Didanosine to Prevent HIV-Resistance Mutations

Efficacy and Safety of 1-Month Postpartum Zidovudine-Didanosine to Prevent HIV-Resistance Mutations after Intrapartum Single-Dose Nevirapine.

Intrapartum single-dose nevirapine plus third trimester maternal and infant zidovudine are essential components of programs to prevent mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings. The persistence of nevirapine in the plasma for 3 weeks postpartum risks selection of resistance mutations to nonnucleoside reverse-transcriptase inhibitors (NNRTIs). The authors hypothesized that a 1-month zidovudine-didanosine course initiated at the same time as single-dose nevirapine would prevent the selection of nevirapine-resistance mutations. HIV-infected pregnant women in the PHPT-4 cohort with CD4 cell counts >250 cells/mm(3) received antepartum zidovudine from the third trimester until delivery, single-dose nevirapine during labor, and a 1-month zidovudine-didanosine course after delivery. These women were matched on the basis of baseline HIV load, CD4 cell count, and duration of antepartum zidovudine to women who received single-dose nevirapine in the PHPT-2 trial (control subjects). Consensus sequencing and the more sensitive oligonucleotide ligation assay were performed on samples obtained on postpartum days 7-10, 37-45, and 120 (if the HIV load was >500 copies/mL) to detect K103N/Y181C/G190A mutations. The 222 PHPT-4 subjects did not differ from matched control subjects in baseline characteristics except for age. The combined group median CD4 cell count was 421 cells/mm³ (interquartile range [IQR], 322-549 cells/mm³), the median HIV load was 3.45 log(10) copies/mL (IQR, 2.79-4.00 log(10) copies/mL), and the median duration of zidovudine prophylaxis was 10.4 weeks (IQR, 9.1-11.4 weeks). Using consensus sequencing, major nonnucleoside reverse-transcriptase inhibitors resistance mutations were detected after delivery in 0% of PHPT-4 subjects and 10.4% of PHPT-2 controls. The oligonucleotide ligation assay detected resistance in 1.8% of PHPT-4 subjects and 18.9% of controls. Major nonnucleoside reverse-transcriptase inhibitors resistance mutations were detected by either method in 1.8% of PHPT-4 subjects and 20.7% of controls. A 1-month postpartum course of zidovudine plus didanosine prevented the selection of the vast majority of nonnucleoside reverse-transcriptase inhibitors resistance mutations.

Although antiretroviral treatment is used increasingly during pregnancy to prevent mother-to-child transmission of HIV, women who are diagnosed late in pregnancy or at delivery often receive only intrapartum nevirapine. Because it has a long tail, meaning that it has a long half-life, nevirapine drug pressure during viral replication after childbirth can lead to selection of resistant viruses which will have implications for the mother’s treatment choices when she needs antiretroviral therapy for her own health. The results of this study are important in Asian and other settings with high levels of hepatitis B prevalence where use of lamivudine, emtricitabine, or tenofovir to ‘cover the tail’ might cause acute hepatitis due to hepatitis B flares. This one-month course of zidovudine and didanosine postpartum reduced the selection of mutations to nonnucleoside reverse-transcriptase inhibitors (NNRTI) by 91%. WHO should consider adding this option for high hepatitis B prevalence settings to its November 2009 rapid advice on mother-to-child transmission.