In 2006, a survey of transmitted human immunodeficiency virus (HIV) drug resistance (TDR) was conducted in Lilongwe, Malawi. The survey followed the World Health Organization method to classify TDR to nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) among primigravid women aged <25 years. Results of the 2006 survey showed <5% TDR in all drug classes. In 2009, TDR surveys using the same method were repeated in Lilongwe and expanded to Blantyre. Findings show that in Lilongwe TDR to NRTIs and PIs was <5%, whereas TDR to NNRTIs was 5%-15%. In Blantyre, TDR was <5% to all drug classes. Observed moderate TDR in Lilongwe is cause for concern and signals the need for closer monitoring of Malawi's antiretroviral therapy progra

Banda, Richard

Chiwaula, Mabvuto

Jordan, Michael R.

M'bang'ombe, Maurice

Moyo, Kundai

Porter, Carol

Wadonda-Kabondo, Nellie

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S U P P L E M E N T A R T I C L EPrevalence of Transmitted HIV Drug ResistanceAmong Newly Diagnosed AntiretroviralTherapy–Naive Pregnant Women in Lilongweand Blantyre, MalawiNellie Wadonda-Kabondo,1 Richard Banda,1,2 Kundai Moyo,1 Maurice M'bang'ombe,1 Mabvuto Chiwaula,1Carol Porter,3 and Michael R. Jordan4,51Community Health Sciences Unit, Ministry of Health, Lilongwe, Malawi; 2World Health Organization, Harare, Zimbabwe; 3Howard University TechnicalAssistance Project, Lilongwe, Malawi; 4World Health Organization, Geneva, Switzerland; and 5Tufts University School of Medicine, Boston,MassachusettsIn 2006, a survey of transmitted human immunodeficiency virus (HIV) drug resistance (TDR) was conductedin Lilongwe, Malawi. The survey followed the World Health Organization method to classify TDR tonucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs),and protease inhibitors (PIs) among primigravid women aged <25 years. Results of the 2006 survey showed<5% TDR in all drug classes. In 2009, TDR surveys using the same method were repeated in Lilongwe andexpanded to Blantyre. Findings show that in Lilongwe TDR to NRTIs and PIs was <5%, whereas TDR toNNRTIs was 5%–15%. In Blantyre, TDR was <5% to all drug classes. Observed moderate TDR in Lilongwe iscause for concern and signals the need for closer monitoring of Malawi’s antiretroviral therapy program.Malawi is one of the countries most affected by the hu-man immunodeficiency virus (HIV) epidemic in Africa,with an estimated prevalence of 12% among adults aged15–49 years [1]. The epidemic is predominantly spreadvia heterosexual contact, and prevalence estimates in-dicate that urban areas are more heavily affected than arerural areas [1].Malawi provides antiretroviral therapy (ART) free ofcharge using a public health approach where tasks areshifted from more specialized to less specialized health-care workers and where ART is provided at peripheralhealth facilities. Patients are predominantly prescribedstandardized first-line ART regimens and monitored bynonphysicians using World Health Organization (WHO)clinical staging guidelines with limited laboratorymonitoring. The first-line ART regimen and 3 alternatefirst-line regimens consist of 2 nucleoside reverse transc-riptase inhibitors (NRTIs) combined with a nonnucleo-side reverse transcriptase inhibitor (NNRTI). Since 2004,about 383 000 patients have initiated ART, of whom277 000 (72%) remained alive and on therapy by June2011 [2].Because ART is provided on a massive scale withoutthe benefit of individual viral load or drug resistancetesting, the emergence and transmission of HIV drugresistance (HIVDR) remains a fundamental concern.The lack of individual HIVDR testing has not limitedMalawi’s ability to optimize patient care, and the countryhas developed a comprehensive HIVDR prevention andassessment strategy based on WHO guidance consistingof routine monitoring of HIVDR early warning indicatorsand routine surveillance of transmitted and acquiredHIVDR [3].Prior to 2007, most African countries reported trans-mitted HIV drug resistance (TDR) prevalence estimatesof ,5% [4–9] attributed mostly to low ART coverage;Malawi was no exception, with,5% TDR reported to allCorrespondence: Nellie Wadonda-Kabondo, PhD, MSc, BSc, Ministry of Health,Lilongwe, Malawi (nelliewadonda@hotmail.com).Clinical Infectious Diseases 2012;54(S4):S324–7 The Author 2012. Published by Oxford University Press on behalf of theInfectious Diseases Society of America. All rights reserved. For Permissions,please e-mail: journals.permissions@oup.com.DOI: 10.1093/cid/cir993S324 d CID 2012:54 (Suppl 4) d Wadonda-Kabondo et aldrug classes in a 2006 survey conducted in Lilongwe [10]. How-ever, recently, a number of cities in East Africa, includingEntebbe, Uganda, and Kigali, Rwanda, have reported TDRprevalence of .5% [11]. Southern Africa also has not beenspared, and TDR prevalence of .5% was recently reported inCape Town, South Africa, and in Lusaka, Zambia [11, 12].However, it is noteworthy that studies that have previouslyreported TDR prevalence estimates of .5% in this regionhave not used the WHO method, making comparison ofresults difficult. Despite these methodological differences,a trend toward increasing TDR prevalence estimates is sup-ported by a recent meta-analysis by Gupta et al [13], whichreports more countries with moderate (5%–15%) TDRprevalence after 2007 compared with pre-2007.The presence of HIVDR prior to ART initiation is an impor-tant predictor of virological response to antiretroviral regimens[14, 15]. Therefore, the existence of significant population-levelTDR may undermine the success of the national ART scale-upinitiative. Surveys to classify TDR provide important pro-grammatic information regarding likely efficacy of futurefirst-line ART, current pre- and postexposure prophylactic reg-imens, and HIV prevention programs. The expected prevalenceof TDR partly depends on the extent of ART scale-up and theduration that antiretroviral drugs (ARVs) have been in usewithin a defined geographical area [11, 12].Blantyre and Lilongwe are 2 major urban areas where ARTwas first provided in Malawi and currently have the largestnumber of patients on ART; thus, if TDR were to be observed,it is likely to be seen in these locations. In 2009, TDR surveyswere performed in Lilongwe City and Blantyre City. Resultsare reported here.METHODSHealthcare facilities within the designated 2 catchment areasof Lilongwe and Blantyre City were selected if they providedantenatal care and prevention of mother-to-child transmissionof HIV services and were seeing adequate numbers of pregnantwomen in order to contribute to the minimum sample size(N # 47) within a reasonable period. Additionally, sites wereselected based on capacity to implement the survey, includingability to perform routine CD4 counts for all newly diagnosedHIV-positive antenatal attendees. Three health facilities(Kawale, Area 25, and Bwaila) were selected in Lilongwe, and2 health facilities (Ndirande and Limbe) were selected in theBlantyre urban area.As a proxy for recently HIV-infected individuals, only primi-gravid women ,25 years without clinical evidence of advancedHIV infection (only WHO clinical stage 1, as determined byhealthcare providers), who self-reported naivete´ to ARVs andwho tested HIV positive for the first time, were eligible toparticipate in the survey. After routine CD4 cell count testing,remnant blood was used to prepare dried blood spots (DBSs)from consecutively eligible women.HIVDR genotyping was performed by the WHO accreditedNational HIV and Retrovirology Laboratory, Public HealthAgency, Ottawa, Canada. Complete HIV protease and part ofreverse transcriptase were sequenced using previously describedmethods [16].The WHO TDR survey method permits classification ofTDR as low (,5%), moderate (5%–15%), or high (.15%) ina specific population in a defined geographic region using#47 specimens.For each geographic region, 60 HIV-positive specimens basedon HIV rapid tests performed at the sites were consecutivelycollected between January 2009 and April 2009 to generate atleast 47 specimens for genotyping (taking into account a pro-portion of specimens that would fail to amplify). Due to theconcern for preserving the routine nature of the health systemsat the participating facilities, no behavioral questionnaires wereused. All specimens were prepared, processed, and stored inMalawi following WHO DBS guidance and were shipped to thegenotyping laboratory for testing [17].Neighbor-joining distance method was used to assess forpossible contamination, and subtyping was performed using theREGA subtyping tool [18, 19]. TDR for each drug class wasdetermined using the 2009 WHO TDR mutations list availablethrough the Stanford HIVDR Calibrated Population Resistancetool [20–22].RESULTSBlantyre Geographical AreaA total of 61 DBS specimens were collected; 54 (88.5%) weresuccessfully amplified. All sequences were HIV subtype C.Among the first 47 specimens, 3 had TDR mutations. Onespecimen had both NNRTI (G190E) and NRTI (M184V)mutations. The second specimen had 1 NRTI TDR mutation(D67DN), and the third specimen had 1 NNRTI TDR mu-tation (Y188CY). No PI resistance was detected. When thesedata were analyzed by drug class as per WHO TDR guidance,the classification of transmitted resistance was ,5% forNNRTI, NRTI, and PI drug classes.Lilongwe Geographical AreaA total of 68 DBS specimens were collected, and 55 (80%)were successfully amplified. All sequences were HIV subtype C.Among the first 47 specimens, 3 had 1 detected NNRTI TDRmutation: K103S, K103N, or V106A. No NRTI or PI mutationswere detected. Following WHO guidance, NNRTI TDR wasclassified as moderate (5%–15%), and NRTI and PI TDR wasclassified as low (,5%).Transmitted HIV Drug Resistance in Malawi d CID 2012:54 (Suppl 4) d S325DISCUSSIONART scale-up began rapidly in Malawi in 2004. Some degreeof HIVDR is inevitable even when appropriate regimensare prescribed and optimal adherence to treatment is sup-ported. Routine surveillance of TDR provides importantpublic health information regarding the efficacy of currentpre- and postexposure prophylaxis and may predict pop-ulation level efficacy of first-line regimens when recentlyinfected populations require future ART. As part of itsART program, Malawi has adopted WHO guidance for theroutine monitoring of site factors associated with theemergence of HIVDR (HIVDR Early Warning Indicators)and the routine surveillance of transmitted and acquiredHIVDR.In 2006, in Lilongwe TDR was classified as low (,5%) forall drug classes. We observed moderate (5%–15%) NNRTITDR in Lilongwe and low TDR (,5%) in Blantyre for alldrug classes. Although specimens were obtained only fromwomen who were naive to ARVs, it is possible that some didnot disclose previous ART exposures. Nonetheless, the prev-alence classification of 5%–15% NNRTI TDR in Lilongwe istroubling and merits attention.Malawi is one of the first countries in sub-Saharan Africato report moderate TDR using the WHO TDR surveymethod, although studies that have used other methodologieshave previously suggested similar prevalence estimates inSouth Africa and Zambia [11, 12]. In the current survey, newinfections were based on self-reports of drug naivete´, age,25 years, testing positive for the first time, and primi-gravidity. This definition of recent infection may not havehigh specificity because some women may have falsely re-ported their characteristics. However, given recent evidencesuggesting that TDR may be increasing in sub-Saharan Africa[13, 23, 24], these results may truly reflect increasing TDR inMalawi.In order to confirm the findings of this survey, surveil-lance of TDR was repeated in Lilongwe by integrating theWHO TDR survey method into routine antenatal seros-urveillance in 2010. Specimens from this follow-up surveyawait genotyping. Additionally, in 2011, Malawi plans tomonitor WHO HIVDR early warning indicators in severalregions of the country including Lilongwe and Blantyre inorder to assess clinic function in minimizing the emergenceof possible HIVDR by containing rates of losses to follow-up,ensuring drug supply continuity, and maximizing patientadherence. In addition, as high rates of loss to follow-uphave previously been identified as problematic in Malawi,a special survey to characterize reasons for loss to follow-upand assess strategies to link patients back into care is plannedfor 2012.CONCLUSIONSIn conclusion, although findings of moderate TDR merit at-tention and warrant concern, these results must be treatedcautiously. Survey results showing moderate TDR to the NNRTIdrug class are insufficient to support changing current ARTguidelines in Malawi but do signal the importance of robustprogrammatic monitoring of factors known to be associatedwith the emergence of HIVDR at all ART sites in Malawi andthe need for routine surveillance of transmitted and acquiredHIVDR. Additionally, results highlight the need to evaluate andpossibly strengthen prevention messages geared to populationsreceiving ART and to populations recently diagnosed with HIVwho are not yet eligible to initiate ART in order to both mini-mize HIV and HIVDR transmission.NotesDisclaimer. The conclusions and opinions expressed in this articleare those of the authors and do not reflect those of the World HealthOrganization.Financial support. This work was supported by grants from The Bill &Melinda Gates Foundation (38180), the Public Health Agency of Canada(6962-15-2008/8360001), and the National Institutes of Health (NIH K23AI074423-05 to M. R. J.).Supplement sponsorship. This article was published as part ofa supplement entitled ‘‘The World Health Organization HIV DrugResistance Prevention and Assessment Strategy: Global, Regional, andCountry Progress,’’ sponsored by The Bill & Melinda Gates Foundation(38180).Potential conflicts of interest. All authors: No reported conflicts.All authors have submitted the ICMJE Form for Disclosure of PotentialConflicts of Interest. Conflicts that the editors consider relevant to thecontent of the manuscript have been disclosed.References1. Ministry of Health. HIV sentinel surveillance report. Lilongwe, Malawi,2007.2. Ministry of Health. Quarterly HIV programme report, HIV testing andcounseling, prevention of mother to child transmission, antiretroviraltherapy, treatment of sexually transmitted infections. Lilongwe, Malawi,2010.3. WHO, UNAIDS, and UNICEF. Towards universal access: scaling uppriority HIV/AIDS interventions in the health sector. Progress report,September 2009. 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Prevalence of Transmitted HIV Drug Resistance Among Newly Diagnosed Antiretroviral Therapy-Naive Pregnant Women in Lilongwe and Blantyre, Malawi

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