Suppression of maternal virus load with zidovudine, didanosine, and indinavir combination therapy prevents mother-to-fetus HIV transmission in macaques.
Recently, we developed a maternal-fetal macaque model using a highly pathogenic HIV-2 strain, HIV-2287, to study the time course of HIV transmission in utero. Most pregnant macaques (Macaca nemestrina) infected with HIV-2287 (10-103 infective doses) transmitted HIV to their fetuses, as verified by positive identification of virus-infected mononuclear cells and free viral RNA in fetal blood. To determine whether an antiretroviral drug combination therapy composed of two dideoxynucleosides, azidothymidine (15 mg/kg) and dideoxyinosine (15 mg/kg), and a protease inhibitor, indinavir (25 mg/kg), could completely inhibit mother-to-fetus HIV transmission, we administered these drugs orally through gastric catheters to five pregnant macaques infected with 10 infective doses of HIV-2287. Beginning 30 minutes after HIV inoculation, the dams were given the combination antiviral therapy three times daily until delivery by cesarean section. Drug treatment reduced the maternal virus load to a minimally detectable level but did not prevent primary HIV-2287 infection. All fetal and infant blood samples were virus negative by internally controlled RNA polymerase chain reaction (QC-RNA-PCR) and virus coculture assays. Fetal and infant CD4+ T-cell levels remained normal throughout the experiment. These findings strongly suggest that combination chemotherapy with azidothymidine, dideoxyinosine, and indinavir can suppress maternal viral load enough to prevent mother-to-fetus transmission of HIV.
Ho
R J
RJ
Department of Pharmaceutics, University of Washington, Seattle, Washington, 98195, USA. rodneyho@u.washington.edu
Larsen
K
K
Bui
T
T
Wang
X Y
XY
Herz
A M
AM
Sherbert
C
C
Finn
E
E
Nosbisch
C
C
Schmidt
A
A
Anderson
D
D
Agy
M
M
Morton
W R
WR
Unadkat
J D
JD
D000818:Animals; D016049:Didanosine / Q000627:therapeutic use* / Q000633:toxicity; D004359:Drug Therapy, Combination; D005260:Female; D005333:Fetus / Q000821:virology; D015483:HIV Antibodies / Q000097:blood; D015658:HIV Infections / Q000188:drug therapy / Q000635:transmission*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015498:HIV-2; D019469:Indinavir / Q000627:therapeutic use* / Q000633:toxicity; D018445:Infectious Disease Transmission, Vertical; D008254:Macaca nemestrina; D011247:Pregnancy; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets; D019562:Viral Load; D015215:Zidovudine / Q000627:therapeutic use* / Q000633:toxicity
D015483:HIV Antibodies; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D019469:Indinavir; D016049:Didanosine