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C l in i c a l T h e r a p e u t i c s

w as t i n g w as amo n g t h e mo s t f r eq u en t l y o ccu r r i n g

AID S-def in ing con di t ions . 3 Since the in t ro duc t ion o f

H A A R T , t r ea t ed p a t i en t s r ema i n s e ro p o s i ti v e fo r l o n g -

er before the onse t o f AIDS; never the less , was t ing may

o ccu r b e fo re t h e p ro g re s s i o n t o A ID S an d can b e a

s ign i f i can t comorb id i ty in the p re-AIDS HIV-pos i t ivepat ie nt . 3 ,4

H IV -as s o c i a t ed w as t i n g h as b een d es c r i b ed a s a

fo rm of cachex ia , o r as invo lv ing cachex ia . 5,6 Cach ex ia

i s a s t a te o f genera l il l hea l th and m alnu t r i t io n charac-

t er i zed by excess ive weigh t loss and acce lera ted loss o f

s k e l et a l mu s c l e in t h e co n t ex t o f a ch ro n i c i n f l amma-

t o ry r e s p o n s e ; i t m ay o ccu r i n n u m ero u s ch ro n i c i n f ec -

t ions and mal ignan t cond i t ions , such as cancer , seps i s ,

conges t ive hear t fa i lu re , chron ic obs t ruc t ive pu lmonary

d i sease , and HIV. 5,7 Ho we ver , there i s no co m m on ly

acce p ted def in i t ion o f cach ex ia . 7,8The e t io logy of HIV-associa ted was t ing /cachex ia ap-

pears to be mult i factorial (Table I) , and the underlying

pathogenes i s i s no t c l ear ly unders tood . Never the less ,

ev idence sugges ts tha t red uced ca lo r i c in take an d m eta-

bo l i c and endocr ine fac to rs p lay an imp or tan t ro le in the

developm ent o f thi s cond i t ion . W eigh t loss m ay oc cur in

associa t ion wi th some HIV-associa ted oppor tun i s t i c in -

fec t ions (eg , microspor id ia , Cryptosporidium, Giardia

lamblia, cy tomegalov i rus , Mycobacterium avium) an d

m ay b e re la ted to gas t ro in tes t ina l ma labsorp t ion . 7

T h e re a r e f ew av a i l ab l e g u id e l in e s fo r t h e m an ag e -m e n t o f H I V - a s so c i a te d w a s ti n g . N o r t h A m e r i c a n a n d

E u ro p ean d i e t e t i c a s s o c i a t i o n s h av e p ro d u ced a n u m-

ber o f gu ide l ines fo r nu t r i t ional in terven t ion in pa-

t i en t s w i t h H IV i n f ec t i o n , i n c l u d i n g t h o s e w i t h w as t -

ing . 9 ,1° Ho we ver , the on ly o f f i c i a l gu ide line on o ther

a s p ec t s o f ma n ag em en t w as i s s u ed b y t h e A mer i can

G as t ro en t e ro l o g i ca l A s s o c i a t i o n an d d a t e s b ack t o

1996 .11 This gu ide l ine recommends the use o f appet i t es t imulan t s to increase ca lo r i c in take and nu t r i t ional

s u p p l emen t a t i o n .

Thi s rev iew d i scusses the c l in ica l impact and pa tho-

genes is o f HIV -associa ted was t ing /cachex ia , wi th em -

p h a si s o n t h e r o le o f th e g r o w t h h o r m o n e ( G H ) /

insu l in - l ike g rowth fac to r - I ( IGF-I ) ax i s in the pa tho-

phys io logy of th i s cond i t ion and the ra t ionale fo r i t s

t r e a t m e n t w i t h r e c o m b i n a n t h u m a n G H ( r h G H ) .

M E T H O D S

M E D L I N E w a s s e a r c h e d u s i n g H I V A N D wastingO R weight loss O R cachexia. St u d i e s o n G H w ere

iden t i f i ed us ing the sam e search , wi th inc lus ion o f the

term G H O R growth hormone. The search was l imi t -

ed to ar t i c l es pub l i shed in Engl i sh th rough Augus t

2007 . In evalua t ing ar t i c l es fo r inc lus ion , p reference

was g iven to c l in ica l s tud ies ( inc lud ing randomized

cl in ica l s tud ies ) , meta-analyses , and gu ide l ines . Re-

v i ew a r t i c l e s t h a t f o cu s ed o n H IV -as s o c i a t ed w as t i n g

w ere ev a l u a t ed an d t h e i r r e f e r en ce l i s t s ex ami n ed fo r

ad d i t i o n a l r e l ev an t p u b l i ca t io n s . O u r an a l y si s w as r e -

s t r i c t ed t o s t u d i e s co n d u c t ed i n d ev e l o p ed co u n t r i e s ;s t u d i e s co n d u c t ed i n A f r i ca an d So u t h eas t A s i a w e re

ex c l u d ed .

T a b l e I . C a u s es o f H IV - a s s o c i a t e d w a s t in g , g r o u p e d b y s y m p t o m .

I n a d e q u a t e n u t r i e n t i n t a k e

O r a l a n d u p p e r g a s t r o i n t e s ti n a l

A n o r e x i a

P s y c h o s o c i a l - e c o n o m i c

M a l a b s o r p t i o n

A l t e r e d m e t a b o l i s m

U n c o n t r o l l e d H I V i n f e c t io n

M e t a b o l ic d e m a n d s o f H A A R T

O p p o r t u n i s t i c i n f e c t io n s o r m a l i g n a n c i e s ( A I D S - d e f i n i n g c o n d i t i o n s )

H o r m o n a l d e f i ci e n c ie s ( t e s t o s te r o n e o r t h y r o i d )

C y t o k i n e d y s r e g u l a t io n

Reproduced w i th permiss ion f rom Ma ngi l i e t a l . Nutr i t ion and H IV in fec tion : Rev iew o f we ight loss and wast-

ing in the era o f h igh ly ac tive anti re trov ira l therap y f rom the N utr i t ion fo r H ea l thy L iv ing cohor t . Cl in In fec t

D is . 200 6;42 :836 -842 . © The Un ivers i ty o f-Ch icago Press.

HA AR T = highly active antiretroviral therapy.

2 2 7 0 V o lu m e 2 9 N u m b e r 1 1



M . G e l a t o e t a l.

T H E C L I N I C A L I M P A C T O F W A S T I N G

Wast ing i s a ser ious and deb i l i t a t ing cond i t ion tha t

can be l i fe - th rea ten ing . 3 I t invo lves a loss o f LB M that

may b e s i g n i f i c an t l y an d p o s i t i v e l y co r r e l a t ed w i t h

loss o f s t reng th and ab i l i ty to funct ion . In a p rospec-

t iv e s t u d y i n 2 4 H IV -p o s i t i v e ad u l t s u b j ec ts w i t h w as t -i n g (mean b o d y w e i g h t l o s s o f 1 5 % ) , t h e r e w as a

s i gn i fi c ant p o s i t iv e co r r e l a t io n b e t w een L BM an d m u s -

c le s t reng th in the lower ex t remi t i es ( r 2 = 0 .76 ; P <

0 .001) . 12 In ano ther p rospe ct ive s tud y in 201 pa t i en t s

enro l l ed in 3 HIV p rac t i ces in the Uni ted Sta tes, weigh t

l o ss (mean o f 2 . 3 k g o v e r 8 m o n t h s ) w as a s i g n i fi c an t

pred ic to r o f a dec l in ing ab i l i ty to car ry ou t ac t iv i t i es

of da i ly l iving (P < 0.001 ). 13

H IV -as s o c i a t ed w as t i n g h as a l s o b een a s s o c i a t ed

w i t h a r ed u ced ab i l i t y t o w i t h s t an d o p p o r t u n i s t i c

i n f ec t i o n s . I n t h e CD C A d u l t / A d o l e s cen t Sp ec t ru m o fH W D i s eas e (A SD ) P ro j ec t , 1992-1999,14 t h e 6 mo s t

co mmo n l y o ccu r r i n g (> 2 0 0 ca s e s p e r 1 0 0 0 p a t i en t -

years ) oppor tun i s t i c i l lnesses in pa t i en t s wi th HIV-

as s o c i a t ed w as t i n g w ere cy t o meg a l o v i ru s i n f ec t i o n

inc lud ing re t in i t i s (325 cases per 1000 pa t i en t -years ) ;

in fec t ious d iar rhea (304) ; d i s seminated M avium c o m -

plex in fec t ion (276) ; Pneumocystis carinii p n e u m o n i a

(2 6 9) ; an d b ac t e r em i a w i t h o r w i t h o u t s ep si s ( 2 42 ) . I n

a r e t ro s p ec ti v e an a l y s is o f 2 3 8 3 p a t i en ts w i t h H I V i n -

f ec t io n , t h o s e w i t h H W -as s o c i a t ed l o s s o f b o d y w e i g h t

(5 % -1 0 % w e i g h t l o s s o v e r 4 mo n t h s ) h ad a s i g n i f i -can t l y i n c r ea s ed r i s k o f o p p o r t u n i s t i c co mp l i ca t i o n s

o v e r a 2 - y e a r p e r i o d c o m p a r e d w i t h t h o s e w i t h n o

we igh t loss ( re la t ive r i sk [RR] = 1 .89 ; P < 0 .001) . 15

T h i s i n c r ea s ed r is k w as a l s o o b s e rv ed i n th e s u b g ro u p

o f p a t i en ts w h o l o s t 5 % t o 1 0 % o f t h e ir b o d y w e i g h t

b u t h ad n o h i s t o ry o f o p p o r t u n i s t i c co mp l i ca t i o n s

(RR = 1 . 8 6 ; P < 0 . 0 0 1 ) .

M o r t a l i t y r i s k h a s r ep ea t ed l y b een fo u n d t o i n c r ea se

i n p a t i en t s w i t h H W -as s o c i a t ed w as t i n g , b o t h b e fo re

the wide spread avai l ab i l i ty o f H A A RT 4,7,16-18 and af -

terw ard . 3 ,15,19,2° In a 12-y ear p rosp ect iv e s tu dy in no n-H A A RT - t r ea t ed p a t i en t s w i t h H IV i n f ec t i o n (N =

6 3 0 ) , t h e r i s k o f d ea t h i n c r ea s ed mo re t h an 2 - fo l d i n

p a t i en ts w i t h a s e l f -r ep o r t ed b o d y w e i g h t lo s s o f > 1 0 %

co m p ared w i t h p a t i en t s w h o d i d n o t r ep o r t t h i s d eg ree

of weigh t loss (hazard ra t io = 2 .4 ; P < 0 .001) . 20

E P I D E M I O L O G Y A N D

C L I N I C A L P R E S E N T A T I O N

T h e i n t ro d u c t i o n o f H A A R T i n 1995 i s l ikely to have

affec ted the inc idence o f HW-associa ted was t ing , a l -

though d i f feren t s tud ies have repor ted an increase in

wa sting, 14,21 no chan ge, 22,23 an d a decr ease. 19 Th e AS D

Pro jec t , a na t ional su rvei l l ance p rogram, p rov ided da ta

on the incidence o f wa st ing (using the C D C defini tion)

in the Uni ted Sta tes bo th before and af t e r the wide-

spread use o f HAART in a d iverse cohor t o f pa t i en t swi th H W infec tion (N = 46 ,678) . 14 The inc idence o f

was t ing was 30 .2 cases per 1000 pa t i en t -years in 1992

and 11 .9 cases per 1000 pa t i en t -years in 1999, w i t h a

significant decline in incidence after 1995 (P < 0.001). In

an analys i s o f da ta f rom the US Women and In fan t s

Transmiss ion Study (WITS), 21 which exam ined AIDS-

defining events ( including wast ing, using the CDC defi-

n i t ion) in 2255 women enro l l ed be tween 1989 an d

2002 (mean dura t ion o f fo l low-up , 22 .2 months ) , the

inc idence o f was t ing per 1 000 pa t i en t -years was 7 .6

f r o m D e c e m b e r 1989 t h ro u g h Feb ru a ry 1994, 2 .3 f romM a r c h 1994 th rough Ju ly 1996, an d 2 . 4 f ro m A u g u s t

1996 th rough June 200 2 . Th e ra tes repor ted in the per i-

ods af te r Marc h 1994 we re s ignificant ly low er than tho se

in the earl ies t period (P < 0.05). No pat ients received

H A A R T in 1989-1995, co mp ared w i t h > 6 0 % i n 2 0 0 3 .

A long i tud ina l observat ional analys i s o f pa t i en t s

enro l l ed in the Johns Ho pkin s AIDS serv ice repor te d an

inc idence o f was t ing (CD C def in it ion) per 100 pa t i en t -

years o f 1 .2 in 1994, 1.4 in 1996, and 1.1 in 1998,

with no s ign i f ican t d i f ferences across th i s per io d . 23

Similarly, a n I tal ian s tu dy in 35,31 8 pa t ients diag-n o s e d w i t h A I D S b e t w e e n 1990 an d 1998 r e p o r t e d

t h a t th e i n t ro d u c t i o n o f H A A R T h a d n o i m p a c t o n t h e

prop or t ion o f pa t ien t s w i th wa s t ing as an AIDS-defining

even t . 22 Ho we ver , the p rob ab i l i ty o f su rv iv ing >2 years

a f t e r t h e d i ag n o si s o f w as t i n g w as m o re t h an d o u b l ed

f ro m t h e p r e -H A A RT e ra , i n c r ea s i n g f ro m 0 . 2 4 i n

1990-1995 (9 5 % CI , 0 . 2 2 -0 . 2 6 ) t o 0 . 5 9 i n 1995-1998

(9 5 % CI , 0 . 5 5 -0 . 6 3 ) .

In an analys i s o f 713 pa t i en t s enro l l ed in the Nu-

t r i t i o n fo r H ea l t h y L i v i n g (N FH L ) s t u d y i n Bo s t o n ,

M a s s a c h u s e t ts , b e t w e e n 1995 a n d 2 0 0 3 ( e n c o m p a s s -i ng t h e i n t ro d u c t i o n o f H A A R T ) , 2 0 % o f p a ti e nt s

w i t h H IV i n f ec t i o n h ad 2 o ccu r r en ces o f u n i n t en t i o n -

a l lo s s o f _> 5% o f b o d y w e i g h t b e t w een 6 -m o n t h l y a s -

sessments . 19 Ho wev er , un l ike the A SD a nd W ITS data ,

which sugges ted a decreas ing inc idence , the resu l t s o f

t h is s t u d y i n d i ca t ed t h a t t h e r is k o f 6 -m o n t h u n i n t en -

t i o n a l l o s s o f _> 5% o f b o d y w e i g h t w as i n c r ea s ed f ro m

the ear l i e r per iod (1995-1997) to the l a t er per iod

(1 9 9 8 -2 0 0 3 ) (RR = 1 . 5 2 ; 9 5 % CI , 1 . 1 7 -1 . 9 7 ) , i n di -

ca t i n g t h a t u n i n t en d ed l o s s o f b o d y w e i g h t r ema i n s a

N o v e m b e r 2 0 0 7 2 2 7 1



Clinical Therapeutics

p ro b l em i n p a t i en t s r ece i v i n g H A A RT . U n i n t en t i o n a l

l o s s o f b o d y w e i g h t an d w as t i n g may o ccu r d e s p i t e

ad eq u a t e co n t ro l o f H IV i n f ec t io n , a s d e t e rmi n ed b y

H I V v i r al l o ad an d CD 4 cell co u n t . 19 Mo reo v e r ,

H A A RT h as n o t b een a s s o c i a t ed w i t h s u b s t an t i a l i n -

c r ea s e s i n L BM amo n g H IV - i n f ec t ed p a t i en ts , 24 an db o d y w e i g h t lo s s h a s r ema i n ed an i n d ep en d e n t r i s k

f ac t o r f o r mo rb i d i t y an d mo r t a l i t y i n t h e e r a o f

HA AR T. 3 ,19,2° Indeed , in the cur ren t e ra , w as t ing and

cach ex i a may h av e a mo re s u b t l e p r e s en t a t i o n t h an

wh en AIDS w as t ing w as f i r s t iden t i f i ed in the 1 980s . 25

L o s s o f > 1 0 % o f to t a l b o d y w e i g h t ( ie , t h e C D C d e f i-

ni t ion of wast ing) is s ti ll seen today , al tho ugh less fre-

qu ent ly tha n in the ea rly 19 90s. 14,26

In add i t ion to exper iencing loss o f body weigh t and

L BM, s o me p a t i en t s w i t h H W -as s o c i a t ed w as t i n g may

also lose b od y fat . 27 Sex2 s an d b o d y co m p o s i t i o n b e fo rethe loss o f bod y w eigh t 29 in f luence bo d i ly changes in

pat i en t s wi th HW -assoc ia ted was t ing . I t i s imp or tan t to

moni to r body weigh t ; however , i t i s a l so impor tan t to

b e aw are t h a t f a t lo s s w i t h l i p o a t ro p h y can co n t r i b u t e

to loss o f bod y weigh t in pa t i en t s w i th H W infec tion . 29

RISK FACTORS FOR HIV-ASSOCIATED WASTING

A n u m b er o f s tu d i e s h av e u s ed mu l t i v a r i a te an a l y si s t o

ex ami n e f ac t o r s a s s o c i a t ed w i t h t h e d ev e l o p men t o f

u n i n t en t i o n a l w e i g h t l o s s i n p a t i en t s w i t h H IV i n f ec -

t ion (Tab le II) . 19,30-33 Ris k facto rs con sis ten t ly associ-a t ed w i t h w e i g h t l os s o r w as t i n g ac ro s s > 1 s t u d y w ere

l o w C D 4 c e l l co un t, 19,31,32 hig h viral loa d, 19,31 high

basel ine we ight 31,32 or bo dy ma ss index, 19 and the pres-

ence of thr ush , diarrh ea, or fever. 19,31 Ho w eve r, in the

s tudy b y Tang e t a l , 19 d iar rhea was (som ew hat su rpr i s-

i n gl y) r ep o r t ed t o b e a s s o c i a t ed w i t h a r ed u ced r i sk o f

was t ing . You nger age (_<50 years ) , 33 nonw hi te race , 33

an d f ema l e s ex 32 h av e a l s o b een r ep o r t ed t o i n c r ea s e

the r i sk fo r was t ing , a l though the f ind ings have no t

b een co n s i s t en t . L o w CD 4 ce l l co u n t , h i g h H W -1

R N A l ev e ls , a n d p o o r K a r n o f s k y s c o r e w e r e f o u n d t ob e a s s o c i a t ed w i t h an i n c r ea s ed r i s k o f w as t i n g i n t h e

AIDS Cl in ica l Tr ia l s Gr oup analys i s , 32 and recen t

t r av e l to t r o p i ca l co u n t r i e s w as a s s o c i a t ed w i t h an i n -

c r ea s ed r i s k i n t h e Sw i ss H I V Co h o r t S t u dy . 3 °

M E C H A N I S M S U N D E R L Y I N G

W A S T I N G / C A C H E X I A I N H I V

M u l t i p l e co ex i s t i n g m ech an i s ms o f w as t in g f fcach exi a

h av e b een i d en t i fi ed . A n ex ces s i v e p ro i n f l am m at o ry

c y t o k i n e r e s p o n s e a p p e a r s t o b e a c o m m o n m e c h a -

n i sm. 5 ,7 ,34 Oth er p ro po sed me chan i sms inc lude endo-

cr ine abnormal i t i es such as low tes tos terone l evel s ,

an d G H " r e s i s tan ce , " w h i ch a r e d i s cu s s ed i n t h e fo l-

lowing sec t ions .

T h e C y t o k i n e P r o i n f l a m m a t o r y P a t h w a yCy t o k i n es a r e a d i v e r s e g ro u p o f p ro t e in s t h a t p l ay

k ey ro l es in imm u n o reg u l a t i o n an d n o rm a l p h y s i o -

log ic p rocesses , as wel l as in var ious pa thophys io log ic

i n f l am ma t o ry p ro ces s e s . 35 Cy t o k i n e ex p re s s i o n is

e levated in respon se to in fec t ion o r ce l l in ju ry , d r iv ing

the in i ti a l in f l am ma tory response . 35 E levated l evels

o f t h e p ro i n f l ammat o ry cy t o k i n es i n t e r l eu k i n ( IL ) - I ,

IL-2 , IL-6 , in ter feron- 7 (IFN-7) , a nd /or tum or necros i s

fac to r -o~ (TNF-00 (a l so known as cachect in o r cachex-

in ) have been observed in acu te ly i l l pa t i en t s and pa-

t i en t s wi th excess ive weigh t loss , usual ly wi th d i spro-p o r t i o n a t e mu s c l e w as t i n g , i n t h e s e t t in g o f co n g es ti v e

hear t fa i lu re , chron ic renal fa i lu re , chron ic obs t ruc t ive

pu lm ona ry d i sease , cancer, and H W -assoc ia ted was t -

ing . 5 Al though cy tok ines genera l ly ac t loca l ly on p ro-

te in metabo l i sm, som e ( in par t i cu lar IL-6) m ay ac t sys-

t emical ly , fo r example , reducing fo od in take th rough a

d i rec t e f fec t on the hyp othalam ic nucle i o r ac t ing ind i-

r ec tl y o n th e h y p o t h a l am u s t h ro u g h med i a t o r s s u ch a s

cor t i co t roph in- re leas ing hor m one or sero ton in . 7

E f f e ct o f C y t o k in e s o n P r o t ei n M e t a b o l i s mT h ere i s ev i d en ce t h a t cy t o k i n es med i a t e cach ex i a

b y a l t e ri n g m u s c l e p ro t e i n m e t ab o l i s m. E l ev a t ed lev e ls

of TNF-cz and IF N-7 ac t iva te nuclear t ra nscr ip t ion

fac to r KB (NFKB), which i s expressed in ma ture mu s-

c le . In an in v ivo an imal model , NFKB suppressed the

s y n t hes i s o f M y o D , a t r an s c r i p ti o n f ac t o r r e s p o n s i b l e

for ske le ta l myoblas t d i f feren t i a t ion , a p rocess funda-

me nta l to musc le repair . 36 In add i t ion , an in v i t ro s tudy

fo u n d t h a t a d o w n s t r ea m t a rg e t o f N FKB, th e n i tr i c

ox ide syn thase gene , s t imula ted loss o f M yo D mR NA . 37

In b o t h i n v i t ro an d i n v i v o mo d e l s o f mu s c l e w as t i n g ,TNF-cz and IFN -7 redu ced l evel s o f the m yof ib r i l l a r

p ro t e i n my o s i n h e av y ch a i n . 38

Elevated cyto kine levels also cause al terat ions in mus-

c le p ro te in metabo l i sm v ia ac t iva t ion o f the ub iqu i t in -

p ro t ea s o me s y s t em. T h i s i s a s e l ec t i v e p ro t e i n -

d e g r a d a t i o n p a t h w a y r e s p o n s i b l e f o r a c c e l e r a t e d

p ro t eo l y s i s i n ca t ab o l i c co n d i t i o n s ; t h e mo l ecu l a r

p a t h w ay s i n v o l v ed i n mu s c l e w as t i n g h av e b een r e -

v i ew ed i n d ep t h b y J ack m an an d K an d a r i an . 39 T h e

re l ea s e o f T N F-cz an d IL s f ro m ac t i v a t ed mac ro -

2 2 7 2 V o lu m e 2 9 N u m b e r 1 1



M . G e l a t o e t a l .

T a b l e II. P r e d i c t o r s o f H I V - a s s o c i a t e d w e i g h t l o s s o r w a s t i n g : R e s u l ts o f m u l t i v a r ia t e a n a l y s e s . ( T h e r e f e r e n c e c a t e -

g o r y i s t h e a b s e n c e o r o p p o s i t e o f t h e v a r ia b l e , u n l e s s o t h e r w i s e s t a t e d . )

Relat ive

V a r i a b l e H a z a rd 95% CI P

P a t i e n t - r e p o r t e d w e i g h t l o ss in H C S U S s t u d y ( N = 2 8 6 4 ) 3 3~

A g e _ < 50 y 1 . 3 6 0 . 9 2 - 2 . 0 1 N S

N o n w h i t e r a c e 1 . 3 0 1 . 0 4 - 1 . 6 1 < 0 . 0 5

P a t i e n t - r e p o r t e d w e i g h t l o s s in V A C S 3 s t u d y ( N = 8 8 1 ) 33 ~

A g e _ < 50 y 1 . 4 6 1 . 0 6 - 2 . 0 1 < 0 . 0 5

N o n w h i t e r a ce 0 . 7 9 0 . 5 5 - 1 . 1 5 N S

_ >5% W e i g h t l o s s in N F H L s t u d y

( N = 4 0 9 8 6 - t o o t r e a t m e n t i n te r v al s )1 9 f

1 9 9 5 - 1 9 9 7 1 . 0 0

1 9 9 8 - 2 0 0 3 1 . 52 1.1 7 - 1 . 9 7 0 . 0 0 6

H i s t o r y o f IV d r u g u s e 1 . 3 7 1 .1 6 - 1 . 6 3 < 0 . 0 0 1I m p o v e r i s h e d 1 . 2 2 1 . 0 3 - 1 . 4 5 0 . 0 2

B o d y m a s s i n de x , k g / m 2

< 2 5 1 . 0 0

_ > 2 5 -< 3 0 1 . 6 0 1 . 3 2 - 1 . 9 2 < 0 . 0 0 1

_>30 1.70 1.3 4-2 .15 <0.001

CD 4 cou n t _<200 ce l ls / la L 1 .26 1 .04 -1 .53 0 .02

V i ra l l o a d >1 0 s c o p ie s /m L 1 .38 1 .0 8 -1 .7 5 0 .0 0 9

D ia r rh e a 0 .7 9 0 .6 8 -0 .9 2 0 .0 0 3

Nausea 1 .40 1 .20 -1 .64 <0 .001

Thrush 1 .33 1 .07 -1 .65 0 .01

S e l f - r e p o r te d u n in te n t i o n a l l o s s o f >1 0 I b o r d o c u m e n te d

los s o f> 5 % F ro m b a s e l in e in M A C S , 1 9 8 5 -1 9 9 5 (N = 1 5 5 8 ) 3 1t

H I V R N A , c o p i e s / m L

<500 1 .00

500-1 0 ,000 1 .56 1 .10 -2 .22 0 .013

>1 0 ,0 0 0 -3 0 ,0 0 0 1 .92 1 .3 2 -2 .7 9 <0 .0 01

>30 ,0 00 2 .53 1 .72 -3 .73 <0 .001

C D 4 c o u n t , c e l l s /m m 3

_>730 1.00

3 9 0 -7 2 9 1 .08 0 .8 8 -1 .3 2 0 .4 6

<390 1 .42 1 .1 2 -1 .80 0 .004

N e o p t e r i n , m m o l / L

<8 .43 1 .008 .4 3 -1 5 .6 0 1 .1 1 0 .9 0 -1 .3 5 0 .3 3

>15 .60 1 .36 1 .06 -1 .73 0 .15

[~-Mic rog lobu l in , lag /L

_<2.22 1.00

>2 .22 1 .25 1 .06 -1 .49 0 .01

Or a l cand id ias is , feve r , o r d ia r rh ea 1 .30 1 .04 -1 .61 0 .019

Age , pe r 10 -year inc rease 1 .05 0 .92 -1 .19 0 .5

In i t ia l we igh t , pe r 20 -1b inc rease 1 .11 1 .03 -1 .1 9 0 .005

( c o n t i n u e d )

N o v e m b e r 2 0 0 7 2 2 7 3



C l i n i c a l T h e r a p e u t i c s

T a b l e II . ( C o n t i n u e d )

V a r i a b l e

R e la t i ve

H a z a r d 95% C I P

> 1 0 % L os s o f b o d y w e i g h t f r o m b a s e l i n e in A C T G t r i a l sc o m p l e t e d b y 1 9 9 6 ( N = 5 4 5 2 ) 32§

A I D S

C D 4 c o u n t , p e r S 0 - c e l l / m L i n c re a s e

W e i g h t

K a r n o f s k y s c o r e , p e r 1 0 - p o i n t i n c r e a s e

H e m o g l o b i n

T r i g l y c e r id e s , p e r 1 0 0 - g / d L i n c r e a s e

F e m a l e s e x

D i d a n o s i n e m o n o t h e r a p y

I n v o l u n t a r y w e i g h t l os s o f > 1 0 % a n d p e r s i s t e n t d i a r r h e a o r

f e v e r w i t h o u t s p e c i fi c c a u s e i n Sw i ss H I V C o h o r t S t u d y ,

1 9 8 8 - 1 9 9 8 ( N = 4 5 4 9 ) 3°11

T r a v el to t r o p i c a l o r s u b t r o p i c a l c o u n t r y

1 .46 I . I 0 - I .96 _<0 .05

0 . 8 9 0 . 8 4 - 0 . 9 3 _ < 0 . 0 5

I . I 9 I . I 0 - I .27 _<0.05

0 . 6 7 0 . 6 2 - 0 . 7 4 _ < 0.0 5

0 . 8 7 0 . 9 1 - 0 . 9 3 _ < 0 . 0 5

1 . 0 9 1 . 0 1 - 1 . 1 8 _ < 0. 05

1.55 1.08-2.20 _<0.05

0 . 7 8 0 . 6 2 - 0 . 9 9 _ < 0 . 0 5

2 . 1 6 1 . 0 9 - 4 . 3 0 _ < 0. 05

HCSUS = HIV Co st an d Service Utilization Study; VACS 3 = Veterans Ag ing Co ho rt 3 Site Study; N FHL = Nutrition for Healthy

Living; MACS = M ulticenter AIDS Coh ort Study; AC TG = AIDS Clinical Trials Group.

*Adjusted fo r sex, income, c urrent hom elessness, drug d epen den ce, h eavy alcohol use, exposure risk factor, any antiretroviral

drug use, lowest ever CD4 co unt, and history ofPneum ocystis carinii pneumonia, herpes , or Candida/thrush.

fAdjusted fo r calen dar period; white race; history of IV drug use; insecure housing; impoverishment; bo dy ma ss index

->25 kg/m2; CD4 count 200 cells/IJL; HIV viral load >10 s copies/mL; albumin <3.4 g/dL; an y opp ortu nistic infection; trying

to lose weight; presence of-diarrhea, nause a, painful gu ms, fever, coug h, or thrush; use of-highly active antiretroviral therap y;

nucleoside reverse transc riptase inhibitor use ; resting energy expenditure >31.0 per kg fat-free mass ; and caloric intake

>25.9 kcal/kg.

*Model accounting for all markers simultaneously and adjusted for baseline age and weight.§Adjusted for baseline an d week-8 CD4 co unt, baseline serum album in, tr iglyceride levels, hem oglo bin, K arnofsky score, bo dy

weight, b ody m ass index, diagnosis of AIDS, history o f IV drug use, increasing age, a nd fema le sex.

IIAdjusted for age, CD4 c ou nt at baseline and during follow-up, Centers for Disease Control an d Prevention clinical stage, and

transmission group.

p h a g e s a n d e n d o t h e l i a l c e ll s s t i m u l a t e s th e u b i q u i t i n -

p r o t e a s o m e p a t h w a y i n m u s c l e .

I n a d d i t i o n , c y t o k i n e s c a u s e a l t e r a t i o n s i n l i p i d m e -

t a b o l i s m a s p a r t o f th e i n f l a m m a t o r y r e s p o n s e . F o r e x -

a m p l e , T N F - c z a n d / o r I L -1 m e d i a t e i n c r e a s es i n s e r u m

t r i g l y c e r i d e l e v e ls 4 ° a n d u p r e g u l a t e l o w - d e n s i t y l i p o -p r o t e i n r e c e p t o r a c t iv i t y . 41 A l t h o u g h H I V - a s s o c i a t e d

w a s t i n g i s c h a r a c t e ri z e d b y h y p e r t r i g l y c e r id e m i a , 7 t h e

c o n t r i b u t i o n o f i n c r e a s e d s e r u m t r i g l y c e ri d e l e ve l s t o

t h e d e v e l o p m e n t o f c a c h e x i a r e m a i n s c o n t r o v e r s i a l .

E l e v a t e d l ev e ls o f T N F r e c e p t o r ( T N F R ) , I L - 1 r ec e p -

t o r a n t a g o n i s t ( I L -1 R a , a n i n d i r e c t i n d i c a t o r o f I L - 1

l e v e ls ) , a n d I F N -c z h a v e b e e n o b s e r v e d i n p a t i e n t s w i t h

H I V - a s s o c i a t e d l o s s o f b o d y w e i g h t . 4 2-4 4 A n a l y s e s o f

s u b g r o u p s o f p a t i e n t s w i t h H I V - a s s o c i a t e d w a s t in g ,

d e f i n e d as u n i n t e n t i o n a l l o s s o f > 1 0 % o f b o d y w e i g h t

w i t h o u t c o n c o m i t a n t o p p o r t u n i s t i c i n f e c t i o n ( n =

8 / 7 9 ) 42 o r a s s i g n i f i c a n t l o s s o f b o d y w e i g h t ( m e a n ,

1 4 % ; r a n g e , 8 % - 3 6 % ) i n t h e pr e v io u s 3 m o n t h s (n =

1 2 / 6 1 ) , 43 f o u n d t h a t m e a n l e v e ls o f I F N - c z42 and

I L - 1 R a 43 w e r e s i g n i fi c a n t l y g r e a t e r i n p a t i e n t s w i t h w a s t -

i n g c o m p a r e d w i t h t h o s e w i t h o u t w a s t i n g ( P < 0 .0 0 1 ) .T h e e l e v a t i o n s in I L - 1 R a w e r e i n d e p e n d e n t o f t h e d e -

g r e e o f i m m u n e d e f ic i e n c y . 43 M o r e o v e r , a n o t h e r s t u d y

r e p o r t e d t h a t c o m p a r e d w i t h h e a l t h y c o n t r o l s ( n = 7 ),

p a t i e n t s w i t h H I V i n f e c t i o n ( n = 4 5 ) h a d s i g n i f i c a n t l y

e l e v a te d l ev e ls o f s e r u m s o l u b l e T N F R ( s T N F R ) ( P <

0 . 0 5 ) , a m a r k e r o f T N F - c z l e v e ls . 44 A m o n g t h e 4 5 p a -

t i en t s w i t h H I V i n f e ct i o n , 1 6 h a d u n i n t e n t i o n a l l o ss o f

> 5 % o f b o d y w e i g h t ; t h e r e w a s a s i g n i fi c a n t p o s i t i v e

c o r r e l a t i o n b e t w e e n s T N F R c o n c e n t r a t i o n s a n d t h e

m a g n i t u d e o f w e i g h t l o ss i n t h i s g r o u p ( r = 0 . 5 9 ; P <

2 2 7 4 V o l u m e 2 9 N u m b e r 1 1




0 . 0 2 ). I n t h e lo n g i t u d i n a l N F H L s t u d y in 1 7 2 p a t i e n t s

w i t h H I V i n f e c t i o n , m u l t i v a r i a t e r e g r e s s i o n a n a l y s i s

i n d i c a t e d a s i g n i f i c a n t i n v e r se r e l a t i o n s h i p b e t w e e n

c h a n g e i n L B M o v e r a m e a n o f 8 . 7 m o n t h s a n d l e v e l s

o f T N F- 0~ ( P < 0 .0 2 ) a n d I L - I ~ ( P < 0 .0 1 ) i n p e r i p h e r -

a l b l o o d m o n o n u c l e a r c e l ls . 34 I n t h i s c o h o r t , 3 5 % o fp a t i e n t s h a d a lo s s in L B M o f > 1 k g ; 6 5 % h a d a s m a l l -

e r l o s s , n o c h a n g e , o r a g a i n i n L B M . W h e t h e r t h e r e

i s a d i r ec t c au s e - an d - e f f ec t r e l a t i o n s h i p b e t w een t h e s e

e l e v a t e d c y t o k i n e l ev e ls a n d c a c h e x i a i n p a t i e n t s w i t h

H I V i n f ec t i o n is u n k n o w n .

Resting Energy Expenditure

P a t i e n t s w i t h H I V - a s s o c i a t e d w a s t i n g h a v e a n e l e -

v a t e d r e s t in g e n e r g y e x p e n d i t u r e 45 (R E E ) a n d n e e d t o

c o n s u m e m o r e c a l o r ie s t h a n n o r m a l , w h i c h i t s e l f p r e -

s en ts a c l i n ica l m a n ag em en t ch a l l en g e . H o w ev e r , t h e ex -t e n t t o w h i c h e l e v a t ed R E E m a y c o n t r i b u t e t o w a s t i n g

i s co n t r o v e r s i a l . 46,47 I n t h e N F H L s t u d y , 34 t h e m ean

i n c r e as e i n R E E ( 6. 8 k c a l /d ) a m o n g H I V - i n f e c t e d p a -

t i e n ts w a s s i g n i fi c a n t l y a n d p o s i t iv e l y a s s o c i a te d w i t h

T N F - R o v e r a m e a n 6 . 5 m o n t h s o f o b s e r v a t i o n ( r e-

g r e s s i o n co e f f i c i en t = 9 .0 ; P = 0 .0 4 ) . A l t h o u g h t h e i n -

c r e a se i n R E E w a s s m a l l , th e i n v e s t i g a t o r s c o n s i d e r e d

t h e e f f ec t t o b e c l i n i ca l l y s i g n i f i c an t b ecau s e o f t h e p o -

t e n t i a l f o r c u m u l a t i v e e f fe c t s o f i n c r e a se d R E E o v e r

m a n y m o n t h s . R E E d a t a w e r e c o l le c t e d e v e r y 6 m o n t h s

f r o m 1 3 2 p a t i e n t s ; m o s t ( 7 7 % ) o f t h e s e p a t i e n t s m a i n -t a i n e d a s t a b l e w e i g h t ( n o c h a n g e i n b o d y w e i g h t

o r _ < 2% l o s s) o v e r t h e co u r s e o f t h e s t u d y , an d o n l y

2 % h a d H I V - a s s o c i a te d w a s t i n g , a l t h o u g h 1 2 % o f

m e n h a d a lo s s o f > 5 % i n L B M . N o c o r r e l a t i o n w a s

f o u n d b e t w e e n c h a n g e i n L B M a n d c h a n g e i n R E E . 34

T h u s , t h e r e d o e s n o t a p p e a r t o b e a c a u s a l r e l a t i o n -

s h i p b e t w e e n e l e v a t e d R E E a n d H I V - a s s o c i a t e d

w a s t i n g . 46

T h e i n c r e a s e d R E E i n H I V - a s s o c i a t e d w a s t i n g m a y

s e e m p a r a d o x i c a l , a s R E E i s n o r m a l l y d e p e n d e n t o n

L B M . S h e v i tz e t a 148 s u g g e s t e d t h a t H A A R T r e g i m e n si n c r e a s e m e t a b o l i c d e m a n d s t h r o u g h a n u n k n o w n

m e c h a n i s m t h a t i s i n d e p e n d e n t o f th e i r e f f ec t o n v i r a l

b u r d e n . P r o p o s e d m e c h a n i s m s i n c l u d e d d i r e c t s t i m u -

l a t io n o f m e t a b o l i s m b y H A A R T t h r o u g h a c t i v a ti o n

o f th e s y m p a t h e t i c n e r v o u s s y s t e m o r a n i n c r ea s e i n

m e t a b o l i c d e m a n d a s s o ci a te d w i t h r e j u v e n a t io n o f t h e

i m m u n e s y s te m .48 E x c ep t i n t h e s e t t i n g o f an acu t e o p -

p o r t u n i s t i c i n f e c t i o n ,49 r ed u ced ca l o r i c i n t ak e ap p ea r s

t o p l a y a g r e a t e r r o l e i n t h e e t i o l o g y o f w a s t i n g t h a n

d o es e l ev a t ed R E E . 46

T e s t o s t e r o n e

G o n a d a l d y s f u n c t i o n is c o m m o n i n m e n w i t h H I V

i n f e c t i o n , w i t h 2 6 % o f i n f e c t e d m e n h a v i n g l o w e r -

t h a n - n o r m a l l ev el s o f f ree t e s t o s t e r o n e . 5 ° T es t o s t e r o n e

h as n o t b een d e f i n i t i v e l y i d en t i f i ed a s a c au s e o f H I V -

as s o c i a t ed w as t i n g ; s ev e r a l s t u d i e s , b u t n o t a l l , h av ef o u n d a n a s s o c i a t i o n b e t w e e n l o w t e s t o s t e r o n e l e v e l s

a n d w a s t i n g i n p a t i e n t s w i t h H I V i n f e c t i o n .28,34,51-53

I n t h e N F H L s t u d y, 34 n o r e l a t i o n s h i p w a s f o u n d b e -

t w e e n c h a n g e s i n L B M o v e r 9 m o n t h s a n d f r e e t e s t o s -

t e r o n e c o n c e n t r a t i o n s . H o w e v e r , i n th e s a m p l e s t u d i e d ,

o n l y 2 % o f p a t i e n t s h a d s e v e re A I D S w a s t i n g .

O v e r a l l , i t is n o t c l ea r w h e t h e r d ec r ea s ed t e s t o s t e r o n e

l ev e ls a r e a p o t e n t i a l c a u s e o r a c o n s e q u e n c e o f w a s t -

i n g . 46 A s m a l l s t u d y s p ec i f i c a l l y co m p ar i n g en d o c r i n e

f u n c t i o n i n p a t i e n t s w i t h H I V i n f e c t i o n w i t h a n d w i t h -

o u t w a s t i n g f o u n d t h a t t o t a l a n d f r e e t e s t o s t e r o n el eve l s w e r e s i g n i f ic an t l y l o w e r i n t h e 1 4 p a t i en t s w i t h

H W - a s s o c i a t e d w a s t i n g c o m p a r e d w i t h t h e 1 8 p a t i e n t s

w i t h n o w a s t i n g a n d C D 4 c o u n t s < 2 0 0 c e l l s /r a m 3 ( P =

0 . 0 0 3 ) . 51 I n a c a s e - c o n t r o l s t u d y i n 1 3 m e n w i t h H I V -

as s o c i a t ed w as t i n g , s i g n i fi c an t r ed u c t i o n s i n t e s t o s t e r o n e

( f r ee , serum, and b ioavai lab le) over the 6 months befo re

t h e d i ag n o s i s o f w as t i n g ( P < 0 .0 5 ) s u g g es t ed a ro l e f o r

r e d u c e d t e s t o s t e r o n e l e ve ls i n t h e d e v e l o p m e n t o f H W -

a s s o c i a t e d w a s t i n g . 52 M a t c h e d c o n t r o l s h a d n o s ig n if i-

c a n t c h a n g e s i n a n y t e s t o s t e r o n e l e v e l.

A s t u d y ex a m i n i n g t e s t o s t e ro n e l eve ls i n H W - p o s i t i v ew o m e n w i t h n o w a s t i n g ( n = 1 2) , e a rl y w a s t i n g ( n =

1 0 ) , o r l a t e w as t i n g ( n = 9 ) f o u n d t h a t t h e p r ev a l en ce

o f b e l o w - n o r m a l ag e - ad j u s t ed l ev el s o f fr ee te s t o s t e r o n e

i n c r e a s e d w i t h t h e d e v e l o p m e n t o f w a s t i n g , o c c u r r i n g

i n 3 3 % , 5 0 % , a n d 6 6 % o f t h e r e s p e ct i v e g r o u p s o f

p a t i en t s . 28 F ree t e s t o s t e r o n e l ev e ls w e r e s i g n i f i c an t l y

l o w e r i n t h e p a t i e n t s w i t h e a r l y o r l a t e w a s t i n g c o m -

p a r e d w i t h h e a l t h y H I V - n e g a t i v e c o n t r o l s ( 0 . 7 , 0 . 6 ,

a n d 2 . 0 n g / d L , r e s p e c t i v e l y ; P < 0 . 0 5 ) . F u r t h e r m o r e ,

t h e r e w a s a s i g n i f ic a n t p o s i ti v e c o r r e l a t i o n b e t w e e n

l o s s o f m u s c l e m as s a n d f r ee t e s t o s t e r o n e l ev e l s (r =0 . 3 7 ; P < 0 .0 5 ) . A s t u d y i n 7 7 m a l e p a t i e n t s w i t h H I V

i n f e c t i o n , a p p r o x i m a t e l y h a l f w i t h w a s t i n g , h a d s i m i -

la r f ind ings : f r ee tes tos tero ne levels we re low er tha n no r -

m a l ( m e a n , 8 .3 n g / m L ; n o r m a l r a n g e , 1 2 . 0 - 3 5 . 0 n g / m L )

a n d w e r e s i g n i fi c a n t l y p o s i t iv e l y c o r r e la t e d w i t h m u s -

c le mass ( r = 0 .45 ; P < 0 .05) . 53

Myostatin and Myopathies

E l e v a t e d l e v e l s o f t h e g r o w t h f a c t o r m y o s t a t i n , a

m e m b e r o f t h e t ra n s f o r m i n g g r o w t h f a c t o r - ~ s u p e r-

November 2007 2275



C l i n i c a l T h e r a p e u t i c s

f ami l y o f p ro te i n s , a r e a s s o c i a t ed w i t h w as t i n g i n p a -

t i en t s wi th H IV in fec t ion . 54 M yo s ta t i n se lec t ive ly and

p o t en t l y i n h i b i t s my o g en es i s an d may b e a p r i mary

cau s a t i v e f ac t o r i n H IV w as t i n g . G H h as b een fo u n d

to ef fec t ive ly suppress m yos ta t in ex press ion , resu l t ing

in an anab o l ic e f fec t . 55 A para l l e l exam inat ion o f mus-c l e b i o p s i e s f ro m G H -d e f i c i en t ad u l t s w h o r ece i v ed

r h G H o r p l a c e b o a n d m y o c y t e s t r e a te d i n v i tr o h a v e

i n d i ca t ed t h a t G H s u p p re s s e s my o s t a t i n ex p re s s i o n . 55

S e r u m m y o s t a t i n - i m m u n o r e a c t i v e p r o t e i n c o n c e n t r a -

t ions were s ign i f i can t ly h igher in 23 men wi th HIV-

as s o c i a t ed w as t i n g (> 1 0 % l o s s o f b o d y w e i g h t ) co m-

p a red w i t h 3 8 p a t i en t s w i t h o u t w as t i n g (4 9 9 . 7 v s

363 .3 ng pep t ide B equ ivalen t /mL; P _< 0 .001) . 54 The

s p ec i f i c mech an i s m o f ac t i o n o f my o s t a t i n i n H IV -

as s o c i a t ed mu s c l e w as t in g i s u n k n o w n . L o s s o f mu s c l e

m a s s m a y a l s o p r e se n t s e c o n d a r y t o a n i n f l a m m a t o r ymy o p a t h y , s u ch a s p o l y a r t e r i t i s n o d o s a o r p o l y my o s i -

t i s f 6 t h a t i s p ro b ab l y n o t d i r ec tl y r e l a ted t o t h e g en e r -

a l p h e n o m e n o n o f H I V w a s ti n g .

V i r o l o g i c F a c t o r s , L e a n B o d y M a s s , a n d

t h e E f f e c t s o f H A A R T

Viro log ic fac to rs may cause a l t e ra t ions in muscle

ami n o ac i d me t ab o l i s m 57 t h a t may co n t r i b u t e t o t h e

muscle was t ing observed in pa t i en t s wi th HIV in fec-

t ion. 5s In a s tu dy in 11 p at ients wit h H IV infec t ion, s ig-

n i f ic an t r ed u c ti o n s f ro m b as e li n e in p l a s ma H IV RN Al ev els a f t e r 4 mo n t h s o f H A A R T (P = 0 . 0 0 3 ) w e re a s s o -

c ia ted wi th increases in the ra te o f muscle p ro te in syn-

thes i s and reduct ions in muscle p ro te in degradat ion ,

a l t h o u g h n e i t h e r v a r i ab l e w as n o rma l i zed F T h es e p a -

t i en t s d id no t have HIV-associa ted was t ing and exper i -

enced no s ign i f i can t changes in body mass index , fa t -

f ree mass , m uscle mass , fa t mass , o r to ta l bo dy weigh t .

W h e t h e r t h e i mp ro v emen t s i n mu s c l e p ro t e i n me t ab o -

l is m w ere a t t r ib u t ab l e t o H A A RT o r t o t h e r ed u c ti o n i n

v i ral load ach ieved wi th t rea tm ent i s no t kn ow n. N ever-

the less , m anag em ent o f pa t i en t s wi th HIV-associa tedwas t ing requ i res ade quate c on t ro l o f the v ira l load as

the p r imary therapeu t i c t a rge t .

Stud ies condu cted in the p re-HA AR T era found an in-

d e p e n d e n t a s s o c i a t i o n b e t w e e n H I V R N A l e v e l s a n d

loss o f b od y w eight. 31,32,59 Ho we ver , in a cross- section al

s t ud y , b o d y w e i g h t in men (n = 2 0 3 ) an d w o m en (n =

62) wi th HIV in fec t ion d id no t d i f fer s ign i f i can t ly

b e t w e en t h o s e r ece iv i n g an d n o t r ece iv i n g H A A RT . 24

T h e e f f ec t o f H A A RT o n L BM i s n o t c l ea r , w i t h d i f -

ferent s tudies having differing resul ts . Al though 2 cross-

s ec t io n a l s t u d ie s fo u n d n o d i f fe r en ce b e t w een t o t a l o r

t r u n k L B M i n m e n r e c e i v i n g H A A R T c o m p a r e d w i t h

ma le no nrec ip ien t s o f HA AR T, 24 ,27 one o f these s tud-

ies found tha t a f t e r ad jus tment fo r age , weigh t , he igh t ,

an d s t r en g t h t r a in i n g , t r u n k L B M w as 0 . 8 k g g r ea t e r

i n m a l e H A A R T u s e r s t h a n i n n o n - H A A R T u s e r s(9 5 % CI , 0 . 1 -1 . 5 k g ; P = 0 . 0 3 ). 24 N e i t h e r s t u d y fo u n d

ev i d en ce t h a t H A A RT h ad a s i g n i f i c an t i mp ac t o n

e x t r em i t y L B M i n m a le s , b u t o n e o f t h e m f o u n d t h a t

a f t e r ad j u s t men t f o r o t h e r p ro g n o s t i c v a r i ab l e s , t o t a l

LBM (including the t runk and l imbs) increased l inearly

in men wi th a longer dura t ion o f HA AR T (P _< 0 .001) . 24

T h e s ame s t u d y fo u n d t h a t a f t e r ad j u s t men t f o r

weight , age, height , an d s t rength t raining, H A A R T use in

wo m en w as no t associa ted wi th a s ign if icant e f fec t on

to ta l o r reg ional LBM . 24 Ano ther s tudy f ound a s ign if i-

can t i nc r eas e o f 2 . 5 % p e r y ea r i n tr u n k L BM i n w o m enw h o u se d H A A R T c o m p a r e d w i th w o m e n w h o d id n o t

use H AA RT (P _< 0 .05) . 60 Af ter a d jus tmen t fo r H AA RT ,

sex , and age , an increase in CD4 count was the on ly

virologic factor s ignificant ly associated with an increase

i n L BM , an d t h a t o n l y i n ex tr emi t y L BM (m ean , 0 . 5 9 %

for every 100-ce l l/mm 3 increase ; 95% CI , 0 .05-1 .1 ; P =

0 .03) . In the combined cohor t (bo th sexes , wi th ad jus t -

me nt fo r C D4 count , v i ra l load , energy in take <35 g /kg ,

and s t reng th t ra in ing) , saqu inav i r and r i tonav i r were

s ign i f i can t ly associa ted wi th loss o f ex t remi ty LBM

co m p ared w i t h n o n u s e r s o f p ro t ea s e i n h i b it o r s ( lo s se sof 1 .4 % and 1 .8% per year , respect ive ly ; P _< 0 .05) ,

w h e r e a s i n w o m e n , l o s s o f t r u n k L B M w a s a s s o c i a t ed

with use of zalci tabine (3.5% per year; P _< 0.05) and di-

dano sine ( 6.4% per year; P _< 0.01). Lam ivudine w as as-

s o c i a t ed w i t h a g a i n in t r u n k L BM o f 3 . 0 % p e r y ea r in

p a t ien t s o f b o t h s ex es co mp a red w i t h t h o s e u s i n g o t h e r

nucleos ide reverse t ranscr ip tase inh ib i to rs (NRT Is ) (P _<

0 . 0 5 ) . T h e re fo re , d i f f e r en t N RT Is may h av e d i f f e r en t

e f fec ts o n L BM an d b o d y w e i g h t. I n t h e C o l l ab o ra ti o n s

i n H I V O u t c o m e s R e s e a rc h / U S 61 (C H O R U S ) o b s e r v a-

t i o n a l co h o r t s t u d y (N = 2 1 1 0 ) , t h e i n c i d ence o f A ID S-def in ing was t ing was s ign i f i can t ly h igher in pa t i en t s

rece iv ing s t avud ine than in those rece iv ing z idovudine

(8 .3% vs 5 .2%, respective ly ; P = 0 .004) , de sp i t e simi lar

H I V R N A a n d C D 4 l ev e ls . H A A R T i s a l so a s s o c ia t e d

wi th changes in bo dy fa t d i s t r ibu t ion , 24 d i scuss ion o f

w h i ch is b ey o n d t h e s co p e o f t hi s r ev iew .

L e a n B o d y M a s s V e r s u s F a t

HIV-associa ted was t ing , o r cachex ia , i s charac ter -

i z ed b y ab n o rma l i t i e s o f i n t e rmed i a ry m e t ab o l i s m, r e -

2 2 7 6 V o l u m e 2 9 N u m b e r 1 1




s u l ti n g i n b o d y w e i g h t l o s s, i n ap p ro p r i a t e d ep l e t i o n o f

LBM , an d p reserva t ion o f bo dy fa t . 62,63 This p arado xi -

ca l p r e s e rv a t i o n o f f a t , w h i ch h as b een r e f e r r ed t o

as f u t i l e c y c l i n g , 4 9 m a y o c c u r w h e n f a t ty a c id s a r e m o -

b i l i zed f rom ad ipose s to res and , ra ther than be ing ox i -

d ized , a re re-es ter i f i ed in to t r ig lycer ide , secre ted f romthe l iver , and re-s to red in fa t . Th i s p rocess was tes

energ y. 64

N o n s p ec i f i c H IV -as s o c i a t ed l o s s o f b o d y w e i g h t i s

a ma j o r cau s e o f w eak n es s i n in d i v id u a l s o f b o t h s ex es ;

however , there are d i f ferences be tween the sexes . Al -

t h o u g h b o t h mu s c l e an d f a t may b e l o s t i n p a t i en t s o f

b o t h s ex es , mu s c l e l o s s may b e mo re p ro mi n en t i n

m e n a n d l os s o f f a t m a s s m o r e p r o m i n e n t i n w o m e n - -

at le ast in the ini t ial s tages of infe ct ion. 27 Later, in

m o r e a d v a n c e d s t a ge s o f H I V i n f e c ti o n , w o m e n p r e -

sen t wi th g rea ter loss o f muscle than fa t . 2s M uscle lossi s a ma j o r cau s e o f w eak n es s i n t h o s e w h o h av e l o s t

> 1 0 % o f t h e ir b o d y w e i g h t . 12

W h i l e t h e r e may b e a p o s s i b l e s u rv i v a l ad v an t ag e

to excess ad ipos i ty in pa t i en t s wi th cer t a in chron ic

d i seases ( the obe s i ty para dox ) , 65 therap ies tha t in -

c r ea s e f a t h av e n o t b een a s s o c i a t ed w i t h i mp ro v ed s u r -

v iva l in pa t i en t s wi th H IV was t ing . 66 A re t rosp ect ive

an a ly s is w as p e r fo rme d o n d a t a f ro m 3 5 5 pat i en t s wi th

H I V / M D S was t ing who were enro l l ed in 2 Phase I I I

p l a c e b o - c o n t r o l le d t r ia ls o f r h G H c o n d u c t e d i n

1 9 9 2 - 1 9 9 5 (p re -HA AR T era) . 66 Pat i en t s in theses t u d i e s r ece i v ed s u b cu t an eo u s rh G H (0 . 1 mg / k g p e r

d ay o r 6 mg / d ) o r p l aceb o fo r 1 2 w eek s an d w ere

fo l l o w ed fo r u p t o 4 y ea r s . Med i an s u rv i v a l w as

8 8 . 7 w eek s , an d t h e 1 -y ea r s u rv i v a l r a t e w as 7 0 % . A s

ex p ec t ed , s u b j ec t s w h o g a i n ed l ean w e i g h t h ad a

g rea t e r s u rv i v a l r a t e t h an t h o s e w h o d i d n o t . A n e s t i -

ma t ed 6 . 7 % d ec rea s e i n mo r t a l i t y w as a s s o c i a ted w i t h

each 1 % i n c rea s e i n L BM . Becau s e t h e mean i n c r ea s e

i n L BM w as 5 % , t h e o v e ra l l i mp ro v emen t i n s u rv i v a l

w a s e s t i m a t e d to b e - 3 4 % . H o w e v e r , t h e c h a n g e in f a t

w as n o t a s s o c i a t ed w i t h an y s i g n i f i c an t i mp ro v emen tin survival . 66 Alth oug h a direct cau sal relat ionsh ip can-

no t be in fer red based on th i s re t rospect ive analys i s ,

t h e i mp ro v emen t i n s u rv i v a l a s s o c i a t ed w i t h a g a i n i n

b o d y w e i g h t i n p a t i en t s w i t h H IV / A ID S w as t i n g ap -

p ea r s t o b e med i a t ed b y g a i n s i n L BM, n o t f a t .

T h e G r o w t h H o r m o n e / I n s u li n -L i k e

G r o w t h F a c t o r - I A x i s

H IV w as t i n g may b e cau s ed b y d i s t u rb an ces i n t h e

G H / IG F- I ax i s . 67 M a i n t en an ce o f mu s c l e p ro t e i n mas s

i n v o l v es a d y n ami c b a l an ce b e t w een p ro t e i n s y n t h es i s

an d d eg rad a t i o n . P ro t e i n me t ab o l i s m i s u n d e r t h e

c o n t r o l o f n u m e r o u s h o r m o n e a n d s e c o n d - m e s se n g e r

sys tems , inc lud ing g lucagon , g lucocor t i co ids , insu l in ,

t h y ro i d h o rmo n es , r eg u l a t o ry ami n o ac i d s (g l u t ami n e ,

l eu c i n e ) , t h e p o l y p ep t i d e g ro w t h f ac t o r s IG F- I an dIGF-I I , and GH . 68 ,69 The GH /IG F ax i s and the b io log -

ic ac t ions o f IGFs have been rev iewed in de ta i l e l se-

wh ere. 68,7°-73 Briefly, G H is synth esize d and secre ted

by som ato t r oph ic ce ll s in the an ter io r p i tu i t a ry , and

s t imula tes m uscle g r ow th and p ro te in syn thes i s . 7° In

G H -d e f i c i en t s t a t e s , ex o g en o u s G H h as an ab o l i c an d

an t i ca t ab o l i c p ro p e r t i e s . T h e e f f ec t s o f G H a re med i -

a ted d i rec t ly o r ind i rec t ly by s t imula t ion o f IGF-I and

o t h e r s o ma t o me d i n h o rm o n es . 7° I t is w e l l k n o w n t h a t

G H cau s es t h e r e l eas e o f IG Fs (u s u a ll y IG F- I ) f r o m t h e

l i v e r i n t o t h e b l o o d , an d h as au t o c r i n e an d p a rac r i n eeffects on oth er tissues, resulting in th e release o f IGFs. 7°

T h e e f f e ct s o f G H o n m u s c l e a p p e a r t o b e m o s t ly m e -

d i a t ed v i a IG Fs , w h i ch h av e an ab o l i c e f f ec t s s u ch a s

s t i mu l a t io n o f mu s c l e g ro w t h an d m y o b l a s t d if f e r-

en t i a t ion . 7°,74 These po lyp ep t ides a l so have p ro te in -

spar ing ef fec t s ; fo r example , IGF-I suppresses p ro te in

deg rada t ion and p reven t s p ro teo lys i s . 68,75

IG F- I i s h i g h l y p ro t e i n b o u n d t o an IG F-b i n d i n g

pro te in ( IGFBP) , m os t ly IGFB P-3 . 71,76 IGFBP s regu-

la te the ac t iv i t i es o f IGFs , fo r example , by ex tend ing

thei r serum hal f - li fe , by t ransp or t ing them to t a rge tcel ls (eg, muscle, cart i lage, bone, l iver, kidney, nerves,

sk in , and lungs ) , and by poss ib ly po ten t i a t ing o r in -

hibit ing the interact ion b etw een IGFs and their cel l me m-

brane recep tors . 71 ,76 The type 1 IGF r ece p tor ( IGFR )

med i a t e s t h e ac t i o n s o f b o t h IG F- I an d i n s u l i n .

N u mero u s ce l l - s i g n a l i n g p a t h w ay s ( eg , t h e A K T [p ro -

t e i n k i n a s e B] p a t h w ay ) a r e ac t i v a t ed b y b i n d i n g o f

IG F- I t o IG FR . 77 T h e A K T s i gn a l in g p a t h w a y is a

s t i mu l a t o r o f c ell g ro w t h an d m u l t ip l i c a ti o n , an d a

p o t en t i n h i b i t o r o f p ro g ram me d ce ll d ea t h . 77

Direct D isruption o f the Axis by H IV Infection

Pre l i mi n a ry d a t a s u g g es t t h a t H IV i n f ec t i o n may

cause a d i rec t d i s rup t ion o f the G H/IG F-I ax i s . A d i s -

s o c i a t ed H IV -1 en v e l o p e p ro t e i n (g p 1 2 0 ) t h a t i s h o -

m o l o g o u s t o G H - r e le a s in g h o r m o n e ( G H R H ) b i nd s to

G H RH recep t o r s i n t h e p i t u i t a ry g l an d , p o t en t i a l l y

suppress ing G H re lease . 7s Ev idence f rom s tud ies in

pat i en t s wi th HIV in fec t ion ind ica tes tha t pa t i en t s

w i t h w as t i n g h av e acq u i r ed a G H - IG F ax i s t h a t i s a l -

tere d relat ive to th e n orm al phy siolog ic s tate. 53,67,79

N o v e m b e r 2 0 0 7 2 2 7 7



Clinical Therapeut ics

Inappropr ia te ly Low Insul in-Like Growth Factor -I

a nd P o s s ib l e "G r o w t h H o r m o ne Res i s ta nce"

T h e l o s s o f L BM ch a rac t e r i s t i c o f H IV -as s o c i a t ed

wa s t ing 29 i s p re sum ably s imi lar to the loss associa te d

wi th muscle was t ing in o ther ca tabo l i c s t a t es , resu l t -

ing f rom increased m uscle p ro teo lys i s , s ° Oth er changesi n mu s c l e p ro t e i n me t ab o l i s m i n cach ex i a h av e b een

sugges ted , inc lud ing increased u r inary n i t rogen loss ,

increased p ro te in tu rnover , decreased ske le ta l muscle

pro te in syn thes i s , increased hepat i c p ro te in syn thes i s

( acu t e i n f l ammat o ry r e s p o n s e ) , an d d ec rea s ed p l a s ma

l eve l s o f b r an ch ed -ch a i n ami n o ac id s . 7 T h e i n f lamm a-

to ry ca tabo l i c s t a t e ob ta ins essen t i a l amino ac ids f rom

skele ta l musc le fo r hepat i c g luconeo genes i s , s ° In pa-

t i en t s w i t h H IV -as s o c i a t ed w as t i n g , t h e ch an g es i n

m u s c l e p r o t e i n m e t a b o l i s m m a y b e m e d i a t e d i n p a r t

b y p e r t u rb a t i o n s i n t h e G H / IG F- I ax i s , i n c l u d i n g e l e -va ted serum GH level s and reduced serum IGF-I l eve l s .

I n a s t u d y i n 7 p a t i en t s w i t h H IV i n f ec t i o n w h o h ad

l o s t > 1 0 % o f t h e ir i d ea l b o d y mas s an d 1 0 h ea l th y v o l -

u n t ee r s, t h e p a t i en t s w i t h H IV -as s o c i a t ed w as t i n g h ad

s i g n i f i c an t r ed u c t i o n s co mp ared w i t h h ea l t h y s u b j ec t s

in serum levels o f IGF-I (81 vs 1 79 t lg /L , respect ive ly ) ,

IGF-II (226 vs 776 t lg/L), and insul in (29 vs 23 7 pm ol/L)

(a ll , P < 0 .05) . 67 The pa t i en t s w i th H IV wa s t ing a l so

h ad r e l a t i v e l y l o w er IG FBP-3 l ev e l s an d r ed u ced

IG FBP-3 l i g an d b i n d i n g o n W es t e rn b l o t an a l y s i s .

T h e s e d a t a w e r e s u p p o r t e d b y a n o t h e r s t u d y in w h i c h2 0 h y p o g o n a d a l m e n w i t h H I V - a s s o c i a t e d w a s t i n g

h ad s i gn i f ic an t ly h i g h e r G H l eve l s co m p ared w i t h ag e -

ma t ch ed h ea l t h y v o l u n t ee r s ( 3 . 0 3 v s 0 . 9 0 n g / mL , r e -

spect ive ly ; P < 0 .01) and s ign i f i can t ly lower IGF-I

levels (167 vs 225 ng /mL; P < 0 .01) . 53

A d m i n i s tr a t i o n o f t e s t o s te ro n e i n h y p o g o n ad a l m a l e

an d an d ro g en -d e f i c i en t f ema l e p a t i en t s w i t h H IV -

as s o c i a t ed w as t i n g may a f f ec t t h e G H / IG F- I ax i s i n

a s s o c i a t io n w i t h i mp ro v em en t s i n L B M. s l, s2 Fo r ex -

amp l e , i n h y p o g o n ad a l men w i t h H IV i n f ec t i o n , mean

overn igh t GH level s decreased by 0 .9 t lg /L in thoset r ea t ed w i t h t e s t o s t e ro n e , co mp ared w i t h an i n c r ea s e

of 0 .2 t lg /L in those who rece ived p lacebo ; the change

in G H levels w as s ign i f i can t ly inverse ly cor re la ted wi th

the increase in LBM (r = -0 .49 ; P = 0 .024) . s l Th i s was

con t rary to the in i t i a l hypo thes i s tha t t es tos terone ad-

min i s t ra t ion in these pa t i en t s wi th HIV in fec t ion migh t

have s t imula to ry ef fec t s on GH and IGF-I secre t ion , as

o b s e rv ed in o t h e r p o p u l a t i o n s o f h y p o g o n ad a l men .

IGF-I l eve l s have been found to decrease wi th in -

creased sever i ty o f i l lness , s l a nd pa t i en t s wi th H I V -

as s o c i a t ed w as t i n g may h av e an ab n o rma l r e s p o n s e t o

ex o g en o u s G H . Fo r ex am p l e , t h e i n c rea s e i n IG F- I lev -

e l s a f t e r a s ing le dose o f rhGH 0 .1 mg/kg was s ign i f i -

can t l y b l u n t ed i n p a t i en t s w i t h A ID S an d cach ex i a

(n = 2 1 ) co mp ared w i t h h ea l t h y v o l u n t ee r s ( n = 2 3 )

(P < 0 .02) ; in o ther words , the increase was 141 t lg /Li n t h e g ro u p w i t h A ID S an d cach ex i a , co mp ared w i t h

194 t lg/L in contr ols . 79 This is con sis ten t with "resis-

t an ce" t o G H ' s ab i li t y t o i n c r ea se IG F- I .

C L I N IC A L E F FE C T S O F R E C O M B I N A N T

H U M A N G R O W T H H O R M O N E

P h a r m a c o c l y n a m i c S t u d i e s

T h ree s ma l l p h a rmaco d y n ami c s t u d i e s ex p l o red t h e

an ab o l i c e f f ec ts o f ad m i n i s tr a t i o n o f r h G H i n p a ti en t s

with HIV -assoc iated wa st ing. 74,83,84 O ne s tud y investi -

g a t ed d i s ea s e - s ev e r it y - r e l a ted i mp ro v eme n t s i n mu s c l ep ro t e i n s y n t h es i s w i t h rh G H 6 mg / d SC g i v en fo r

2 w eek s (N = 2 6 ) . 74 In the o ther s tud ies , admin i s t ra-

t i o n o f r h G H g i v en a s 0 .1 mg / k g SC d a i l y fo r 7 d ay s 84

o r 2 . 5 o r 5 mg SC Q O D fo r 1 2 w eek s s3 w as a s s o c ia t -

ed w i t h i mp ro v ed n i t r o g en r e t en t i o n ( i e , r ed u ced u r i -

n a ry n i t r o g en ex c re t i o n ) . T h i s i mp ro v emen t r each ed

s ta t is t i ca l s ign i f icance in the 7 -day s tudy (P < 0 .01) ; in

t h i s s t u d y , r h G H w as a s s o c i a t ed w i t h r ed u ced p ro t e i n

ox idat ion (P < 0 .01) . Al though the l a t t e r 2 s tud ies d id

n o t s p ec i f i c a l l y a s s e s s mu s c l e p ro t e i n me t ab o l i s m,

ch an g es i n n i t r o g en an d p ro t e i n - s p a r i n g l i p i d o x i d a -t i o n a r e s t r o n g l y s u g g est iv e o f r h G H ' s an ab o l i c an d

an t i ca tab o l i c e f fec t s , respect ive ly . In add i t ion , these

s t u d ie s r ep o r t ed b en e f ic i a l e f fec t s o f r h G H o n L BM s3

and bo dy w eigh t , s3, s4 In cache ct i c pa t i en t s wi th HI V

i n fec ti o n o r A ID S, 1 2 w eek s o f t r e a t men t w i t h rh G H

5 m g S C Q O D w a s a s s o c i a t e d w i t h i m p r o v e d L B M

an d b o d y w e i g h t an d r ed u ced b o d y f a t ( n = 5 ) ; t h i s

ef fec t wa s no t seen w i th the 2 .5 -m g dose (n = 5 ) . s3

H o w ev e r , t h e s e b en e f i c ia l e f f ec ts w e re n o t ma i n t a i n ed

a t f o l lo w - u p a f t e r 6 w e e k s w i t h o u t r h G H t r e a tm e n t .

A small , 2 -w eek s tudy in pa t i en t s wi th H IV in fec t ionspeci fi ca lly assessed changes in m uscle p ro te in syn thes is

a f t e r t r e a t men t w i t h rh G H 6 mg / d SC. 74 Pat ien t s were

grouped by d i sease sever i ty : 9 pa t i en t s were asympto-

mat ic ; 11 had CD 4 ÷ count s <200 ce l l s/mm 3 bu t no

l o ss o f b o d y w e i g h t; an d 6 h ad A ID S (CD 4 ÷ co u n t

<200 ce l l s /mm 3) and subs tan t i a l HIV -associa ted loss

o f b o d y w e i g h t ( > 1 0 % o f p r e m o r b i d w e i g h t ). A f t e r

rh G H t r ea t men t , h ea l t h y co n t ro l s h ad a 2 7 % i n c rea s e

i n p ro t e i n s y n t h esi s , w h e rea s p a t i en t s i n t h e a s y m p t o -

ma t i c H IV g ro u p h a d an 1 1 % i n c reas e in p ro t e i n s y n -

2 2 7 8 V o l u m e 2 9 N u m b e r 1 1



M. Gela to e t a l .

thesis . The re was a s ign i f ican t negat ive cor re la t ion be-

tween ch an g es in m u sc le p r o t e in sy n th es i s an d d i sea se

sever i ty (Spearman rank cor re la t ion , P = 0 .002) ; in -

c r ea se s in m u sc le p r o t e in sy n th esi s we r e sm a l l er w i th

worsen ing d isease sever i ty . In fac t , pa t ien ts wi th an

AIDS-def in ing condi t ion and >10% loss o f body weigh th ad a 4 2 % d ec r ea se in t h e r a t e o f p r o t e in sy n th esi s .

However , IGF-I leve ls increased s ign i f ican t ly in re-

sp o n se to ad m in i s t r a t io n o f ex o g en o u s r h G H in th e se

p a t i en ts ( P < 0 .0 0 1 ). Th e in v es t ig a to rs co n c lu d ed th a t

i t was n o t p o ss ib l e t o d e t e r m in e wh e th e r t h e in ab i l it y

o f m u sc le t o r e sp o n d to r h GH in th e g ro u p w i th AIDS

an d > 1 0 % lo ss o f b o d y we ig h t r ep r e sen ted a f a ilu r e t o

r e sp o n d to th e d i r ec t e f f ec t s o f r h GH o n m u sc le o r a

fa i lu re to resp ond to e levated IGF-I levels ( ie, a fo r m

of d i rec t " IGF-I res is tance") .

O t h e r r e p o r t e d e ff ec ts o f r h G H o n b o d y c o m p o s i -t i o n in p a t i en t s w i th HI V- asso c ia t ed was t in g in c lu d e

in c r ea sed LB M an d d ec r ea sed fat . s3,sS-s7 So m e o f t h e se

r ed u c t io n s in b o d y f a t m ay f u r th e r ex ace r b a te l i p o -

a t r o p h y a sso c ia t ed wi th HAAR T t r ea tm en t , wh ich

usual ly involves no ntru nk fa t . How ever , a f te r 12 weeks

o f t rea tm en t w i th r h GH , a su b se t o f p a ti en ts i n wh o m

b o d y c o m p o s i t i o n was a sse ssed b y d u a l - en e r g y x - r ay

ab so r p t io m e t r y los t ad ip o se t i ssu e th a t w as p r im ar i ly

t r u n k f a t, w i th n o n t r u n k f a t m in im a l ly a ff ec t ed ,s5 Th e

p a t i en t s wh o g a in ed b o d y we ig h t an d LB M d u r in g

t r ea tm en t w i th r h G H f o r HI V- asso c ia ted was t in g a l sor ep o r t ed o v e r a l l im p r o v em en t s i n t h e i r ap p ea r an ce

a f t e r t r ea tm e n t .

Th e m e tab o l i c e f f ec t s a s so c ia t ed wi th a 1 2 - week

co u r se o f r h GH in p a t ien t s w i th H I V- asso c ia t ed was t -

ing inclu de increa ses in REE , 84,86 l ipid catab olism , 84,86

ser um or pla sm a IGF -I levels, 84,85,87 and plas m a glu-

cose levels. 84,87 Th e imp licatio ns of ele vations in REE

f o r t h e lo n g - t e r m m a in ten an ce o f b o d y we ig h t g a in in

p a t i en ts r ece iv ing r h G H th e r ap y a r e n o t y e t k n o wn .

G r o w t h H o r m o n e in C h i ld r e n a n dA d o l e s c e n t s w i t h H I V

I n HI V- in f ec t ed ch i ld ren , r h G H h as b een a sso c ia t -

ed wi th im p r o v em en t s i n l i n ea r h e ig h t an d r ed u ced

p r o te in ca t ab o l i sm , s s Po o r l i n ea r g r o w th an d loss o f

b o d y w e ig h t h av e b een we l l d e sc r ib ed in ch i ld r en wi th

HIV infec t ion , and loss o f lean t i ssue mass has been

r ep o r t ed in a s so c ia t io n wi th in c r ea sed r a te s o f p r o t e in

ca tabo l ism, s9 In a recen t unc ontro l led , open- label s tu dy

in 6 HIV - infec ted ch i ld ren (m ean age , 9 .2 years ;

Tanner s tage I ; he igh t and weigh t in <10th percen t i le

d esp i t e ad eq u a te ca lo r i c i n t ak e ) , l e an t i s su e m ass

imp rove d s ign i f ican t ly in a l l sub jec ts rece iv ing rhG H

( P < 0 . 0 5 ) . 89 At base l ine , the g rowth ve loc i ty in these

ch i ld ren was 3 .9 cm per year , increasing to 7 .9 cm per

y ea r a f te r 6 m o n th s o f r h G H th e r ap y ( P < 0 .0 5 ). Th e

leu c in e r a t e o f ap p ea r an ce was u sed a s a m easu r e o fp r o te in ca t ab o l i sm . Th e f a s t in g r a t e o f ap p ea r an ce

was h igh a t base l ine bu t decrea sed s ign i f ican t ly af te r

6 m o n th s o f r h G H th e r ap y ( P = 0 .0 4) . Th ese r e su l t s

in d ica t e t h a t r h GH m ay p o s i t i v e ly a f f ec t h e ig h t an d

r ed u ce p r o t e in ca t ab o l i sm in HI V- in f ec t ed ch i ld r en .

No ad v e r se e ff ec t o n v i r a l b u r d en w as n o ted .

C l i n i c a l S t u d i e s o f r h G H i n P a t i e n t s w i t h

H I V - A s s o c i a te d W a s t i n g

Th e e f f icacy o f r h G H in in c rea s in g LB M an d p h y s i -

ca l en d u r an ce in p a t i en t s w i th HI V- asso c ia t ed was t in gh as b een r ep o r t ed in a n u m b er o f l a r g e , p r o sp ec -

t iv e , 1 2 - week , r an d o m ized , d o u b le - b l in d , p l aceb o -

con troll ed studiesS5,87,9°-93; the m os t re cen t we re co n-

d u c ted in p a t i en t s r ece iv in g HAA R T. Th e s tu die s a r e

su m m ar ized in Tab le I ll .

M oyle e t a185 repo r ted the la rgest t r ia l o f rh G H in

HIV wast ing to da te (757 pa t ien ts enro l led , 5 5 5 evalu-

ab le , 88% rece iv ing HA AR T) , assess ing the ef fec ts o f

12 weeks of t rea tme nt on physica l funct ion , endurance ,

and o ther ou tcomes. In p lacebo rec ip ien ts (n = 199) ,

wo r k o u tp u t d ec r ea sed f r o m b ase l in e b y 0 .2 5 k J , an dL B M d i d n o t i n c r e a s e . T h e m e d i a n m a x i m u m c y c l e

wo r k o u tp u t i n c r ea sed b y - 9 % in b o th ac t iv e - t rea tm en t

arms (2 .35 and 2 .60 kJ f rom base l ine) in pa t ien ts re -

ce iv in g r h G H 0 .1 m g /k g ( m ax im u m , 6 m g /d ) d a i ly o r

on a l te rna te da ys, respect ive ly (P < 0 .001 vs p lacebo) .

Th e co r r e sp o n d in g in c r ea se s in LB M wer e 5 .2 1 an d

3 .33 kg (bo th , P < 0 .001 vs p lacebo) .

Su b g r o u p an a ly se s we r e p e r f o r m ed to co m p ar e th e

ch an g e in ex e r c i se in t en s ity d u r in g r h G H t r ea tm en t i n

p a t i en t s w i th p o o r en d u r an ce a t b a se l in e ( m ax im u m

o u tp u t <2 0 k J , co n s i st en t w i th s t ab le m o d e r a t e t o se-vere chro n ic obst ruc t ive pu l m ona ry d isease) . 91 Af ter

1 2 week s o f r h GH t r ea tm en t , ex e r c ise cap ac i ty ( m ea -

su r ed b y b i cy c le e r g o m e t r y ) was im p r o v ed b y - 2 5 %

(P = 0 .03 vs p lacebo) . The au tho rs suggested tha t th is

d eg r ee o f im p r o v em e n t i n p h y s i cal f u n c t io n f r o m b ase-

l in e m ay t r an s l a t e i n to p r ev io u s ly h o u seb o u n d p a -

t i en t s b e in g ab le t o wa lk o u td o o r s an d in d ep en d en t ly

per form tasks o f da i ly li fe .

Th e m o s t co m m o n ly rep o r t ed ad v e r se ev en ts in

th is s tu d y wer e p e r ip h e r a l ed em a , a r th r a lg i a , m y a lg i a ,

N o v e m b e r 2 0 0 7 2 2 7 9



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C l i n i c a l Therapeutics

pares thes ia , and hypoes thes ia , occurr ing in 51 .8% and

4 9 . 8 % o f t h e rh G H g ro u p s (o n ce -d a i ly an d a l t e rn a te -

d ay d o s i n g , r es p ec ti v e ly ) an d 2 8 . 7 % o f th e p l aceb o

group , s5 Adve rse even t s in the ac t ive- t rea tm ent g roup s

w ere r e l a t ed t o f l u i d r e t en t i o n a s s o c i a t ed w i t h rh G H

t rea t men t an d w ere g en e ra l l y r a t ed a s mi l d t o mo d e r -a te in sever ity. Pa t i en t s w ere exclude d fo r e l evat ions in

fast ing blood glucose levels (>6.7 mmol/L). Small in-

creases in mean fas t ing b lood g lucose l evel s were ob-

served dur ing the f i r s t 2 to 4 wee ks o f t rea tm ent in the

rh G H g ro u p , o f t en n o rma l i zi n g a s t h e r ap y w as co n t i n -

u ed t o w e ek 1 2 ; t h e o v e ra l l mean ch an g e f ro m b as e li n e

in fas t ing b lood g lucose was 0 .3 to 0 .5 mmol /L . There

h av e b een r ep o r t s o f n ew -o n s e t i mp a i r ed g l u co se t o le r -

an ce o r t y p e 2 d i ab e t e s me l l i t u s an d ex ace rb a t i o n o f

p reex i s t i n g d i ab e t e s i n p a t i en t s o n H A A RT w h o h av e

rece iv ed rh G H fo r H IV w as t i n g. 94 In t h e s t u d y b yM oyle e t a l, s5 1 pa t i en t deve loped new -onse t d iabetes

an d 2 d ev e l o p ed h y p e rg ly cemi a .

A l t h o u g h H IV r ep l i ca t i o n h as b een fo u n d t o b e en -

han ced by rh G H in v i t ro , 95 no s ign i f ican t ch anges in

p l a s ma H W -1 R N A l ev el s w e re o b s e rv ed in t h e p l aceb o -

con t ro l l ed c l in ica l t r i a ls o f rhG H in pa t i en t s rece iv ing

con com i tan t an t i re t rov i ra l t re a tm ent , sS ,s7

Concerns h ave been ra i sed regard ing the po ten t i a l fo r

rhGH to enhance tumor g rowth th rough i t s e f fec t s on

IGF-I, which s t imulates cel l growth and inhibi ts apopto-

s i s . 9 6 ,9 7 H o w ev e r , co n s en s u s p an e l s f ro m t h e G ro w t hH o rmo n e Res ea rch So c i e t y9s and Europ ean Socie ty fo r

Paed ia t r i c Endocr ino logy 99 concluded that there is no

defini tive e vidence of increased ca ncer r isk with G H re-

p lacement . The long- term safe ty o f rhGH in pa t i en t s

wi th H IV-associa ted was t ing has no t b een s tud ied ex ten-

sively, but the drug is often given as a s ingle 12-week

course . Both IGF-I and IGFBP-3 l evel s rose c lose to

or abo ve the upper l imi t o f the norm al range dur ing

1 2 w eek s o f d o u b l e -b l i n d t r ea t men t w i t h rh G H . s5

Epidemiologic observat ions suggest that elevated levels

of IGFBP-3 , as observe d in the s tudy b y M oyle e t a l , s5m ay am el io ra te the re la t ive r i sk a t t r ibu tab le to e levated

IGF-I concen t ra t ions . 1°° How ever , carefu l mon i to r ing o f

pat ients is wa rrante d. This is especial ly im por tant in pa-

t ients with HIV/AIDS who may be a t increased r i sk fo r

ma lignancy by virtue of their underlying disease, part icu-

larly i f they are receiving long-ter m therapy.

Adverse even t s genera l ly improved wi th a reduct ion

in dose o r d i sco n t inuat ion o f rhG H. sS,s7 In the s tu dy b y

M o y l e e t a l, s5 t r ea t men t w i t h rh G H 0 . 1 mg / k g Q O D

w as a s s o c i a t ed w i t h f ew er ad v e r s e e f f ec t s co mp ared

wi th da i ly dos ing , wi th g rade 3 o r 4 adverse even t s

(World Heal th Orga n iza t ion c lass if i ca tion) occurr ing in

35 pa t i en t s in the a l t e rna te-day dos ing g roup and 87 in

the da i ly dos ing g roup ; however , there was a s imi lar im-

p ro v emen t i n p h y s i ca l f u n c t i o n , a s meas u red b y w o rk

outpu t (kJ ) and hear t ra t e a t exhaus t ion , wi th bo thdai ly and a l t e rna te-day dos ing . Therefore , a lower

s tar t ing dose (eg , 0 .1 mg/kg QOD) may be cons idered

in pa t i en t s a t increased r i sk fo r adverse even t s re la ted to

rhGH therapy (eg , those wi th p rev ious g lucose in to ler -

ance o r a fami ly h i s to ry o f g lucose in to leranc e) ) °1

Com binat ion rhGH and rh lGF-I Therapy

In 3 randomized , double-b l ind s tud ies in HIV or

AIDS pat ients with wa st ing, 93,]°2,]°3 low doses of

r h G H i n c om b i n a t i o n w i th r e c o m b i n a n t h u m a n I G F -I

(rhlGF-I) 5 mg BID (10 rag/d) were not gene ral ly asso-c ia ted wi th s ign i f i can t improvements f rom base l ine in

b o d y w e i g h t a t 1 2 w eek s co m p ared w i t h p l aceb o . L ee

et a l 1°3 found tha t a com binat ion o f rh lGF-I 5 m g BID

and a low dose o f rhGH (0 .34 mg BID) had no s ign i f i -

can t an abo l i c e f fec t in 142 pa t i en ts w i th HIV -associa ted

was t ing . E l li s e t a l 1°2 com pare d the com binat ion o f

rhGH and rh IGF-I , g iven a t the same dosages as in the

prev ious s tudy, wi th p lace bo in 66 me n wi th H W infec-

t i o n an d > 1 0 % l o ss o f b o d y w e i g h t f ro m t h e ir p r emo r -

b i d w e i g h t (mean b o d y w e i g h t , 6 3 . 7 k g ) . T h e co mb i -

nat ion was associa ted wi th a smal l bu t s t a t i s t i ca l lys ign i f i can t increase in body weigh t a t week 6 ( f rom

62.8 to 64 .3 kg ; P < 0 .05 vs p lacebo) , bu t th i s was no t

ma in ta ined a t week 12 ( f ina l body weigh t , 63 .0 kg) .

LBM increased s ign i f i can t ly wi th combinat ion therapy ,

f rom 50 .5 kg a t base l ine to 52 .6 kg a t week 6 (P <

0 .001) and 51 .6 kg a t week 12 (P < 0 .05 vs p lacebo) .

N o s ign if i can t changes w ere seen in e i ther param eter in

the p lace bo gro up . In the s tud y by W aters e t a l , 93 15 pa-

t i en t s e ach w ere r an d o mi zed t o 4 t r ea t men t s f o r

12 weeks : rhGH 1 .4 mg/d , rh IGF-I 5 mg BID, the com-

b i n a t io n o f r h G H an d rh IG F- I , an d p l aceb o . A s in t h estud y by El lis et al, a s tat is t ical ly s ignificant increase in

b o d y w e i g h t a t w eek 6 i n b o t h t h e rh G H a l o n e an d

combinat ion- therapy g roups (P < 0 .01 vs base l ine) was

n o t ma i n t a i n ed a t w eek 1 2 , a l th o u g h t h e co m b i n a t i o n -

therapy g roup had a s ign i f i can t increase in LBM at

week 12 (mean change , +3 .2 kg ; P = 0 .006 vs base l ine)

and a s ign i f i can t decrease in fa t mass (mean change ,

-1 .7 kg ; P = 0 .02 vs base l ine) . The doses o f rhGH in

these t r i a l s were approx imate ly 4 - to 9 - fo ld lower than

those used in the mo noth era py t r ia ls . T he in jec t ion bur-

2 2 8 2 V o l um e 2 9 N u m b e r 1 1




den of this regimen is high (3 or 4 inject ions per day),

and the a t t r it ion ra tes in these s tud ies were h igh ( 33 % -

41 % in the com binat ion- t re a tm ent g roups) ,93 ,1°2 which

may have con t r ibu ted to the l ack o f s t a t i s t i ca l s ign i f i -

can ce a t w eek 1 2 . Co mb i n a t i o n t h e r ap y w i t h rh G H

and rh lGF-I i s no t an approved reg imen fo r the t rea t -me nt o f HIV -associa ted was t ing in the U ni ted S ta tes . 1°1

C L I N I C A L C O N S I D E R A T I O N S I N

r h G H T H E R A P Y

T h e ap p ro v e d d o s e o f r h G H i s 0 . 1 mg / k g , w h i ch is

equ ivalen t to 6 mg/d in pa t i en t s weigh ing >55 kg ,

5 mg / d i n t h o s e w e i g h i n g 4 5 t o 55 k g , an d 4 mg / d i n

those w eigh ing 35 to < 45 kg . 1°1 The usual d ura t io n o f

t r ea t men t i s 1 2 w eek s , b u t an ex t en s i o n p h as e o f t h e

s t u d y b y Mo y l e e t a l f o u n d t h a t i mp ro v emen t s i n

w o r k o u t p u t , L B M , a n d b o d y w e i g h t w e r e m a i n t a i n e ddur ing an a dd i t iona l 12 wee ks o f t rea tmen t . 91 A t rea t -

me n t d u ra t i o n o f > 48 w eek s h a s n o t b een ev a l u a t ed

sys temat ica l ly , and the re are no da ta o n the ef f i cacy o r

s a f e t y o f in t e rmi t t en t t r e a t men t w i t h rh G H . 1°1

Becau s e rh G H ma y i n c r ea s e t h e l i k e l ih o o d o f d ev e l -

o p i n g g l u co s e i n t o le r an ce , s o m e ex p e r t s r eco m me n d

an o ra l g l u co s e s c r een i n g t e s t b e fo re i n i t i a t i n g

rh G H . s s In ad d i t i o n , g l u co s e l ev e ls s h o u l d b e m o n i -

t o r ed d u r i n g rh G H t h e rap y , s s I f a p a t i en t d ev e l o p s a

c l in ica l ly s ign i f i can t increase in b lood g lucose (eg ,

f a s ti n g p l a s ma g l u co s e > 7 . 0 mmo l / L ) o r o t h e r ad v e r s ee f f ec t s w h i l e r ece i v in g rh G H 6 mg / d , t h e d o s e m ay b e

d i s co n t in u ed . A l t ern a ti v e ly , i t may b e r ed u ced t o 6 mg

Q O D w h i l e r e t a i n in g t h e ab i l i ty t o ach i ev e s i g n if i c an t

b u t s ma l l e r i n c r ea s e s i n L BM (P < 0 . 0 0 1 v s p l aceb o ;

P = 0 .017 vs da i ly dos ing) and phys ica l endurance (P <

0 . 0 0 1 v s p l aceb o ; P = N S b e t w e en d a i l y an d a l t e rn a t e -

d ay d o s i n g , a l t h o u g h t h e m ag n i t u d e o f in c r ea s e w as

smal ler in the a l t e rna te- day dos ing g rou p) , s s

O t h e r co m m o n ad v e r s e ev en t s o ccu r r i n g i n p a t i en ts

r ece i v i n g rh G H i n t h e s t u d y b y Mo y l e e t a l i n c l u d ed

ar th ra lg ia (36 .4%), myalg ia (30 .4%), per iphera l edema(2 6 . 1 % ) , h ead ach e (1 2 . 6 % ) , a r t h ro s i s ( 1 0 . 7 % ) , n au -

sea (9 .1% ), a nd p ares thes ia (7 .9% ). l°1 In tha t t r i a l ,

w h i ch w as t h e l a rg es t p l aceb o -co n t ro l l ed s t u d y i n p a -

t ien t s w i t h H IV -as s o c i a t ed w as t i n g , 1 0 % o f p a t i en ts

d i s co n t i n u ed t r ea t m en t b ecau s e o f ad v e r se ev en t s, an d

2 3 % req u i r ed a d o s e r ed u c t i o n . 1°1

S T U D Y U M I T A T I O N S

This rev iew of the pu b l i shed l i te ra tu re , a l though thor-

o u g h , w as n o t co mp reh en s i v e b ecau s e o f i ts ex c l u s io n

of art icles publ ished in languages other than Engl ish

and of stud ies conduc ted in the develop ing wor ld . H ow -

ever , i t was fe l t tha t fac to rs associa ted wi th food acces -

s ib il i ty and ca lo r i c in take in de velop ing count r i es m igh t

have compl ica ted analys i s o f the e t io logy and c l in ica l

impa ct o f HIV-associa ted was t ing , and fe w s tud ies o frh G H h av e b een co n d u c t ed i n t h e d ev e l o p i n g w o r l d .

Similarly, at tent ion was focused on t r ials having a ran-

domized , con t ro l l ed des ign , and smal l uncon t ro l l ed

studies , which might have had different f indings, were

ex c l u d ed . N o a t t emp t w as mad e t o an a l y ze t h e r e s u l t s

o f the inc luded t r i al s accord ing to the p r inc ip les o f

meta-analys i s o r ev idence-based medic ine .

C O N C L U S I O N S

In t h e e r a o f H A A R T , w as t i n g co n t i n u es t o b e a d eb il i-

t a t i n g co n d i t i o n i n p a t i en t s w i t h H IV i n f ec t i o n . Asal i en t fea tu re o f HIV-associa ted was t ing i s the loss o f

L BM, p ro d u ced b y an i mb a l an ce i n mu s c l e ca t ab o l i s m

an d an ab o l i s m. T h e G H / IG F- I ax i s i s o n e o f th e ma n y

reg u l a t o r s o f mu s c l e p ro t e i n m e t ab o l i s m t h a t is a l-

t e r ed i n p a t i en t s w i t h H IV -as s o c i a t ed w as t i n g , an d

t h e re i s ev i d en ce o f G H " r e s i s t an ce , " i n w h i ch G H i s

u n ab l e t o e f f ic i en tl y s t i mu l a te t h e p ro d u c t i o n an d

re lease o f IGF-I . Th i s ev idence l ed to t r i a l s o f phar-

m a c o l o g i c do s e s o f r h G H t h a t m a y o v e r c o m e G H

" res i s t an ce" i n H IV w as t i n g .

Imp ro v i n g L BM, p a r t i cu l a r l y mu s c l e p ro t e i n mas s ,i s an i mp o r t an t g o a l o f t re a t me n t i n p a t i en t s w i t h

HIV-associa ted was t ing . In wel l -des igned c l in ica l t r i -

a l s , r h G H 6 mg / d fo r 1 2 w eek s w as a s s o c i a t ed w i t h

s i g n i f i c an t i mp ro v emen t s i n b o d y w e i g h t an d L BM i n

pat i en t s wi th > 10% loss o f body weigh t ; however , there

w ere a l s o mo d es t an d t r an s ien t i n c rea s e s in mea n f a st -

i n g b l o o d g l u co s e o f - 0 . 6 mmo l / L .

T h e re i s st ill mu ch t o b e l e a rn ed ab o u t r h G H t h e ra -

py in pa t i en t s w i th HIV -associa ted was t ing , such as the

o p t i ma l d u ra t i o n o f t r e a t men t , t h e b en e f it s an d r i sk s

o f co n t i n u ed o r r ep ea t ed co u r s e s o f t r e a t men t , an d t h el o n g - t e rm i mp ac t o f t r e a t men t o n mo rb i d i t y an d s u r -

v i va l . O v e ra l l, r h G H p ro mi s e s t o b e an e f f ect iv e t r ea t-

ment fo r se lec ted pa t i en t s , a l though the ind iv idual

pa t i en t ' s metabo l i c p rof i l e and c l in ica l needs mus t be

t ak en i n t o co n s i d e ra t i o n w h e n s e l ect in g an y t r ea t men t

fo r w as t i n g .

A C K N O W L E D G M E N T S

Fi n an c i a l s u p p o r t f o r t h i s p ap e r w as p ro v i d ed b y

E MD Se ro n o , I n c . T h e au t h o r s t h an k Ca t h e r i n e Rees ,

N o v e m b e r 2 0 0 7 2 2 8 3



Cl i n i ca l Ther apeut i cs

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m e n t o f th e m a n u s c r i p t .

D r . F r e e d l a n d i s a n e m p l o y e e o f E M D S e r o n o , I n c.

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m a n u s c r i p t , p r o v i d e d e x t en s iv e c o m m e n t s a n d r e vi ew ,

p e r f o r m e d a n a l y s i s a n d i n t e r p r e t a t i o n o f t h e d a t a , a n d

r e a d a n d a p p r o v e d t h e f i na l m a n u s c r i p t .

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t r ia l o f c o m b i n e d i n s u l in - l i k e

g r o w t h f a c t o r I a n d l o w d o s e

g r o w t h h o r m o n e t h e r a p y fo r w a s t-

i n g a s s o c ia t e d w i t h h u m a n i m -

m u n o d e f i c i e n c y v i r u s i n f e c t i o n

[ p u b l i s h e d c o r r e c t i o n a p p e a r s i n

J C/in Endocrinol Metab. 1996;81:

3696]. J C]in Endocrino[ Metab.

1996;81:2968-2975.

Address c orrespo nden ce to: Eric Freedlan d, M D, Director, Me dical Affairs

(Endocrinology), E M D S erono, Inc. , One Technology Place, Ro cklan d, M A

02370. E-mai l : er ic . f [email protected]

role of recombinant human growth hormone in

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