COMMENTARIES

Impact of New HepatitisC Treatments inDifferent Regionsof the World

he rapid development of new

Tantiviral drugs for hepatitis C(HCV) and the availability of interferon(IFN)-free and soon ribavirin-freetreatment regimens of �12 weeksduration with sustained virologicresponse (SVR) rates of >90% hasstimulated predictions that HCV will beeradicated. This commentary discussesthe impact of these new treatments indifferent regions of the world and thebarriers to HCV eradication.

Prevalence of HCV andDisease Burden inDifferent Regionsof the World

The World Health Organization(WHO) estimates that >185 millionpeople worldwide or 2.8% of the hu-man population have been infectedwith HCV; of these 130–170 million arechronically infected and 350,000deaths occur each year as a result ofHCV-related cirrhosis and liver can-cer.1 The prevalence of HCV varies

Figure 1.Global prevalenc

from 1.2% to 3.8% in different regionsof the world (Figure 1). Although HCVis recognized as the most commoncause of hepatocellular carcinoma(HCC) and the most frequent indicationfor liver transplantation in NorthAmerica, Western Europe, and Japan(Supplementary Table 1), the diseaseburden from HCV is much higher inmany regions of the world where HCVreceives little attention. When coun-tries are grouped into Global Burden ofDisease regions, the estimated preva-lence of HCV infection is highest inCentral Asia, East Asia, and North Af-rica/Middle East regions. Egypt has thehighest prevalence of approximately15%. It is estimated that 2 denselypopulated regions in Asia—East Asiaand South Asia—each has >50 millionpeople chronically infected with HCVcompared with 15 million in NorthAfrica/Middle East, 10 million inWestern Europe, and 4.4 million inNorth America.1 Within each country,the prevalence of HCV varies accordingto risk of exposure. In the UnitedStates, the overall prevalence is 1.6%with an higher prevalence amongblacks, people born between 1945 and1965, and those with a history of in-jection drug use.2 In China, the overallprevalence is estimated to be 2.2%with a range of 2.1% in Fujian province

e of anti-hepatitis C, with data derived from

to 9.6% in Henan province, with anhigher prevalence in injection drugusers and hemodialysis patients.3

HCV is grouped into seven geno-types (1-7) and a number of subtypes.The distribution of HCV genotypesvaries in different regions of the world(Figure 2).4 Worldwide, genotype 1b ismost common. In the United States,however, genotype 1a is most preva-lent, and in India and Pakistan, geno-type 3 is predominant. In Egypt, it isalmost exclusively genotype 4. HCVgenotype has major bearing onresponse to IFN-based treatment andantiviral activity of some direct-actingantiviral agents (DAAs). HCV geno-type may also play a role in liver dis-ease progression, for example,genotype 3 is more commonly associ-ated with hepatic steatosis and accel-erated progression to cirrhosis.5

Left untreated, chronic HCV infec-tion can cause liver cirrhosis, liverfailure, and HCC. The risk of cirrhosis is5%–30% within 20 years of infectionand the risk of HCC in patients withcirrhosis is 2%–4% per year. In addi-tion to liver damage, HCV also con-tributes to a wide range of extrahepaticdiseases, including insulin resistanceand diabetes, mixed cryoglobulinemia,glomerulonephritis, and B-cell lym-phomas. Sustained virological response

Mohd Hanafiah et al.1

Gastroenterology 2014;146:1145–1150

Figure 2.Distribution of hepatitis C virus genotypes by country. World Health Organization Global Burden of Disease Regionsare shown in different colors; data derived from Wartelle-Bladou et al4 and literature review (see Supplementary Materials).Studies were reviewed and scored as follows: *Estimates without a formal study; **small study in a select population (<100) orstudy in blood donors only; ***large study in a select population (>100); ****small study in the general population (<100); and*****large study in the general population (>100).

COMMENTARIES

(SVR) to HCV treatment had beenshown to improve quality of life, reverseliver fibrosis including cirrhosis,decrease HCC, and reduce liver-relatedas well as overall mortality.6–8

Standard-of-Care HCVTreatment

Until recently, standard-of-care HCVtreatment has utilized a combination ofpegylated (PEG)-IFN and ribavirin. SVRrates of 65%–75% can be achievedwith a 24-week course of PEG-IFN andribavirin in patients with HCV geno-types 2 or 3, but SVR rates are lower(w45%), even with a 48-week courseof treatment in those with HCV geno-type 1. SVR rates are intermediate inpatients with HCV genotypes 4, 5, or 6.

Several host, viral, and disease fac-tors have been found to modulate theresponse to PEG-IFN and ribavirintreatment. Of these, polymorphism inthe interleukin (IL)28B or IFNl3 pro-moter region stimulated the greatest

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interest. A favorable IL28B gen-otype—rs12979860 CC (vs CT or TT)or rs8099917 TT (vs GT or GG)—isassociated with 2- to 3-fold greaterSVR rate to PEG-IFN and ribavirintherapy for HCV genotype 1, regardlessof the race of the patient.9,10 Themarked difference in prevalence offavorable IL28B genotype in differentregions of the world (Figure 3;Supplementary Table 2), approxi-mately 30% in North America andWestern Europe compared with 70%in East Asia accounts for the higherSVR rates reported in Japan andTaiwan.11 Indeed, studies in Taiwanfound that SVR rates as high as 58%can be achieved in patients with HCVgenotype 1 with a 24-week course ofPEG-IFN and ribavirin.12 These find-ings suggest that the incrementalbenefit of DAAs would be lower incountries with a high prevalence offavorable IL28B genotype.

In 2011, 2 DAAs, telaprevir andboceprevir, were approved for

treatment of HCV genotype 1. Tripletherapy of telaprevir or boceprevir incombination with PEG-IFN and riba-virin increased SVR rates to 67%–75%,but the treatment regimens arecomplicated and adverse reactions arefrequent and sometimes serious.13,14

Indeed, preliminary data from theFrench Early Access Programme foundthat 40% of patients had seriousadverse events and 6.4% had severecomplications (severe infections, he-patic decompensation, or death).15

New Era of HCVTreatment

After 2 decades of intense research,we now enter an exciting era when newdrugs for HCV are expected to beapproved every year in Western coun-tries for the next 4–5 years. The avail-ability of multiple DAAs with distinctviral targets promises highly efficacious,well-tolerated, IFN-free combinationswith short treatment duration.

Figure 3.Global distribution of interleukin (IL)28B genotypes; data derived from Huang et al12 and literature review (seeSupplementary Materials). Studies were reviewed and scored as in Figure 2.

COMMENTARIES

In late 2013, 2 additionalDAAs—simeprevir, a protease inhibi-tor and sofosbuvir, a nucleotide poly-merase inhibitor—were approved bythe US Food and Drug Administration.Sofosbuvir was approved by the Eu-ropean Medicines Agency in January2014. Approval of these new DAAs inmany countries where no DAA has yetbeen approved may not occur for �1years. Within the next year, additionalDAAs—notably faldaprevir, a proteaseinhibitor, and daclatasvir, an NS5A in-hibitor, in combination with PEG-IFNand ribavirin, along with several IFN-free regimens—are expected to beapproved in the United States andEurope. Preliminary results of phase 3clinical trials in patients with HCV ge-notype 1 showed SVR rate of 96% aftera 12-week course of sofosbuvir andledipasvir (NS5A inhibitor) with orwithout ribavirin in treatment-naïve aswell as treatment-experienced patients,including patients with compensatedcirrhosis. An equally high SVR rate wasreported after a 12-week course ofABT-450/r (protease inhibitor with ri-tonavir boost), ABT-267 (NS5A

inhibitor), ABT-333 (non-nucleosidepolymerase inhibitor), and ribavirin intreatment naïve as well as treatmentexperienced patients with no cirrhosis.For details regarding efficacy of thesenew DAAs, please refer to the accom-panying review by Pawlotsky in thisissue of Gastroenterology.16

Thus, there is reasonable optimismthat within the next 5 years, multipleIFN-free well-tolerated regimens ad-ministered for 8–12 weeks can result inSVR rates of>95% in a broad spectrumof HCV patients. Contrary to IFN-basedregimens, IFN-free regimens are ex-pected to have similar efficacies in pa-tients with the same HCV genotype,stage of liver disease, and treatmentstatus regardless of which region of theworld they are in. The simplicity ofthese regimens and the infrequentoccurrence of adverse events greatlyimprove adherence and ease of moni-toring; however, drug–drug interactionsand adverse events can occur withsome regimens and the knowledge andexperience of treating physicians canmake a difference in the safety andeffectiveness of these regimens.

Limitations of NewHCV Treatment

The availability of IFN-free regi-mens permits many patients whocould not be treated previouslybecause of medical or psychiatriccontraindications or an inability totolerate IFN to receive treatment.Nonetheless, SVR rates remain lower insome patient populations, for example,those with cirrhosis and HCV geno-types 3 and 1a (for some DAAs). Moreimportant, many patient groups havebeen largely neglected because drugdevelopment and clinical trials aredriven by market needs in developedcountries. Patient populations forwhich limited or no data are availableinclude patients with genotypes 5, 6, or7; decompensated cirrhosis; renal fail-ure; and liver or other organ trans-plantations. Although off-label use canbe attempted in these patients, the lackof data on safety, efficacy, and appro-priate dosing exposes patients andprescribing physicians to risks and thehigh cost of these drugs makes it un-likely that they will be covered by

1147

COMMENTARIES

health insurance or national healthpolicies. Another group that has beenforgotten is children. It has been esti-mated that, worldwide, �5 million in-fants each year will acquire HCV frominfected mothers, with the vast major-ity unnoticed until they present withadvanced liver disease in adult life.This problem is more serious in coun-tries where the prevalence of HCV ishigh and a large proportion of HCV-infected mothers are coinfected withHIV.

Implementation of NewHCV Treatments inDifferent Regionsof the World

The rapid pace of HCV drug devel-opment has led to the optimistic pre-diction that eradication of HCV isfeasible. This would be the first chronicviral infection that can be eradicated inthe absence of a prophylactic vaccine.Although HCV eradication is poten-tially feasible, that time is not immi-nent; there remain many barriers thatneed to be overcome (Table 1). Suchbarriers include the development ofsimplified and highly effective drugregimens, improving the rates ofdetection of infection, and the avail-ability of resources (including financialand medical expertise).

The easiest barrier to overcome isthe development of drugs that aremore potent than current ones, trulypangenotypic, active against variantsassociated with resistance to first-generation DAAs, with minimal drug–drug interactions, and safe to use inpatients with hepatic and renal

Table 1.Barriers That Need to Be Overco

Detect persons who are infectedIdentification of high-risk/high-prevalence gAvailability of sensitive, specific, and affordScreening programs that are practical and tPublic awareness of risk groups, sequelae,

Link infected persons to careAccess to care for all infected personsAvailability of trained health care providers

Eradicate HCV with safe and effective drugsDevelopment of drugs that are potent, safeDevelopment of treatment regimens that arAvailability of safe and efficacious drugs at

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impairment. Ten years ago, this sce-nario would have been considered animpossible dream, even by optimists;however, with >30 DAAs in phase 2 or3 clinical trials, including some second-generation protease inhibitors andNS5A inhibitors with activity againstresistance variants to first-generationdrugs of the same class, this goal canbe realistically accomplished in thenext 5–10 years.17 Nevertheless, theavailability of treatment regimens thatcan result in higher SVR rates alonewill have very little impact on globalburden of HCV. A modeling study per-formed in 2009 showed that improvingrates of diagnosis and treatment has agreater impact on reducing diseaseburden than improving efficacy oftreatment.18 Indeed, even treatmentsof 100% efficacy will have no impacton patients with undiagnosedinfection.

Thus, the first barrier to overcomeis to improve the detection of thosewho are infected. Worldwide, it isestimated that <15% of personsinfected with HCV are aware of theirinfection. In the United States, <50%of those infected with HCV had beendiagnosed, 32%–38% had beenreferred to care, and only 7%–11%had received treatment.19 In Europe,up to 90% in parts of the EuropeanUnion are unaware of their infection20

and as of 2006, <16% of the HCV-infected persons in any country hadreceived HCV treatment.21 In China, itis estimated that <3% of those infec-ted had been diagnosed and as of2012, only half of those diagnosed hadbeen treated.

To improve diagnosis, each countryneeds to have information on national

me to Achieve HCV Eradication

roupsable tests for screening and for confirmation ofailored to individual countries or settingsand treatment options

and resources to manage infected persons

, and have pangenotype activitye simple and effective against all HCV genotypeaffordable price

prevalence and characteristics of thosegroups with higher prevalence so thatscreening programs can target high-risk or high prevalence groups; sensi-tive, specific, and affordable tests forscreening and confirmation of HCVinfection must be available. In Westerncountries, reliable HCV assays arereadily available and risk groups areknown, but risk-based screening hasnot been effective because most infec-ted persons do not recognize oracknowledge that they are at risk andprimary care physicians seldom assessHCV risks owing to competing de-mands on their time. In August 2012,the US Centers for Disease Control andPrevention recommended 1-timetesting of all individuals born be-tween 1945 and 1965 because thiscohort is estimated to comprise twothirds of all HCV-infected persons inthe United States.22 The barriers toimproving diagnosis are greater inresource-limited countries, whereepidemiologic data are lacking. Even ifthe high-risk groups are known, manyof these countries do not have the re-sources or the availability of reliabletests for HCV testing. It was not until2010 that the WHO passed a resolutionto include hepatitis among major pub-lic health priorities. In 2014, the firstever WHO guidelines on HCVscreening, care and treatment will bereleased. These guidelines will helplocal governments to develop HCVscreening and care programs tailoredfor their country but the success ofthese programs will require commit-ment of resources, marketing, andeducation to raise public awareness.

The benefit of increased diagnosiscan be materialized only if infected

infection

s and all stages of liver disease

COMMENTARIES

persons have access to care so thatthey can be counseled, evaluated forliver damage, and considered fortreatment. Even in developed coun-tries, only a small fraction of thosediagnosed had received treatment.The reluctance of providers torecommend and patients to accepttreatment had been attributed to lowefficacy and frequent adverse re-actions of PEG-IFN and ribavirin.These concerns are rapidly eliminatedwith the new HCV drugs, but a majorbarrier to implementing these newtreatments is cost. The wholesaleprice of 1 tablet of sofosbuvir in theUnited States is estimated to beUS$1,000 putting the price tag of a-12week course of sofosbuvir alone atUS$84,000.23 Although studies oftelaprevir- or boceprevir-based regi-mens showed that HCV treatment iscost effective in the United States,24

the cost of DAAs will be prohibitivein low-income countries where re-sources are limited and there aremany competing health priorities. Asof 2013, none of the drugs used fortreatment of HCV is included in theWHO List of Essential Medications.Concerted efforts of the WHO, gov-ernment authorities, nongovernmentorganizations, and patient advocacygroups are needed to negotiateagreements with the pharmaceuticalcompanies that will make these newDAAs accessible and affordable. Thesemeasures have proven successful forHIV, and Gilead recently announcedthat generic sofosbuvir will be pro-duced in India.25 Egypt has shownthat commitment from the govern-ment and tough negotiations can payoff. In 2006, Egypt established ahighly specialized network of treat-ment centers and brought the price of48 weeks of PEG-IFN and ribavirin to<US$2,000 (<10% of that in theUnited States).26 Within 6 years of theprogram, 300,000 Egyptians havebeen treated.

While waiting for the price of newDAAs to become more affordable,an alternative strategy is to deter-mine the incremental value and costeffectiveness of DAAs in countrieswith a high prevalence of favorableIL28B genotype in patients who donot have contraindications to the use

of IFN. This strategy is particularlyrelevant in East Asian countries.Another strategy is to use combina-tion DAA regimens with high SVR ratefor genotype 1b in countries where itis predominant. These “second-line”regimens with limited utility incountries where genotype 1a iscommon might be priced lower. Oneexample is the combination of asu-naprevir, a protease inhibitor, anddacalatasvir, an NS5A inhibitor,27

which is under consideration forapproval in Japan, where genotype 1bpredominates.

Beyond drugs, there are other is-sues, such as medical expertise toevaluate liver disease and to monitortreatment. Thus, training of healthcare providers must go hand in handwith the implementation of screeningand treatment programs. Having anadequately prepared work force isnecessary not only in low-incomecountries, but also in developedcountries, because the availability ofsimpler, safer, and more efficacioustreatment will encourage patients toseek testing and treatment. In bothlow- and high-income countries ef-forts to raise public awareness suchthat persons at risk are informed ofthe potential sequelae of HCV infec-tion and the ever-improving treat-ment options are essential if HCV is tobe eradicated.

LAI WEIPeking University People’s Hospital andBeijing Key Laboratory for Hepatitis Cand Liver Disease Immunotherapy,Beijing, China andUniversity of Michigan Health System –Peking University Health Sciences CenterJoint Institute for Clinicaland Translational Research

ANNA S. F. LOKUniversity of Michigan Health SystemAnn Arbor, Michigan andUniversity of Michigan Health System –Peking University Health Sciences CenterJoint Institute for Clinicaland Translational Research

SupplementaryMaterialsNote: To access supplementary mate-rial accompanying this article, visit the

online version of Gastroenterology atwww.gastrojournal.org, and at http://dx.doi.org/10.1053/j.gastro.2014.03.008.

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et al. Genetic variation in IL28Band spontaneous clearance ofhepatitis C virus. Nature 2009;461:798–801.

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on how the treatment of HCV in-fection will change in the nearfuture as a result of recentdevelopments. Available at: http://www.hepbcppa.org/newsletter.Published December 2013.

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AcknowledgmentsThe authors thank Drs Wei Zhang and Hui-ying Raofor their assistance with the literature review andconstruction of Figures 2 and 3.

Conflicts of interestThe authors disclose the following: Lai Wei hasserved on advisory boards of Gilead and GSKand receives research grants from Bristol-MyersSquibb and Roche. Anna S.F. Lok has served onadvisory boards of Gilead and Janssen andreceives research grants from AbbVie, Bristol-Myers Squibb, Gilead, Idenix, and Merck.

FundingLai Wei and Anna S.F. Lok are supported by a grantfrom the University of Michigan Health System –

Peking University Health Sciences Center JointInstitute for Clinical and Translational Research.Lai Wei is also supported by the National Scienceand Technology Major Project for InfectiousDiseases Control during the 12th Five-Year PlanPeriod (2012ZX10002003), the National Scienceand Technology Basic Work Program of China(2013FY113900), the National Key ClinicalSpecialty Construction, and the National MajorScientific and Technologic Special Project for“Significant New Drugs Development” during the12th Five-Year Plan Period (2012ZX09303019).

© 2014 by the AGA Institute0016-5085/$36.00

http://dx.doi.org/10.1053/j.gastro.2014.03.008

Supplementary MaterialsLiterature Search andReferences for Figures 2and 3

A search of PubMed and Googlewas performed with MeSH terms orkey words (‘Hepatitis C’) AND (‘geno-type’) AND (‘human’) for Figure 2 and(‘Hepatitis C’) AND (‘IL28B’ OR ‘IFNl3’OR ‘rs12979860’) AND (‘human’) forFigure 3. In addition, the reference listsof all original articles and previousreviews were hand searched for otherrelevant papers. No restrictions wereplaced on the time period, sample size,population, or language. When multi-ple reports were available for a singleunique study population, we includedonly the most recent or largest report.Studies were reviewed and scored ac-cording to the following scale1,2:

* Estimates without a formalstudy

** Small study in a select popu-lation (<100) or study inblood donors only

*** Large study in a select pop-ulation (>100)

**** Small study in the generalpopulation (<100)

***** Large study in the generalpopulation (>100)

Data from countries were groupedaccording to the WHO Global Burdenof Disease classifications.3 Eligiblestudies4 met the following criteria: 1)Studies with a score that is >1*; 2) thehighest ranking study was selected foreach region.

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Rondonia, Brazil. Virol J 2011;8:165.

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with hepatitis C virus. Gastroen-terology 2012;47:596–605.

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Supplementary Table 1.Detailed Data Showing Distribution of HCV Genotypes by Country and World Health OrganizationGlobal Burden Disease Regions for Figure 2, Percent With Mixed or Unknown Genotypes Not Shown

CountryLevel ofEvidence

Genotype1(%)

Genotype 2(%)

Genotype 3(%)

Genotype 4(%)

Genotype 5(%)

Genotype 6(%) Ref.

USA ***** 70.00 16.00 12.00 1.00 <1 <1 [4]Canada ***** 60.00 15.40 22.30 NR NR NR [5]Germany *** 61.70 6.90 28.00 3.20 NR NR [6]United Kingdom *** 45.00 10.00 40.00 5.00 NR NR [7]Switzerland *** 51.00 9.00 30.00 10.00 NR NR [8]France *** 56.00 9.00 21.00 9.00 3.00 NR [9]Greece *** 45.10 7.00 34.00 13.90 NR NR [10]Spain *** 65.40 3.10 19.60 11.60 0.30 NR [11]Poland *** 79.40 0.10 13.80 4.90 NR 0.09 [12]Romania *** 98.00 NR 0.8 1.2 NR NR [13]Russia ***** 50.30 4.70 44.80 NR NR NR [14]Korea *** 51.60 45.80 1.10 0.10 NR NR [15]China *** 58.40 24.10 9.10 NR NR 6.30 [16]Viet Nam ** 47.10 NR 5.80 NR NR 47.10 [17]Philippines *** 67.30 26.30 NR 0.20 NR 0.20 [18]Thailand ** 29.00 14.00 39.00 NR NR 18.00 [19]Indonesia *** 72.70 16.00 11.40 NR NR NR [20]Myanmar *** 11.00 0.70 39.30 NR NR 49.00 [21]India ***** 31.20 0.50 61.80 4.50 0.04 1.90 [22]Pakistan ***** 7.03 3.81 78.96 1.59 0.1 0.13 [23]Australia *** 52.00 9.30 32.00 5.50 NR 1.70 [24]Iran *** 63.70 0.20 33.40 0.90 NR NR [25]Saudi Arabia *** 24.10 7.40 5.90 62.00 0.30 NR [26]Turkey *** 97.10 0.90 1.40 0.60 NR NR [27]Egypt *** 6.00 NR 31.00 63.00 NR NR [28]Mexico ***** 70.20 21.80 7.20 NR NR NR [29]Brazil ** 77.20 13.60 9.00 NR NR NR [30]Argentina ** 50.00 35.00 5.00 NR NR NR [31]

*Estimates without a formal study.****Small study in the general population (<100).**Small study in a select population (<100) or study in blood donors only.***Large study in a select population (>100).*****Large study in the general population (>100).

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Supplementary Table 2.Detailed Data Showing Distribution of Interleukin-28B Genotypes by Race, Ethnicity, and WorldHealth Organization (WHO) Global Burden of Disease Regions for Figure 3

WHO Global Burden of Disease Region CountryLevel ofEvidence Race/Ethnicity

rs12979860,Allele C (%) Ref.

High-income North America USA *** Caucasian 62.50 [32]African 38.50Hispanics 53.00Other 79.00

High-income Western Europe Italy **** Caucasian 51.00 [33]Central Europe Romania *** Caucasian 55.60 [34]Central Europe Hungary ***** Caucasian 65.10 [35]Eastern Europe Russia ***** Caucasian 68.50 [35]High-income Asia Pacific Japan *** Asian 87.45 [36]High-income Asia Pacific Korea ** Asian 93.85 [37]East Asia China *** Asian 91.75 [16]Southeast Asia Lao ***** Asian 93.60 [35]Southeast Asia Cambodia **** Asian 97.90 [35]South Asia India **** Other 65.50 [35]Oceania NR **** Other 92.50 [35]High-income Australia Australia *** Caucasian 59.50 [38]

Asian 90.00Hispanic 55.00Other 60.50

North Africa and Middle East Iran ***** Caucasian 68.00 [25]North Africa and Middle East Morocco ***** Other 67.80 [39]Central sub-Saharan Africa NR ***** African 23.50 [35]Eastern sub-Saharan Africa NR ***** African 40.70 [35]Western sub-Saharan Africa NR ***** African 33.40 [35]Central Latin America Mexico ***** Other 46.60 [35]Tropical Latin America Brazil *** Hispanics 51.50 [40]Southern Latin America Argentina *** Hispanics 49.50 [41]

*Estimates without a formal study.**Small study in a select population (<100) or study in blood donors only.***Large study in a select population (>100).****Small study in the general population (<100).*****Large study in the general population (>100).

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