Jpn. J. Infect. Dis" 55, 2002

Laboratory and Epidemiology Communications

Discordant Movement of CD4‑Positive T‑Cell Countin HIV‑1 Infected Patients with HAART Failure
Aiko Okano, Masakazu Matsuda, Tomoko Chiba, Kenji Moriya,

Kaneo Yamadal and Watam Suglura*
AIDS Research Center, National Institute of Infectious Diseases,
Gakuen 4‑7‑1, Musashimurayama, Too;0 208‑0011 andJSt. Marianna UniversitySchool of Medicine,
SLigaO 2‑1 6‑1, Miyamae‑ku, Kawasaki, Kanagawa 21 6‑8511
Communicated by Naoki Yamamoto(Accepted June 7, 2002)

Highly active antiretroviral treatment (HAART) With atdrug administration. lnsufrlCient suppression of virus replica‑

least oTe protease inhibitor (PI) and two nucleoside reverse
transcrlptaSe inhibitors (NRTIs) is now the recommended
first‑line antiretroviral prescription for HIV‑ 1 infection ( 1 ,2).

tion, gradual decrease ofperipheral CD4+ T‑cell count, andconsequent accelerated disease progression are frequent

outcomes (8‑10). Recently, however, several groups havereported cases in which therise and fall ofCD4+ T‑cell counts

While its introduction has greatly improved the prognoses ofmany of patients (3‑5), HAART has been unsuccessful in aand viral copy numbers during HAART did not fわllow theconsiderable number of cases (6,7). This treatment failure ismle above (ll,12).

due mainly to the emergence of drug resistant HIVl. Once

We examined 236 HIV‑1 infected patients who had been

the dmg resistant vims appears, it will quickly predominate intreated in 17 hospitals collaboratlng With our laboratory andthe virus population due to selective advantage under continued

followed up for more than 4 years (from November 1996 toSeptember 2000),

CD4+ T‑cell count and clinical data were provided bythecollaborating hospitals. Viral load (VL) was measured by*Co汀eSpOnding author: Fax: +8 1 ‑ 42‑56 1 ‑7746, E‑mail: wsuglura@nih.go.jp
62Jpn. J. Infect. Dis., 55, 2002

uslng AMPLOCOR HIVI MONITORTM Test Version 1.5

Table 1. Classification of236 cases by treatment response and change

in peripheral CD4+ T‑cell count(Roche Diagnostics, Branchburg, N.J., USA).
HIV‑1 pol sequences were analyzed for drug resistanceCD4+ T‑cell count
Increase No change Decrease

gePotypes･ RNA was extracted form200 LEI ofplasma byusing an RNA purification kit (Boehringer Mannheim,Responding

Indianapolis, Ind., USA), and the 821 bp reverse transcriptaseVL ResponsePT) and 3 80 bp protease (PR) regions yere reverse transcribed* Underline: Discordant cases

Nand amplified by nested PCR in a previously reported manneron十reSP80On

ding2241

16422( 1 3). The amplified kagments were directly sequenced using

dye‑terminator chemistry ( 1 4) andthe auto‑sequencer ABl‑377 (Applied Biosystems, Foster City, Calif., USA).

of category (a), i.e., cases with increased CD4+ T‑cell count,

The 236 cases were classified according to their VL
response and changes in CD4+ T‑cell count (Table 1). VL

significantly high numbers of categories (b) + (C), cases whose(P < 0.001). In contrast, the non‑responding group had

CD4+ T‑cell did not increase during the therapy (P < 0.001).

responses Were Classified into two groups, either (i) respondl

lng: VL achieved below the detectable level (<50 copies/mL)

As has been previollSly reported, and fわund as well in ouror >2 log copies/mL of reduction from the baseline before

samples, Some cases have shown discordance between VL

treatment, or (ii) non‑responding: not applicable to category

response and CD4十T‑cell response. Forty‑one VL non‑(i). Each VL response class was categorized into three

responding cases demonstrated increased CD4+ T‑cell count,Fccording to CD4+ T‑cell counts: (a) increase: absolute
Increase kom the baseline before treatment, (b) decrease:absolute decrease &om the baseline before treatment, (C) noT‑cell count.

and seven ⅥJ responding cases showed a decrease in CD4+

Patient profiles of each category are surrmarized in Table
2. No significant difference was seen in regard to sex, sexual
behaviors and treatment protocols. Only parameter in whichchange: no slgMICantincrease or decrease during the observa‑
tion period.

Assummarized in Table 1, in the VL responding group (na significant difFerence could be seen was the lower median‑ 109), the number of cases applicable to categories (a), (b),age, 30,5 years, of the patientswith"VL non‑responding‑and (C) were 80, 22, and 7, respectively, In the VL non‑CD4+ increase", i.eり(ii) (a) cases.

responding group (n ‑ 127), the number of cases applicable

In the drug resistance genotype comparison (Table 3),to (a), (b), and (C) were 41, 64, and 22 cases, respectively.

the incidence of D67N, KIO3N, and M184Vn RT‑relatedThus, the responding group had a slgnificantly high number

resistance mutations was slgniflCantly higher in the discordant

Table 2. Patients profiles of 236 study participants classified into 6 groups

RespVL ResponsecD4+蒜lcounts

ondingN

on‑responding
Tわtallncrease*

Nochange(n‑80)

Decrease**(n‑22)(n‑7)

Increase**(n‑41)

Nochange(n‑64)

Decrease*(n‑236)(n‑22)

SexMaleFemale

Median age

73

22

7

70

36.0

38

0

33.5

36.0

61

320

3

30.5

34.0

221

2

15

35･05‑ 7 1 3750478311

36.0
n川川u(Range)(20,63)(21,53)(19,62)(15,71)(17,56)(18,ヽ▲

170)

Sexual behavior

Hemophiliacs

4 1 1 4 2 父U 3 つん 1 0日H′0 0 1 0 0 0 05151000

23 0ノ luノ l 1 0 0

3 1 7493001

1 1 2450000

Homosexual
H eteros exual

Homo/Hetero

Transfusi on
Unknown
Oth erTre atm ent

NRTIAZT

7 5 2 4 47 0 0ノ ′hU 0111

7 0 ′hU n7 833233

5253

3224

つJ 3 2 3 1hUノ 0 6 7 (uノ′0 9 3 8 353235

2 1 1 1 20 7 1 7 0qノ 9 7 0 3

21 11 0 4 9 5 8d4T

ddC
dd1

3TCPIIndinav ir

4 2 ′0 5 0 00 8 1

Rit ollaV i r
SaqulnaVir

Nelfinavir*Concordant group** Discordant group

12231 2 3 0 7

つA l つん 3′0 7 2 4′0 2 0ノ 3

一. J l 'l

1 1 '･▲ l00240833

pnuJpn. J. Infect. Dis., 55, 2002
Table 3. Summary of drug resistance mutations observed in 6 groups of patients

VL Response
CD4十cell collntS

Responding

N on‑resp on ding

Increase Nochange Decrease

Increase Nochange Decrease(n‑80)(n‑22)(n‑7)(n‑41)(n‑64)(n‑22)a.

Mutations to PI
KI Ol作UV

1 2814 21 560146 503 18059

3 0 1 nU0O ′0 1 1 9 4 0 5 1 0 231010130 140 1 1 22 日4614日1 521 23 61 6323日5日1 42 905231 61 2364 2 03 1日369

7 6 1 0 3 9 6 1 5 17 4 0 9 5 1 3 62 621 871 302 10 2 80 2 87

1 0 2 1 0 0 ′hl0O 2 1▲

201 21 0 0 40 31

1 702 日1 43 70 13 0 2 5日

1 0 93560 201 0101 048265 010 0 80 日5V0 0 0 0 0 0 血. 09 7460546 254 95 74 091 257 32 5㌔706960253720401406

辛K2 0M/R
L24I

D30N*
V32I
L33F

M36I
M4 6Ⅰ/L*G48V*
Ⅰ5 4V/L

L63P

A7 1V/TG73S
V77Ⅰ

V 82A/F/T *Ⅰ84VN88D

L90M*
Mutations to RT

M41L
墨壷5旦

D67N
T69D
K70R*
L74V *V75T*

KIO3N*
VIO6A*
VIO8Ⅰ*Y181C/Ⅰ*
M 1 84V/Ⅰ*

Y1 88L/C/H*
G1 90A/S*
T2 1 5Y/F*
K219(〕*

Primary mutations** P value was calculated with data of the concordant "VL non‑responding‑CD4+ decrease" group (n‑22) anddiscordant "VL non‑responding‑CD4+ increase" group (n‑41 )"VL non‑responding‑CD4+ increase" group (n ‑ 41) than in

Gonzales‑Lahoz, J. and Jens, D. Lundgren for theEuroSIDA Study Group (1998): Changes in use of

the concordant "VL non‑responding‑CD4+ decrease" group (n‑ 22) (P ‑ 0.045, 0.040, and 0.004, respectively). Regarding

antiretroviral therapy ln reglOnS Of Europe over time.

AIDS, 12, 2031‑2039.
2. Carpenter, C. C., Fischl, M. A., Hammer, S. M., Hirsch,
M. S., Jacobsen, D. M., Katzenstein, D. A., Montaner, J.

protease inhibitor‑resistant mutations, no significant associa‑tion could be seen between mutations and the discordance
pattem.

result in acute irrmunologic failure. The cause of this discor‑Our results confirmed that virologic failure did not always

S., Richman, D. D,, Saag, M. S., Schooley, R. T.,
Thompson, M. A., Bella, S., Yeni, P. G. and Volberding,dance remains unclear, necessitatlngfurther research. The

P. A. (1 998): Antiretroviral therapy for HIV infection infurther studymight help answerfundamental questions

1 998: updated recommendations of the International

regarding HIV‑1 pathogenesis and may provide clues to theAIDS Society‑USA panel. JAMA, 280, 78‑86.

proper timing for changlng antiretroviral regimens after

3. Notermans, D. W, Pakker, N. G., Harrman, DりFoudraine,

N. A., KaufFmann, R. H., Meenhorst, P. L., Goudsmit,

virologic failure.

J" Roos, M. T., Schellekens, P. T., Miedema, F. andDanner, S. A. (1 999): Immune reconstitution after 2 years

REFERENCES

of successRll potent antiretroviral therapy ln previously

untreated human immunodeficiencyvirus type 1 ‑infected

1. Kirt, 0., Mocroft, A., Katzenstien, T. L., Lazzarin, A.,
Antunes, F., Francioli, P., Brettle, R. P., Parkin, J. M.,

adults. J. Infect, Dis., 180, 1050‑1956.

64

Jpn. J. Infect. Dis., 55, 2002

4. Rosenberg, E. S., Billingsley, J. M., Caliendo, A. M"
Boswell, S. L., Sax, P. E., Kalams, S. A. and Wakler, B.

HIV‑1 infection predicted by the quantity Ofvirus inplasma. Science, 272, 1167‑1 170.

10. Grabar, S., Le Moing, V., Goujard, C., Leport, C,,

D. (1997): Vigorous HIV‑1 specific CD4+ T cell
responses associated with control of viremia. Science,Kazatchkine, M. D., Costagliola, D. and Weiss,し. (2000):278, 1447‑1450.

Clinical outcome of patientswith HIV‑1 infection

5. Li, T S., Tubiana, R,, Katlama, C., Calvez, V.,Ait, Mohand,according to immunologlC and virologlC response after

H･ and Autran, B･ (1 998): Long‑lasting.recovery in CD4

6 months of highly active antiretroviral therapy. Ann.

T‑cellfunction and viral‑load reduction after highly

Intem. Med., 133, 401‑410.
1 1. Marimoutou, C., Chene, G., Mercie, P., Neau, D., Farbos,S., Morlat, P" Ceccaldi, J., Dabis, F. and Groupe d'Epide‑

active antiretroviral therapy ln advanced HIV 1 disease.
Lancet, 351, 1682‑1686.

6. 0'Brien, W. A., Hartigan, P. M., Martin, D., Esinhart, J.,
Hill, A., Benoit, S., Rubin, M" Simberkoff, M. S. andmiologie Clinique du SIDA en Aquitaine (2001): Prog‑
nostic factors ofcombinedviral load and CD4+ cell count

Hamilton, ∫. D. (1996): Changes in plasma HIVI RNA

responses under triple antiretroviral therapy, Aquitaineand CD4+ lymphocyte counts and the risk ofprogres‑cohort, 1996‑1998. J. Acquired Immune Defic. Syndr.,

sion toAIDS. New Engl. ∫. Med., 334, 426‑431.

27, 161‑167.

7. Chene, G., Binquet, C., Moreau, J. F., Neau, D., Pellegnn,I., Malvy, D" Ceccaldi, I., Lacoste, D., Dabis, F. and the

12. Teri, ∫.し., Matthew, S. H., Liegler, T. ∫., Hayden, M. S.,
Lee, K. H., Hob, 氏., Deeks, S. G. and Grant, 良. M. (2001):

Group d'Epidemiologie Clinique du SIDA en Aquitaine

Protease inhibitor‑resistant HIV‑1 from patients with(1998): Changes in CD4+ cell count and the risk ofpreseⅣed CD4 cell counts is cytopathic in activated CD4T lymphocytes. AIDS, 15, 179‑184.
13. Kitsutani, P. T" Naganawa, S., Shiino, T., Matsuda, M.,

opportunistic infection or death after highly active

antiretroviral treatment. AIDS, 12, 23 13‑2320.

Honda, M., Yamada, K., Taki, M. and Sugiura, W. (1 998):

8. Lepri, A. C" Katzenstien, T.し., Ullum, H., Phillips, A.

N" SkinhDj, P" Gerstoft, J. and Pedersen, B. K. (1998):

HIV Type 1 subtypes of nonhemophiliac patients in

The relative prognostic value ofplasma HIV RNA levels

Japan. AIDS Res. Hum. Retrovimses, 14, 1099‑1 103.

and CD4 1ymphocyte counts in advanced HIV infection.

14. San岩er, F., Nickeln, S. and Coulson,A. 良. (1977): DNA

AIDS, 12, 1639‑1643.

sequenclng With chain‑te‑inatlng inhibitors･ Proc･ Natl･

9. MeHors, J. W., Rinaldo, C. R., Jr., Gupta, P., White, R.

Acad. S°i. USA, 74, 5463‑5467.

M., Todd, ∫. A. and Kingsley, L A. (1996): Prognosis in65