Assessing the impact of HAART on the incidence of defining and non-defining AIDS cancers among patients with HIV/AIDS: A systematic review

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REVIEW

Assessing

the

impact

of

HAART

on

the

incidence

of

defining

and

non-defining

AIDS

cancers

among

patients

with

HIV/AIDS:

A

systematic

review

Ricardo

Ney

Oliveira

Cobucci

a,b,∗

,

Paulo

Henrique

Lima

a

,

Pollyana

Carvalho

de

Souza

b

,

Vanessa

Viana

Costa

b

,

Maria

da

Conceic

¸ão

de

Mesquita

Cornetta

d

,

José

Veríssimo

Fernandes

c

,

Ana

Katherine

Gonc

¸alves

d

aCenterforHealthSciencesoftheFederalUniversityofRioGrandedoNorte,Natal, Brazil

bDepartmentofGynecologyandObstetricsofthePotiguarUniversity,Natal,Brazil cDepartmentofBiosciencesoftheFederalUniversityofRioGrandedoNorte,Natal, Brazil

dDepartmentofGynecologyandObstetricsoftheFederalUniversityofRioGrande doNorte,Natal,Brazil

Received13February2014 ;receivedinrevisedform27May2014;accepted24August2014

KEYWORDS Acquired immunodeficiency syndrome; Highlyactive antiretroviraltherapy; Carcinoma; Incidence

Summary Afterhighlyactiveantiretroviraltherapy(HAART)becamewidespread, severalstudiesdemonstratedchangesintheincidenceofdefiningandnon-defining AIDScancersamongHIV/AIDSpatients.Weconductedasystematicreviewof obser-vational studies evaluating the incidence of malignancies before and after the introductionofHAARTinpeoplewithHIV/AIDS.Eligiblestudiesweresearchedup toDecember2012inthefollowing databases:Pubmed, Embase,Scielo, Cancerlit andGoogleScholar.Inthisstudy,wedeterminedthecancerriskratiobycomparing thepre-andpost-HAARTeras.Twenty-one relevantarticleswerefound,involving more than 600,000 peoplewith HIV/AIDS and10,891 newcases of cancers. The riskfor thedevelopmentofanAIDS-definingcancerdecreasedafterthe introduc-tionofHAART:Kaposi’s sarcoma(RR=0.30,95% CI:0.28—0.33)andnon-Hodgkin’s lymphoma (RR=0.52, 95% CI:0.48—0.56), in contrasttoinvasive cervical cancer (RR=1.46, 95% CI:1.09—1.94).Among the non-AIDS-definingcancers, theoverall riskincreasedaftertheintroductionofHAART(RR=2.00,95%CI:1.79—2.23).The

Correspondingauthorat:AvenidaAbelCabral2035casa105,Parnamirim,RioGrandedoNorte,Brazil.Tel.:+558420209051.

E-mailaddresses:rncobucci@hotmail.com,rncobucci@unp.br(R.N.O.Cobucci). http://dx.doi.org/10.1016/j.jiph.2014.08.003

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incidenceofAIDS-definingcancersdecreasedandtheincidenceofnon-AIDS-defining cancersincreasedaftertheearlyuseofHAART,probablyduetobettercontrolofviral replication,increasedimmunityandincreasedsurvivalprovidedbynewdrugs. ©2014KingSaudBinAbdulazizUniversityforHealthSciences.PublishedbyElsevier Limited.Allrightsreserved.

Contents

Introduction ... 2

Methods ... 3

Inclusioncriteria... 3

Searchandselectionofliterature... 3

Dataextraction ... 3

Analysis... 3

Results... 3

Discussion... 6

Non-AIDS-definingcancers(NADCs)... 6

Analcancer ... 6

Hodgkin’slymphoma ... 6

Livercancer... 6

Lungcancer... 7

Prostatecancer ... 7

AIDS-definingcancers(ADCs)... 7

Kaposi’sSarcoma(KS)... 7

Non-Hodgkin’sLymphoma(NHL)... 7

Invasivecervicalcancer(ICC)... 8

Conclusion... 8 Funding... 8 Competinginterests ... 8 Ethicalapproval ... 8 References... 8

Introduction

Since1996,whenhighlyactiveantiretroviral ther-apy(HAART)becamewidespreadinNorthAmerica, Europe and Australia, the mortality rate in HIV-infected patients dropped dramatically, mainly becauseofthedecreaseintheincidenceof oppor-tunistic infections. In addition to life expectancy, the therapy also affected the epidemiology of non-AIDS-defining cancers (NADCs) and has an importantimpactontheevolutionofthesetumors

[1].

BeforeHAART,cancerswereresponsibleforless than10%ofdeathsamongHIV-infectedpatients[1]. AfterHAART,28%ofdeathsinthispopulationhave been attributed to neoplastic causes [2], despite the substantial decline in the risk of acquiring AIDS-defining cancers (ADCs), especially Kaposi’s sarcoma (KS) and non-Hodgkin’s lymphoma (NHL)

[3]. It is believedthat this phenomenonoccursas

a function of the increase in the incidence and mortalityofNADCs[4].However,itisstillnotclear in the literature whether the higher incidence of carcinomas in the post-HAART era is only due to the larger number of new cases of NADCs or if thereareotherfactorsinvolved,suchasthelonger lifeexpectancyaffordedbyHAART[3].

SomestudiesspeculatethatasHIVpatientslive longer after the introduction of HAART, there is a greater potential to developcancers [5]. Other authors believe that the association between dif-ferentriskfactors,suchasHIV-infectionchronicity and its probable oncogenic role, maybe involved

[2].

In fact, despitethe advancesin medicine, can-cerisnowoneoftheleadingcausesofdeathamong patientswho livewith HIV[6].Thisarticleaimsto provideasystematicreviewtoevaluatetheimpact of HAART on the incidence of defining and non-definingAIDScancers.

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Methods

ThisstudyadheredtotheMOOSEguidelines[7].

Inclusion

criteria

Studies meeting the following criteria were included:(1)cohortstudiesofpeoplewithHIV/AIDS thatassessedcancerincidencebeforeandafterthe introduction of HAART, (2) studies including adult subjects, (3) studies published between 2001 and 2012 and (4) studiesincludingdata on the cancer incidenceinperson-years.

Search

and

selection

of

literature

Eligible studies were identified by searching the following databases: Pubmed, Embase, Scielo, Cancerlit and Google Scholar. The studies were identified by a literature search of the databases usingthefollowing medicalsubject headingterms and/or text words: ‘‘AIDS’’, ‘‘HIV’’, ‘‘cancer’’, ‘‘HAART’’, ‘‘incidence’’ and ‘‘cohort’’. The ref-erence lists of the identified publications were reviewed for additional pertinentstudies. No lan-guagerestrictionswereimposed.

Three researchers (PHL, PCS and MCMC) searchedfor articles published prior toDecember 2012. After searching the databases, 2392 poten-tially relevant HIV/AIDS papers were identified, 2333ofwhichwereexcluded:1929afterreviewing the title and 404 after reviewing the abstract. Three studies were included after reviewing the References.

Thus,62papersmetthesearchcriteriaandwere evaluatedusingtheNewcastle-Ottawascale[8];35 were excluded.TheNewcastle-Ottawascale eval-uates the quality of cohort studies; articles that scorehigherthanfiveareconsideredtobestudies of ‘‘high methodological quality’’. The scale was independently applied by two researchers (RNOC and MCMC), and any discordance was solved by a thirdresearcher(AKSG).Sixarticleswereexcluded forrepeatedreporting(Fig.1).

Data

extraction

Variousstudy characteristics were extracted from theoriginalstudiesandincludedinthesystematic review. The data included the first authors’ last names, the year of publication, the country, the studydesign,the periodoffollowup,the number of patients, the total person-years and the num-ber ofcancers (Table1). Cancer incidence among HIV/AIDS patients in the pre- and post-HAART

2392 papers indentified

62papers met search criteria

21included

2333excluded: 1929 after review of title and 404 after review of abstract

41 excluded: 35 low Newcastle-Ottawa and 6

repeated reporting 3 included: searched on

papers references

Figure1 Studyselection.

periods were abstracted from each study. Three blind reviewers (RNOC, MCMC and AKSG) used the inclusion criteria to choose eligible articles. Disagreements were solved by means of mutual consensus.

Analysis

DatawereenteredinReviewManager(RevMan)4.2. Thissoftwareallowstheusertoenterprotocols,to completereviews,includingtext,characteristicsof thestudies,comparisontables,andstudydata,and toperformmeta-analysesofthedataentered.

With the incidence in person-years, we deter-mined the risk ratio for each studied malignancy usingfixedand randomeffectsmodelsandtesting for the heterogeneity of effects using the Chi-squaredtestinRevMan4.2.

Results

Wefound 21relevantarticlesinvolving morethan sixhundredthousandHIV/AIDSpatients,who con-tributed more than two million person-years of follow-upandwhowerediagnosedwith10,891new casesofcancers.Thedesignfeaturesofthechosen studiesareindicatedinTable1.

Regarding the ADCs, the beginning of HAART decreased the risk to develop KS (RR=0.30, 95% CI: 0.28—0.33) and NHL (RR=0.52, 95% CI: 0.48—0.56) when compared with the pre-HAART period(Figs.2and3).IncontrasttoKSandNHL,we

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Table1 CohortstudydesignfeaturesofcancerriskinHIV/AIDSpatients. Study,year(reference) Country Studytype Periodof

follow-up Numberof patients Total numberof person-years Numberof cancers

Dorruccietal.,2001[27] Italy Cohort 1981—1998 483 3364 6

Boweretal.,2003[29] UK RLa 1986—2001 8400 22,694 11

Boweretal.,2004[30] UK Cohort 1984—2003 8640 40,126 26 Hessoletal.,2004[31] USA RLa 1994—2001 1554 7909 41

Biggaretal.,2006[15] USA RLa 1980—2002 317,428 477,368 173

D’Souzaetal.,2008[32] USA Cohort 1984—2006 6972 100,000 69 Franceschietal.,2008[33] Switzerland Cohort 1984—2006 12,959 73,412 597 Poleseletal.,2008[34] Switzerland Cohort 1984—2006 12,959 75,222 429 Engelsetal.,2008[35] USA Cohort 1991—2002 57,350 186,157 871 Crum-Cianfloneetal.,2009[4] USA Cohort 1984—2006 4498 33,486 446 Cliffordetal.,2009[36] Switzerland Cohort 1984—2007 14,606 84,611 47 DalMasoetal.,2009[43] Italy RLa 1986—2004 21,951 101,668 1995

Leewenetal.,2009[20] Australia Cohort 1982—2004 37,407 311,496 2283 Powlesetal.,2009[41] UK Cohort 1983—2007 11,112 71,687 156 Buchaczetal.,2010[37] USA Cohort 1994—2007 8070 3000 16 Crum-Cianflone,2010[39] USA Cohort 1985—2008 4506 37,806 66 Franceschietal.,2010[42] Switzerland RLa 1985—2006 9429 53,715 1460

Seabergetal.,2010[40] USA Cohort 1984—2007 6972 77,320 933 Bessonetal.,2011[38] France RLa 1993—1998 80,000 230,173 900

Kirketal.,2001[24] Europe Cohort 1994—2000 8471 26,764 222 Franzettietal.,2012[10] Italy Cohort 1985—2011 5924 50,990 144

aRL,record-linkage.

found thattheriskofdevelopinginvasive cervical cancer (RR=1.46, 95% CI: 1.09—1.94) increased aftertheintroductionofHAART(Fig.4).

In the articles that included data on non-Hodgkin’s lymphoma, we found thatthe introduc-tionofHAARTdecreasedtheratesofnon-Hodgkin’s lymphoma, especially the risk of primary brain lymphoma (RR=0.24, 95% CI: 0.20—0.30). The risk of acquiring diffuse large B-cell lymphoma and Burkitt’s lymphoma, the two most com-mons systemicNHL subtypes among patients with HIV/AIDS, also decreased significantly (RR=0.44,

95%CI:0.40—0.49andRR=0.44,95%CI:0.27—0.73, respectively).

The overall risk ofdevelopingNADCs increased aftertheintroductionofHAART(RR=2.00,95%CI: 1.79—2.23),asshowninFig.5.However,amongthe cancersstudied,wefoundasignificantriskincrease in a group of six malignancies: anus (RR=4.28, 95% CI: 3.25—5.64), colorectal (RR=1.91, 95% CI: 1.03—3.52),Hodgkin’slymphoma(RR=1.40,95%CI: 1.16—1.69), liver (RR=3.58, 95% CI: 2.57—4.99), lung (RR=2.19, 95% CI: 1.54—3.11) and prostate (RR=2.57,95%CI:1.49—4.44).

Figure2 IncidenceratesforKaposi’ssarcomainthepre-andpost-HAARTerasandtheriskratiosofincidencerates inthepre-HAARTcomparedwiththepost-HAARTera.

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Figure3 Incidenceratesfor non-Hodgkin’slymphomainthe pre-andpost-HAARTandtheriskratiosof incidence ratesinthepre-HAARTcomparedwiththepost-HAARTera.

Figure4 Incidenceratesforinvasivecervicalcancerinthepre-andpost-HAARTerasandtheriskratiosofincidence ratesinthepre-HAARTcomparedwiththepost-HAARTera.

Figure5 Incidenceratesfornon-AIDS-definingcancersinthepre-andpost-HAARTerasandtheriskratiosofincidence ratesinthepre-HAARTcomparedwiththepost-HAARTera.

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However, we did not find a statistically signifi-cant increase or decrease in the development of the following NADC types after the initiation of HAART:bladder(RR=1.88,95%CI:0.59—6.00),CNS (RR=1.81, 95% CI: 0.86—3.85), kidney (RR=1.79, 95% CI: 0.72—4.44), leukemia (RR=0.84, 95% CI: 0.44—1.60), melanoma (RR=1.08, 95% CI: 0.71—1.65) and testis (RR=0.84, 95% CI: 0.38—1.89).

Discussion

Non-AIDS-defining

cancers

(NADCs)

Several theories attempt to explain the increas-ing importance of NADCs among HIV-infected patients. Although some studies have demon-strated a direct relationship between HAART and increased incidenceofNADCs[4], itis morelikely that antiretroviral therapy indirectly affects the epidemiology of these cancers because HAART increasesthelifeexpectancyofpeoplelivingwith HIV,thusallowingtheemergenceofthese carcino-mas[4].

Anotherpossibilityis thatthegenomic instabil-ity caused by zidovudine may contribute to the increased incidence of certain types of NADCs. Thefirstnucleosidereversetranscriptaseinhibitors (NRTIs) approved for the therapy of HIV is incorporated into DNA, causes mutations in the hypoxanthine-guanine phosphoribosyl-transferase (HPRT) and thymidine kinase (TK) genes, and induces micronuclei, chromosomal aberrations, sister chromatid exchange, shortened telomeres, andothergenotoxiceffectsinculturedcells[9].

Anal

cancer

There is aproven association between anogenital cancers and infection by human papilloma virus (HPV), and we also know thatpatientsliving with HIVhaveahigherincidenceofHPVinfection, espe-ciallyofhigh-riskstrains[10].Wefoundafourfold increase in the risk for developinganal cancer in thepost-HAARTera(RR:4.28,95%CI:3.25—5.64). Our finding was similar to the results found by Legarthetal.in2013(RR:77.9,95%CI:36.2—167.7)

[11]. Thisfactcanbe explainedpartlybythefact that the use of HAART does not reduce the inci-denceofanogenitalcancerprecursorlesionsandit doesnotseemabletoeliminateHPVinfection[10]. Furthermore, therecommendations ofperforming screeningforanal cancerand itsprecursorsinthe population withHIVcanleadtoanincreaseinthe

numberofdiagnoses [12].Recently, amulticenter studyshowedthattheuseofHAARTwasassociated withalowerprevalenceofanalintraepithelial neo-plasia(AIN)andalowerprevalenceofHPVinfection

[13].However,thisstudyhassomelimitationsthat shouldbe highlighted,includingitscross-sectional design. Additionally, the article does not address theeffectofHAARTonhigh-gradeanal intraepithe-lialneoplasia(HGAIN)specifically,asthesizeofthe study was limited and only a small proportion of thosewithAINhadHGAIN[14].

Hodgkin’s

lymphoma

Hodgkin’slymphoma(HL)isacommonmalignancy among patients with AIDS, congenital immunode-ficiency syndromes or those under immunosup-pressive drug regimens. This fact suggests that immunosuppressionisdirectlyrelatedtothe patho-genesis of HL; however, the relationship is much more complex and multifactorial [15]. We found an increased risk for developing HL after HAART (RR: 1.40, 95% CI:1.16—1.69) that was similar to the standardized incidence ratio (SIR) found by Clifford et al. in 2005 (pre-HAART SIR=17.3 com-pared to post-HAART SIR=36.2) [16] and Herida et al. in 2003 (pre-HAART SIR 22.75 compared to post-HAARTSIR=31.66)[17].Inadditiontothe sub-stantialincreaseintheageofthepopulationliving withHIVaftertheintroductionofHAART(from34.2 years to42.8 years)[16], the increased incidence is related to immune reconstitution: it is known that the incidence of HL decreases with severe immunosuppression and increases with moderate immunosuppression [15]. It is also known that HL isstronglyassociatedwithEpstein—Barrvirus(EBV) infectionandthatimmunereconstitutionincreases the stimulation of B cells, thereby increasing the numberoflymphocytesinfectedwithEBV[15].

Liver

cancer

Ingeneral,theincidenceoflivercancerisincreased in patients with HIV/AIDS. Some studies suggest that this difference may result from a greater prevalenceofinfectionbyhepatitisB virus(HBV), andespeciallyhepatitisCvirus(HCV)[18].The co-infectionofHIVandHBVorHCVseemstoincrease the risk of cirrhosis, end-stage renal disease and hepatocellular carcinoma. Our statistical analysis foundthattheriskfordevelopinglivercancerafter HAARTincreasedmorethanthreetimescompared tothepre-HAARTrisk(RR:3.58,95%CI:2.57—4.99), similartowhatwasfoundbySahasrabuddheetal. in 2012, (RR=2.50, 95% CI: 1.70—3.70) [18]. The main reason for the higher risk is the increase in

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survival of people living with HIV/AIDS after the introduction ofHAART; inaddition,it issuspected thatthe hepatotoxicity ofHAARTmay worsenthe carcinogeniceffectofhepatitisBandC[18].

Lung

cancer

Manystudiesindicatethatlungcanceristhemost common NADC in the HIV-infected population, in both the pre-and post-HAART eras. As smokingis the main risk factor for the development oflung cancer, we established the relationship between the increased incidence of this tumor with the highestrateofsmokingintheHIV-infected popula-tion;infact,35—70%ofpeoplelivingwithHIV/AIDS smoke,whileonly20%ofthegeneralpopulationare smokers[19].However,otherfactorsalsoappearto berelatedtotheincreasedincidenceoflungcancer inthesepatientsbecausetheriskremainshigheven after correcting for smoking status [10]. Although somestudiesdonotshowastatisticallysignificant increaseintheriskofdevelopinglungcancerafter HAART [10,20], our studyfound a doubling ofthe pre-HAARTerariskinthepost-HAARTera(RR:2.19, 95%CI:1.54—3.11),andthisresultissimilartowhat wasfoundbyPoleseletal.in2010(RR:1.8,95%CI: 1.00—3.2)[21].Theincreasedriskmaybeexplained in part bythe long periodfrom the acquisitionof HIV until the diagnosis for lung cancer (11 years on average in the post-HAART era). Thus, studies inthepre-HAARTera,whenthelifeexpectancyof the HIV-infected population was much lower than thatofthepost-HAARTera,madeno diagnosesof lungcancersimplybecausethepatientsdiedfrom other causes first, mainly opportunistic infections andAIDS-definingcancers[19].

Prostate

cancer

Although we found an increased incidence of prostate cancer in the post-HAART era (RR: 2.57, 95%CI:1.49—4.44),veryfewofthepublished stud-ies included this outcome, so we cannot clearly determine the direction of this neoplasia in HIV-positivepatients.Moreover,amongthefewarticles thataddress prostatecancer, the samples studied are small and thus not able to detect significant differences [10]. In 2009, Silberstein et al. [22]

suggested thatHAART may be a protective factor against prostate cancer. However, in 2008, Pan-tanowitzetal.[23]showedthatinacohortstudy, 82% of men diagnosedwith prostate cancer were receiving HAART. We know that the riskof devel-oping prostate cancer is associated with the age andoriginofthepatients;moreover,thepresence or absence of a screening program substantially

alterstheincidenceofthisneoplasia.Manyarticles

[10,22,23] showed that the incidence of prostate cancer in patients living with HIV/AIDS may be equal,lowerorevenhigherthanthatofthegeneral population, which highlights the need to perform more studies before definitive conclusions can be reached.

AIDS-defining

cancers

(ADCs)

Kaposi’sSarcoma(KS)

Sincethe advent ofHAART,there has beena dra-matic and continuing decline in the incidence of KS [20], especially in the late post-HAART period comparedto the earlypost-HAART [19]. Asin the studies of Cianflone et al. (RR: 12.32, 95% CI: 0.24—12.44) [4]and van Leewen et al. (RR: 0.21, 95%CI: 0.18—0.24) [20], we found a reduction in the risk for developing KS after the initiation of HAART(RR:0.30,95%CI:0.28—12.33).Despitethe fact that the restoration of the immune system can lead to a transient increase in KS lesions, a manifestationofimmunereconstitutionsyndrome, HAARTreducestheincidenceofKSbyvarious fac-tors, including the reduction of HIV replication, thusimprovingtheimmuneresponsesagainstHHV8 andthedirectanti-angiogenicactivityofsome pro-tease inhibitors. Recent studies suggest that the incidence of KS in people with HIV is now stabi-lized at a much lower rate, although the rate is still substantially high when compared to that of thegeneralpopulation[12].

Non-Hodgkin’sLymphoma(NHL)

SimilartotheratesofKS,wefoundareductionin theriskfor developingNHL afterthe introduction ofHAART (RR=0.52, 95%CI:0.48—0.56).Although somestudiesshowthatthedeclineintheincidence is stabilizing, others show that the decline con-tinuesevenwhencomparingtheearlypost-HAART periodstothelatepost-HAARTera,suggestingthat in the future, the difference in risk between the generalpopulationandHIV-infectedpopulationwill disappear[12,20].ThereductionintheriskofNHL is directly related to the increased CD4 count; however, for Burkitt’s lymphoma, that is not true becausethistypeofNHLoccurswhentheCD4count isrelativelyhigh(>200cells/mm3)[24].Evenso,we foundareductionintheriskforBurkitt’slymphoma sincetheintroduction ofHAART(RR:0.44,95%CI: 0.27—0.73),aswellasintherisksforprimary lym-phomaofthecentralnervoussystem(RR:0.24,95% CI:0.20—0.30) and diffuse large B-cell lymphoma (RR:0.44,95%CI:0.27—0.73).

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Invasivecervicalcancer(ICC)

Unlike other AIDS-defining malignancies, the inci-dence of invasive cervical cancer does not seem to have diminished after the advent of HAART

[25]. Cohort studies with individual patient data on HAART use have produced conflicting results withareducedriskassociatedwithHAARTreported in some but not all studies [12]. We found an increasedriskfordevelopinginvasivecervical can-cer after the introduction of HAART (RR: 1.46, 95% CI: 1.09—1.94), similar to what was found by Gingues and Gill [26] in 2006. The increased incidence for developing invasive cervical cancer, evenafter theadventofHAART,mayhaveseveral explanations, including the fact that the female populationwithHIVislivinglonger,that antiretrovi-raltherapydoesnotpreventtheappearanceofICC asitwasthoughttopreviously,oreventhatthereis aninadequatescreeningprogramforwomenliving with HIV[27].Thus,itis unclearhowthe immune reconstitutioninducedbyHAARTaffectsthelesions inducedbyHPV;moreresearchisneededto estab-lishasecureassociation[28].

When comparingthe data between these stud-ies, some limitations in the source data must be considered. In the included studies, most reports included person-years from the 5 years before the onset of AIDS, but others included only the post-AIDS period, and the duration of the post-AIDS follow-up period varied. This may explain the heterogeneity among the studies included in thissystematicreview.Becauseimmunedeficiency variesconsiderablyduringthenaturalhistoryofHIV infection and is also affected by treatment, the degreeofimmunedeficiencyprobablyvariedacross theHIV/AIDSstudies.Finally,somestudiesdidnot reportdatacoveringallcancertypes.Nonetheless, therewasnodemonstrablepublicationbias.

Conclusion

Arguably,HAART contributedtotheincreased sur-vivalofpeoplelivingwithHIVbyprovidinggreater controlofviralreplicationandincreasedimmunity. Thissomewhatexplainsthereductionofnewcases ofAIDS-definingcarcinomas suchasKSand NHLin thepost-HAARTerabecausetheincidenceofthese cancersdecreasesin theimmunocompetent popu-lation.

In addition, the increased survival allowed the detectionofmalignanttumors,asNADCs(liver,lung andprostate)weregreatlyundiagnosedbeforethe introduction of HAART because these carcinomas arisinginHIV-infectedindividualswereuncommon inthepre-HAARTera.

Moreover, other factors are associated with the lower or higher incidence of cancers follow-ing the introduction of HAART. Some are already welldefined, suchasthe hepatotoxicityofHAART that may predispose patients to the emergence of hepatic carcinoma and immune reconstitu-tion, which increases the number of lymphocytes infected with EBV. However, it is not completely knownhowthesefactorsincreasethecarcinomasof thelung,prostateandcervixinthepost-HAARTera, and larger studies are needed to elucidate these interactions.

Funding

Nofundingsources.

Competing

interests

Nonedeclared.

Ethical

approval

Notrequired.

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