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Kaposi's sarcoma and human herpesvirus 8 infection do not protect HIV-1 infected homosexual men from AIDS dementia complex

Renwick, Neil; Weverling, Gerrit Jana; Halaby, Teysirb; Portegies, Peterc; Bakker, Margreet; Schulz, Thomas F.d; Goudsmit, Jaap

CLINICAL SCIENCE: CONCISE COMMUNICATION
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Objective To examine the association between Kaposi's sarcoma (KS), human herpes virus 8 (HHV8) and AIDS dementia complex (ADC).

Design A total of 599 HIV-1 infected homosexual men participated in a prospective cohort study (Amsterdam, 1984–1996).

Methods The risk for ADC in patients with prior KS or HHV8 infection was estimated using the Cox proportional hazards method with adjustments for antiretroviral medication and low CD4 cell counts.

Results Of the 599 participants, 290 (48.4%) had HHV8 antibodies, 99 (16.5%) had KS and 30 (5.0%) had ADC. ADC was diagnosed 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% seronegative individuals and thus was not associated with KS or HHV8 infection. Using a time-dependent Cox proportional hazards analysis with the date of KS as risk factor, the risk for ADC was 2.7 [95% confidence interval (CI), 0.92–7.96;P = 0.07) and when only definite ADC was considered it was 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 ratio for participants with KS to develop ADC was 2.0 (95% CI, 0.66–5.77;P = 0.23) and 2.6 (95% CI, 0.73–9.12;P = 0.14), respectively. HHV8 seropositivity, adjusted for the same variables, showed 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 were observed.

Conclusions KS or HHV8 does not significantly influence the risk for developing ADC in a group with a uniform risk for developing KS therefore we recommend caution in searching for a KS-associated or HHV8-derived therapy for ADC.

From the Department of Human Retrovirology and the aDepartment of Clinical Epidemiology and Biostatistics, Academic Medical Center, University of Amsterdam, the bDepartment of Medical Microbiology, Academic Hospital Maastricht, the cDepartment of Neurology, Academic Medical Center, University of Amsterdam, The Netherlands, and the dDepartment of Virology, Medizinische Hochschule Hannover, Germany.

Acknowledgements Sponsorship: This study was performed as a part of the Amsterdam Cohort Studies on AIDS, a collaboration between the Municipal Health Service, the Academic Medical Centre and the Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands. This study was supported by grants from The Netherlands Foundation for Preventive Medicine (28-2370), the Medical Research Council of Great Britain (69517856PB), and the NHS Biomedical Research Fund (RDO/22/9) and the European Concerted Action on the Pathogenesis of Kaposi's Sarcoma (BMH 4-97-2302).

Requests for reprints to: J. Goudsmit, Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.

Received: 2 February 2001;

revised: 8 June 2001; accepted: 13 June 2001.

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Introduction

Interest in the decreased risk that a diagnosis of Kaposi's sarcoma (KS) confers on AIDS dementia complex (ADC) was rekindled following the demonstration that a human herpes virus 8 (HHV8)-encoded chemokine, viral macrophage inflammatory protein (vMIP)-II, blocks the entry of HIV-1 into CD4 cell lines, such as microglia, that express CCR3 [1,2]. Boshoff et al. hypothesized that patients with KS, or high HHV8 load, may be less likely to develop ADC [2]. The majority of epidemiological studies have subsequently demonstrated a protective association between KS and ADC [3–8]. No association was seen in one case–control study; however, the authors concluded that in order to make reliable statements concerning the protective effects that complete neurological, neuropathological and clinical data are required [9].

We have demonstrated previously that HHV8 antibodies are a strong risk factor for KS in the Amsterdam Cohort Studies on HIV-1 infection [10,11] and note that the influence of HHV8 antibodies on ADC has been examined in two studies; no association was seen in one study whereas a higher geometric mean titer of HHV8 antibodies was seen in HIV patients without ADC than in those with ADC [7,8].In our prospective study we focus on a single HIV transmission group with a uniform risk for KS to investigate whether a diagnosis of KS or the presence of HHV8 antibodies is associated with a low risk for ADC and find no evidence for a protective effect of HHV8 infection or KS against ADC among homosexual men.

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Methods

Study population and study period

The study population consisted of 599 HIV-1 infected homosexual men who participated in the Amsterdam Cohort Studies on HIV infection and AIDS between December 1984 and December 1996.

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Serologic assays and study design

The enzyme immunoassay system and Western blot assays for the detection of HHV8 and HIV antibodies respectively and the study design, have been described in a previous publication [10].

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Diagnostic criteria

The diagnoses of definite ADC were made according to the 1987 Centers for Disease Control and Prevention surveillance case definition [12]. Those patients who met the clinical criteria for definite ADC but lacked either cerebrospinal fluid, computed tomography or autopsy findings to exclude other illnesses, were termed provisional ADC. Central nervous system diseases including toxoplasmosis, progressive multifocal leukoencephalopathy, and cerebral lymphoma were excluded by computed tomography or magnetic resonance imaging; metabolic and toxic encephalopathies were excluded by extensive blood or urine tests.

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Statistical methods

All participants were homosexual men who were either HIV seropositive at enrolment in the cohort or who became HIV seropositive during follow-up and the date of HIV seroconversion was taken as the start of observation time. Prevalences of KS, HHV8 antibodies and ADC were calculated for the 599 participants at the end of the study period. For individuals who tested positive for HHV8, the date of seroconversion was determined by testing earlier samples. The risk of ADC as predicted by a diagnosis of KS or the presence of HHV8 antibodies was estimated using a time-dependent Cox proportional hazards model. In this model, observation time started at either the moment of HIV-1 seroconversion or the date of study entry for HIV-1 seropositive participants; the date of HHV8 seropositivity or KS diagnosis were time-dependent factors. In addition, to adjust for deterioration of the immune system, the moment that the CD4 cell count dropped below 100 × 106 or 50 × 106 cells/l was included in the time-dependent model. Finally, we entered a time-dependent variable for the use of antiretroviral medication to adjust for the protective effect of antiretroviral medication on the occurrence of ADC. Data were censored at 31 December 1996.

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Results

Cross sectional analysis

Of the 599 participants 290 (48.4%) had HHV8 antibodies and 99 (16.5%) had KS. Thirty (5.0%) of the 599 participants met the criteria for definite or provisional ADC, of whom 19 (3.2%) were diagnosed with definite ADC. ADC was diagnosed after KS in five (5.2%) of 97 participants, in two participants before KS, and in 25 (5.0%) of 502 participants who were never diagnosed with KS [odds ratio (OR), 1.5; 95% confidence interval (CI), 0.5–3.7]. ADC was diagnosed in 14 (4.8%) of 290 HHV8 positive individuals and 16 (5.2%) of 309 HHV8 negative individuals (OR, 0.93, 95% CI; 0.41–2.07). All ADC diagnoses were after HHV8 seroconversion.

KS was diagnosed in five (16.7%) of 30 participants with ADC and in 92 (16.2%) of 569 participants without ADC (OR, 1.0; 95% CI, 0.4–2.9). Antibodies against HHV8 were detected in 14 (46.7%) of 30 participants with ADC and 276 (48.5%) of 569 participants without ADC (OR, 0.9; 95% CI, 0.4–2.0). For comparison, the OR between KS and HHV8 seropositivity was 8.9 (95% CI, 4.3–18.3) [10].

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Prospective analysis

The hazards ratio for participants with KS to develop ADC was 2.7 (95% CI, 0.92–7.96;p = 0.07) and only definite ADC was 3.5 (95% CI, 1.00–12.26;P = 0.05). These risks do not change significantly when adjusting for low CD4 cell counts. When adjusting the model for the use of antiretroviral medication, the risks for KS and ADC were 2.0 (95% CI, 0.66–5.77;P = 0.23) and 2.6 (95% CI, 0.73–9.12;P = 0.14) for definite ADC; the risk for ADC decreased when antiretroviral therapy was used: 0.19 (95% CI, 0.07–0.57;P = 0.003) and 0.26 (95% CI, 0.07–0.90;P = 0.03) for definite ADC. Inclusion of the variables on KS, CD4 cell count and use of antiretroviral medication in the same model does not significantly alter the results reported above (data not shown).

The risk for participants with HHV8 to develop ADC was 0.84 (95% CI, 0.41–1.75;P = 0.65) and 0.69 (95% CI, 0.28–1.73;P = 0.43) for definite ADC. Again, adjustment for low CD4 cell counts shows no changes. When adjusting this model for the use of antiretroviral medication, the risk for HHV8 positive patients to develop ADC was 0.85 (95% CI, 0.41–1.77;P = 0.66) and 0.69 (95% CI, 0.27–1.73;P = 0.42) for definite ADC. The hazards ratio of antiretroviral medication use for developing ADC was 0.18 (95% CI, 0.06–0.53;P = 0.002) and 0.23 (95% CI, 0.07–0.81;P = 0.02) for definite ADC. Inclusion of all variables on HHV8 serostatus, low CD4 cell count and use of antiretroviral medication does not significantly alter the results reported above (data not shown).

The hazards ratios for KS and HHV8 are presented separately above as not all KS patients are HHV8 seropositive in this study and not all HHV8 positive individuals developed KS. The risk of having either KS or HHV8 and developing ADC or definite ADC, having adjusted for low CD4 cell count, use of antiretroviral or anti-herpesviral medication, and age was similar to the results reported above (data not shown).

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Discussion

Several groups have shown that there is a negative or protective association between KS and ADC in HIV-1 infected individuals. In contrast we did not find a significant difference in occurrence of ADC in HIV-1 infected patients with or without KS. In contrast, our analyses show that KS, although not statistically significant, is associated with an increased risk for ADC in a cohort study of HIV-1 infected homosexual men and we interpret KS to be a marker of disease progression (Table 1). Once antiretroviral medication is initiated, the risk of ADC dropped dramatically to 20% of participants without antiretroviral medication; this finding has been reported previously by Portegies et al.[13]. When all variables on KS, CD4 cell count and medication were analysed, KS still provided no protection against ADC and, although not statistically significant, patients with KS appear to have twice the risk for ADC as compared to those without KS.

Table 1

Table 1

A similar analysis based on HHV8 seropositivity showed no significant difference in HHV8 seroprevalence between those with and without ADC and also yielded no significant protective effect for HHV8 antibodies against ADC. An analysis using KS and HHV8 antibodies also demonstrated a lack of protective effect. Despite disagreement on the negative association between KS and ADC, we agree with Rezza et al.[7] that there is no association between HHV8 antibodies and ADC and consider that the higher geometric mean titer in the study by Dupin et al.[8] reflects a decline in CD4 cell count and is not necessarily involved in ADC pathogenesis [11].The previously reported OR of 8.9 (95% CI, 4.3–18.3) between HHV8 antibodies and KS in this same group helps to validate our analysis [10].

We consider that the strengths of this study lie in investigating the association between KS and ADC by adjusting for immune deterioration by means of low CD4 cell count and the use of antiretroviral medication and also in focusing on one HIV transmission group with a uniform risk for KS. There are several other differences between published studies in this field: geographic location; study populations; prevalences of KS, HHV8 and ADC in the study group; study design; comparison of ADC in HIV transmission groups which have differing risks for KS; use of different clinical or pathological criteria for defining ADC; and approach to adjusting for the confounding effects of changes in CD4 cell count, HIV-1 RNA load and administration of medication. The association between KS and ADC in AIDS patients may be explained by combining people from different HIV-1 transmission groups with dissimilar disease risks; HIV-1 infected homosexual men are more likely to have KS than any other HIV-1 transmission group, such as drug users, whereas injecting drug use is contentiously associated with ADC [1,7,14]. Under these circumstances KS would appear to protect against ADC in a group of AIDS patients composed of homosexual men and drug users.

In individuals with untreated HIV-1 infection, brain tissue is commonly infected with HIV-1 whereas KS is a rare neurological event [15,16]. Studies to detect HHV8 by PCR in cerebrospinal fluid or brain tissue have yielded conflicting results; HHV8 DNA was detected in none of the cerebrospinal fluid samples from nine patients with ADC whereas another study reported that 19 (63.3%) of 30 healthy brains contained detectable HHV8 [17,18]. This would suggest that only small amounts of HHV8, if any at all, are present in brain tissue and that vMIP-II is unlikely to be produced in adequate amounts to block HIV-1 entry into microglia at the CCR3 receptor. It is possible to counter-argue that vMIP-II is produced at or before the blood–brain barrier and we are not able to comment on differences in HHV8 viral load, KS tumor burden or vMIP-II in patients with and without ADC, as suggested by Brew [19]. We, however, have found no evidence that KS or HHV8 protects against ADC in a prospective cohort study of HIV-1 infected homosexual men and therefore cannot confirm the epidemiological association upon which the search for novel KS-associated or HHV8-derived therapies for ADC is based.

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Keywords:

AIDS dementia complex; epidemiology; HHV8; KSHV; Kaposi's sarcoma; risk

© 2001 Lippincott Williams & Wilkins, Inc.