To the Editors:
The current standard of care for prevention of mother-to-child transmission (PMTCT) of HIV is the use of highly active antiretroviral therapy (HAART).1–3 Being one of the first antiretroviral, a lot of data are available concerning the effectiveness of zidovudine (ZDV) during pregnancy in HIV-infected women.4 At present, research is focusing on ZDV short-term and long-term hematological,4,5 mitochondrial,6,7 and neurological8,9 toxicities in mothers and their infants. In pregnant women, given these potential toxicities, ZDV-sparing triple regimens have been used with increasing frequency in Europe.10 Lopinavir/ritonavir (LPV/r) monotherapy has recently shown to be effective for PMTCT in women without antiretroviral therapy (ART) indication for themselves,11 whereas lamivudine (3TC)/protease inhibitor (PI) dual therapies (DT) have been successfully used in patients12–14 but not reported in pregnant women.
This descriptive study was performed to assess whether a 3TC/PI DT could control maternal viral load (VL) and prevent toxicities in naive and pretreated women who delivered in our hospital between January 2006 and 2012.
Patient’s data were collected from the database of the infectious diseases department at Pitié Salpetrière hospital, in which they were registered after informed consent. In this observational analysis, women were included if they received a DT (3TC+ PI or PI/r) at any time during pregnancy, but regimen were not implemented for the purpose of this analysis. Two groups were defined.
“Initiation” group: patients ART naive and starting a DT during pregnancy and “Switch” group: patients treated with 2 nucleoside analogues nucleoside reverse transcriptase inhibitor (NRTIs) + PI (with or without ZDV) and for whom all NRTIs were removed except 3TC, right before (2 women) or soon after diagnosis of pregnancy.
A control group included naive or pretreated women who delivered in the same hospital and at the same time as the studied group and who received triple therapy (TT) with 3TC/ZDV + PI or PI/r at any time during pregnancy. Pretreated women had received different regimens before pregnancy and were switched to TT before or after pregnancy was diagnosed.
Baseline characteristics were recorded at initiation of or switch to DT and TT. In case of repeated pregnancy during the inclusion period, only the first was selected to avoid patient duplication. Variables included were as follows: year of delivery, gestational age at initiation of DT/TT, duration of DT until delivery, levels of plasma HIV-1 RNA copies per milliliter and CD4 cell count at baseline, 1 month after initiation, and at delivery (±2 weeks), ART modifications during pregnancy, gestational age at delivery, and mode of delivery.
Safety outcomes included ART changes due to intolerance from baseline until delivery and for infants, hematological parameters, number of clinical anomalies at birth, and serious adverse events during the first 18 months of life.
The established primary endpoint was the effectiveness of DT at delivery (VL ≤ 50 copies/mL). Secondary endpoints included the following: (1) percentage of women with VL ≤400 copies per milliliter after 1 month of DT; (2) percentage of patients who remained under DT until delivery; (3) a combined criteria: DT maintained until delivery and VL ≤50 copies per milliliter at delivery, (4) safety outcomes for mothers and infants.
The HIV VL assays had a lower limit of detection of 200 copies per milliliter before 2007 and 50 copies per milliliter or less after 2007; therefore, data on delivery VL were analyzed with 2 cutoffs: 50 and 200 copies per milliliter. Virological failure (VF) that required switch to TT was defined as less than 2 log reduction after 1 month of DT for the initiation group and as 1 VL higher than 100 HIV RNA copies per milliliter during DT for the switch group. Pretherapeutic genotype analysis for resistance testing were available only for VF situations. Analyses were conducted using the Epi Info 7 software (Epi Info, CDC, Atlanta, GA). All P values are 2-tailed and considered significant if <0.05.
Forty-five women (17 naive, 28 pretreated) were included in the DT group and 49 (22 naive, 27 pretreated) in the TT group from January 2006 to January 2012.
Groups were not different for baseline characteristics, except that there were more patients on DT in 2010 to 2011 than in 2006 to 2007 (Table 1). The median gestational age at initiation of DT was 19.6 weeks [interquartile range (IQR): 11.7–25.3], compared with 18 weeks (IQR: 11–25) at initiation of TT. The PI backbone was mainly LPV/r and not different between groups. At DT initiation, naive women had a median VL of 21,692 copies per milliliter (IQR: 6589–31,269), compared with 11,818 copies per milliliter (IQR: 11,610–39,112) in the TT group (P = 0.34). At inclusion, the median VL for switched women was 43 copies per milliliter (IQR: 20–200) in the DT group and 200 copies per milliliter (IQR: 40–435) in the TT group (P = 0.27). In the intent-to-treat analysis, 91.1% of women [95% confidence interval (CI): 78.7%–97.5%] achieved a VL ≤50 copies per milliliter at delivery in the DT group, compared with 88.5% (95% CI: 73.2% to 96.8%) in the TT group (P= 0.72). At 1 month of therapy, 91.1% (76.4% initiated, 100% switched) of women under DT had VL ≤400 copies per milliliter compared with 73.4% in the TT group (P = 0.03). All women in the DT group had VL below 400 copies per milliliter at delivery allowing for vaginal delivery.15 Thirty-nine (86.7%) women remained on DT until delivery and 82.2% (95% CI: 68% to 92%) maintained the DT until delivery and had VL ≤ 50 copies/ml compared to 85.7% (95% CI: 69.7% to 95.2%) in the TT group (P = 0.76). There were 6 changes from DT to TT or other HAART as follows: 4 VF (2 initiations, 2 switches) and 2 reinforcements. Two naive patients with initial VL >30,000 copies per milliliter initiated DT at 21 gestational weeks and required switch to TT after 1 month. The pretherapeutic genotypes showed wild-type strains. In the switch group, 1 patient started DT in the first trimester but required reinforcement through TT after 2 months, without any resistance mutation. The other patient had a pretherapeutic genotype displaying a M184V mutation conferring resistance to 3TC, so when simplified to DT was actually receiving a fosamprenavir/r monotherapy. Two other switched women were reinforced through TT after a decrease of less than 2 log at 4 weeks of DT (1 had a VL >50 copies/mL at delivery). Another 2 (1 naive, 1 switched) failed to achieve a VL ≤50 copies per milliliter at delivery. Proportions of reported intolerance to ART were equal in both arms (13.3 vs. 14.2%, P = 1). Safety outcomes for infants are presented in Table 1. Of note, there was 1 case of MTCT in the TT group (upper 95% CI limit: 10.8%) and none in the DT group.
These results showed that in naive women, with a median VL of 21,692 copies per milliliter and switched women with a median VL of 43 copies per milliliter a 3TC + PI DT strategy during pregnancy is effective, with 91.1% of women achieving a VL ≤50 copies per milliliter at delivery. In addition, the DT strategy for PMTCT of HIV resulted in better safety outcomes than TT for exposed infants. We could argue that for naive patients with a VL> 10,000 copies per milliliter at baseline, DT should be initiated sooner to optimize the conditions to achieve a VL ≤50 copies per milliliter at delivery.16 The intolerance to antiretroviral was minimal in the studied groups. Hepatic cytolysis was observed in 4 women who received 3TC + LPV/r. In other studies, hepatotoxicity was especially reported in relation to ritonavir-boosted PIs.17–20 Newborns had better hematological parameters at birth, as previously stated for ZDV-sparing regimens.5,11 The HIV MTCT case occurred in a woman with late diagnosis of HIV infection, short duration of HAART, and premature delivery.21 Our study is retrospective and on a modest number of women. We were unable to obtain sufficient reliable data on drug adherence, plasma drug levels, and resistance in most cases. Despite these limitations, to our knowledge, this is the first analysis of a 3TC + PI DT for PMTCT.
Patients were elected on the basis of ART received during pregnancy and year of delivery; and because treatment groups were not randomly assigned, we cannot exclude confounding factors. For instance, in pretreated women, it is likely that physicians did not use DT in women with previous failure or evidence of resistance to 3TC. However, VL and CD4 cell counts at baseline were similar between groups. The only difference was that fewer women received DT in 2010/2011 compared with 2006/2007, probably because of increasing data regarding ZDV toxicity and availability of new NRTIs, like tenofovir and abacavir recommended as first-line treatment in HIV-infected adults.1,2 Thus, physicians have taken a conscious decision of using ZDV-sparing simplified regimens.10 Our data suggest that naive women with moderately elevated VL and pretreated women displaying an undetectable VL can safely achieve and, respectively, maintain a VL ≤50 copies per millliliter up to delivery when using a 3TC + PI DT for PMTCT. Optimal criteria for selection of patients and time for commencement of such dual therapy strategy deserve further studies.
The authors thank all the mothers who agreed to participate in this study, and their families.
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