M E D iC A L
JO U R N AL
C O M 1 \1 U N IC f\1 'IO ~
S I - I O R T
J o s e E d u a r d o N ic o la u , G il B e n a r d , L u is A u g u s to M a r c o n d e s F o n s e c a ,
J o r g e S im a o R o s a r io C a s s e b , M a r ia N a to m i S a to , M a r c ia C ia n g a ,
M a u r i M a s s a n i T a n ji, T h e r e z in h a F e r r e ir a L o r e n z i,
A lb e r to J o s e d a S ilv a D u a r te
H I V h e te r o s e x u a l tr a n s m is s io n
to s ta b le s e x u a l p a r tn e r s
o f
H I V - in f e c te d b r a z ilia n h e m o p h ilia c s
H e m o p h i l i a U n i t , H o s p i t a l B r i g a d e i r o , S i l o P a u l o S t a t e H e a l t h D e p a r t m e n t a n d t h e I m m u n o g e n e t i c s a n dE x p e r i m e n t a l T r a n s p l a n t a t i o n L a b o r a t o r y , L I M 5 6 , C o l l e g e o f M e d i c i n e , S i l o P a u l o U n i v e r s i t y - S i l o P a u l o , B r a z i l
N in e te e n B ra z ilia n H IV -in fe c te d h e m o p h ilia c s a n d th e ir s ta b le h e te ro s e x u a l s e x u a l p a rtn e rs w e re s tu d ie d w ith th e a im o f a s s e s s in g th e
ra te o f H IV tra n s m is s io n in th is a t ris k g ro u p . T h e m e a n le n g th o f re la tio n s h ip b e tw e e n c o u p le s w a s 7 .4 y e a rs . T h e h e m o p h ilia c m e n w e re C la s s II (n = 6 ), III (n = 1 1 ) a n d IV a (n = 2 ) o f th e C D C c la s s ific a tio n . T h e y h a d d e c re a s e d C D 4 + a n d e le v a te d C D 8 + c e ll n u m b e rs ; fiv e h a d p 2 4 a n tig e n e m ia . W e fo u n d 3 H IV -in fe c te d w o m e n (1 5 .8 p e rc e n t) b y ro u tin e a n d c o n firm a to ry te s ts , a p re v a le n c e s im ila r to
th a t s e e n in o th e r c o u n trie s . T h e y w e re a s y m p to m a tic a n d h a d n o d e te c ta b le p 2 4 a n tig e n e m ia . T h e 3 s e ro p o s itiv e w o m e n 's p a rtn e rs
w e re C la s s II a n d III-C D C , a n d h a d n o rm a l C D 4 + a n d C D 8 + v a lu e s a n d n o p 2 4 a n tig e n e m ia . A ll s e ro n e g a tiv e w o m e n a ls o h a d n o rm a l C D 4 + a n d C D 8 + n u m b e rs , e x c e p t fo r e le v a te d C D 8 + c e lls in th re e o f th e m , b u t im m u n e a b n o rm a litie s h a d a lre a d y b e e n s e e n in s o m e s e ro n e g a tiv e p a rtn e rs a t h ig h ris k fo r H IV in fe c tio n . O u r re s u lts re in fo rc e p re v io u s s u g g e s tio n s th a t h e te ro s e x u a l tra n s m is s io n to
s ta b le fe m a le p a rtn e rs o c c u rs p re fe re n tia lly e a rly a fte r in itia tio n o f s e x u a l e x p o s u re , a n d p o s s ib ly w h e n th e tra n s m itte r h a s h ig h le v e ls o f v ire m ia a n d re g u la r s e x u a l a c tiv ity .
U N IT E R M S : H IV In fe c tio n , h e te ro s e x u a l tra n s m is s io n , h e m o p h ilia , C D 4 + ly m p h o c y te .
IN T R O D U C T IO N
B
f a c t o rr a z i l i a nc o n c e n t r a t e sh e m o p h i l i a c sf r o mw h o1 9 8 0r e c e i v e dt o 1 9 8 5 a r e a t h i g hc o a g u l a t i O i f r i s k f o r a c q u i r i n g H I Y . T h i s h i g h - r i s k g r o u p h a sr a t e s o f H I V i n f e c t i o n i n B r a z i l a n d o t h e r c o u n t r i e s t h a t
r e a c h 5 0 p e r c e n t o r h i g h e r .I
-3 S t u d i e s i n t h i s g r o u p u s u a l l y
r e p o r t r a t e s o f h e t e r o s e x u a l t r a n s m i s s i o n t o t h e i r p a r t n e r s
o f 1 0 - 2 0 p e r c e n t .4
.5 A l t h o u g h B r a z i l i s r a n k e d f o u r t h i n
t h e w o r l d i n n u m b e r o f A I D S p a t i e n t s , t h e r e i s n o d a t a o n
A d d r e s s f o r c o r r e s p o n d e n c e :
A lb e r to J o s e d a S ilv a D u a r te
F a c u ld a d e d e M e d ic in a - U S P
A v . D r . A r n a ld a , 4 5 5 , s a la 1 0 5 A - C e r q u e ir a C e s a r
S a o P a u lo /S P - B r a s il- C E P 0 1 2 4 6 - 9 0 3
t h e c l i n i c a l c o u r s e o f B r a z i l i a n H I V - i n f e c t e d h e m o p h i l i a c s
a n d t h e i r r o l e a s h e t e r o s e x u a l t r a n s m i t t e r s .
H e r e w e s h o w t h e i m m u n o l o g i c p a r a m e t e r s o f 1 9
p a t i e n t s f r o m a h e m a t o l o g y c e n t e r i n S a o P a u l o : 1 4 w i t h
h e m o p h i l i a A a n d 5 w i t h h e m o p h i l i a B ( a g e r a n g e , 2 1 - 5 4
y e a r s ) ; a n d t h e i r s t a b l e f e m a l e s e x u a l p a r t n e r s ( 1 8 - 4 9
y e a r s ) . R e s u l t s w e r e c o m p a r e d t o 1 5 n o r m a l a d u l t s u b j e c t s
( c o n t r o l s ) s t u d i e d a t t h e s a m e t i m e . T h e m e a n l e n g t h o f
r e l a t i o n s h i p w a s 7 . 4 y e a r s , a n d a l l c o u p l e s d e n i e d u s i n g
c o n d o m s b e f o r e t h i s s t u d y . T h e s e x u a l p a r t n e r s h a d n o
o t h e r k n o w n r i s k f a c t o r s f o r H I Y .
T h e H I V - i n f e c t e d h e m o p h i l i a c s w e r e C l a s s I I ( n = 6 ) ,
I I I ( n = 1 1 ) a n d I V a - C D C ( n = 2 ) . F i v e o f t h e m h a d p e r i p h e r a l
b l o o d C D 4 + c e l l s b e l o w 4 0 0 / 1 : 3 C l a s s I I I a n d 2 C l a s s I V a
p a t i e n t s ; m e a n C D 4 + c e l l c o u n t s o f t h e p a t i e n t s w e r e
s i g n i f i c a n t l y l o w e r c o m p a r e d t o t h e c o n t r o l s ( F i g . I) .T h e i r
C D 8 + c e l l c o u n t w a s h i g h e r t h a n t h e c o n t r o l s i n 7 ( 6 4
p e r c e n t ) a n d 2 ( 3 3 p e r c e n t ) o f t h e c l a s s I I I a n d I I p a t i e n t s ,
S a o P a u lo M e d ic a l J o u rn a l/R P M 1 1 4 (3 ): 1 1 8 6 -1 1 8 9 , 1 9 9 6 N IC O L A U , J .E .; B E N A R D , G .; F O N S E C A , L A M . e t a l. - H IV h e te ro s e x u a l tra n s m is s io n to
2000 CELLS1}l1
1500
0
4t
At
B1000 Ii.
t
a~
[IJ 900~
800Of
700 600 a 500a
400°
0 0 200 a CD4+ CD8+1187
T h e th re e h e m o p h ilia c s w h o se p a rtn e rs w e re
in fe c te d h a d C D 4 + c e ll c o u n ts a b o v e 5 0 0 /u l (5 3 6 ,
9 0 2 a n d 6 0 8 /u l, re sp e c tiv e ly ), a n d e le v a te d C D 8 +
n u m b e rs (1 4 2 1 , 1 5 1 6 a n d 1 1 0 5 /m l, re sp e c tiv e ly ).
T h e y w e re a t S ta g e s II, II a n d III-C D C , re sp e c tiv e ly ,
a n d h a d n o p 2 4 a n tig e n e m ia .
T h e h e te ro se x u a l tra n sm issio n ra te o f
B ra z ilia n h e m o p h ilia c s to th e ir fe m a le p a rtn e rs,
1 5 .8 p e rc e n t a fte r a m e a n re la tio n sh ip o f7 .4 y e a rs
(2 .1 p e r 1 0 0 p e rso n y e a rs), is sim ila r to th a t o f
o th e r c o u n trie s. S o m e a u th o rs c o u ld a sso c ia te a n
in c re a se d risk o f m a le -to -fe m a le tra n sm issio n to
fa c to rs re la te d to th e tra n sm itte r, su c h a s: m o re
a d v a n c e d sta g e s o f d ise a se ; m o re p ro lo n g e d tim e
o f e x p o su re ; o r m o re p ro n o u n c e d la b o ra to ry
a b n o rm a litie s.4
-6 O f th e la tte r, a d e c re a se in
p e rip h e ra l C D 4 + c e ll n u m b e rs a n d th e p re se n c e
o f p 2 4 a n tig e n e m ia a re p a rtic u la rly im p o rta n t.
H o w e v e r, a n o th e r stu d y 9 sh o w e d th a t tra n sm issio n
p re fe re n tia lly o c c u rre d a t a n e a rlie r ti m e a fte r
Figure 1 -
C D 4 + a n d C D 8 + p e rip h e ra l b lo o d ly m p h o c y te se n u m e ra tio n fro m h e m o p h ilia c s (., n = 1 9 ), th e ir fe m a le
se x u a l p a rtn e rs (., n = 1 9 ) a n d 1 5 h e a lth y su b je c ts a s
c o n tro ls (D ). E m p ty c irc le s re p re se n t re su lts o f th e th re e
H IV -in fe c te d w o m e n . B a rs re p re se n t m e a n s a n d sta n d a rd
e rro rs. D a ta w a s a n a ly z e d th ro u g h a n a ly sis o f v a ria n c e
a n d th e m e a n s o f th e g ro u p s c o m p a re d w ith th e N e u lm a n
-K e u s te st. C D 4 + a n d C D 8 + m e a n v a lu e s o f h e m o p h ilia c s
w e re sig n ific a n tly d iffe re n t (p < 0 .0 5 ) fro m th o se o f th e
fe m a le p a rtn e rs a n d c o n tro ls. M e th o d o lo g y : in d ire c t
im m u n o flu o re sc e n c e w ith m o n o c lo n a l a n tib o d ie s.
re sp e c tiv e ly . M e a n C D 8 + c e ll c o u n ts o f p a tie n ts
w e re sig n ific a n tly h ig h e r c o m p a re d to th e c o n tro ls
(F ig .
I).
F iv e p a tie n ts h a d p 2 4 a n tig e n e m ia : 3 o fth e m w e re C la ss III a n d 2 C la ss IV a -C D C .
H y p e rg a m m a g lo b u lin e m ia (1 .6 g /d l), d u e to h ig h
Ig G a n d Ig A le v e ls, w a s se e n in 1 8 o f th e 1 9
p a tie n ts (F ig . 2 ).
O f th e 1 9 a sy m p to m a tic se x u a l p a rtn e rs, th re e
(1 5 .8 p e rc e n t) w e re se ro p o sitiv e fo r H IV b y E L IS A
a n d W e ste rn b lo t a ssa y s. T h e y w e re c la ssifie d C D C
C la ss II. N o n e o f th e m sh o w e d th e se n c p 2 4 a n tig e n .
T h e C D 4 + c e ll c o u n ts w e re w ith in n o rm a l ra n g e s in
m o st p a rtn e rs, in c lu d in g th e th re e se ro p o sitiv e w o m e n
(F ig . 1 ). T h e th re e se ro n e g a tiv e p a rtn e rs sh o w e d a n
e le v a te d n u m b e r o f C D 8 + c e lls, b u t th e m e a n C D 8 +
c o u n t o f th e p a rtn e rs' g ro u p w a s sim ila rto th e c o n tro ls
(F ig . 1 ). Ig G le v e ls w e re n o rm a l in a ll b u t fo u r w o m e n ;
tw o o f th e m w e re se ro p o sitiv e (F ig . 2 ). Ig M a n d Ig A
le v e ls w e re w ith in n o rm a l ra n g e s.
Ii (1 1 0 3m o /d l)
.
..
.
if
i
at
-eo i;f
.
l 6~+
;
~+f+
~+,+
T O T A L1 0 Ig G lO A 1 0 M
Figure 2 -
T o ta l a n d19
c la sse s d e te rm in a tio n s in h e m o p h ilia c s (., n = 1 9 )a n d th e ir fe m a le se x u a l p a rtn e rs (., n = 1 9 ). E m p ty c irc le s re p re se n t re su lts
o f th e th re e H IV -in fe c te d w o m e n . B a rs re p re se n t m e a n s a n d sta n d a rd
e rro rs. M e a n v a lu e s a n d sta n d a rd e rro rs fo r 1 5 c o n tro ls w e re : to ta l Ig :
1 .0 4:t0 .2 g /d l; Ig G : 1 .5 5 :t0 .3 8 6 g /d l; Ig A ; 0 .3 1 7 :t0 .1 0 2 g /d l; Ig M ; 0 .2 7 9
:t0 .1 1 3 g /d l. D iffe re n c e s w e re sig n ific a n t (p < 0 .0 5 ) fo r to ta l Ig , Ig < ;3 ,a n d
Ig A le v e ls b e tw e e n h e m o p h ilia c s a n d se x u a l p a rtn e rs, a n d b e tw e e n
h e m o p h ilia c s a n d c o n tro ls. S ta tistic a l a n a ly sis w a s d o n e a s in th e F ig u re
1 le g e n d . D iffe re n c e s b e tw e e n se x u a l p a rtn e rs a n d c o n tro ls w e re
sig n ific a n t o n ly fo r Ig G le v e ls (p < 0 .0 5 ). M e th o d o lo g y : L a se r n e p h e lo m e try .
NICOLAU, J.E.; BENARD, G.; FONSECA, LAM. et al. - HIV heterosexual transmission to stable sexual partners of HIV-inlected brazilian hemophiliacs
1188
initiation
of sexual
exposure
(median
of lOA months).
Transmission
at later periods was considered
improbable.
These
results
were
related
to the fact that the immune
evaluation
was
performed
at the presumed
period
of
transmission,
and not after, as in other studies. The three
hemophiliacs
who infected their sexual partners had normal
CD4+
cell
counts,
elevated
CD8+
cells,
and
p24
antigenemia.
This result would be in accordance
with the
assumption
of an early transmission.
W e could not evaluate,
however,
the
influence
of
sexual
practices
in the
transmission
rate. The fact that transmission
occurs early
may also indicate
that transmittibility
could be related to
the virus burden of the transmitter.
Serum titers of HIV are
high shortly after infection occurs, low during asymptomatic
stages, and rise again when disease develops
(at this stage
sexual activity
is usually compromised).7
The three infected
partners
were asymptomatic,
p24
antigen
negati
ve
and
had
preserved
lymphocyte
subpopulations.
The only abnormal
laboratory
feature was
elevated
levels of IgG in two of the women.
None had a
mono-like
syndrome.
It is noteworthy,
however,
that we
did
find
some
laboratory
abnormalities
in the
HIV-seronegative
partners, namely, elevated CD8+ cell numbers
and hypergammaglobulinemia.
Similar
findings
were
noted by other authors,
8who suggested
the participation
of other infections
in the genesis
of these findings.
Alternatively,
the
presence
of HIV
particles
or
fragments
in the serum of HI V-negative
sexual partners
has
been
documented,
raising
the
possibility
of the
existence
of HIV-infected
seronegative
persons.
This
possibility
has been
discarded
by others
authors
who
have
demonstrated
the
absence
of HIV
infection
in
seronegative
persons
at high riskY.lll They hypothesized
that
such
seronegative
sexual
partners
were
exposed
to fragments
of the
virus,
thus
becomi ng reacti ve to
assays
that
detect
the
virus
or
its
fragments.
Alternatively,
it
has
been
suggested
that
some
individuals
at risk
for the
infection
could
mount
an
effective
immune
response
against
the virus
based
on
a predominant
T-helper-l
immune
response."
W e conclude
that
the
Brazilian
HIV-infected
hemophiliacs
studied
here show features
similar to those
of other countries,
and behave
as important
heterosexual
transmitters.
A C K N O W L E D G M E N T S
W e thank Danilo
F. Nunes
and Luis F. M . Brfgido
for crucial advice.
1189
REFERENCES
1 . M a th e z D , L e ib o v itc h J, S u lta n Y , M a iso n n e u v e P . L A V /
H T L V III se ro c o n v e rsio n a n d d ise a se in h e m o p h ilia c s in
F ra n c e . N E n g 1 J M e d 1 9 8 6 ;3 1 4 : 1 1 8 -9 .
2 . R a g n i M V , W in k le ste in A , K in g sle y L A , S p e ro JA ,
L e w is JH . U p d a te o f H IV se ro p re v a le n c e ,
se ro c o n v e rsio n , A ID S in c id e n c e , a n d im m u n lo g ic
c o rre la te s o f H IV in fe c tio n in p a tie n ts w ith h e m o p h ilia
A a n d B . B lo o d 1 9 8 7 ;7 0 :7 8 6 -9 0 .
3 . Z a n ic h e lli M A . A v a lia < ;a o im u n o l6 g ic a d e p a c ie n te s
h e m o fflic o s. T h e sis, C o lle g e o f M e d ic in e , S a o P a u lo
U n iv e rsity , B ra z il, 1 9 8 6 .
4 . G o e d e rt JJ, E y ste r M E , B ig g a r R J, B la ttn e r W A .
H e te ro se x u a l tra n sm issio n o f H IV : a sso c ia tio n w ith se v e re
d e p le tio n o f th e T -h e lp e r ly m p h o c y te s in m e n w ith
h e m o p h ilia . A ID S R e s H u m R e tro v iru se s 1 9 8 7 ;3 :3 5 5 -6 1 .
5 . L a u ria n Y , P e y n e t J, V e rro u st F . H IV in fe c tio n in se x u a l
p a rtn e rs o f H IV se ro p o sitiv e p a tie n ts w ith h e m o p h ilia . N
E n g l J M e d 1 9 8 9 ;3 2 0 : 1 8 3 .
6 . S a ra c c o A , M u sic c o M , N ic o lo si A , e t a l. M a n -to -w o m a n
se x u a l tra n sm issio n o f H I V : a lo n g itu d in a l stu d y o f 3 4 3
ste a d y p a rtn e rs o f in fe c te d m e n . J A c q u ir Im m u n o d e f
S y n d r 1 9 9 3 ;6 :4 9 7 -5 0 2 .
7 . R a g n i M V , K in g sle y L A , N im o rv ic z G u p ta P , R in a ld o C .
H IV h e te ro se x u a l tra n sm issio n in h e m o p h ilia c o u p le s: la c k
o f re la tio n to T 4 n u m b e r, c lin ic a l d ia g n o sis, o r d u ra tio n o f
e x p o su re . J A c q u ir Im m u n o d e f S y n d r 1 9 8 9 ;2 :5 5 7 -6 3 .
8 . F isc h l M A , D ic k in so n G M , S c o tt G B , K lim a s N , F le tc h e r
M A , P a rk s W . E v a lu a tio n o f h e te ro se x u a l p a rtn e rs, c h ild re n
a n d h o u se h o ld c o n ta c ts o f a d u lts w ith A ID S . JA M A
1 9 8 7 ;2 5 7 :6 4 0 -4 .
9 . C ra w e S M , E lb e ic k T , U lric h P P , M ills J, M o ss A . L a c k o f
e v id e n c e o f o c c u lt h u m a n im m u n o d e fic ie n c y v iru s in
se ro n e g a tiv e in d iv id u a ls a t v e ry h ig h risk o f in fe c tio n . J
M e d V iro I1 9 9 1 ;3 5 :1 6 0 -4 .
1 0 . Ja c k so n JB , K w o k S Y , H o p sic k e r JO , e t a l. A b se n c e o f
H IV in fe c tio n in a n tib o d y -n e g a tiv e se x u a l p a l1 n e rs o f H IV
-in fe c te d h e m o p h ilia c s. T ra n sfu sio n 1 9 8 9 ;2 9 :2 6 5 -7 .
1 1 . S h e a re r G M , C le ric i M . T -h e lp e r im m u n e d y sfu n c tio n in
a sy m p to m a tic , H IV -I se ro p o sitiv e in d iv id u a ls: th e ro le o f
T H 1 -T H 2 c ro ss re g u la tio n . In : C o ffm a n R L , e d . R e g u la tio n
a n d F u n c tio n a l S ig n ific a n c e o f T -c e ll S u b je c ts. B a se l:
K a rg e r. C h e rn Im m u n o l 1 9 9 2 ;5 4 :2 1 -4 3 .
SPONSORSHIP
T h is w o rk w as p artially
su p p o rted
b y
L IM -H e .
N IC O LA U , J.E .; B E N A R D , G .; FO N S E C A , LA M . et al. - H IV heterosexual transm ission to stable sexual partners of H IV -infected brazilian hem ophiliacs
