ORI GI N AL ARTI CLE
GREATER SURV I V AL AM ON G PATI EN TS W I TH I M M UN OGEN ETI C
M ARKERS ASSOCI ATED W I TH RAPI D PROGRESSI ON TO AI D S:
I M PLI CATI ON S FOR N URSI N G CARE
IAna Pa u la M Fe r n a n de sI I, M a r ia Alice G Gon ça lve sI I I, Alcyon e A M a cha doI V, M iye k o H a ya sh idaV, Elu cir GirVI, Edu a r do A D ona diI V, M a r ia de Lou r de s V Rodr igu e sI V
ABSTRACT
Obj ect ive: This st udy sought t o verify t he influence of changes in sexual behavior aft er HI V-infect ion diagnosis, including t he adopt ion of safe sex pract ices, am ong AI DS pat ient s w it h im m unogenet ic m arkers of rapid disease progression.
Met hods: Tw ent y- seven AI DS pat ient s, genet ically predisposed t o rapid AI DS progression, w ere int erview ed. DRB1 and DQB1 alleles w ere charact erized using PCR- am plified DNA hybridized w it h sequence specific oligonucleot ide probes or by sequence- specific pr im er analyzis. HLA class I ant igens were t yped using a m icrolym phocyt ot oxit y assay.
Result s: I n spit e of t he presence of im m unogenet ic fact ors associat ed wit h individual predisposit ion t o a rapid evolut ion of t he disease, changes in sexual behavior com bined wit h t he use of ant iret roviral t herapy, m ay result in great er survival.
Conclusion: This suggest s t hat counseling, det ect ion of unsafe sexual pract ices and healt h educat ion focusing on posit ive healt hy behavior are t ools nursing m ust use wit h HI V- posit iv e pat ient s. These t ools m ay help t o lead t o a great er survival am ong t hese individuals, even am ong t hose wit h genet ic predisposit ion t o rapid disease progression, w it h im plicat ions for im provem ent of nursing care program s for HI V- infect ed pat ient s.
D e scr ipt or s: AI DS, HI V, HLA, behavior, survival rat e, nursing.
I N TROD U CTI ON
The AI DS epidem ic is charact erized by ext rem e het erogeneit y in t he clinical course as w ell as in t he incidence of HI V- 1 infect ion am ong exposed individuals and has st im ulat ed
I Funded by t he Br azilian Scient ific and Technological Developm ent Council – CNPq ( 350541/ 1994- 9)
I I Junior Professor, Univer sit y of São Paulo at Ribeirão Pret o College of Nur sing, Brazil, WHO Collaborat ing Cent re for
Nursing Resear ch Developm ent , e- m ail: anapaula@eerp.usp.br
I I I Post - doct oral fellow , Univ ersit y of São Paulo at Medical School I V Associat e Professor , Univer sit y of São Paulo at Medical School V PhD, RN, Lab Pr ofessor
VI Associat e Professor Universit y of São Paulo at Ribeirão Pr et o College of Nur sing, Br azil, WHO Collaborat ing Cent re
longit udinal cohort st udies designed t o docum ent het erogeneit y as well as t o m it igat e fact ors t hat regulat e HI V- 1 infect ion, disease progression, and im m une defenses( 1).
I ndividuals have been ident ified who dem onst rat e disparat e abilit ies t o cont rol HI V- 1 infect ion. Alt hough t he average t im e t o develop AI DS in people w it h unt reat ed infect ion is t en years. A subset of infect ed persons ( 1- 5% ) has been ident ified who m aint ain low t o undet ect able HI V- 1 v ir al loads, norm al CD4+ T cell count s, and no m anifest at ions of HI V- 1 clinical im m unocom prom ise or disease despit e docum ent ed infect ion w it h HI V- 1. This group of individuals, who are considered long- t erm nonprogressors present ing wit h slow progression t o AI DS, m anifest a unique abilit y t o successfully cont rol HI V- 1 virem ia in t he absence of ant iret roviral t herapy, in som e cases for up t o 20 years. On t he ot her hand, individuals t hat develop AI DS 2- 3 years aft er infect ion w it h t he virus w ere considered t o have rapidprogression t o AI DS ( 2).
Host genet ic fact ors, such as HLA alleles w hich have an ext raordinary degree of polym orphism and have a m aj or r ole in t he HLA locus in cont rolling t he im m uneresponse, have associat ions wit h different rat es of progression t o AI DS and have been ext ensively st udied( 3). Various cohort st udies have ident ified associat ions bet ween HLA genes ( class I and class I I ) and progression t o AI DS. I n t his respect , t he HLA- B14, - B27, - B57, and - B44 were found t o be associat ed wit h slow progressiont o AI DS, while t he rapid progr ession from HI V- 1 infect ion t o AI DS has been st rongly associat ed wit h HLA- A1- Cw7- B8- DR3- DQ2 and HLA- A11- Cw4- B35- DR1- DQ1 haplot ypes, conferring a high risk of rapid progression t o AI DS( 4).
I n a previous st udy, when we com pared t he frequencies of HLA m arkers t hat have been associat ed wit h rapid progression t o AI DS in several populat ions. These m arkers in AI DS pat ient s present ing w it h cyt om egalov irus ret init is ( CMV- R) w ere overrepresent ed ( 75% in pat ient s wit h and 46.2% in t hose w it hout CMV- R) , indicat ing t hat w it h t he developm ent of CMV- R, t he frequency of HLA- B35 and - DQ2 m arkers associat ed wit h rapid progression t o AI DS is increased( 5).
I n Brazil, t he period of survival aft er AI DS diagnosis has changed. Median survival was 5 m ont hs for cases of AI DS diagnosed in t he 1980s, 18 m ont hs for t hose diagnosed in 1995, 58 m ont hs for t hose diagnosed in 1996( 6- 7), and finally, in 2002 t he m ean was seven years( 8). The am ount of t hese gains and t he analyzis of t he predict ors of survival bot h indicat e t here are several fact ors t hat m ay be associat ed wit h prolonged life expect ancy, such as early diagnosis and ant iret roviral t reat m ent ( 8).
evaluat ed t he influence of sexual behavior, before and aft er HI V- infect ion diagnosis, on t he survival of AI DS pat ient s who have HLA ant igens associat ed wit h rapid progression t o AI DS.
M ATERI ALS AN D M ETH OD S
Su bj e ct s
This st udy was conduct ed by analyzing dat a collect ed in 1997- 1999, t hat was based on t he t wo pat ient groups evaluat ed in Dr Rodrigues’ t hesis( 9). This st udy det erm ined t he HLA class I and I I alleles frequency am ong AI DS pat ient s exhibit ing or not exhibit ing cyt om egalovirus ret init is ( CMV- R) , and addit ionally, ident ified t he associat ion bet ween t he HLA m arkers and CMV- R developm ent am ong AI DS pat ient s.
Group I was com posed of AI DS( 10) pat ient s w it h CMV- R ( n= 44) confirm ed by ret inal
exam inat ion by a t rained opht halm ologist using indirect binocular opht halm oscopy. These sam ple w as select ed from t he Out pat ient Opht halm ology Clinic of t he Universit y Hospit al of t he Facult y of Medicine of Ribeirão Pret o, Universit y of São Paulo, Brazil. Group I I pat ient s w it hout CMV- R ( n= 80) w ere select ed from t he Out pat ient Special Unit for Treat m ent of I nfect ious Diseases of t he Universit y Hospit al of t he Facult y of Medicine of Ribeirão Pret o, Universit y of São Paulo, Brazil; a regional cent er for t his t ype of care.
DNA ext ract ed from peripheral blood leukocyt es using a salt ing- out procedure w as perform ed for t he t ypificat ion of t he HLA alleles. DRB1 and DQB1 alleles w er e ident ified using PCR- am plified DNA, hybridized w it h sequence specific oligonucleot ide probes or by sequence- specific prim er analyzis using com m ercial kit s ( One Lam bda, Canoga Park, CA, and Ruprecht - Karls- Universit ät , Heidelberg, Germ any or One Lam bda, Canoga Park, CA) , as described by Fernandes et al.( 11). The HLA class I ant igens were t yped using a m icrolym phocyt ot oxit y assay, using peripheral blood lym phom ononuclear cells( 12).
To perform t his st udy, t he only pat ient s select ed were t hose who were ident ified as having HLA ant igens associat ed wit h rapid pr ogression t o AI DS, nam ely, HLA- A1- Cw7- B8-DR3- DQ2 and HLA- A11- Cw4- B35- DR1- DQ1, and t hat also displayed a healt hy m ent alit y in t he int erview process.
room in t he healt h facilit y previously described, when t he pat ient s were wait ing for t heir followup appoint m ent .
D a t a Colle ct ion
Dat a collect ion w as conduct ed using a sem ist ruct ured int erview guide t o elicit inform at ion from t he part icipant s based on our goal of ident ifying sexual pract ices, charact erist ics of past and present sit uat ions w hich have placed persons in high- risk sexual sit uat ions, and dem ographic inform at ion such as age, m arit al st at us, gender and durat ion of AI DS.
Et h ica l a spe ct s
The Medical Et hics Com m it t ee of t he Universit y Hospit al of t he Facult y of Medicine of Ribeir ão Pret o, Brazil, approved t he st udy prot ocol ( process num ber 7679/ 2001) . Part icipant s w ere inform ed t hat involvem ent w as volunt ary, t hat t hey could refuse t o answ er any quest ions, and t hat t hey could cease part icipat ion at any t im e w it hout penalt y. Prior t o t he st art of each int erview , w rit t en inform ed consent was obt ained.
St a t ist ica l a na lyz is
Fisher's exact t est and t he GraphPad soft ware ( I nst at program , CA, USA) were used for all analyzes. I n a 95% confidence int erval, P values less t han or equal t o 0.05 w ere considered t o be significant .
RESULTS
Pa r t icipa nt ch a r a ct e r ist ics
The st udy sam ple was com prised of 27 part icipant s. The m aj or it y of individuals were m ale ( 55.6% ) , caucasians ( 77.8% ) , single ( 37.1% ) . The m ean age of t he sam ple was bet ween t he ages of 35 and 39 ( 40.7% ) , and AI DS diagnosis t im e was over six years ( 51.8% ) .
An t ir e t r ovir a l u se
During t he int erview, t he m aj orit y of pat ient s ( 24 of 27 or 88.9% ) report ed t aking t he ant iret roviral t herapy. I n addit ion, it was found t hat t he m aj orit y of deceased pat ient s ( 20 of 30 pat ient s) and pat ient s wit h cognit ive im pair m ent ( 8 of 13 pat ient s) were also undergoing ant iret rovir al t herapy, based on t heir m edical records.
H I V in fe ct ion cha r a ct e r ist ics
D ia gn osis t im e
Am ong t he 27 pat ient s select ed in t his st udy, 13 of 27 ( 48.2% ) were HI V infect ed for 2- 5 years, 8 of 27 ( 29.6% ) for 6- 9 years and 6 of 27 ( 22.2% ) for over 10 years.
Risk sit u a t ion s for H I V t r a n sm ission
The m aj or risk sit uat ion for HI V infect ion was sexual, st at ed by 18 of 27 pat ient s ( 66.7% ) . Of t hese, 6 of 27 ( 33.3% ) pat ient s indicat ed m arit al relat ions as t he t ransm ission agent and 5 of 27 ( 27.8% ) acquired HI V infect ion from casual sexual int ercourse.
Se x u a l be h a vior be for e a nd a ft e r H I V infe ct ion
The m aj or changes of sexual behavior, in relat ion t o num ber of sexual part ners, unsafe sex pract ices including having sex wit h m ult iple part ners and failure t o use condom s, frequency and charact erist ics of past and present sit uat ions which have placed persons at risk for HI V infect ion are shown in Table 1.
Se x u a l pa r t n e r s
Before HI V infect ion, 13 of 27 ( 48.1% ) pat ient s had m ore t han four previous sexual part ners, aft er diagnosis t his num ber had significant ly decreased, nam ely, no pat ient had as m any part ners as before t he diagnosis ( p= 0.0001) . Addit ionally, 14 of 27 ( 51.9% ) pat ient s st at ed t hat t hey have had only one sexual part ner ( p= 0.02) and 12 of 27 ( 44.4% ) pat ient s relat ed having no sexual part ner aft er HI V infect ion ( p= 0.0001) .
Fr e qu e n cy of se x u a l in t e r cou se
Frequency of sexual int ercourse changed aft er HI V infect ion as w ell. I t w as found t hat 22 of 27 ( 81.5% ) pat ient s decreased t he frequency of sexual int ercouse aft er infect ion ( p= 0.0001) , of t hose 5 of 27 ( 18.5% ) pat ient s st at ed sexual abst inency ( p= 0.05) , 10 of 27 ( 37% ) pat ient s last had t heir sexual int ercourse over six m ont hs ago ( p= 0.001) and 7 of 27 ( 25.9% ) pat ient s last had sexual int ercourse one m ont h ago.
Se x u a l pr a ct ice
Am ong t he 10 of 27 ( 37% ) pat ient s t hat st at ed having had anal sex before HI V infect ion, only 3 of 27 ( 11.1% ) pat ient s cont inued t his pract ice, w hich is a significant decrease ( p= 0.05) .
Con dom use
TABLE 1 - Com parision of sexual behavior before and aft er HI V- infect ion individuals present ing w it h HLA ant igens associat ed wit h rapid progression t o AI DS.
SEX UAL BEH AV I OR BEFORE
H I V - I N FECTI ON ( n = 2 7 )
p= *
AFTER H I V - I N FECTI ON
( n = 2 7 ) p= *
Num ber of sex ual part ner s nº % nº %
None - - 12
p= 0.0001 *
44.4
One 05 18.6 14
p= 0.02*
51.9
Tw o- t hr ee 09 33.3 01
p= 0.01*
3.7
Over four 13 48.1 0
p= 0.0001 *
0
Sexual pract ice nº % nº %
None - - 05
p= 0.05*
18.5
Vaginal 17 63 19 70.4
Anal 10 37 03
p= 0.05*
11.1
Condom use nº % nº %
Never 18 66.7 05
p= 0.0008 *
18.5
Som et im es 06 22.2 03 11.1
Alw ays 03 11.1 17
p= 0.0002 *
63.0
No sex ual int er cour se - - 02 7.4
Sexual pract ice and condom use nº % nº %
None 18 66.7 05
p= 0.0008 *
18.5
Vaginal 07 25.9 15
p= 0.05*
55.6
Anal 01 3.7 01 3.7
No sex ual int er cour se - - 02 7.4
Sexual orient at ion nº % nº %
Hom osexual 01 3.7 02 7.4
Het er osex ual 24 88.9 25 92.6
Bisexual 02 7.4 - -
* Fisher’s exact t est .
D I SCUSSI ON
Several genet ic m arkers are associat ed wit h progression t o AI DS and, t o a lesser ext ent , ot hers are associat ed w it h resist ance t o HI V infect ion. AI DS epidem icit y is charact erized by ext rem e het erogeneit y in t erm s of t he course of t he disease and incidence of HI V- 1 infect ion am ong exposed individuals( 2,3). These findings probably reflect t he genet ic
variant s of HI V- 1 st rains and host genet ic polym orphic genes, including chem okine and chem okine recept or st ruct ural genes and HLA alleles( 1). The progression from HI V- 1 infect ion
t o AI DS has been st rongly associat ed wit h HLA- A1- Cw7- B8- DR3- DQ2 and HLA- A11- Cw4-B35- DR1- DQ1 haplot ypes, conferring a high risk of rapid progression t o AI DS( 4) .
cells and t he evidence indicat ing t hat cyt ot oxic T cells ( CTLs) play an im por t ant role in prot ect ion against HI V- 1. Anot her m echanism t o explain rapid progression t o AI DS in individuals wit h cert ain HLA genot ypes m ay involve t he regulat ion of nat ural killer ( NK) cell act ivit y. A num ber of st udies have indicat ed t hat rapid disease progression aft er HI V- 1 infect ion is correlat ed wit h decreased NK cell act ivit y. Like CTLs, NK cells ar e involved in surveillance and killing of foreign or infect ed cells t hrough a m echanism involving HLA m olecules( 13) .
St udies of survival am ong adult Brazilian AI DS pat ient s dem onst rat es a subst ant ial increase in life expect ancy. This im provem ent coincides w it h t he w idespread availabilit y of ant iret rovir al t reat m ent in Brazil( 8,14). I n t his st udy, about 1/ 3 ( 38.6% ) of HI V- infect ed
individuals present ing wit h HLA ant igens associat ed wit h rapid progression t o AI DS were available t o part icipat e. These pat ient s had AI DS for six years ( 51.8% ) and t he m aj orit y of part icipant s were t aking t he ant iret roviral t herapy ( 88.9% ) and prophylact ic m edicat ion against opport unist ic infect ions ( 37% ) . Bot h cont ribut ed t o increased life expect ancy of HI V-infect ed pat ient s and also t heir qualit y of life im proved( 15).
Analyzis about ant iret roviral t herapy use revealed t hat t he m aj orit y of HI V- infect ed individuals who were exhibit ing HLA ant igens associat ed wit h rapid progression t o AI DS, bot h t hose eligible and not eligible, w ere t aking t he highly act ive ant iret roviral t herapy, suggest ing t hat ot hers fact ors m ay be associat ed w it h survival of pat ient s included in t he st udy. As w ell, st udies have show n t hat level of educat ional, gender( 16) and opport unist ic infect ions( 17) have an effect on AI DS pat ient s’ survival. Moreover, fact ors such as changes of
sexual behavior focusing on risk reduct ion m ay be associat ed t oo.
To evaluat e changes of sexual behavior in t hese pat ient s, com parat ive analyzis on unsafe sexual pract ices before and aft er HI V- infect ion showed a significant increased of condom use ( p= 0.0001) , decreased num ber of sexual part ners ( p= 0.0001) , decreased frequency of sexual int ercouse ( p= 0.0001) and a decrease of anal pract ices ( p= 0.05) aft er HI V- infect ion.
Changes in sexual behavior along wit h safe sex pract ices t oget her wit h ant iret roviral t herapy m ay cont ribut e t o and im prove life ex pect ancy of AI DS pat ient s.
Finally, t hese result s suggest s t hat counseling, det ect ion of unsafe sexual pract ices and healt h educat ion focusing on healt hy behavior are t ools nursing m ust use w it h HI V-posit ive pat ient s. These t ools m ay help t o lead t o a great er survival am ong t hese individuals, even am ong t hose wit h genet ic predisposit ion t o rapid disease progression, w it h im plicat ions for im provem ent of nursing care program s for HI V- infect ed pat ient s.
REFEREN CES
1. Fernandes APM, Gonçalves MAG, Gir E, Donadi EA. I m m unogenet ic fact ors involved in t he progression t o aids. J Bras Doenças Sex Transm 2002; 14: 36- 8.
2. Carringt on M, Nelson G, O'brien SJ. Considering genet ic profiles in funct ional st udies of im m une responsiveness t o HI V- 1. I m m unol Let t 2001; 79: 131- 40.
3. Phair JP. Keynot e address: variat ions in t he nat ural hist ory of HI V infect ion. AI DS Res Hum Ret roviruses 1994; 10: 883- 5.
4. Flores- Villanueva PO, Hendel H, Caillat - Zucm an S, Rappaport J, Burgos- Tiburcio A, Bert in- Maghit S, et al. Associat ions of MHC ancest ral haplot ypes wit h resist ance/ suscept ibilit y t o AI DS disease developm ent . J I m m unol 2003; 170: 1925- 9. 5. Fernandes AP, Gonçalves MA, Zavanella RB, Figueiredo JF, Donadi EA, Rodrigues ML.
HLA m arkers associat ed wit h progression t o AI DS are also associat ed w it h suscept ibilit y t o cyt om egalovirus ret init is. AI DS 2003; 17: 2133- 6.
6. Chequer P, Hearst N, Hudes ES, Cast ilho E, Rut herford G, Loures L, et al. Det erm inant s of survival in adult Brazilian AI DS pat ient s, 1982- 1989. The Brazilian St at e AI DS Program Co- Ordinat ors. AI DS 1992; 6: 483- 7.
7. Marins JR, Jam al LF, Chen SY, Barros MB, Hudes ES, Barbosa AA, et al. Dram at ic im provem ent in survival am ong adult Brazilian AI DS pat ient s. AI DS 2003; 17: 1675- 82. 8. Gadelha AJ, Accacio N, Cost a RL, Galhardo MC, Cot rim MR, de Souza RV, et al. Morbidit y
and survival in advanced AI DS in Rio de Janeiro, Brazil. Rev I nst Med Trop Sao Paulo 2002; 44: 179- 86.
9. Rodrigues, MLV. Análise de ant ígenos e alelos de hist ocom pat ibilidade de classe I e I I , em pacient es com aids e com aids e ret init e por cit om egalovírus. Livre docência. Faculdade de Medicina de Ribeirão pret o da USP, Ribeirão Pret o. 2000, 1- 130.
11.Fernandes APM, Louzada- Junior P, Donadi, EA. HLA- DRB1, DQB1 and DQA1 allele profile in Brazilian pat ient s present ing wit h t ype 1 diabet es m ellit us. Ann N Y Acad Sci 2002; 958: 305- 8.
12.Deghaide NHS, Dant as RO, Donadi EA. HLA classI and I I profiles of pat ient s present ing wit h Chaga’s disease. Dig Dis Sci 1998; 43: 246- 52.
13.Carringt on M, Nelson GW, Mart in MP, Kissner T, Vlahov D, Goeder t JJ, et al. HLA and HI V- 1: het erozygot e advant age and B* 35- Cw* 04 disadvant age. Science 1999; 283: 1748- 52.
14.Casseb J, Fonseca LA, Veiga AP, de Alm eida A, Bueno A, Ferez AC, et al. AI DS incidence and m ort alit y in a hospit al- based cohort of HI V- 1- seroposit ive pat ient s receiving highly act ive ant ir et roviral t herapy in Sao Paulo, Brazil. AI DS Pat ient Care STDS 2003; 17( 9) : 447- 52.
15.Van Sighem AI , van de Wiel MA, Ghani AC, Jam broes M, Reiss P, Gyssens I C, et al. Mort alit y and progression t o AI DS aft er st art ing highly act ive ant iret roviral t herapy. AI DS 2003; 17: 2227- 36.
16.Sant oro- Lopes G, Harrison LH, Moult on LH, Lim a LA, de Pinho AM, Hofer C, et al. Gender and survival aft er AI DS in Rio de Janeiro, Brazil. J AI DS Hum Ret rov 1998; 19: 403- 7. 17.Erice A, Tierney C, Hirsch M, Caliendo AM, Weinberg A, Kendall MA, et al. AI DS Clinical
