.The two goals of the Mashi Plus Study areto examine whether breast-feeding by HIV-infected women is associated with a higherrate of disease and death, and to assess theresponse of women to antiretroviral therapyafter receiving single-dose nevirapine for theprevention of MTCT.

The Infant Health Outcomes study in-volved all 1,200 of the Mashi infants whowere divided into three groups: 1) infantsborn to HIV-infected women randomizedto breast-feed, 2) infants born to HIV-in-fected women randomized to formula feed,

and 3) infants born to HIV-uninfectedmothers and who are encouraged to breast-feed. Scientists determined the rates of diar-rheal and respiratory illnesses and blood-stream infections, the range of pathogenspresent among each of these groups, and therate of infant mortality for formula-fed andbreast-fed babies.

Scientists hope that these studies willprovide a more complete picture of the ben-efits and risks of breast-feeding for Africanwomen living with HIV, and help informinfant feeding strategies for the future.

HIV Negative Profiles StudyThe link to determining the likelihood ofmother to infant transmission of HIV(MTCT) may in part lie in the genomic dif-

ferences found in HIV positive and negativeblood. Researchers at the Boston UniversitySchool of Medicine, the Boston UniversitySchool of Public Health and the BHP aretrying to answer that question while creat-ing a baseline profile of an HIV negativepopulation in Botswana. Using data ob-tained from subjects enrolled in the BHPMashi Study, the HIV Negative ProfilesStudy may help to determine which genesare linked to transmission and may also helpto determine which genes respond to thera-peutic intervention. Although whole ge-nomic analysis is currently underway, thebaseline differences suggest that immunehistory revealed in gene expression patternsmay play a significant role in infection andtransmission outcome.

Research & Intervention Programs (continued from previous page)

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Upcoming HAI-related Events on summer hiatus. Look for new events in the next issue.

Women and AIDS in Africa: Hope for the FutureIn May, HAI held its first online auction:“Women and AIDS in Africa: Hope for theFuture.” The auction celebrated the courageof women living with AIDS in Africa andfostered hope for a healthy future for them-selves and their children. Items in the auc-tion ranged from a spectacular wildlife safariadventure in Botswana and a fishing expe-dition on the Botston Harbor to a dazzlingset of South Sea pearl and diamond earringsand a handcrafted gemstone globe. All itemswere donated by members of the HAI In-ternational Advisory Council and otherHAI supporters. The auction raised over$16,000, which will provide researchers andscientists at HAI the tools they need to con-tinue their global efforts to fight the AIDSepidemic through research, education, andtraining. HAI thanks all its supporters forparticipating in this exciting event.

AIDS Research in Africa: Opportunities and ChallengesAfrica continues to carry the greatest bur-den of the AIDS epidemic. More than80% of the world’s total number of HIV-infected women and infants live in sub-Sa-haran Africa. Dr. Max Essex, chair of HAI,spoke about efforts of HAI scientists to ad-dress the crisis at a recent June lecture,sponsored by the Office of InternationalPrograms at Harvard Medical School Divi-sion of AIDS. The lecture was entitled,"AIDS Research in Africa: Opportunitiesand Challenges." Dr. Essex spoke aboutthe high rate of genomic variation of theHIV virus which is a significant impedi-ment to AIDS research. Although thiscomplicates vaccine design and ARV ther-apy efforts, scientists devise innovativestrategies to meet these challenges. Fromdeveloping a vaccine candidate that isbased on a recombinant anthrax protein to

formulating a new treatment strategy toavoid drug resistance for HIV-infectedmothers and their infants, scientists willcontinue to tailor interventions andchemoprophylaxis to target the specificsubtypes that are predominant withinAfrican countries.

News & Events

SPOTLIGHT is published by the

Harvard School of Public Health AIDS Initiative651 Huntington AvenueBoston, MA 02115 USAPhone: 617-432-4400Fax: 617-432-4545Email: info@eci.harvard.eduWeb: aids.harvard.edu

Chair: Max EssexSenior Research & Executive Director: Richard Marlink

PUBLICATIONS STAFFEditor: Yvonne NgPrint Designer: Kim MorrisseauContributing Writers: LeAnna Alderman Sterste,Patricia Burns, Monty Montano

The efforts of HAI depend very much on your sup-port. Contributions to the HAI are tax deductible. To learn more, please call Michael Voligny at 617-384-8980.

Support the Botswana Harvard School of Public Health AIDS Initiative PartnershipWear the AIDS in Africa Ribbon - Handmade by HIV+ Women in Botswana

By purchasing this beautiful, handmade beaded AIDS ribbon, you will help us battle AIDS in Africa. The pro-ceeds from the sale of these ribbons contribute to research in Botswana, including programs that prevent HIV+mothers from passing the virus to their infants. Hundreds of babies’ lives have been saved already. But we have somuch farther to go…Please help us help them. To order the AIDS in Africa Ribbon, please go to www. aids.harvard.edu/orderform, download the order form

and mail to HAI at 651 Huntington Ave, Boston, MA 02115, or fax it to us at 617-432-4545.