SYSTEMATIC REVIEW UPDATE Open Access

Treatment of pre- and confirmed cervicalcancer in HIV-seropositive women fromdeveloping countries: a systematic reviewWitness Mapanga1,2,3*, Elvira Singh4,5, Shingairai A. Feresu6 and Brendan Girdler-Brown1

Abstract

Background: Cervical cancer has become a major public health challenge in developing countries with a reportedage-standardised incidence rate of about 17.9/100,000/year and lifetime risks approaching 1 in 20 in some settings.Evidence indicates that HIV-seropositive women are 2 to 12 times more likely to develop precancerous lesions thatlead to cervical cancer than HIV-negative women. There is a lack of rigorous evidence on which treatment methodsare being utilised for HIV-positive women, and this review aims to synthesise available evidence on treatmentmodalities for both cervical neoplasia and cervical cancer in HIV-seropositive women in developing countries.

Methods: A systematic review guided by a published protocol was conducted. Online databases includingMEDLINE/PubMed, Embase, CINAHL and Emerald (via EBSCOhost), PsycINFO, Cochrane Library, and healthdatabases, which cover developing countries (3ie Systematic Reviews, WHO library and databases, World Bankwebsite), were searched for published articles. Additional articles were found through citation, reference listtracking, and grey literature. Study design, treatment category, geographic country/region, and key outcomes foreach included article were documented and summarised.

Results: Thirteen research articles from sub-Saharan Africa, Asia, and South America were included. Eight (61.5%)articles focused on the treatment of cervical cancer with the remaining five (38.5%) assessed cervical neoplasiatreatment. The available cervical cancer treatments, radiotherapy, chemotherapy, chemoradiation, and surgery areeffective for HIV-seropositive patients, and these are the same treatments for HIV-negative patients. Bothcryotherapy and LEEP are effective in reducing CIN2+ among HIV-seropositive women, and a choice between thetreatments might be based on available resources and expertise. Radiation, chemotherapy, concurrent treatmentusing radiotherapy and chemotherapy, and surgery have shown the possibility of effectiveness among HIV-seropositive women. Cervical cancer stage, immunosuppressive level including those on HAART, and multisystemtoxicities due to treatment are associated with treatment completion, prognostic, and survival outcomes.

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© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

* Correspondence: witnessmapanga@yahoo.co.uk1School of Health Systems and Public Health, Epidemiology & Biostatistics,University of Pretoria, 5-10 H.W. Snyman Building, Pretoria, South Africa2Non-Communicable Diseases Research (NCDR) Division of the Wits HealthConsortium, Faculty of Health Sciences, University of the Witwatersrand,Johannesburg, South AfricaFull list of author information is available at the end of the article

Mapanga et al. Systematic Reviews (2020) 9:79 https://doi.org/10.1186/s13643-020-01345-2

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Conclusions: Treatment of cervical cancer is based on the stage of cancer, and poor outcomes in most developingcountries might be due to a lack of optimal treatment regimen. Those infected with HIV were younger and hadadvanced cervical cancer as compared to those who were HIV-negative. Facilitation and putting HIV-infectedpeople on life-long ART is of importance and has been found to have a positive impact on cervical cancertreatment response. Research on precancerous lesions and cervical cancer management of HIV-seropositive patientsfocusing on the quality of life of those treated; the effectiveness of the treatment method considering CD4+ countand ART is required.

Systematic review registration: PROSPERO CRD42018095707

Keywords: Cervical neoplasia, Cervical cancer, Treatment, HIV, Developing countries

BackgroundPersistent infection with human papillomavirus (HPV) isthe main risk factor for developing cervical cancer [1–4].The HIV burden has seen an increase in morbidity andmortality due to cervical cancer, especially in developingcountries, where HIV incidence and prevalence are high[5–7]. In these developing countries, the reported age-standardised incidence rate can be as high as 17.9/100,000/year [8]. Also, most of these patients are mostly diag-nosed at an advanced stage due to a lack of coordinatedand systematic screening [9, 10]. The management of bothcervical neoplasia and cervical cancer in HIV-seropositivewomen, who mostly reside in developing countries, isbound to be challenging especially with the potential riskof medical complications, and resource constraints includ-ing unavailability of treatments [7]. There are severaltreatment modalities for cervical cancer, namely, chemo-therapy, surgical management, and radiation therapy [7,11, 12]. Treatment modalities for precancerous lesionsand cervical cancer are based on the stage of the lesionsand available resources; the associated poor outcomes oftreatment among HIV seropositive women in developingcountries may be due to lack of optimal treatment regi-men [10, 13]. Most developing countries lack skilled sur-geons to carry out radical surgery for cervical cancer, andthis has left HIV-seropositive cervical cancer patients withfew treatment options. In cases where surgeons are avail-able, surgery is expensive and out of reach of many, whohappen to be poor [14]. In developing countries especiallysub-Sahara Africa, many women with cervical cancer haveno access to radiotherapy, further limiting their treatmentoptions. However, little or no information exists that hasshown that any of the current treatments are effectivecompared to other treatments when it comes to treatingcervical cancer in HIV-seropositive women. In sub-Saharan Africa, treatments like radiation therapy andother surgical procedures are not fully utilised because oflack of equipment and qualified personnel; hence, littlehas been documented on which treatment procedures arebeing used for the treatment of cervical cancer in HIVseropositive women [15]. Therefore, there is a lack of

evidence-based guidelines and strategies for the treatmentof cervical cancer in HIV-seropositive women in most de-veloping countries. Coupled with this, there is little rigor-ous evidence on the global epidemiology of the treatmentof cervical cancer in HIV-seropositive women [15]. Thisreview aims to answer the following questions: What arethe treatment modalities that are being used to treat andmanage cervical cancer in HIV-seropositive women in de-veloping countries? Are these the same treatment modal-ities that are being used for HIV-negative women? Are thetreatment modalities effective in HIV-seropositivewomen? This review will investigate and identify the exist-ing treatment modalities used for cervical cancer in HIV-seropositive women in some of the developing countries.

MethodsSearch strategyThis review was guided by a protocol [16] and registeredwith PROSPERO (CRD42018095707). The PRISMAguidelines (Fig. 1) informed the reporting of this system-atic [17]. Two independently working reviewers (WMand SF) searched MEDLINE/PubMed (1966 to present,using Medical Subject Heading (MeSH) terms), Embase(1980 to present) via the OVID interface, and Cochrane,PsycINFO, Emerald, and CINAHL (all from 1961 topresent) via EBSCOhost, using a combination of the fol-lowing words: “Cervical Neoplasm”, “Cervical Cancer”,“treatment”, and “HIV”. The initial results (2753 records)were further narrowed down by adding “developingcountries” (individual database search strategies are in-cluded in Additional file 1). In addition, the two re-viewers (WM and SF) also searched the 3ie SystematicReviews, WHO library and databases, World Bank web-site and WHO ICTRP and cliniccaltrials.gov [16] andidentified an additional 4 studies. All the searches in-cluded articles published up to 31 January 2020, whichwas also the last date of the searches.

Eligibility criteriaStudies were eligible for inclusion if they investigatedcervical neoplasia or cervical cancer treatment methods

Mapanga et al. Systematic Reviews (2020) 9:79 Page 2 of 16

(cryotherapy, loop electrosurgical excision procedure(LEEP), chemotherapy, surgery, and radiation therapyamong others) for HIV-positive women in developingcountries, peer-reviewed, grey literature (dissertations,conference papers, government reports), and done for orin countries or regions considered developing by theUnited Nations [16]. Studies were excluded if they hadunrepresentative samples.

Study selectionThe search of databases and grey literature yielded 1637results, and an additional four studies were identifiedthrough reference tracking to make a total of 1641 arti-cles (Fig. 1). All the articles were combined into End-Note reference management software, and 332duplicates were removed. The remaining 1309 articleswere exported to Covidence software, where duplicatescreening was performed. Two independently workingreviewers (WM and SF) conducted title and abstractscreening based on the relevance to the review question.Studies were excluded when the title and abstract men-tioned cervical cancer screening or vaccination or de-scribed the implementation process of cervical cancertreatment. Disagreements related to the screeningprocess were resolved as a team through discussions asreported in the published protocol [16]. Through titleand abstract screening, 1112 articles were excluded. Twoindependent reviewers (WM and BGB) conducted full-text screening on the remaining 197 articles, and 184

articles did not meet the eligibility criteria and were ex-cluded. A total of 13 articles met the eligibility criteriaand included in the final analysis (Fig. 1).

Data extractionTwo independent reviewers (WM and SF) conducteddouble data extraction in Covidence software on the 13articles that were included in the final analysis, whilstthe rest of the team checked for quality and consistency.A data extraction form, as indicated in the publishedprotocol [16], guided the data extraction process. Thequality of the data extraction form was determined bypiloting 5 articles and the team discussing and resolvingall the inconsistencies through consensus. The followingvariables were extracted from the studies: first authorand publication year, the title of the study, study type,aim of the study, participants and their age, study set-ting, stage of cervical cancer, treatment method, out-comes, results, and authors’ conclusions.

Quality assessment of included studiesFor quality assessment of the studies, the team utilised acombination of the NIH Study Quality Assessment Toolsfor observational cohort and cross-sectional, case-control,and before-after studies, together with a modified versionof the Newcastle-Ottawa Quality Assessment Scale [18, 19].For the quality assessment process to be easy to conduct,studies were grouped into observational studies without acontrol group(s), observational studies with a control

Fig. 1 PRIMSA flowchart. The search strategy is reported according to PRISMA guidelines

Mapanga et al. Systematic Reviews (2020) 9:79 Page 3 of 16

group(s), and randomised controlled trials [16]. The follow-ing factors were considered of importance during the qual-ity assessment process: a clearly defined and specified studypopulation, clearly defined and valid exposure and out-comes measures, adequate sample sizes, randomisation ofparticipants, and a prespecified inclusion and exclusion cri-teria for being in the study. Two independent reviewers(WM and SF) conducted the quality assessment, and dis-agreements during the process were resolved through dis-cussion by all the four authors. Answers to the questions ofthe two checklists gave an overall score of each article. Eachpaper was scored to a maximum of 12 points, with every‘yes’ answer carrying 1 mark and ‘no’ answer carrying zeromarks. An average of the scores from the two reviewers be-came the final quality score for each study. Quality wasbenchmarked as low if the average score of the two asses-sors was between 0 and 4, moderate if the average scorewas from 5 to 8, and high if average score was from 9 to 12.However, no studies were excluded based on quality.

ResultsStudy selection and characteristics of the included studiesOut of the initial 1309 (after 332 duplicates were re-moved), 13 studies (of over 2800 patients) met the in-clusion criteria and were included to form the basisof the analysis. Most of the studies were excluded inthe title and abstract screening stage because theywere not relevant to the topic under review. Underfull-text screening, studies were excluded because theywere non-empirical, evaluating the feasibility and im-plementation of cervical cancer treatment methods,and assessing different stages of precancerous lesionsand stages of cervical cancer in HIV-positive women.Most of the included studies (69.2%) were publishedafter the year 2010. The studies represented three

regions, sub-Saharan Africa 8 (61.5%), Asia 4 (30.8%),and South America 1 (7.7%), as indicated in Fig. 2.The 13 included studies evaluated, assessed, or com-

pared the effectiveness, treatment response, and out-comes of different cervical neoplasia and cervical cancertreatment methods for HIV-seropositive women. The re-sults are presented in themes, that is, treatment methodsof cervical neoplasia first, followed by treatmentmethods of confirmed cervical cancer. Five of the in-cluded studies (38.5%) are prospective cohort, evaluatingtreatment response and toxicity to a combination ofradiotherapy and chemotherapy, treatment with surgeryand radiation, and treatment with loop electrosurgicalexcision procedure (LEEP). Four (30.8%) retrospectivecohort studies and one (7.7%) evaluated the survivaloutcomes of chemotherapy, treatment outcomes ofradiotherapy, and complications with LEEP, and com-pared clinical characteristics after radiation andchemotherapy. Two (15.4%) randomised controlledtrials compared the efficacy of LEEP vs cryotherapyand cryotherapy with no treatment. One (7.7%) casestudy examined the results of a radical hysterectomysurgery on two different patients. All the 13 studieswere almost consistent in defining their outcomes,such as treatment response, clinical/prognostic char-acteristics, survival response, and mortality rates.However, baseline characteristics of participants includedin the studies were different, with age ranging from 18years old to well above 55 years old. Sampling and recruit-ment of the participants were also different. In addition,participants had different stages of both precancerous le-sions and cervical cancer, some were on highly active anti-retroviral therapy (HAART), whilst others were not onHIV treatment, and the follow-up intervals were differentas well (see Table 1).

Fig. 2 Research of cervical cancer treatment among HIV-seropositive women by country

Mapanga et al. Systematic Reviews (2020) 9:79 Page 4 of 16

Table

1Tableof

eviden

ceFirstauthor

&pu

blication

year

Stud

ytype

Purpose

Popu

latio

n&

age

Cou

ntry

Stageof

cancer

Treatm

entmetho

dOutcome(s)

Results

Autho

rs’C

onclusions

Quality

score

Simon

ds

etal.,

2012

[20]

Retrospe

ctive

coho

rtstud

yTo

compare

theclinical

characteristics,radiation,

and

chem

othe

rapy

treatm

ents,

outcom

esin

acoho

rtof

HIV-

positiveandHIV-neg

ative

wom

enwith

cervicalcancer

59HIV-positive

(med

ianage41

years)and324

HIV-neg

ative

(med

ianageof

50years)

patients

South

Africa

IBi–IIIB

Radiationand

chem

othe

rapy

Che

mothe

rapy

cycles,respo

nseat

timeof

brachytherapy,and

6-weekfollow-up

88.1%

ofHIV-positive

pa-

tientspresen

tedwith

IIIBdis-

ease

comparedto

65.7%

ofHIV-neg

ativepatients(p

=0.009).79.7%

HIV-positive

and89.8%

HIV-neg

ativepa-

tientscompleted

radiation

dose

of68

GyEBRT

andHDR

brachytherapy(p

=0.03).For

concurrent

chem

othe

rapy,

53.1%

HIV-positive

and

74.6%

HIV-neg

ativepatients

completed

four

ormore

weeklycycles

ofplatinum

-basedtreatm

ent.

At6weeks,p

oorrespon

sewas

associated

with

stage

IIIBdisease(OR=2.39,95%

CI1.45–3.96)andreceiving

less

than

68GyEQ

D2

radiation(OR=3.14,95%

CI

1.24–794).

Goo

dmed

icalcare

ofHIV-

positivepatientscanen

able

patientsto

completetreat-

men

tforlocally

advanced

cervicalcancer

andmight

improverespon

seto

treatm

ent.

Mod

erate

Shrivastava

etal.,20

05[21]

Retrospe

ctive

review

Tode

term

inetheeffect

ofradiothe

rapy

inHIV

seropo

sitivecervicalcancer

patients,tumou

rrespon

seandtoxicity,and

compliance

ofpatientsto

thetreatm

ent.

42HIV

seropo

sitive

patients,mean

ageof

41years

India

IIIB–

IVA

Radiothe

rapy

Age

andsymptom

sof

presen

tatio

n,clinicalstage,

respon

se,

compliance,and

toleranceto

radiothe

rapy

Allpatientspresen

tedwith

thesymptom

sof

cervical

disease.Ofthesepatients31

(74%

)patientshad‘Karno

fsky

Perfo

rmance

Scale’(KPS)

morethan

80%.Twen

ty-one

(50%

)of

thepatientswereof

stageIIIb–

IVa.Thirty-tw

o(76%

)werestartedon

radio-

therapywith

radicalinten

t.Com

plianceto

radiothe

rapy

was

poor

with

24%

patients

discon

tinuing

afterfew

frac-

tions

ofradiothe

rapy.Seven

(17%

)patientsweregiven

palliativeradiothe

rapy.

Twen

ty-twopatientscom-

pleted

prescribed

radical

radiothe

rapy

and50%

oftheseachieved

completere-

spon

se.G

rade

III–IVacute

gastrointestinaltoxicity

was

seen

in14%

ofthepatients,

andgradeIIIacuteskin

tox-

icity

was

seen

in27%

ofpa-

tients,leadingto

treatm

ent

delays.The

rewas

good

relief

ofsymptom

sin

patients

treatedwith

palliativeintent.

Radiothe

rapy

iseffectivein

thissetof

patients.Palliative

fractionatio

nsche

dulesare

effectiveforpatientswith

poor

perfo

rmance

status

and

locally

advanced

cancersin

relieving

thesymptom

srelatedto

carcinom

acervix.

Anem

phasisshou

ldbe

givento

theincreasedacute

mucosalandskin

toxicity

andto

improving

complianceandclinical

outcom

eof

thesepatients.

Low

Mapanga et al. Systematic Reviews (2020) 9:79 Page 5 of 16

Table

1Tableof

eviden

ce(Con

tinued)

Firstauthor

&pu

blication

year

Stud

ytype

Purpose

Popu

latio

n&

age

Cou

ntry

Stageof

cancer

Treatm

entmetho

dOutcome(s)

Results

Autho

rs’C

onclusions

Quality

score

Gicha

ngi

etal.,20

06[22]

Prospe

ctive

coho

rtstud

yTo

determ

inetheim

pact

ofHIV

infectionon

acute

morbidity

andpe

lvictumou

rcontrolfollowingexternal

beam

radiothe

rapy

(EBRT)

forcervicalcancer

218patients,

20%

ofthem

HIV-positive

Kenya

Radiothe

rapy

Acute

treatm

ent

toxicity

andpe

lvic

tumou

rcontrol

Overall,53.4%

ofthepatients

hadradiation-relatedacute

toxicity

(grade

3–4).H

IVin-

fectionwas

associated

with

a7-fold

high

erriskof

multi-

system

toxicity:skin,gastro-

intestinaltract(GIT),and

genitourinarytract(GUT)

sys-

tems.Itwas

also

aninde

-pe

nden

triskfactor

for

treatm

entinterrup

tions

(ad-

justed

relativerisk2.2).A

bout

19%

ofthepatientshadre-

sidu

altumou

rat

4and7

mon

thspo

st-EBRT.HIV

infec-

tionwas

inde

pend

ently

and

sign

ificantlyassociated

with

6-fold

high

erriskof

residu

altumou

rpo

st-EBRT.Thehaz-

ardratio

ofhaving

residu

altumou

rafterinitialEBRT

was

3.1-tim

eslarger

forHIV-

positivethan

forHIV-

negativepatients(p

=0.014).

HIV

isassociated

with

increasedriskof

multisystem

radiation-relatedtoxicity;

treatm

entinterrup

tions

and

pelvicfailure

(residu

altumou

r)followingEBRT.H

IVinfectionisan

adverseprog

-no

sticfactor

forou

tcom

eof

cervicalcancer

treatm

ent.

Mod

erate

Mdletshe

etal.,20

16[23]

Prospe

ctive

quantitative

comparative

stud

y

Toevaluate

inde

tail

treatm

entrespon

se,its

toxicitiesandcomplianceof

HIV-positive

wom

ento

rad-

icalcombinatio

ntherapy

(radiothe

rapy

with

chem

othe

rapy)

55HIV-positive

(med

ianageof

40years)and55

HIV-neg

ative

(med

ianageof

55years)pa-

tientswith

per-

form

ance

status

ECOGI&

II

Zambia

IB2–IIIB

Com

binatio

nof

radiothe

rapy

and

chem

othe

rapy

givenconcurrently

Acute

reactio

nsto

radicalche

mo-

radiationand

toxicity

Allparticipantscompleted

EBRandHDRas

prescribed

.Average

EBRdo

sede

livered

was

48Gy,andthe

differencein

dose

received

was

sign

ificant

with

regard

toHIV

status

(p=0.022).

58%

ofHIV-positive

were

treatedwith

6.5Gy×4

brachytherapyfractions

ascomparedto

58%

HIV-

negativepatientstreated

with

8Gy×3fractions.

Therewereno

statistically

sign

ificant

differences

intoxicity

betw

eenHIV-positive

andHIV-neg

ativepatients

with

regard

toskin,G

ITsys-

tem,G

Usystem

,and

haem

o-po

ietic

system

.

Radicalche

mo-radiationin

conven

tionald

oses

was

safelytoleratedby

awell-

selected

cervicalcancer

HIV-

positivegrou

pon

HAART

andcouldbe

considered

suitableforsimilarpatients.

Mod

erate

Bou

paijit

and

Suprasert,

2016

[24]

Retrospe

ctive

stud

yTo

evaluate

thesurvival

outcom

esof

chem

othe

rapy

andtheprog

nosticfactorsin

thissetting

173patients

(meanageof

50.9year),with

4.1%

ofthem

HIV-positive

Thailand

IVB

Che

mothe

rapy

Survivalou

tcom

esandprog

nostic

factors

Med

ianoverallsurvivalo

fall

stud

iedpatientswas

13.2

mon

ths.

Onlyarecurren

ce-free

inter-

valo

fless

than

12mon

ths

was

aninde

pend

entprog

-no

sticfactor

forsurvival

outcom

e

Che

mothe

rapy

treatm

entfor

advanced

andrecurren

tcervicalcancer

patients

show

edmod

estefficacy

with

ashorterrecurren

ce-

freesurvivalless

than

12mon

thsas

asign

ificant

poor

prog

nosisfactor

Mod

erate

Mapanga et al. Systematic Reviews (2020) 9:79 Page 6 of 16

Table

1Tableof

eviden

ce(Con

tinued)

Firstauthor

&pu

blication

year

Stud

ytype

Purpose

Popu

latio

n&

age

Cou

ntry

Stageof

cancer

Treatm

entmetho

dOutcome(s)

Results

Autho

rs’C

onclusions

Quality

score

Ferreira

etal.,

2017

[25]

Coh

ortstud

yTo

assess

mortality,

treatm

entrespon

se,and

relapseam

ongHIV-in

fected

andHIV-uninfectedwom

enwith

cervicalcancer

inRio

deJane

iro,Brazil

87HIV-in

fected

and336HIV-

uninfected

wom

enwith

cervicalcancer

Brazil

IA/IB

1,IB2/II,

III,IVA

/IVB

28%

treatedwith

surgery,23%

with

radiation,

30%

with

chem

o-radiation,

and36%

received

additio

nal

brachytherapy

Mortality,treatm

ent

respon

seand

relapse

70%

HIV-in

fected

wom

enand76%

HIV-uninfected

wom

encompleted

recom-

men

dedtreatm

ent.

58HIV-in

fected

and176

HIV-uninfectedwom

endied

.Amon

gHIV-in

fected

wom

en,

overallm

ortalitywas

324pe

r1000

person

-years,w

ith82%

ofde

aths

dueto

cancer.

Amon

gHIV-uninfected

wom

en,o

verallmortality

was

209pe

r1000

person

-years,with

93%

ofde

aths

from

cancer.

Amon

g222patientstreated

with

radiothe

rapy,H

IV-

infected

hadsimilarrespon

seratesto

initialcancer

therapy

asHIV-uninfectedwom

en(HR0.98,95%

CI0.58–1.66).

How

ever,amon

gwom

enwho

weretreatedandhada

completerespon

se,H

IVwas

associated

with

elevated

risk

ofsubseq

uent

relapse(HR

3.60,95%

CI1.86–6.98,ad-

justed

forclinicalstage)

HIV

infectionwas

not

associated

with

initial

treatm

entrespon

seor

early

mortality,bu

trelapseafter

attainingacomplete

respon

seandlate

mortality

wereincreasedin

thosewith

HIV.

Thereisaroleforan

intact

immun

esystem

incontrolo

fresidu

altumou

rbu

rden

amon

gtreatedcervical

cancer

patients

Mod

erate

Moo

dley,

2017

[26]

Casestud

ies

Topresen

tradical

hysterectomyexpe

rienceto

inform

managem

entof

early-stage

invasive

cervical

cancer

18-year-old

nulliparous,36-

year-old

prim

-iparou

s,and39-

year-old

para

2HIV-positive

wom

en

South

Africa

Differen

tiated

squamou

scell

carcinom

a(LVSI)

Surgery(radical

hysterectomy)

Managem

ent

outcom

esafter

radical

hysterectomy

Allthreemadeun

even

tful

postop

erativerecoveriesand

allvaginalvaultcytologic

smearshave

been

negative.

The18-year-oldiswell6

yearspo

stsurgeryas

arethe

36-and39-year-olds

at3

yearsfollow-upvisits.

The39-year-oldpatient

need

eduretericre-

implantatio

ndu

eto

ureteric

stricture,w

hich

couldoccur

asarecogn

ised

complication

even

inHIV

Non

-infected

patients.

With

reason

able

levelsof

immun

osup

pression

,managem

entof

HIV-positive

wom

enwith

early

cervical

cancer

with

radicalh

ysterec-

tomycanprod

ucereason

-ableou

tcom

esandsurvival.

Low

Kietpee

rako

olet

al.2

006

[27]

Retrospe

ctive

coho

rtstud

yTo

evaluate

thetreatm

ent

outcom

esandcomplications

inhu

man

immun

odeficiency

virus(HIV)-infectedwom

enun

dergoing

loop

electrosurgicale

xcision

proced

ure(LEEP)

forcervical

neop

lasia

60HIV-in

fected

(meanageof

35.9years)and

61HIV-neg

ative

(meanageof

40.1years)

wom

enwith

cervical

neop

lasia

Thailand

LSIL–H

SIL

LEEP

LEEP

treatm

ent

outcom

esand

complications

inHIV-positive

wom

en

97.1%

and88%

ofHIV-

positivewom

enwere

disease-fre

eat

6and12

mon

ths,respectivelyafter

LEEP.

1.7%

hadsevere

intraope

rativehaem

orrhage,

5%hadearly

andlate

postop

erativehaem

orrhage,

11.7%

hadlocalised

infection

ofthecervixand3.3%

LEEP

appe

arsto

besafe

and

effectivein

HIV-in

fected

wom

en.

Mod

erate

Mapanga et al. Systematic Reviews (2020) 9:79 Page 7 of 16

Table

1Tableof

eviden

ce(Con

tinued)

Firstauthor

&pu

blication

year

Stud

ytype

Purpose

Popu

latio

n&

age

Cou

ntry

Stageof

cancer

Treatm

entmetho

dOutcome(s)

Results

Autho

rs’C

onclusions

Quality

score

develope

dcervicalsten

osis

at6mon

thsafterLEEP.

Nosign

ificant

differencein

overallcom

plications

(p=

0.24)be

tweenHIV-positive

andHIV-neg

ativepatients.

Firnha

ber

etal.2

017

[28]

Rand

omised

controlled

trial

Tocompare

cervical

cryotherapyto

observation

inHIV-in

fected

wom

enwith

CIN1on

histolog

y

202HIV-positive

wom

en(m

edian

ageof

37.9

years)with

CIN1

South

Africa

CIN1

Cryothe

rapy

CIN2/3by

histolog

yat

mon

th12.

Regression

ofcervicalhistolog

yto

noeviden

ceof

NILM

CIN2/3at

mon

th12,

occurred

in2of

99(2%)

wom

enin

thecryotherapy

arm

ascomparedwith

15of

103(15%

)wom

enin

theno

treatm

entarm

[86%

risk

redu

ction,

95%

confiden

ceinterval(CI)61

to97%;p

=0.0016].

Nocervicalcancersin

both

arms.Fortyof

99(40%

)wom

enin

thecryotherapy

grou

pexpe

rienced

regression

ascompared14

of103(14%

)wom

enin

the

notreatm

entgrou

p(69%

redu

cedregression

,95%

CI

58%

to83%,p<0.0001).

Treatin

gCIN1with

cryotherapyredu

ces

prog

ressionto

CIN2/3.The

bene

fitwas

exclusively

amon

gthosewith

hrHPV.

Cryothe

rapy

was

safe

inthis

popu

latio

nwith

noserio

usadverseeven

ts.

High

Woo

etal.,

2011

[29]

Prospe

ctive

coho

rtstud

yTo

estim

atethesafety,

tolerability,andacceptability

ofloop

electrosurgical

excision

proced

ure(LEEP)

for

cervicalintraepithelial

neop

lasia(CIN

2/3)

inHIV-

positivewom

en

180HIV-positive

wom

enKenya

CIN2/3

LEEP

Safety,tolerability

andacceptability

ofLEEP

after4weeks

post-procedu

re

179(99%

)repo

rted

“very

mild”to

mild

symptom

s,while1(n

=1%

)participant

describ

edthesymptom

sas

mod

erate.

MeanCD4+

coun

twas

sign

ificantlyhigh

eram

ong

wom

enwho

repo

rted

any

symptom

scomparedto

wom

enwho

repo

rted

nosymptom

spo

stLEEP

(419

cells/m

m3vs.349

cells/m

m3 ,

p<0.05)

Only16%

(CI11–22%,n

=29)of

wom

enrepo

rted

early

resumptionof

intercou

rse

priorto

their4-weekfollow-

upvisit

LEEP

perfo

rmed

byclinical

officerswas

well-accep

ted

byHIV

positivewom

enand

appe

arssafe,resultin

gin

minim

alside

effects,even

amon

gwom

enwith

early

re-

sumptionof

intercou

rse

Mod

erate

Kietpee

rako

olet

al.,20

06[27]

Prospe

ctive

stud

yTo

assess

outcom

ein

HIV-

positivewom

enun

dergoing

theloop

electrosurgicale

xci-

sion

proced

ure(LEEP)

70HIV-positive

(meanageof

37.5)and719

HIV-neg

ative

(meanage45.8)

wom

en.

Thailand

CIN1/2/3,IA1-

IB1

LEEP

Safety

ofLEEP

amon

gHIV-positive

patients

HIV

infectionwas

not

sign

ificantlyassociated

with

theincide

nceof

LEEP

complications

(adjusted

odds

ratio

,0.41;95%

CI,

0.15–1.15;p=0.10).

Therewereno

statistically

sign

ificant

differences

inop

erativetim

e,size

ofexcisedspecim

ens,incide

nce

of2or

morepasses

ofthe

LEEP

issafe

inHIV-in

fected

wom

enwith

cervicalne

opla-

siatreatedin

outpatient

set-

tings,and

whe

ntechnically

possible,a

repe

atinterven

-tio

nissafe,w

ithan

accept-

ablesuccessrate,even

thou

ghHIV-in

fected

wom

enhave

ahigh

erriskof

resec-

tionmargininvolvem

ent.

Mod

erate

Mapanga et al. Systematic Reviews (2020) 9:79 Page 8 of 16

Table

1Tableof

eviden

ce(Con

tinued)

Firstauthor

&pu

blication

year

Stud

ytype

Purpose

Popu

latio

n&

age

Cou

ntry

Stageof

cancer

Treatm

entmetho

dOutcome(s)

Results

Autho

rs’C

onclusions

Quality

score

loop

,oruseof

Mon

selp

aste

betw

eenthe2grou

ps.

Therewas

ahigh

erprevalen

ceof

LEEP

margin

involvem

entin

theHIV-

positivethan

intheHIV-

negativegrou

p(60.0%

vs49.4%).

Einstein

etal.,

2019

[30]

Rand

omised

controlled

Tode

term

inethefeasibility,

safety,and

tolerabilityof

concom

itant

chem

oradiotherapy

administeredat

standard

dosesin

HIV-in

fected

wom

enwith

locally

ad-

vanced

cervicalcancer

(LACC)receivingantiretro-

viralthe

rapy

(ART).

38HIV-

seropo

sitive

wom

enover

18yearsold

Sub-

Saharan

Africa

LACC

Con

comitant

chem

oradiotherapy

Feasibility,safety,

andtolerabilityof

concom

itant

chem

oradiotherapy

administeredat

standard

doses

Sixty-four

wom

enwere

screen

edat

twositesin

sub-

SaharanAfrica,o

fwho

m40

eligibleparticipantswereen

-rolled,

forascreen

ingratio

of1.60.O

fthe38

eligible

participantswho

initiated

stud

ytreatm

ent,31

(82%

)completed

treatm

ent.By

the

12-m

onth

follow-upvisit,7

wom

enhaddied

ofdisease

and29

of31

(94%

)returned

forfollow-up.

One

-year

prog

ression-fre

esurvivalwas

76.3%

(95%

CI,59.4–86.9%

),anddidno

tsign

ificantlydif-

feraccordingto

stageat

entry(p

=0.581).Participant-

repo

rted

adhe

renceto

ART

was

high

;by12

mon

ths,93%

ofparticipantshadan

un-

detectableviralload.

The

mostcommon

grade3or

4adverseeven

twas

decreased

lymph

ocytecoun

tthat

af-

fected

alltreated

partici-

pants.Non

-hem

atolog

icserio

usadverseeven

tswere

similarto

thoseob

served

inwom

enwith

LACCwith

out

HIV

infection.

Themajority

ofHIV-in

fected

wom

enwith

LACCcan

completeconcom

itant

che-

moradiotherapywith

the

samecisplatin

dose

used

inHIV-uninfectedwom

enwith

comparabletolerabilityand

high

ART

adhe

rencewhile

ontreatm

ent.

High

Smithet

al.,

2017

[31]

Rand

omised

controlled

trial

Toiden

tifyeffective

treatm

entmetho

dsforhigh

-gradecervicalprecursors

amon

gHIV-serop

ositive

wom

enby

comparin

gthe

differencein

theefficacyof

loop

electrosurgicale

xcision

proced

urevs

cryotherapyfor

thetreatm

entof

high

-grade

cervicalintraepithelialn

eo-

plasia(grade

≥2)

166HIV-

seropo

sitive

wom

enaged

18–65years

South

Africa

CIN2+

Cryothe

rapy

vsLEEP

Efficacyof

LEEP

and

cryotherapy

Cum

ulativecervical

intraepithelialn

eoplasia

grade≥2incide

ncewas

high

erforcryotherapy

(24.3%

;95%

confiden

ceinterval,16.1–35.8)than

LEEP

at6mon

ths(10.8%

;95%

confiden

ceinterval,5.7–19.8)

(p=.02),alth

ough

by12

mon

ths,thedifferencewas

notsign

ificant

(27.2%

;95%

confiden

ceinterval,18.5–

38.9vs

18.5%;95%

confiden

ceinterval,11.6–

28.8,p

=.21).C

umulative

Both

treatm

entsappe

ared

effectivein

redu

cing

cervical

intraepithelialn

eoplasia

grade≥2by

>70%

by12

mon

ths.Thedifferencein

cumulativecervical

intraepithelialn

eoplasia

grade≥2incide

nce

betw

eenthe2treatm

ent

metho

dsby

12mon

thswas

notstatisticallysign

ificant.

Relativelyhigh

cervical

intraepithelialn

eoplasia

grade≥2recurren

cerates,

indicatin

gtreatm

entfailure,

High

Mapanga et al. Systematic Reviews (2020) 9:79 Page 9 of 16

Table

1Tableof

eviden

ce(Con

tinued)

Firstauthor

&pu

blication

year

Stud

ytype

Purpose

Popu

latio

n&

age

Cou

ntry

Stageof

cancer

Treatm

entmetho

dOutcome(s)

Results

Autho

rs’C

onclusions

Quality

score

cervicalintraepithelial

neop

lasiagrade≥1

incide

nceforcryotherapy

(89.2%

;95%

confiden

ceinterval,80.9–94.9)didno

tdifferfro

mLEEP

(78.3%

;95%

confiden

ceinterval,68.9–

86.4)at

6mon

ths(p

=.06);

cumulativecervical

intraepithelialn

eoplasia

grade≥1incide

nceby

12mon

thswas

high

erfor

cryotherapy(98.5%

;95%

confiden

ceinterval,92.7–

99.8)than

LEEP

(89.8%

;95%

confiden

ceinterval,82.1–

95.2)(p

=.02).C

umulative

high

-grade

cytology

inci-

dencewas

high

erforcryo-

therapy(41.9%

)than

LEEP

at6mon

ths(18.1%

,p<.01)

and12

mon

ths(44.8%

vs19.4%,p

<.001).Cum

ulative

incide

nceof

low-grade

cy-

tology

orgreaterin

cryother-

apy(90.5%

)didno

tdiffer

from

LEEP

at6mon

ths

(80.7%

,p=.08);b

y12

mon

ths,cumulativeinci-

denceof

low-grade

cytology

orgreaterwas

high

erin

cryotherapy(100%)than

LEEP

(94.8%

,p=.03).

wereob

served

inbo

thtreatm

entarmsby

12mon

ths.Adifferent

treatm

entprotocol

shou

ldbe

considered

toop

timally

treatcervicalintraepithelial

neop

lasiagrade≥2in

HIV-

seropo

sitivewom

en

Mapanga et al. Systematic Reviews (2020) 9:79 Page 10 of 16

Treatment options for cervical neoplasia for HIVseropositive womenFive (38.5%) of the 13 included studies evaluated efficacy,treatment outcomes, and complications in HIV-seropositivewomen with cervical neoplasia treated with LEEP or cryo-therapy. Three studies evaluated LEEP [27, 29, 32], one com-pared cryotherapy with no treatment [28], and the othercompared LEEP and cryotherapy to identify effective treat-ment [31].

LEEPThree studies reviewing LEEP among HIV-positivewomen concluded that the procedure is safe and effect-ive. A retrospective cohort study in Thailand evaluatedtreatment outcomes and complications of HIV-infectedand HIV-negative women with a low-grade squamousintraepithelial lesion (LSIL) or high-grade squamousintraepithelial lesions (HSIL) undergoing LEEP [27]. TheHIV-infected cohort had a mean age of 35.9 years ascompared to 40.1 years of the HIV-negative cohort. After6 and 12 months of LEEP, 97.1% and 88.0% of HIV-infected women had no cervical neoplasia, respectively.In terms of complications, there was no significant dif-ference (p = 0.24) when compared to HIV-negativewomen [27]. These findings were almost similar to evi-dence generated in the same country 2 years later, whichfound out that there was no significant association be-tween HIV and LEEP complications among women withcervical intraepithelial neoplasia (CIN) grades 1, 2, 3,and cervical cancer stage 1A1–1B1 [32]. In Kenya, a pro-spective cohort study also confirmed that LEEP was welltolerated and accepted by HIV-positive women who hadCIN 2 and 3, with 99.0% of participants reporting ‘verymild’ symptoms of complications. Also, women with ahigher mean CD4+ count were likely to report symp-toms of complications as compared to women withlower mean CD4+ counts [29].

CryotherapyIn a randomised controlled trial in South Africa amongHIV-infected women with CIN1, treatment with cryo-therapy was found to significantly reduce progression toCIN2/3. After 12 months, only 2% of women undergoingcryotherapy treatment as compared to 15% not receivingtreatment (86% risk reduction, 95% CI 69–97%, p =0.0016) progressed to CIN2/3. Regression was also sig-nificant in women receiving cryotherapy as compared tothose not receiving treatment (69% reduced regression,95% CI 58–83%, p = 0.0001) [28].

Cryotherapy vs. LEEPTo try and identify an effective treatment method be-tween cryotherapy and LEEP for high-grade cervical pre-cursors (CIN2+) among HIV-seropositive women, a

randomised controlled trial was conducted in South Af-rica [31]. After 6 months of treatment, there was ahigher cumulative CIN2+ incidence for cryotherapy(24.3%, 95% CI 16.1–35.8) as compared to LEEP (10.8%,95% CI 5.7–19.8) at p = 0.02. However, after 12 monthsof treatment, there was no significant difference betweenthe two (27.2%, 95% CI 18.5–38.9 vs. 18.5%, 95% CI11.6–28.8) at p = 0.21 [31]. Both cryotherapy and LEEPare effective in reducing CIN2+, and a choice might bebased on available resources and expertise.

Treatment options for cervical cancer for HIV seropositivewomenTreatment of cervical cancer with radiation, chemother-apy, concurrent treatment using radiotherapy andchemotherapy, and surgery among HIV-seropositivewomen was evaluated in 8 (61.5%) out of the 13 in-cluded studies. The results of the treatment options arereported as themes as follows.

ChemotherapyA retrospective study in Thailand on 173 HIV-positiveand HIV-negative patients (with a mean age of 50.9years) with stage IVB cervical cancer showed modest ef-ficacy, with overall median survival among all patients of13.2 months. The only independent prognostic survivaloutcome was a recurrence-free interval of fewer than 12months [24]. In Brazil, HIV was found not to be associ-ated with mortality due to cervical cancer during thefirst year post-treatment, but the association was signifi-cant after more than 1 to 2 years post-diagnosis (overallmortality: adj HR = 2.02; 95% CI 1.27–3.22; cancer-specific mortality 4.35, 1.86–10.2) [25].

RadiotherapyA retrospective review conducted in India to determineradiotherapy’s effect on HIV-seropositive women ofmean age of 41 years with cervical cancer stage IIIB–IVA indicated that radiotherapy is effective, but compli-ance to the treatment is poor (with only 52.4% ofwomen completing the prescribed radical radiotherapyand 50.0% of them achieving complete response) [21].To overcome poor compliance, palliative radiotherapyschedules were prescribed, and these were identified tobe effective for HIV-seropositive women with cervicalcancer [21]. Despite it being effective, evidence hasshown that those undergoing radiotherapy present withacute skin toxicity (grade III) and grade III–IV acutegastrointestinal toxicity [21]. These findings were sup-ported by a prospective cohort study conducted inKenya, which showed that there was a 7-fold higher riskof developing multisystem (skin, gastrointestinal, andgenitourinary) toxicity if HIV-infected and have under-gone through radiotherapy [22]. This multisystem

Mapanga et al. Systematic Reviews (2020) 9:79 Page 11 of 16

toxicity was found as a factor contributing to the inter-ruption of treatment (adj. RR = 2.2) [22]. Follow-ups at4- and 7-months post-radiotherapy indicate that HIV-seropositive is 6-fold at risk of having a residual tumour(HR = 3.1, p = 0.0014) as compared to patients who areHIV-negative [22]. This finding was in accord with whatwas suggested in Brazil where there was an elevated riskof subsequent relapse for HIV-seropositive women ascompared to HIV-negative women (HR = 3.60; 95% CI1.86–6.98) [25].

Radiation and chemotherapyTo compare the clinical characteristic outcomes after ra-diation and chemotherapy among HIV-positive (medianage of 41 years) and HIV-negative women (median ageof 50 years) with cancer stage IBi-IIIB, a retrospectivecohort study was conducted in South Africa [20]. Treat-ment completion rates between the two patient cohortswere different, with 79.7% of HIV-positive and 89.8%HIV-negative completing their radiation dose andbrachytherapy (p = 0.03). For concurrent chemotherapy,only 53.1% HIV-positive and 74.6% HIV-negative man-aged to complete 4 or more weekly cycles. After 6 weeks,poor response to treatment was significantly associatedwith stage IIIB (OR = 2.39, 95% CI 1.45–3.96) and re-ceiving less than recommended radiation dose (OR =3.14, 95% CI 1.24–7.94) [20].

Combination of radiotherapy and chemotherapyA prospective quantitative comparative study in Zambiaevaluated the treatment response, treatment toxicities,and compliance to radical chemo-radiation among bothHIV-positive (median age of 40 years) and HIV-negative(median age of 55 years) women with stage IB2-IIIB can-cer [23]. As opposed to a failure to complete treatmentas indicated by evidence in South Africa [20], all partici-pants in this prospective study completed their treat-ments. Well-selected HIV-positive cervical cancerpatients on HAART can safely tolerate radical chemo-radiation in conventional doses [23]. The difference inchemo-radiation doses (6.5 Gy × 4 for 58% of HIV-positive women vs. 8Gy × 3 for 58% of HIV-negativewomen) was significant to HIV status (p = 0.022). Interms of toxicity (regarding GIT system, skin, haemopoi-etic system, and GU system), there were no significantdifferences between HIV-positive and HIV-negative pa-tients [23]. In a study of 38 HIV-positive women with lo-cally advanced cervical cancer, the safety, tolerability,and feasibility of concomitant chemoradiotherapy wereassessed in two sites in sub-Saharan Africa. Results indi-cated that HIV-infected women (82%) who adhere toART can tolerate and complete concomitant chemora-diotherapy as HIV-negative women. After 1 year with 7women dead due to cervical cancer, 29 of the remaining

31 (94%) returned for a scheduled clinical visit andprogression-free survival was at 76.3% (95% CI, 59.4–86.9%) [30].

Surgery (radical hysterectomy)Three case studies in South Africa of HIV-positivewomen with LVSI, an 18-year-old nulliparous, 36-year-old primiparous, and 39-year-old para-2, examined theradical hysterectomy to inform management of early-stage invasive cancer [26]. After 6 years post-surgery, the18-year old has recovered, and all the vaginal vault cyto-logic smears have come negative. At 3 years of follow-upvisits, both the 36- and 39-year olds have also recoveredand with negative vaginal vault cytologic smears [26].

Quality assessment of included studiesFew studies (n = 2, 15.4%) were determined to be of‘high’ quality using a combination of the modifiedNewcastle-Ottawa Quality Assessment Scale and theNIH Study Quality Assessment Tools for observationalcohort cross-sectional case-control and before-afterstudies [18, 19]. Most of the studies (n = 9, 69.2%) wereof ‘moderate’ quality, and two (15.4%) were of ‘low’ qual-ity. Adequate randomisation, enough sample sizes, pre-specified inclusion and exclusion criteria, specified studypopulation, and clearly defined exposure and outcomesmeasures were all available in both controlled interven-tions [28, 31], and this increased the confidence that thereported results might have been attributable to theintervention than the difference in groups. For thebefore-after studies, 6 out of 9 studies had a controlgroup [20, 23, 25, 27, 29, 32], specified inclusion and ex-clusion criteria, and defined exposure and outcome mea-sures, and this also increased confidence that thereported improvements between before and after evalua-tions were not merely by chance. However, differentparticipants’ selection, small sample sizes, and shortfollow-up periods among other studies [20–22, 28, 31],including two descriptive studies [24, 26] that did notmention how study participants were chosen or how ex-posure and outcomes measures were defined, might re-quire their results to be interpreted with caution. Also,inadequate follow-up periods, failure to measure or in-clude confounders in analyses, and lack of validity of re-ported outcomes might have resulted in some studiesoverestimated the effectiveness of the reportedinterventions.

DiscussionThis systematic review aimed to synthesise available evi-dence on treatment modalities for both cervical neopla-sia and cervical cancer in HIV-seropositive women indeveloping countries. Most cervical cancer patients arereported to be diagnosed at an advanced stage of the

Mapanga et al. Systematic Reviews (2020) 9:79 Page 12 of 16

disease because of the lack of coordinated and system-atic screening [9, 10]. Besides, lack of optimal treatmentregimen due to factors such as lack of infrastructure, fi-nancial, and human resources has been found to contrib-ute to poor outcomes of treatment among HIV-seropositive women in developing countries [10, 13]. Thefindings of this systematic review have shown that theavailable cervical cancer treatments, radiotherapy, chemo-therapy, chemoradiation, and surgery appear to be effect-ive for HIV-seropositive patients and are the sametreatments being used for HIV-negative patients as well asin developed countries. This review has also shown thatopportunities to improve cervical neoplasia and cervicalcancer management in HIV-positive women exist. How-ever, developing countries need to prioritise early diagno-sis and treatment of precancerous lesions to reducecervical cancer and align with 2030 Sustainable Develop-ment Goals to reduce non-communicable diseases mortal-ity. As most developing countries put plans and measuresin place for universal health coverage by 2030, it is para-mount that benefits packages to be offered should includecervical cancer screening, HPV vaccination, testing, andtreatment especially for HIV-positive women if they are toachieve the same impact as developed countries.The introduction of life-long antiretroviral (ART) has

been found to moderately reduce HPV infection inci-dences [33]. Despite the moderate effect on HPV infec-tion, ART is prolonging the life span of those infectedwith HIV, thereby granting time for the development ofcervical neoplasia and cervical cancer especially in coun-tries with not well-established cervical cancer screeningprograms. This systematic review has confirmed that theavailable treatments for both cervical neoplasia and cer-vical cancer (if detected early) among HIV-seropositivewomen appear to be effective. However, clinical, methodo-logical, and statistical heterogeneity, such as participants’baseline characteristics, immunosuppressive status,follow-up time, randomisation versus non-randomisation,sample sizes, and statistical calculations, among the 10studies, might explain some the differences in the findings.In this review, almost all the included studies had HIV-seropositive women who were younger than HIV-negativewomen were.This systematic review demonstrated that LEEP and

cryotherapy treatments have the possibility of reducingprogression from LSIL to HSIL as well as causing regres-sion of cervical neoplasia [27, 29, 31, 32]. However, thistreatment benefit was exclusively significant amongwomen with high-risk HPV and might point to a needfor further multicentre research to explore the reasonsfor such a finding.In as much as LEEP was reported to be safe, several

complications, such as severe intraoperative haemorrhage,early and late postoperative haemorrhage, localised

infection of the cervix, and cervical stenosis, were experi-enced in both HIV-positive and HIV-negative women al-though the difference was insignificant [27]. Despite nodifference in complications between HIV-positive andHIV-negative women, further research on reasons forsuch complications need to be assessed and explored toinform best clinical practices.In India, treatment with radiotherapy was seen to be

effective among HIV-seropositive women with cervicalcancer stage IIIB-IVA [21], and these findings were sup-ported by evidence from Kenya [22]. However, the asso-ciated acute treatment toxicity of radiotherapy amongHIV-positive women was seen to be an independent sig-nificant risk factor that interrupts or delay treatmentresulting in most of these women not completing theirprescribed treatments [22]. Acute gastrointestinal, skin,and genitourinary tract toxicity is the most prominentradiation-related acute toxicities and is associated withHIV [21, 22]. These multisystem acute toxicity findingscontrast with what was identified in a radical chemoradi-ation prospective study which reported no statisticallysignificant differences between HIV-positive and HIV-negative patients [23]. Therefore, further studies examin-ing patients’ baseline characteristics such as time ofHAART or CD4+ counts will need to be conducted toanalyse why studies are reporting different findings.Being HIV-seropositive prevents the success of radio-

therapy as most patients will not complete prescribedtreatment due to associated multisystem toxicities henceresulting in poor response and outcomes in some cases.After 7months post-radiotherapy, HIV-seropositivewomen were 3.1 times likely to have a residual tumour ascompared to HIV-negative [22]. These findings indicatethat completing radiation is a predictor of treatment re-sponse among HIV-seropositive women [20, 34]. Palliativeradiotherapy fractionation has been reported to be effect-ive in HIV-seropositive patients with poor performanceand advanced cancer [22], but having an intact immunesystem and a higher CD4+ count is a positive indicator totreatment response and reduction of tumour [25].Despite completing prescribed treatment being an indi-

cator of treatment response in radiotherapy [21, 22], evi-dence on chemotherapy indicates that treatmentcompletion did not have a greater effect or impact on theresponse after 6 weeks as compared to radiotherapy [20].Besides, cervical cancer stage IIIB was indicated to be as-sociated with poor chemo-radiation after 6 weeks [20],and this might suggest that offering a full dose of radiationcoupled with good medical care in terms of associatedtoxicities [21, 22] might be beneficial to HIV-seropositivewith advanced cervical cancer. This suggestion is sup-ported by findings that show that chemo-radiation incre-mental benefit as compared to radiotherapy is minimal[35]. However, these findings required further studies to

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be conducted with large numbers of patients to assess thereported treatment outcomes because the evidence inZambia has indicated that conventional doses of radicalchemo-radiation are well tolerated and effective for HIV-seropositive women who are on HAART [23].Three radical hysterectomies on reasonably stable im-

munosuppressive HIV-seropositive patients with cervicalcancer stage IB-IIA appeared to produce better treat-ment and survival outcomes, with all three patients hav-ing negative vault cytologic smears after 3- and 6-yearspost-surgery [26]. However, because of the few patientsreported in this radical hysterectomy study, there mightbe a need to explore further the impact of this treatmentand associated outcomes.

LimitationsDespite the overall quality of the included studies beingmoderate, some of the reported results were affected bythe risk of bias associated with the comparability of ef-fects, populations, and information including lack of ex-planations on the conducted statistical analyses. Bylimiting our study searches to those reported in English,this systematic review might have missed some relevantstudies published in other languages.

ConclusionsThose infected with HIV were younger and have ad-vanced disease as compared to those who were HIV-negative [20–25, 27–29, 31, 32]. In as much as the massHPV vaccination is targeting 9- to 13-year-old younggirls, it can be argued, based on the findings from thisreview, that developing countries must offer targetedvaccination [36] to HIV-positive adolescents and youngwomen between the ages of 13 and 26 years throughalready established HIV clinics, to increase vaccinationcoverage and consolidated potential benefits. This is inline with the Guidelines for Prevention and Treatmentof Opportunistic Infections in HIV-Infected Adults andAdolescents [37]. Offering routine cervical cancerscreening and HPV testing in HIV clinics might help inearly identification of these at high-risk women who arerelatively ignorant and lack knowledge about cervicalcancer risk factors. Facilitation and putting HIV-infectedpeople on life-long ART is of importance and has beenfound to have a positive impact on cervical cancer treat-ment response.

Implications of the review’s results to evidence-based health careBased on this review, the following key messages on thereliability of the findings have emerged:

� Both cervical neoplasia and cervical cancer in HIV-seropositive women are treatable with the available

treatment, and better outcomes are associated withearly diagnosis and treatment availability. Also, theseare the same treatments that are available indeveloped countries and have made a tremendousimpact. However, the differences between developingand developed countries are around lack of optimaltreatment regimen and underutilisation of availablecervical cancer services due to cost, lack of knowledge,lack of infrastructure, and human resources thatcontinue to hamper developing countries. There is aneed for good clinical management of HIV-seropositive women undergoing chemo-radiation tomanage multisystem toxicities that have a bearing ontreatment completion, prognostic, and survivaloutcomes. Research on cervical cancer managementof HIV-seropositive patients focusing on the quality oflife of those treated, the effectiveness of the treatmentmethod considering CD4+ count, and ART isrequired.

� As HPV infections continue to be high among HIV-positive women regardless of ART, primaryprevention through HPV vaccination is criticallyneeded among young HIV-positive girls at therecommended ages since the vaccine is safe andbeneficial to them. Most HIV-seropositive womenwith cervical cancer are young, and screening fromthe age of 15 years, taking into consideration earlysexual debut and high HIV incidence, might increaseearly identification of at-risk young women. There isa need to strengthen health systems by establishingrobust and regular cervical cancer screening andHPV testing beginning at age 21 in HIV testing andtreatment clinics. Multicentre research on earlyscreening of young women is required to informfeasibility, appropriateness, meaningfulness, andcost-effectiveness.

Supplementary informationSupplementary information accompanies this paper at https://doi.org/10.1186/s13643-020-01345-2.

Additional file 1. PubMed and OvidSP (MEDLINE and Embase) SearchStrategies. This file contains two examples of the search strategies usedto search for studies that were included in this literature review. Thesearch strategies are for PubMed, MEDLINE and Embase databases.

AbbreviationCINAHL: Cumulative Index to Nursing and Allied Health Literature;CIN2+: Cervical intraepithelial neoplasia grade 2+; EMBASE: Excerpta MedicaDatabase; HIV: Human immunodeficiency virus; HPV: Human papillomavirus;HPV DNA/mRNA: Human papillomavirus deoxyribonucleic acid/messengerRNA; HSIL: High-grade squamous intraepithelial lesion; LEEP: Loopelectrosurgical excision procedure; LSIL: Low-grade squamous intraepitheliallesion; PRISMA: Preferred Reporting Items for Systematic Review and Meta-Analysis; RCT: Randomised controlled trial

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AcknowledgementsThe review team is grateful to Rutendo Chinomona-Mapanga for her com-ments and insights on the systematic review.

Authors’ contributionsThe principal reviewer WM designed this systematic review including itsregistration with PROSPERO. As the principal reviewer, WM led the literaturesearches, screening process, data extraction, and analysis. All the teammembers participated in the literature search and screening, data extraction,and analysis. The final version of the manuscript was critically appraised andapproved by all the authors.

Authors’ informationWM is a Public Health Specialist and Cancer Clinical Epidemiologist, and thisstudy was part of his Ph.D. at the School of Health Systems and PublicHealth, University of Pretoria. WM’s research was focusing on cervical cancerand HIV in developing countries. ES is the Head of the South AfricanNational Cancer Registry. BGB is a professor of Biostatistics at theDepartment of Epidemiology and Biostatistics at the University of Pretoria. SFis a professor of Biostatistics and Epidemiology at the Faculty of HealthSciences, University of Fort Hare.

FundingThe research project, which this systematic review is part of, has beenfunded by the University of Pretoria (program code 10260404). TheUniversity of Pretoria had no role in designing this systematic review, how itwas conducted, writing of the manuscript, or the decision to publish thissystematic review.

Availability of data and materialsThe analysed data and materials are included in this publication.

Ethics approval and consent to participateThis systematic review is part of a bigger research project. Ethical approvalfor the project was obtained from the Research Ethics Committee of theFaculty of Health Sciences, University of Pretoria (ethics reference number:146/2016)

Consent for publicationNot applicable.

Competing interestsThe authors declare that they have no competing interests.

Author details1School of Health Systems and Public Health, Epidemiology & Biostatistics,University of Pretoria, 5-10 H.W. Snyman Building, Pretoria, South Africa.2Non-Communicable Diseases Research (NCDR) Division of the Wits HealthConsortium, Faculty of Health Sciences, University of the Witwatersrand,Johannesburg, South Africa. 3Brooklyn, South Africa. 4Cancer EpidemiologyResearch Group, National Cancer Registry, National Health Laboratory Service,Johannesburg, South Africa. 5Community Medicine Unit, School of PublicHealth, University of the Witwatersrand, Johannesburg, South Africa. 6Facultyof Health Sciences, The University of Fort Hare, P.O. Box 1054, 45 ChurchStreet, Gasson Building, 7th Floor, East London 5201, South Africa.

Received: 29 August 2019 Accepted: 30 March 2020

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