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Human herpesvirus 8 and Kaposi's sarcoma in the Amsterdam cohort studies.
Disease association, transmission and natural history
Renwick, N.M.
Publication date
2001
Link to publication
Citation for published version (APA):
Renwick, N. M. (2001). Human herpesvirus 8 and Kaposi's sarcoma in the Amsterdam cohort
studies. Disease association, transmission and natural history.
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Kaposi'ss sarcoma (KS) and human herpesvirus 8
(HHV8)) infection do not protect HIV-1 infected
homosexuall men from AIDS dementia complex (ADC)
NeilNeil Renwick, Gerritjan Weverling, Teysir Halaby, Peter Portegies, MargreetMargreet Bakker, Thomas F. Schulp Jaap Goudsmit
Abstract t
Objective:: T o examine the association between KS, H H V 8 and ADC.
Design:: 599 H1V-1 infected homosexual men have participated in a prospective cohort study (Amsterdam, 1984-1996).
Methods:: The risk for ADC in patients with prior KS or H H V 8 infection was estimated using the Cox proportional hazards methodd with adjustments for antiretrnviral medication and low CD4+ cell counts.
Results:: 290 (48.4%) of the 599 participants had H H V 8 antibodies, 99 (16.5%) had KS and 30 (5.0"/») had ADC. ADC was diag-nosedd in 5.2% of participants with KS and 5.0% of those without KS, and in 4.8% of HHV8 seropositive compared to 5.2% seronegativee individuals and thus not associated with KS or HHV8 infection. Using a time-dependent Cox proportional hazards analysiss with the date of KS as risk factor, the risk for ADC is 2.7 (95%CI: 0.92-7.96; p=0.07) and when only definite ADC is con-sideredd is 3.5 (95%CI: 1.00-12.26; p=0.05). After adjusting for decreases in CD4+ cell count and use of medication, the hazards ra-tioo for participants with KS to develop ADC is 2.0 (95%CI: 0.66-5.77; p=ü.23) and 2.6 (95%CI: 0.73-9.12; p=0.14), respectively. H H V 88 seropositivitv, adjusted for the same variables, shows a risk for ADC of 0.85 (95%CI: 0.41-1.77; p=0.66) and for definite ADC,, 0.69 (95%CI: 0.27-1.73; p=0.42). The expected neuroprotective effects of antiretroviral medication are observed.
Conclusions:: KS or H H V 8 does not significantly influence the risk for developing ADC in a group with an uniform risk for devel-opingg KS therefore we recommend caution in searching for a KS-associated or HHV8-derived therapy for ADC.
INTRODUCTION N
Interestt in the decreased risk that a diagnosis of Kaposi's sarcomaa (KS) confers on AIDS Dementia Complex (ADC) wass rekindled following the demonstration that an HHV8-encodedd chemokine, vMIP-II, blocks the entry of HIV-11 into C D 4 + cell lines that express CCR3 such as microgliaa (1,2). Boshoff et al. hypothesized that patients withh KS, or high HHV8 load, may be less likely to develop ADCC (2 ). The majority of epidemiological studies have subsequentlyy demonstrated a protective association be-tweenn KS and ADC (3-8 ). N o association was seen in one casee control study however the authors concluded that "in orderr to make reliable statements concerning the protective effectss that complete neurological, neuropathological and clinicall data" were required (9).
Wee have previously demonstrated that HHV8 antibodies aree a strong risk factor for KS in the Amsterdam Cohort Studiess on HIV-1 infectio(10,ll) and note that the influ-encee of HHV8 antibodies on ADC has been examined in twoo studies; no association was seen in one study whereas a higherr geometric mean titer (GMT) of HHV8 antibodies wass seen in HIV patients without ADC than in those with ADCC (7,8). In our prospective study we focus on a single HIVV transmission group with a uniform risk for KS to in-vestigatee whether a diagnosis of KS or the presence of HHV88 antibodies is associated with a low risk for ADC and findd no evidence for a protective effect of HHV8 infection orr KS against ADC among homosexual men.
METHODS S
Studyy population and study period Statistical methods
Thee study population consists of 599 HIV-1 infected ho-mosexuall men who participated in the Amsterdam Cohort Studiess on HIV infection and AIDS between Dec 1984 and Decc 1996.
Serologicc assays and study design
Thee EIA system and Western Blot assays for the detection off HHV8 and HIV antibodies respectively and the study design,, have been described in a previous publication (10).
Diagnosticc criteria
Thee diagnoses of definite ADC were made according to the 19877 CDC surveillance case definition (12). Those patients whoo met the clinical criteria for definite ADC but lacked ei-therr CSF, CT or autopsy findings to exclude other illnesses, weree termed provisional ADC. CNS diseases including toxoplasmosis,, progressive multifocal leukoencephalopa-thy,, and cerebral lymphoma were excluded by CT or MRI; metabolicc and toxic encephalopathies were excluded by ex-tensivee blood or urine tests.
Alll participants were homosexual men who were either HIVV seropositive at enrolment in the cohort or who be-camee HIV seropositive during follow up and the date of HIVV seroconversion was taken as the start of observation time.. Prevalences of KS, HHV8 antibodies and ADC were calculatedd for the 599 participants at the end of the study period.. For individuals who tested positive for HHV8, the datee of seroconversion was distinguished by testing earlier samples.. The risk of ADC as predicted by a diagnosis of KS orr the presence of HHV8 antibodies was estimated using a time-dependentt Cox proportional hazards model. In this model,, observation time started at either the moment of HIV-11 seroconversion or the datee of study entry for HIV-1 seropositivee participants; the date of HHV8 seropositivity orr KS diagnosis were time-dependent factors. In addition, too adjust for deterioration of the immune system, the mo-mentt that the CD4+ cell count dropped below 100 or 50 cells/mm(3)) was included in the time-dependent model. Finally,, we entered a time-dependent variable for the use of antiretrovirall medication to adjust for the protective effect off antiretroviral medication on the occurrence of ADC. Dataa were censored at December 31, 1996.
RESULTS S
Crosss sectional analysis
T w oo h u n d r e d a n d ninety (48.4%) of the 599 participants hadd F I I I V 8 antibodies and 99 (16.5%) had K S . Thirty (5.0%)) o f the 599 participants m e t the criteria for definite or provisionall A D C , o f w h o m 19 (3.2%) were diagnosed with definitee A D C ADC" was d i a g n o s e d after K S in 5 (5.2%) of 977 p a r t i c i p a n t s , in 2 participants before K S , and in 25 (5.0%)) of 502 participants w h o w e r e never diagnosed with K SS ( O R : 1.5, 9 5 % C I : 0.5-3.7). A D C was diagnosed in 14 (4.8%)) o f 290 H H V 8 positive individuals and 16 (5.2%) of 3099 H H V 8 negative individuals (OR: 0.93, 9 5 % C I : 0.412.07).. All A D C d i a g n o s e s w e r e after H H V 8 s e r o c o n -v e r s i o n . .
K SS w a s d i a g n o s e d in 5 (16.7%) o f 3 0 participants with A D C andd in 92 (16.2%) o f 569 participants w i t h o u t ADC' (OR: 1.0,, 9 5 % C I : 0.42.9). A n t i b o d i e s against H H V 8 were d e -tectedd in 14 (46.7%) o f 30 participants with A D C and 276 (48.5%)) o f 569 participants w i t h o u t A D C (OR: 0.9, 9 5 % C I : 0.4-2.0).. F o r c o m p a r i s o n , the o d d s ratio b e t w e e n K S and H H V 88 s e r o p o s i t i v e was 8.9 ( 9 5 % CI: 4.3-18.3) (10).
Prospectivee analysis
T h ee h a z a r d s ratio ( H R ) for p a r t i c i p a n t s with K S to d e v e l o p ADC:: is 2.7 ( 9 5 % C I : 0.92-7.96; p=0.()7) and only definite A D CC is 3.5 ( 9 5 % C I : 1.00-12.26; p = 0 . 0 5 ) . T h e s e risks d o n o t c h a n g ee significantlv w h e n adjusting for low C D 4 + cell c o u n t s .. W h e n adjusting the m o d e l for the use of antiretrovirall m e d i c a t i o n , the risk for KS and ADC" is 2.0 ( 9 5 % C I :: 0.66-5.77; p = 0 . 2 3 ) a n d 2.6 (95%CI: 0.73-9.12;
p=().14)) for definite A D C ; the risk for A D C decreased whenn antiretroviral therapy was used: 0.19 ( 9 5 % C I : 0.07-0.57;; p = 0 . 0 0 3 ) and 0.26 (95%CI: 0.07-0.90; p=0.03) forr definite A D C . Inclusion of the variables o n K S , C D 4 + celll c o u n t and use o f antiretroviral medication in the same modell d o e s n o t significantly alter the results r e p o r t e d a b o v e (dataa n o t s h o w n ) .
T h ee risk for participants with H H Y 8 to d e v e l o p A D C is 0.844 ( 9 5 % C I : 0.41-1.75; p=0.65) and 0.69 ( 9 5 % C I : 0.28-1.73;; p = 0 . 4 3 ) for definite ADC]. Again adjustment for loww C D 4 + cell c o u n t s s h o w s n o changes. W h e n adjusting thiss m o d e l for the use o f antiretroviral medication, the risk forr H H V 8 positive people to develop ADC] is 0.85 ( 9 5 % C I : 0.41-1.77;; p = 0 . 6 6 ) and 0.69 (95%CI: 0.27-1.73; p = 0 . 4 2 ) for definitee ADC]. T h e hazards ratio of antiretroviral medica-tionn use for developing ADC] is 0.18 ( 9 5 % CI: 0.06-0.53; p=0.OO2)) and 0.23 (95%CI: 0.07-0.81; p = 0 . 0 2 ) for definite ADC].. Inclusion of all variables on 1 I H V 8 serostatus, low C D 4 ++ cell c o u n t and use of antiretroviral medication d o e s nott significantly alter the results reported above (data n o t shown). .
T h ee hazards ratios for K S and H H V 8 are p r e s e n t e d sepa-ratelyy a b o v e as not all K S patients are f II1V8 seropositive in thiss study and not all H H V 8 positive individuals d e v e l o p e d KS.. T h e risk o f having either KS or H H V 8 and developing A D CC o r definite A D C , having adjusted for low C D 4 + cell count,, use of antiretroviral o r anti-herpesviral medication, andd age is similar t o the results reported above (data n o t shown). .
Tablee 1: Crude and adjusted hazards ratios {95 percent confidence intervals) for participants with KS and HHV8 to develop ADC {left
panel)) and definite ADC (right panel).
Crudee ratios Adjustedd for CD4+ Adjustedd for ART Adjustedd for Both
Hazardss ratios for ADC
KS* * HR(95%% CI) 2.77 (0.92-7.96) 2.6(0.91-7.87) ) 1.9(0.66-5.76) ) 1.9(0.66-5.78) ) HHV8* HHV8* HR(95%% CI) 0.8(0.41-1.75) ) 0.9(0.43-1.85) ) 0.9(0.41-1.77) ) 0.9(0.43-1.87) )
Hazardss ratios for definite ADC
KS* * HR(95%% CI) 3.5(1.00-12.26) ) 3.4(0.97-11.96) ) 2.5(0.72-9.12) ) 2.6(0.72-9.10) ) HHV8* * HR(95%CI) ) 0.7(0.28-1.73) ) 0.7(0.30-1.86) ) 0.7(0.27-1.73) ) 0.7(0.29-1.87) ) CD4++ CD4+ cell count. ART,, antiretroviral therapy.
Both:: CD4+ cell count and antiretroviral therapy.
DISCUSSION N
Severall groups have shown that there is a negative or pro-tectivee association between KS and ADC in HIV-1 infected individuals.. In contrast we did not find a significant differ-encee in occurrence of ADC in HIV-1 infected patients with orr without KS. In contrast, our analyses show that KS, al-thoughh not statistically significant, is associated with an in-creasedd risk for ADC in a cohort study of HIV-1 infected homosexuall men and we interpret KS to be a marker of dis-easee progression (Table 1). Once antiretroviral medication iss initiated, the risk of ADC dropped dramatically to 20% of participantss without antiretroviral medication; this finding hass been previously reported by Portegies et al. (13). When alll variables on KS, CD4+ cell count and medication are analysed,, KS still provides no protection against ADC and, althoughh not statistically significant, patients with KS seem too have twice the risk for ADC as compared to those with-outt KS.
AA similar analysis based on HHV8 seropositivity showed no
protectivee effect for HHV8 antibodies and ADC. An analy-siss using KS and HHV8 antibodies also demonstrated a lack off protective effect. Despite disagreement on the negative associationn between KS and ADC, we agree with Rezza etal. (7).. that there is no association between HHV8 antibodies andd ADC and consider that the higher GMT in the study by Dupinn et al. (8). reflects a decline in CD4+ cell count and is nott necessarily involved in ADC pathogenesis (11). The previouslyy reported odds ratio of 8.9 (95%CI: 4.3-18.3) be-tweenn HHV8 antibodies and KS in this same group helps to validatee our analysis (10).
Wee consider that the strengths of this study lie in investigat-ingg the association between KS and ADC by adjusting for immunee deterioration by means of low CD4+ cell count and thee use of antiretroviral medication and also in focusing on onee HIV transmission group with an uniform risk for KS. Theree are a number of other differences between published studiess in this field namely; geographic location, study
pop-sionn groups which have differing risks for KS, use of differ-entt clinical or pathological criteria for defining ADC, and approachh to adjusting for the confounding effects of changess in C D 4+ cell count, HIV-1 RNA load and adminis-trationn of medication. The association between KS and A D CC in AIDS patients may be explained by combining peoplee from different HIV-1 transmission groups with dis-similarr disease risks; HIV-1 infected homosexual men are moree likely to have KS than any other HIV-1 transmission group,, such as drug users, whereas injection-drug use is contentiouslyy associated with ADC (1,7,14). Under these circumstancess KS would appear to protect against ADC in a groupp of AIDS patients composed of homosexual men and drugg users.
Inn individuals with untreated HIV-1 infection, brain tissue iss commonly infected with HIV-1 whereas KS is a rare neu-rologicall event (15,16). Studies to detect HHV8 by poly-merasee chain reaction in cerebrospinal fluid (CSF) or brain
tissuee have yielded conflicting results; HHV8 DNA was de-tectedd in none of the CSF samples from 9 patients with ADCC whereas another study reported that 19 (63.3%) of 30 healthyy brains contained detectable HHV8 (17,18). This wouldd suggest that only small amounts of HHV8, if at all, aree present in brain tissue and that vMIP-II is unlikely to be producedd in adequate amounts to block HIV-1 entry into microgliaa at the CCR3 receptor. It is possible to counterarguee that vMIP-II is produced at or before the blood-brainn barrier and we are not able to comment on dif-ferencess in HHV8 viral load, KS tumor burden or vMIP-II inn patients with and without ADC, as suggested by Brew (19),, We, however, have found no evidence that KS or HHV88 protects against ADC in a prospective cohort study off HIV-1 infected homosexual men and therefore can not confirmm the epidemiological association upon which the searchh for novel KS-associated or HHV8-derived therapies forr ADC is based.
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