Jpn. J. Infect. Dis" 53, 2000

Laboratory and Epidemiology Communications●Leukocytopenia due to Zidovudine‑ and Neviraplne‑Containlng●ReglmenS in Elderly Patients with HIV Infection
Yoshihiko Yamamotol･ 2, Akira Yasuoka., Chie YasuokaI , Ikumi Genkal , Katsuji TeruyaI,
Yoshimi Kikuchi1 , Natsuo Tachikawa) and Shinichi OkaI *]AIDS Clinical Center. International Medical Center ofJapan,
Toyama 1‑21‑1, Shinjuku‑ku, To砂0 162‑8655 and2Tlhe Organization for Pharmaceutical SafeoJ and ReseaTICh ofJapan,Kasumigaseki 3‑3‑2, Chiyoda‑ku, Too/0 100‑0013
Communicated by Hiroshi Ybshikura(Accepted December 28, 2000)

Leukocytopenia was observed in three cases among 1 7

was 3,500/LEI, CD4 count 2/ul, and the viral load 610,000

HIV‑ 1 ‑infected patients receiving reglmenS COntainlng bothzidovudine (ZDV) and nevirapine (NVP) (Table). Common

copies/ml. Twenty‑three days later, his body temperature roseto 39oC.AsWBC decreased to 200/lil, HAART was stopped.

features included the occurrence of leukocytopenia within 5

Subcutaneous administration of G‑CSF at 300 JLg daily wasweeks of treatment, good response to granulocyte‑colony

initiated on December 1 2. The nadir WBC was 70/LEI (neutro‑

stimulating factor (G‑CSF), and the advanced age of thephil l%) On December 16. AlthoughWBC recovered to 2,070/

patients. In two of the patients, leukocytopenia was absent〝1 and body temperature retumed to nomal on December

during reglmenS COntainlng either ZDV or NVP alone.

22, the patient died of disseminated candidiasis on February

Case 1 : A 48lyear‑Old HIV‑1‑infected homosexual mancommenced highly active antiretroviral therapy (HAART)with ZDV/NVP/lamivudine (3TC) on January 1 1 , 1999. Two

3, 2000. In this case, transient thrombocytopenia with a nadirload 700 copies/ml･ On February 13, 1999, day 33 0rthe

count of 5,000/LLI was observed on December 1 8.
Case 3 : A 50‑year‑old HIV‑ I ‑infected hemophiliac had beentreated with ZDV/didanosine (ddt) since 1996; ritonavir/saquinavir (RTV/SQV) were added to the regimen in January
1999. Although he showed an excellent response to thistherapy, he developed diarrhea, fever (40oC), and impetigo

reglmen, aChievlng Suppression of viral load to below quanti‑

on his back.Asleukocytopenia (240/LEI; neutrophil O%) was

fiable levels and an elevation of the CD4 count to more than

noted, he was hospitalized. HAART was stopped immedi‑
ately,and subcutaneousadministration of G‑CSF at a dose of

500/LL I, he complained of exacerbation of hemophiliac arthritis
associated with more frequent bleeding episodes alter adding

weeks later, the dose ofNVP was raised to 400 mg/day. At

that time, WBC was 3,800/LEI, CD4 count 263/LEI, and viral

300 LLg daily was started. Both pyrexiaand diarrhea improved

RTV/SqV Therefわre, RTV/SqV were replaced by NVP atwithin 9 days. WBC recovered to 6,200/LEI within 3 days. A

200 mg/day on January 18, 2000, and the dose ofNVP wasnew regimen containing stavudine (d4T)/NVP/3TC wasthen begun. No further episodes of leukocytopenia occurred

increased to 400 mg/day on February 6. However, WBC
declined from 4,900/LLl to 1,000/LEI (neutrophi1 50%) on

subsequently.

February 10. HAART was stopped, and G‑CSF was glVen

Case 2: A 68‑year‑old HIV1 1 ‑infected homosexual man wassubcutaneously f♭r 4 days at a dose of 150 ′上g daily. Wac

admitted to our hospital due to the onset ofPneumocystis

recovered to 5,500/JLl On February 1 5. Twenty days later,

carinii pneumonia (PCP) on September 1 6, 1999. A洗er treat‑HAART was re‑initiated with d4T/3TC/efavirenz. No 組erment of PCP, he commenced HAART, which included ZDV/

episodes of leukocytopenia were experienced.

The incidence of AIDS and mortality due to AIDS have

NVP/nel丘navir on November 19, 1999. At that time, Wac

Table･ Three cases of leukocytopenia caused by ZDV‑ and NVP‑containing regimendmg

WBC(仙1)case (芸) ,eg:ren ,olh.TliT,nD be,.,C

days aAer altemative.nadir c.XySL:C=en. a器器(year) reglmen zvB'tL芯CII before (neu.I::up;il%)

148

23

none

68

50

nolle

3TC

NFV

RFTDvV//sdSIi

ddt

3,

3,500

240

80070(4,900(0%)1%)

1 000 (50%)

33

23

d4T/3TC/NVP

none

24

d4T/3TC侶FVZDV: zidovudine, NVP: neviraplne, 3TC: Iamivudine, d4T: stavudine, NFV: nelfinavir, ddI: didanosine,RTV:ritonavir, SQV: saquinavir, EFV: efavirenz*Corresponding author: Telnax: +8 1 ‑3‑5273‑5 1 93, E‑mail: oka@
imcj.hosp. goJP

244

Jpn. J. Infect. Dis., 53, 2000
been declining markedly in the era ofHAART, which includes

Lipodystrophy syn血ome can cause cardiovascular complica‑

the use or two nucleoside reverse‑transcrlptaSe inhibitors

tions (5). Therefわre, Older patients should likely be given PL(NRTIs) and an HIV‑specinc protease inhibitor (PI)･ However,

sparlng reglmenS tO avoid complications. Our obseⅣations

adherence to these reglmenS is often difficult because of theappear to suggest that the myelotoxIClty Or ZDV can beexacerbated by NVP. lt may therefore be important to be awareof this potential side effect, especially during the first 5 weeks

large number ofpills, side effects, and drug‑drug interactions
related to Pis. Furthermore, reports of unexpected serious sideeffects in patients exposed to PIs over a long period areor ther叩y ln elderly patients.

increaslng ln number. In particular, metabolic disturbancessuch as increased levels of cholesterol or triglycerides andThis study was supported by grants from the Ministry of

insulin‑resistant diabetes in association with abnormal fat

Health and Welfare of Japan, and the Organization forredistribution, which is referred to as lipodystrophy syndrome

Pharmaceutical Safety and Research (OPSR) of Japan.

( I ), have been observed. Non‑nucleoside reverse‑transcriptase

inhibitors (NNRTIs) are advantageous due to the lower burdenREFERENCES

ofpills and fewer drug‑drug Interactions compared with PI.
Therefわre, HAART consistlng Of 2 NRTIs and 1 NNRTl is

1. Car一, A., Samaras, K., Burton, S., Law, M., Freund, ∫.,being prescribed as initial therapy ln treatment‑naive patients,Chisholm, D. ∫. and Cooper, D. A. (1998): A syndromeand ̀switch therapy'with NVP in place or PIs is beingof peripheral lipodystrophy, hyperlipidemia and insulinprescribed for patients with long‑term sustained viral suppres‑resistance in patients receivlng HIV protease inhibitors.

sion (2). Leukocytopenia caused by ZDV was reported soon

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2. Barreiro, P., Soriano, V, Blanco, F., Casimiro, C., de laafter its approval (3). However, there has been little informa‑tion regarding myelotoxicity caused by antiretroviral regimens

Cruz, J. ∫. and Gonzalez‑Lahoz, ∫. (2000): Risks andcontainlng NVP in adults. At our hospital, 44 patients havebeen treated with NVP‑containlng reglmenS Since 1997.

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Seventeen undenVent reglmenS COntainlng NVP and ZDVAs described above, 3 out of 17 patients (17.6%) developed

3. Richman, D. D., Fischl, M. A., Grieco, M. H., Gottleb,M. S., Volberding, P. A., Laskin, 0. L., Leedom, J. M.,

leukocytopenia 3‑5 weeks after the commencement ofantiretroviral therapy. In cases 1 and 2, reglmenS including

Groopman, ∫. E., Mildvan, D., Hirsch, M. S., Jackson,ZDV and NVP were introduced as the first antiretroviral

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replaced by d4T, while 3TC and NVP were not changed inazidothymidine (AZT) in the treatment or patlentS With

the second reglmen, this patient had no further episodes ofAlDS and AIDS‑related complex. A double‑blind, placebo‑controlled trial. N. Engl. J. Med., 317, 192‑197.
4. D'Aquila, R. T., Hughes, M. D., Johnson, V A., Fischl,leukocytopenia. Although case 3 had been treated with ZDV/
ddl since 1 996, he had never developed leukocytopenia until

dual‑PIs were changed to NVP. These observations appear toindicate that luekocytopenia by ZDV might be intensified by

M. A., Sommadossi, J. P., Liou, S. H., Timpone, J., Myers,

NVP.

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Toxic hepatitis and Stevens‑Jolmson 's syndrome have beenzidovudine and didanosine in patients with HIV‑ 1 infec‑

reported as serious adverse events associated with NVP.
However, in previous studies of NVP in combination withZDV, serious leukocytopenia has not been reported among

5. Henry, K., Melroe, H., Huebsch, ∫., Hermundson, ∫.,the more than 400 participants studied (4). In our cases, thepremature coronary artery disease with protease inhibi‑

patients were relatively older. If advanced age is a predispos‑tors. Lancet, 51, 1328.

tion. Ann. Intem. Med., 124, 1019‑1030.
Levine, C., Swensen, L. and Daley, J. (1998): Severeing factor for leukocytopenia, this will have clinical relevance.

245