In our cohort of HIV-1 infected pregnant women with INIs exposure during pregnancy, tolerance and safety for mothers and children were deemed aceptable. Withdrawal of medication due to adverse effects was not necessary and major birth defects in exposed children were not identified. Likewise, treatment with INIs in our cohort showed a high effectiveness in MTCT prevention, even in pregnant women with late diagnosis or high VL during pregnancy.
In recent years, there has been an increase in use of AT regimens that include INIs in pregnant women, which seem safe and effective treatments for preventing MTCT, even in high-risk situations. The criteria for using AT in pregnant women differ from the general recommendations for adults with HIV-1 infection, and safety of treatment should be considered not only for the patient but also for the fetus [4]. Although over last few years information to consider reasonably safe some AT in pregnancy has been avaliable, it is still quite limited [18,19]. INIs have become the preferred combinations with NRTIs as first therapy for patients with HIV-1 infection [14], and despite the limited experience with them in pregnancy, they have increasingly been used due to their potential advantage of leading to a rapid decline in maternal VL [3,11].
RAL has been the most frequently used INI, with demonstrated utility in patients with late diagnosis in pregnancy due to its good placental transfer, as well as in pregnant women with resistant viruses to first-line drugs [2-5,10,11], being currently the preferred INI in pregnancy [3].
RAL seemed to have superior efficacy compared with efavirenz (EFV) in VL suppression rates and increases in baseline CD4+ counts in treatment-naive patients (STARTMRK study [20]). Brites et al [2] studied the efficacy of RAL in late presenting pregnants, also finding statistically significant differences in VL supression before delivery compared to lopinavir boosted with ritonavir, as well as lower proportion of side effects. In the recently published
P1081: Raltegravir vs EFV in naïve pregnant women from 20-37 weeks
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P1081trial, women presenting late in pregnancy were randomized to receive RAL or EFV beyond 20 weeks of gestational age. Although no differences in perinatal transmission were observed, the arm treated with RAL had a median time to achieve less than 200 plasma RNA copies of 8 days compared to 15 days with EFV providing evidence of a faster drop in VL and more effective suppression of RNA replication, a key factor involved in perinatal transmission [21].
This drug has also increasingly been used and effectively as intensification of AT in pregnant women with bad control of infection in late stages of pregnancy [3,5-7,10,11]. In addition, its inclusion in treatment guidelines as elective therapy in adults and since a high proportion of pregnancys are unplanned, an increase in use of INIs in pregnant women may be anticipated. This evidence, along with the important cumulative evidence of low maternal adverse effects and good fetus safety profile [category C according to the FDA (Food and Drug Administration Pregnancy)] [3,7,11,19] makes it one of the most widely ART used in pregnancy. Despite its pharmacokinetics with important inter and intraindividual variability [9], the regimen used in pregnant women is currently the usual third antiretroviral drug in adults.
DTG and EVG have the advantage of being able to be administered co-formulated, promoting adherence to treatment. Although there is less information avaliable about treatment in pregnant women than with RAL, there are favorable data with DTG vs EFV in women with late onset in pregnancy [22].
The case series published so far provide similar information to RAL regarding to VL decreasing, without significant maternal or neonatal adverse effects [2,3,24,25] in the initial publications. Thus in low-income countries such as Bostwana, DTG in combination with Tenofovir (TDF) and emtricitabine has become the first-line regimen for adults with HIV-1 infection since 2016, including the pregnant women [25] due to its: efficacy, good tolerance, low pharmacological interactions and high resistance barrier [26]. However, their safety in pregnancy has yet to been established. In a recent comparative study between two groups of pregnant women starting treatment with DTG and TDF respectively during pregnancy, Zash et al [26] initially did not find differences in the risk of birth defects between both groups. However, in May 2018, the World Health Organization (WHO), European Medicines Agency (EMA) and FDA, warn of the possible increase of neural tube birth defects in NB from mothers treated with DTG at the moment of conception (0.9% vs 0.1% with other antiretroviral drugs), according to data obtained from the same observational study [15]. This prevalence observed in exposed children born to women treated with DTG at the moment of conception in Botswana, without folic acid supplements, was statistically higher than in women´s children treated with other antiretroviral drugs or DTG initiated in other moment of pregnancy in the same population.
In previous reviews, polydactyly was the most common birth defect detected [25]. In our serie, we detected a patient with this malformation but whose mother had received treatment with RAL. Currently, there is no information enough to recommend DTG or EVG during pregnancy [3,13,25]. EVG boosted with cobicistat has a great variability in pharmakokinetics during pregnancy leading commonly to subtherapeutic levels [27].
In our cohort, no severe birth defects were detected, both from mothers treated with INIs before pregnancy and those who started during pregnancy. The detection of some anomalies was probably favored by the active search in the follow-up of the children. These results show a prevalence comparable to that found in previous studies of our cohort [28]. In this study a higher proportion of premature births was not observed, by contrast to previously published data from our global cohort [17].
The main adverse effect reported in literature in women treated with INIs is transient, asymptomatic and reversible hypertransaminasemia [7,11,19,2]. This toxicity was not detected in our pregnant women, who showed good tolerance to treatment in all cases.
It is of utmost importance to achieve virological suppression before delivery in pregnant women with HIV-1 infection, because it greatly modifies the risk of MCTC and could contribute to reduce maternal complications secondary to elective caesarean section [3,5,25]. Currently recommendations of Spanish and British guidelines on the management of HIV-1 in pregnant women, suggest the intensification of treatment in women who do not reach virological suppression during pregnancy [10,15]. Because of the good placental transfer of INIs and the rapid decrease on VL, they might be very useful in pregnant with late diagnosis or with therapeutic failure in the last weeks of pregnancy [4].
In our series, the incorporation of INIs to the AT regimen in women with poor virological control before pregnancy or diagnosis of the HIV-1 infection during the current pregnancy, was very effective for the rapid reduction of plasma VL, and thus probably contributing in the complete prevention of MTCT. Our findings are similar to results published previously in other series [1-3,6-8,11,12,19,25].
The main limitations of our study are its retrospective nature, the absence of a control group of pregnant women without INIs in their regimen of treatment, and the relative small sample size, which preclude from drawing definitive conclusions and extend our findings to other settings. In addition, active surveillance of birth defects was not done in all NB with complementary or image tests.
However, our study provides relevant information on a large number of pregnant women treated with INIs, confirming their high effectiveness and safety shown in previous studies in developed countries. Furthermore, it confirms the potency of INIs to achieve a rapid decrease on VL in mothers with intensification, even when they were administered in the third trimester, leading to a high proportion of women to reach undetectable VL near delivery, a critical goal to achieve since it is the most important factor associated with MTCT.