Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Title
The Effect of Highly Active Antiretroviral Therapy on Human Papilloma Virus Infection and Cervical
Cytological Abnormalities in Women Living With HIV
Background
Human Papillomavirus (HPV) infection causes cervical cancer. The prevalence of HPV-related
dysplastic lesions is significantly higher in patients co-infected with the HI virus and thought to be
linked to possible more persistent HPV infection. There is, however, conflicting evidence as to
whether treatment of Human Immunodeficiency Virus (HIV) infection with antiretroviral agents may
influence cervical HPV infection and the behaviour of Squamous Intraepithelial Lesions (SIL).
Aims
To examine the effect of the initiation of combination antiretroviral therapy (cART) on: 1) the
persistence of cervical Low-grade SIL (LSIL); 2) The progression of cervical LSIL to High-Grade
SIL (HSIL); 3) The effectiveness of excision treatment of HSIL 4) HPV genotypes detected, in HIVinfected
and uninfected women at the Infectious Diseases Clinic and the Colposcopy Clinic,
Tygerberg Teaching Hospital, Cape Town, South Africa.
Design and Methods
We conducted a retrospective cohort analysis of 1720 women with LSIL of the survival of
progression-free-time or time-to-clearance. Time to progression or persistence was compared
according to HIV status, antiretroviral treatment and CD4 count. In another retrospective cohort
analysis, we investigated the effectiveness of excision treatment in 1848 women who underwent
LLETZ or CKC biopsy was used. Logistic regression and survival analysis were used to compare
excision treatment failure and recurrence-free time between groups according to HIV status,
antiretroviral therapy and CD4 count.
To investigate the effect of antiretroviral therapy on the cervical HPV infection, 300 HIV-infected
women were prospectively enrolled and followed at 6-monthly interval. Cytological testing and
cervical HPV sampling were done at each visit. Biopsy of suspicious lesions and excision treatment
were done at colposcopy clinic according to standard a protocol. The Roche Linear array HPV
genotyping test was used for HPV detection. Generalized Estimating Equation (GEE) multivariate
analysis was applied to investigate the effect of cART on the detection of HPV infection, while
adjusting for time-dependent covariates such as CD4 count, sexual activity and excision treatment.
The effect on each HPV type was then also compared to the effect on HPV16.
Results
Overall, we found that there was no difference between the progression of LSIL to HSIL by HIV
status. However, among HIV-infected patients, those who started ART before first LSIL had a
significantly lower risk for progression (HR 0.66, 95% CI 0.54-0.81). CD4 count did not have an
impact on the risk for progression. We also found lower persistence of SIL in the HIV uninfected
group (HR 0.69, 95% CI 0.57-0.85) and that cART was independently associated with decreased
persistence of LSIL. On the other hand, a higher CD4 count at the time of first LSIL was not
associated with lower persistence of the lesion. HIV infected women with HSIL experienced much higher excision treatment failure than uninfected
women (53.8% vs. 26.9%, p<0.001). Factors that improved outcome were higher CD4 count and
complete excision.
cART reduced the risk of detection of any HPV type by 47% (OR 0.53, 95% 0.49-0.58, p<001).
When adjusted for covariates, time of exposure to cART and CD4 had a stronger effect. Every month
of cART exposure reduced the risk detection of any HPV type with 7%. The effect was also
significant on HPV16 alone (OR 0.93, 95% CI 0.90-0.95). All non-oncogenic subtypes were
influenced similarly or more strongly than HPV16, as well as oncogenic HPV52. Only one oncogenic
subtype HPV subtype, HPV39, was influenced marginally less (ratio of OR 0.95, CI 0.90-0.99,
p=0.04).
There was an increased risk for any HPV detection at CD4 count<200 (OR 1.63, 95% CI:1.50-1.77),
but when adjusted, the time of cART exposure again remained the strongest predictor of risk (OR
0.94, 95% CI:0.93-0.95).
Conclusion
cART impact the outcome of cervical HPV infection by increasing clearance, decreasing progression
of LSIL and recurrence after excision treatment. This effect is time dependent and also associated
with CD4 count. Specifically, HPV16 detection risk is also reduced by cART, and all HPV types are
influenced at least as much as HPV16, except possibly HPV39. It seems that increased cervical HIVproviral
load is associated with HPV detection risk, and both are lowered by cART time. / AFRIKAANSE OPSOMMING: Titel
Die Effek van Kombinasie Antiretrovirale Terapie op Menslike Papilloomvirusinfeksie en Servikale
Sitologiese Abnormaliteite in Menslike Immuniteitsgebrekvirus-geïnfekteerde Vroue
Agtergrond
Menslike Papilloomvirusinfeksie (MPV) veroorsaak servikale kanker. Die prevalensie van MPVverwante
displastiese letsels is betekenisvol hoër in pasiënte wie ook met Menslike
Immuniteitsgebrekvirus (MIV) geïnfekteer is en dit word gereken dat dit te wyte is aan meer
persisterende MPV infeksie. Daar is egter teenstrydige bewyse oor of die behandeling van MIV
infeksie met antiretrovirale (ART) middels die infeksie met MPV en die gedrag van Plaveisel
Intraepiletiële letsels (PIL) kan beïnvloed.
Doelwitte
Om die effek van die inisiasie van kombinasie ART op: 1) die persistering van Laegraadse PIL
(LPIL); 2) die progressie van servikale LPIL na hoëgraadse PIL (HPIL) 3) die sukses van
eksisiebehandeling van HPIL; 4) MPV genotypies waarneembaar, in MIV-geïnfekteerde vroue by die
Infeksiesiektekliniek en die Kolposkopiekliniek,Tygerberghospitaal, Kaapstad, Suid-Afrika, te
ondersoek.
Studie-ontwerp en Metodes
`n Retrospektiewe kohort-analise op 1720 vroue met LPIL van die oorlewing van progressive-vrye
tyd en tyd tot opklaring van PIL is gedoen. Tyd tot progressie of opklaring is vergelyk na aanleiding
van die pasiënt se MIV status, behandeling met antiretrovirale terapie en CD4-telling. In nog `n
retrospektiewe kohort-analise is die effektiwiteit van eksisiebehandeling in 1848 vroue wie LLETZ or
Kouemeskonus eksisie ondergaan het, ondersoek. Logistiese regressie en oorlewingsanalise is
toegepas om die voorkoms van onsuksesvolle uitkoms en tyd sonder herhaling van letsels tussen
groepe te vergelyk na aanleiding van MIV status, ART en CD4-telling.
Om die effek van antiretroviral therapie op servikale MPV infeksie te ondersoek, is 300 MIVgeïnfekteerde
vroue opgeneem in `n prospektiewe studie en sesmaandeliks opgevolg. Sitologiese en
MPV servikale smere is met elke besoek geneem. Biopsies van verdagte letsels en eksisiebehandeling
is by die Kolposkopiekliniek gedoen volgens die standaardpraktyk. Die Roche Linear Array HPV
Genotyping toets is gebruik vir MPV deteksie. Algemeen-beraamde vergelyking (GEE)
meerveranderlike analise is toegepas om die effek van die anti-MIV terapie op die teenwoordigheid
van MPV op die serviks te ondersoek. Die aangepaste effek is ook getoets deur die CD4-telling, die
seksuele aktiwiteits- en eksisiebehandelingstatus by elke besoek in ag te neem. Die effek op elke
MPV genotipe is laastens dan ook vergelyk met die effek op ‘n spesifieke basislyn genotype; in
hierdie geval was MPV16 gekies.
Resultate
Daar was geen statisties beduidende verskil tussen die progressie van LPIL na HPIL na aanleding van
HIV status nie, maar pasiënte wie met ART begin het voordat hulle vir die eerste keer met LPIL
gediagnoseer was, het ‘n laer risiko gehad vir progressie (HR 0.66, 95% VI 0.54-0.81). Daar is ook
gevind dat dit onafhanklik van die CD4 telling was. Die persistering van PIL was laer in die MIV
negatiewe groep (HR 0.69, 95% VI 0.57-0.85), maar ook hier was antiretrovirale behandeling
geassosieer met verminderde persistering. Weer eens was daar nie ‘n verband met die CD4 telling nie. MIV-geinfekteerde vroue met HPILwas baie meer geneig tot gefaalde eksisiebehandeling (53.8%
teenoor 26.9%, p<0.001). Verbeterde uitkoms was geassosieer met ‘n hoër CD4-telling en ‘n eksisie
wat as volledig beskryf was. ART wat reeds voor die eksisiebehandeling begin was, het nie die risiko
vir onsuskesvolle uitkoms statisties beduidend verminder nie, maar het egter die risiko vir herhaling
van letsels na die eksisie sterk verlaag.
ART het die kans dat enige MPV tipe waargeneem sou word, met 47% verlaag (OR 0.53, 95% VI
0.49-0.58, p<001). Wanneer aangepas vir ander faktore, was die tyd wat verloop het sedert ART
begin was, sowel as vir die CD4 telling, sterker. Vir elke maand sedert ART begin was, het die kans
dat enige MPV tipe waargeneem word, met 7% verminder. `n Soortgelyke effek is op HPV16 alleen
gevind (OR 0.93, 95%, VI 0.90-0.95). Die effek was net so sterk of sterker op alle subtipes. Slegs een
onkogeniese subtipe, MPV39, was gering minder beïnvloed (ratio van OR 0.95, VI 0.90-0.99,
p=0.04).
Die kans vir waarneming van enige MPV subtype is hoër wanneer die CD4 telling laer as 200 selle/ɥl
is (OR 1.63, 95% VI: 1.50-1.77), maar wanneer aangepas, was die tyd van ART weer eens die sterkste
voorspeller van MPV infeksie (OR 0.94, 95% VI:0.93-0.95).
Gevolgtrekkings
ART verbeter die uitkoms van servikale infeksie met MPV deur progressie en persistering van LPIL
en herhaling van PIL na eksisie te verminder. Die effek is tydsafhanklik en word ook deur die CD4
telling beïnvloed. Die kanse dat MPV16 spesifiek waargeneem word, word ook deur ART verminder,
en all MPV tipes ondervind dieselfde of groter verlaging van waarnemingsrisiko as MPV16, behalwe
miskien MPV39. Ons kon aandui dat verhoogde teenwoordigheid van servikale MIV verband hou met
die risiko vir die waarneming van MPV infeksie, en beide word verminer deur die tyd waarmee die
pasiënt met ARV terapie behandel is.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/86158 |
| Date | 04 1900 |
| Creators | Zeier, Michele D. |
| Contributors | Nachega, Jean B., Botha, Matthys H., Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. General Internal Medicine. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | 157 p. : ill. |
| Rights | Stellenbosch University |
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