Persistence of Genotypic Resistance to Nelfinavir among Women Exposed to Prophylactic Antiretroviral Therapy during Pregnancy

Abstract

We assessed the development of drug resistance in women exposed to antiretroviral therapy (ART) for prevention of mother-to-child transmission (PMTCT) after 24 weeks postpartum in a prospective cohort of HIV-1-infected women. HIV-1-infected women, who received prophylactic ART during pregnancy, had genotypic resistance testing performed at the start (T1) of and 24 weeks after ART interruption (T2). The women had CD4 counts Ͼ 250 cells/ml and no AIDS defining conditions. Of the 30 eligible women, the median age was 27 years [25-75% interquartile range (IQR): 21-32] and the median gestational age of ART initiation was 22 weeks (IQR: 19-27): 19 (63.3%) received zidovudine (ZDV) plus lamivudine (3TC) plus nelfinavir (NFV). At entry, most women (96.7%) were asymptomatic (CDC93 A1/A2), with a median CD4 count of 446 (IQR: 353-686) and median viral load (VL) of 8560 copies/ml (IQR: 3,252-19,515). No HIV-1 vertical transmission was observed. HIV subtype B was the most prevalent (70%). The development of new mutations associated with ART resistance was analyzed at T2. NFV resistance was observed in 4 out of 17 (23.5%) patients exposed to this drug: two major mutations D30N (1/17) and L90M (1/17) and minor mutations (N88S, 2/17). Mutations on positions 44, 69, and 118 (1/28) were present on reverse transcriptase (RT) analysis.No new nonnucleoside reverse transcriptase inhibitor (NNRTI)-associated mutation was observed. In this cohort, ART regimens were very efficient at blocking HIV vertical transmission. However, the high rate of NFV-resistant mutations observed in the postpartum period indicates the need for discussion of ART choices during pregnancy and the potential impact on future therapeutic options for these women. Women previously exposed to ART for PMTCT who will start HIV treatment should have genotypic resistance testing performed. 1515

Protease Inhibitor–Based Antiretroviral Prophylaxis during Pregnancy and the Development of Drug Resistance

“…Furthermore, no details are given in the publication about the mutations detected and the drug regimen used in these women, making it difficult to draw a conclusion about any particular class of antiretroviral drugs. In 2007, Kakehasi et al [20] published a prospective cohort study including 17 HIV-infected women receiving zidovudine, lamivudine, and nelfinavir for MTCT prophylaxis. Postpartum testing showed newly detected resistance mutations against nelfinavir in 4 of these women (23.5%).…”

Resistance to antiretrovirals in HIV-infected pregnant women

“…This was in contrast to others who found resistance mutations in 13-24% of women who received ARV exclusively for PMTCT in different areas of the world. 14,15,17 Factors known to contribute to the development of ARV resistance, such as compliance with therapy, bioavailability of the drugs and genetic barriers of the virus to the development of resistance may have differed across studies, thus explaining the divergent results. In our study, 57 of 117 (49%) of pregnant women received NFV, and half of the NFV recipients with therapeutic drug monitoring during pregnancy required dose increases to compensate for low plasma levels of NFV and its active metabolite (Weinberg et al, submitted for publication).…”

“…1,2 However, the widespread use of ARV increased the prevalence of HIV drug-resistance, which may affect the efficacy of HAART for prevention of MTCT (PMTCT). [3][4][5][6][7][8][9][10][11] Furthermore, ARV resistance can also arise in mothers who receive HAART for PMTCT [12][13][14][15][16][17] and compromise future ARV responses in women [18][19][20][21] and/or complicate the management of HIV infection in infants born to mothers who failed PMTCT. [22][23][24][25] The guidelines for management of HIV infection in pregnancy in resource-abundant countries recommend resistance testing in all patients.…”

Clinical pharmacology of HIV protease inhibitors in pregnancy

“…It is also known that those patients not fully suppressed while on treatment have a significant lower chance of transmitting the disease, as the use of ARV on its own is independently associated with a reduced chance of MTCT. However, the suboptimal treatment during pregnancy can lead to virological failure and make the options for future treatment more limited due to resistance, as was reported by Kakehasi et al [29].…”