Prevalence of Human Herpesvirus 8 Infection in PLWHA

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Journal of Medical Virology 88:2016–2020 (2016)
Prevalence of Human Herpesvirus 8 Infection in
People Living With HIV/AIDS in Pernambuco,
Brazil
Georgea Gertrudes de Oliveira Mendes Cah�u,1,2 Viviane Martha Santos Morais,1,2
Thaisa Regina Rocha Lopes,1 Dayvson Maur�ıcio da Silva,1 Tania Regina Tozetto-Mendoza,3
Claudio Sergio Pannuti,3 and Maria Rosa^ngela Cunha Duarte Coe^lho1,2,4*
1Virology Division, Laboratory of Immunopathology Keizo Asami (LIKA), Federal University of Pernambuco (UFPE),
Recife, Pernambuco, Brazil
2Postgraduate Program in Tropical Medicine, Center for Health Sciences (CCS), Federal University of Pernambuco
(UFPE), Recife, Pernambuco, Brazil
3Departament of Physiology and Pharmacology, Center for Biological Sciences (CCB), Federal University of
Pernambuco (UFPE), Recife, Pernambuco, Brazil
4Laboratory of Virology (LIM52), Institute of Tropical Medicine of S~ao Paulo, University of S~ao Paulo, S~ao Paulo,
Brazil
This cross-sectional study aimed to estimate
the seroprevalence and risk factors for Human
herpesvirus 8 (HHV-8) infection among people
living with HIV/AIDS in Recife, Pernambuco,
Brazil. A total of 500 individuals were tested for
antibodies against HHV-8 using the whole-virus
ELISA. The prevalence of anti-HHV-8 was 28.6%
and the frequency among 140 men who have
sex with men (MSM) was 38.6%. In the univari-
ate model, there were significant associations
with male gender, detectable HIV load, travel
abroad, bissexual, and homossexual orienta-
tion. The first HHV-8 seroepidemiologic study,
in northeast Brazil, documents a highly preva-
lent HHV-8 infection among MSM living with
HIV/AIDS. J. Med. Virol. 88:2016–2020,
2016. # 2016 Wiley Periodicals, Inc.
KEY WORDS: human herpesvirus 8 (HHV-8);
human immunodeficiency
virus (HIV); sexually transmit-
ted disease; prevalence; Brazil
INTRODUCTION
The human herpesvirus 8 (HHV-8), member of the
family Herpesviridae, subfamily Gammaherpesviri-
nae, and genus Rhadinovirus. HHV-8 is associated to
Kaposi sarcoma (KS), primary effusion lymphoma,
and Castleman multicentric disease [ICVT, 2014].
The incidence of KS has declined in people living
with HIV/AIDS under highly active antiretroviral
therapy (HAART) [Leao et al., 2000].
In spite of that, HHV-8 is one of the most oncogenic
human virus currently known in people living with
HIV/AIDS not under HAART, in this condition the
risk of developing Kaposi’s sarcoma is increased by a
factor of up to 20,000 [Rohner et al., 2014]. Further-
more, emerging data show that KS also occurs with
higher CD4þ T lymphocyte count and undetectable
viral loads [Munawwar and Singh, 2016].
In Brazil, the frequency of 3.7% (5/136) was
reported in groups of HIV-soronegatives individuals
without KS [Zago et al., 2000]. Among 3,493 blood
donors, HHV-8 seroprevalence rates of 25% have
been reported, thereby, the country is considered
with intermediate endemicity [Nascimento et al.,
2008]. In people living with HIV/AIDS recruited from
2000 to 2002, the HHV-8 prevalence was of 15.5% in
some states of Brazil, as Par�a [Ishak de et al., 2007].
In S~ao Paulo, the prevalence was 13.9% in 1994 and
25.9% in 2002, a recent period after the introduction
of HAART [Pierrotti et al., 2005; Batista et al., 2009;
Magri et al., 2009]. Therefore, people living with
HIV/AIDS is considered in high risk for the HHV-8
infection, once the viruses have similar transmission
route [Pierrotti et al., 2005; Nascimento et al., 2008;
Batista et al., 2009; Magri et al., 2009].
Grant sponsor: Conselho Nacional de Pesquisa e Desenvolvi-
mento (CNPq); Grant number: 130811/2013-0
�Correspondence to: Maria Rosa^ngela Cunha Duarte Coe^lho,
Setor de Virologia, do Laborat�orio de Imunopatologia Keizo
Asami, da Universidade Federal de Pernambuco, Cidade Uni-
versit�aria, P.O. Box: Av. Prof. Moraes Rego, 1235, Cidade
Universit�aria, Recife-PE, 50670-901, Brasil.
E-mail: rcoelholika@gmail.com
Accepted 6 April 2016
DOI 10.1002/jmv.24550
Published online 28 April 2016 in Wiley Online Library
(wileyonlinelibrary.com).
�C 2016 WILEY PERIODICALS, INC.
Whereas, in Brazil, the scarcity of data on HHV-8
seroprevalence in people living with HIV/AIDS in the
HAART era, the prevalence studies are of prime
importance, to evaluate the sorological profile face
the current context. Besides, the state of Pernambuco
had the highest rate of AIDS in 2013 between the
northeast of the country [Brasil, 2014]. Thereby,
the aim of this study, was to evaluate the seropreva-
lence of HHV-8 and associations with potential risk
factors in people living with HIV/AIDS from Recife,
Pernambuco, northeastern Brazil.
MATERIALS AND METHODS
Between November 2013 and July 2014, this cross-
sectional study recruited a sample of people living
with HIV/AIDS by convenience in the outpatient
clinic of the Hospital das Clinicas, of the Universi-
dade Federal de Pernambuco. The eligibility criteria
were age 18 or above, and residence in the state of
recruitment for the last 5 years.
This research obtained approval by the Ethics
Committee and the Institutional Review Board of the
Universidade Federal de Pernambuco (449.182), and
all patients provided informed consent. All experi-
ments were performed in compliance with relevant
laws and institutional guidelines, and in accordance
with the ethical standards of the Declaration of
Helsinki.
Socio-demographic characteristics and behaviors
information were collected using a structured ques-
tionnaire aiming at specifying the risk-category. After
the interviews, whole blood samples were collected,
and processed by centrifugation. Plasma aliquots
obtained were stored at �20˚C in the Division of
Virology from Laborat�orio de Imunopatologia Keizo
Asami, until testing.
Plasma samples were tested by in-house enzyme-
linked immunosorbent assay (ELISA) produced at a
Brazilian laboratory (Virology Unit of the Instituto
de Medicina Tropical—IMT—of the Universidade de
S~ao Paulo), the IMT whole-virus ELISA, as reported
previously [Nascimento et al., 2007].
The results were considered positive when the
sample rate/cut-off (S/CO) ratios were �1.0. For these
assays the cut-off were 0.212, in a previous evalua-
tion of the performance characteristics of the present
assay, the sensitivity, and specificity were 97% and
86%, respectively [Nascimento et al., 2007].
Associations between HHV-8 seropositivity and
potential risk factors were assessed in univariate
using Chi-square (x2) and Fisher exact tests, and the
significance of measurement was determined by
the Odds ratio (OR), (95% CI), and P-values. The
Mann–Whitney test was used to compare differences
in continuous variables. Multivariate analysis was
carried out based on logistic regression models,
including all P< 0.20 variables in univariate analysis.
These analyses were performed with Epi Info version
7.0 (CDC, Atlanta, GA) and GraphPad Prism (version
5.0) software. Statistical significance was set at
P< 0.05.
RESULTS
Blood samples from 500 individuals were screened,
64% (319/500) were males. The median age was
43 years (18–98 years). A total of 7.2% of the study
population had an education level above high school.
A total of 29.2% (146/500) of patients were classified
as white and 70.8% (354/500) were classified as
nonwhite, which included blacks, indigenous, mulat-
tos, and Asians. Regarding marital status, 10.6% (53/
500) were divorced/widowed, 45.4% (227/500) were
married/cohabiting, and 44% (220/500) were single.
According to Crit�erio Brasil [2013], 28.6% (143/500)
was considered very poor people, from classes D, and
E, 51.8% (259/500) represents class C, and 19.6%
(98/500) of the individuals represents classes A and B.
The median time since HIV diagnosis was 6.49
years (range 0–25.1 years). The median CD4þ T
lymphocyte count was 569 cells/mm3, with a wide
range (11–2,171). The HIV load wasundetected in
36%, the median was 19,121 copies/ml, with a wide
range (<10–1,873,483 copies/ml).
The overall prevalence of anti-HHV-8 was 28.6%
(143/500; 95% CI, 24.72–32.82), and the frequency
among 140 men who have sex with men (MSM) was
38.6%. In univariate analysis, HHV-8 infection
was higher in the male gender (31.9% male
HHV-8þ vs. 22.6% female HHV-8þ, OR: 1.605, 95%
CI: 1.054–2.443; P¼ 0.03). There was no statistically
significant association among the others sociodemo-
graphic factors and HHV-8 infection in people living
with HIV/AIDS. The median age was compared
using the Mann–Whitney test and could not detect
differences, P¼ 0.583, between the HHV-8 seronega-
tive (median¼ 31 years), and seropositive groups
(median¼ 31 years). The infection seroprevalence
was not significantly associated with surgery and
blood transfusion (data not shown).
Among women (181/500), age less than 40 years
(OR: 2.190; 95% CI: 1.06–4.49, P¼ 0.042), and age
<18 years at first sexual intercourse (OR: 2.540; 95%
CI: 1.045–6.173, P¼ 0.051) were more likely to be
seropositive for anti-HHV-8. In neither genders were
HHV-8 infection associated with the remains risk
factors (data not shown).
Table I shows the univariate analysis between
blood route-related factors and drug use related
factors, and HHV-8 infection in people living with
HIV/AIDS.
Participants who had detectable HIV load were
more likely to be positive for anti-HHV-8 (OR: 1.536;
95% CI: 1.005–2.347, P¼ 0.048). Other risk factors
were the �200 CD4þ T lymphocyte cells/mm3 (OR:
1.665; 95% CI: 0.916–3.025, P¼ 0.104) and �15 years
since HIV diagnosis (OR: 1.531; 95% CI: 0.897–1.988,
P¼ 0.184) with a borderline P-value. The univariate
analysis between HHV-8 infection and sexual
J. Med. Virol. DOI 10.1002/jmv
HHV-8 Prevalence in People Living With HIV 2017
behavioral-related, and laboratory factors in people
living with HIV/AIDS are illustrated in Table II.
DISCUSSION
In Brazil, among people living with HIV/AIDS the
mortality rate was substantially decreased, despite
this success, approximately 48% out of 734,000
people living with HIV/AIDS are under HAART, and,
hence, is still considerable the residual risk of
developing KS [Arruda et al., 2014; Brasil, 2014]. In
people living with HIV/AIDS, previous studies of
Brazil reported only an overall seroprevalence of
anti-HHV-8 ranging from 13.9% to 25.9%. These
differences could be in part attributed to different
serological assays employed with different sensitivity
and specificity to detect antibodies against HHV-8
[Pierrotti et al., 2005; Ishak de et al., 2007; Batista
et al., 2009; Magri et al., 2009]. Although, the current
cross-sectional study, a slightly higher HHV-8 sero-
prevalence using the IMT whole-virus ELISA.
Regarding the gender prevalence distribution, the
HHV-8 presence was significantly higher among
males, who constituted the majority in the sample
analyzed, this result agrees with previous reports
[Batista et al., 2009; Magri et al., 2009]. The impor-
tant association between young women and HHV-8
positivity was found, a same pattern was described in
India among young men by Munawwar et al. [2014],
which concluded that only in the past few decades
had occurred active transmission of HHV-8.
Also, the HHV-8 seropositivity was not dependent
from age, suggesting no continuing transmission
through life, this data also does not support the
hypothesis that the main route for HHV-8 spread
was not sexual in people living with HIV/AIDS.
Conversely, the pattern observed in previous studies
in S~ao Paulo–Brazil, Sub-Saharan Africa, and Medi-
terranean areas show that the HHV-8 seroprevalence
increased with age, demonstrating a stabilized HHV-
8 infection [Zavitsanou et al., 2010].
Data have shown that blood route-related factors
were not associated with HHV-8 infection, except the
use of shared cutting tool that remained as a protec-
tor factor for HHV-8 infection in the multivariate
model without a plausible biological explanation. An
unusual finding is the higher prevalence of HHV-8 in
people who travel abroad, interestingly, Pierrotti
et al. [2005] found that the sexual partnership with
foreigners positively associated with HHV-8 seroposi-
tivity. In view of that, this association suggests
a route of recent or continuously introduction of
imported virus.
An overall high HHV-8 seropositivity rate was
found among patients with detectable HIV load, but
not with CD4þ T lymphocyte, and duration of HIV
infection. A possible reason is the HIV influence the
immune surveillance making the host susceptible to
HHV-8 infection. Besides, the HIV Tat activates lytic
cycle replication of HHV-8 via JAK/STAT signaling
or HHV-8 Rta induction, and the Rta is the ORF 50
gene product that controls the transition from latency
to lytic replication [Zeng et al., 2007].
Of notice, a high frequency of HHV-8 infection was
observed among MSM, compared to previous studies
that reported a frequency ranging from 6% to 32.4%
TABLE I. Univariate Analysis Between HHV-8 Infection and Blood Rout-Related Factors, and Drug Use in People Living
With HIV/AIDS, Recife, Brazil (2013–2014)
Variables n HHV-8 infection n (%) ORa (95% CIb) P-value
Tatoo/piercing
No 216 69 (31.9) 1.0 –
Yes 284 74 (26.1) 0.751 (0.508–1.109) 0.162
Injections with glass syringe
No 350 100 (28.6) 1.0 –
Yes 150 43 (28.7) 1.005 (0.658–1.534) 1.000
Ever use of smoked drugs
No 389 108 (27.8) 1.0 –
Yes 111 35 (31.5) 1.198 (0.758–1.894) 0.475
Ever use of inhalated drugs
No 419 123 (29.4) 1.0 –
Yes 81 20 (24.7) 0.789 (0.456–1.364) 0.424
Ever use of injected drugs
No 493 14 (28.6) 1.0 –
Yes 7 2 (28.6) 0.999 (0.191–5.209) 1.000
Use of shared cutting tool
No 201 67 (33.3) 1.0 –
Yes 299 76 (25.4) 0.682 (0.460–1.009) 0.056
Use of shared tooth brush
No 408 119 (29.2) 1.0 –
Yes 92 24 (26.1) 0.857 (0.514–1.430) 0.611
Travel abroad
No 455 124 (27.3) 1.0 –
Yes 45 19 (42.2) 1.951 (1.042–3.650) 0.039
aOR, odds ratio; bCI, confidence intervals.
J. Med. Virol. DOI 10.1002/jmv
2018 de Oliveira Mendes Cah�u et al.
[Pierrotti et al., 2005; Ishak de et al., 2007; Batista
et al., 2009]. This association is related to a greater
number of sexual partners and a history of ISTDs
[Mistro et al., 2012]. Although, it seems pertinent to
observe that in sexual encounters it is difficult to
exclude the possibility of behaviors that involve an
oral route, such as oral sex which presented a
borderline significance. In addition, the HHV-8 was
more easily detected by PCR in the saliva than in
sperm of HIV infected patients, whether they had
KS, or not [Phipps et al., 2014].
Outside HHV-8 endemic regions, where sexual
transmission is reported to be the main transmission
route among people living with HIV/AIDS, besides
the HAART was associated with reductions of HHV-8
levels in blood [Phipps et al., 2014]. Therefore,
measures like safer sexual practices that are widely
recommended and the therapy should, at least, had
stabilized the HHV-8 prevalence. In contrast, the
HHV-8 seroprevalance is increasing over calendar
years, specially, in high-risk groups such as MSM
and people living with HIV/AIDS, suggesting the use
of antivirals could be an option to prevent HHV-8
transmission, and possible clinical manifestations
[Gantt et al., 2014; Rohner et al., 2014].
Strengths of this study, include a well-character-
ized population with detailed information on partic-
ipants’ demographic and behavioral characteristics.
Conversely, some limitations possible contributed to
the findings related to sexual transmission as under-
reported of homosexual intercourse, condom use, or
oral sex. Also the occurrence of some unspecific
seroreactivity with the IMT whole-virus ELISA can-
not be ruled out, the ELISA used yielded sensitivity
comparable to, and higher specificity than comercial
assays,namely ABI1 and DIAVIR1 [Nascimento
et al., 2007].
In conclusion, this first HHV-8 epidemiologic study
in northeast Brazil, a non-endemic region, provides
further evidence that MSM are at high risk of HHV-8
infection, and shows pronounced differences in HHV-
8 seropositivity by gender and HIV load. The findings
suggest a recent route or continuously introduction of
imported virus, therefore, prospective studies on
sexual behaviors, and virus shedding in the saliva
will be required to clarify the interactions of HHV-8
TABLE II. Univariate Analysis Between HHV-8 Infection and Sexual Behavioral-Related Factors in People Living With
HIV/AIDS, Recife, Brazil (2013–2014)
Variables n HHV-8 infection n (%) ORa (95%CI) P-value
Age at first sexual intercourse
>17 years 193 51 (26.4) 1.0 –
15–17 years 203 67 (33.0) 1.557 (0.910–2.663) 0.115
<15 years 104 25 (24.0) 1.135 (0.65–1.971) 0.678
Condom use
Always 348 102 (29.3) 1.0 –
Sometimes 72 20 (27.8) 0.928 (0.52–1.632) 0.887
Never 78 20 (25.6) 0.837 (0.476–1.454) 0.581
Number of sexual partners in the last 12 months
None 84 21 (25.0) 1.0 –
1 249 65 (26.1) 1.060 (0.599–1.873) 0.886
2–5 119 41 (34.5) 1.577 (0.846–2.938) 0.166
�6 48 16 (33.3) 1.500 (0.689–3.264) 0.320
Previous ISTD
No 288 75 (26.0) 1.0 –
Yes 212 68 (32.1) 1.341 (0.907–1.982) 0.161
Condom use in intercourse with oposite sex in the last 6 months
Always 229 64 (27.9) 1.0 –
Sometimes 51 14 (27.4) 0.975 (0.494–1.925) 1.000
Never 28 6 (21.4) 0.703 (0.272–1.814) 0.653
Intercouse for money
No 488 14 (28.9) 1.0 –
Yes 12 2 (16.7) 0.492 (0.106–2.276) 0.523
Sexual orientation
Heterosexual 358 88 (24.6) 1.0 –
Bissexual 58 24 (41.4) 2.166 (1.21–3.850) 0.010
Homossexual 84 31 (36.9) 1.795 (1.08–2.972) 0.028
Ever had homossexual intercourse
No 329 80 (24.3) 1.0 –
Yes 171 63 (36.8) 1.816 (1.217–2.709) 0.005
Oral sex in the last 6 months
Never 299 80 (26.8) 1.0 –
Sometimes 139 39 (28.1) 1.068 (0.681–1.675) 0.818
Always 62 24 (38.7) 1.729 (0.976–3.063) 0.06
ISTD, infectious sexually transmitted disease; 192 patients did not reported intercourse with opposite sex in the last 6 months.
aOR, odds ratio; two patients had no information on condom use.
J. Med. Virol. DOI 10.1002/jmv
HHV-8 Prevalence in People Living With HIV 2019
infection among people living with HIV/AIDS in the
HAART era.
ACKNOWLEDGMENTS
The authors are thankful to the patients of the
Infectious and Parasitic Diseases Clinic of the Hospi-
tal das Clinicas/Universidade Federal de Pernam-
buco, who accepted to participate without direct
benefit from the results, and to the laboratories of
Laboratory of Virology (LIM-52-IMT), Universidade
de S~ao Paulo, where the analyses were carried out.
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2020 de Oliveira Mendes Cah�u et al.