In our study pregnant women infected with HIV presented significant rates of adverse effects, most of low severity. Anemia and hepatic alteration occurred in more than half of the cases and lower platelets count in almost 15%. Less than 3% presented ART-related allergic reaction.
The Obstetric Clinic in CAISM/UNICAMP is a reference service for HIV infected women in the Campinas region and serves a low-income population with less schooling. The great majority of the cases are highly complex including users of psychoactive substances (mainly crack). In this updated cohort of 15 years of medical care, the great majority of women were exposed to ART during pregnancy, delivered by C-section, received intravenous zidovudine during labor, did not breastfeed and their newborns received oral AZT for 6 weeks.
The antiretroviral drugs used in pregnant women during the study years varied according to the Brazilian Ministry of Health’s recommendations. Since 2000, an ART regimen with three combined drugs has been in use .
One unquestionable benefit of using ART during pregnancy is the viral load control which directly impacted MTCT. In our study, analyzing 793 pregnancies of women infected with HIV, the MTCT rate was 2.3%, close to the World Health Organization (WHO) Global Plan’s goal [17, 18]. Nevertheless, it is important to stress that among the 350 infected pregnant women in the cohort’s last 5 years, there were only three cases of MTCT, all from women with lower adherence to treatment and in abuse of substances. Previous studies from the same clinic showed MTCT rates of 2.9% in 2000 and 3.7% in 2009, the last one strongly related to no adherence to antiretroviral treatment during pregnancy [19, 20].
It is known that using complex and potent antiretroviral regimens during pregnancy can cause adverse effects for the mother and the newborn, including the organogenesis period [8, 9]. The physiologic changes in pregnancy affect the kinetics of absorption, distribution, biotransformation and elimination of medication, potentially altering pregnant woman’s susceptibility to the toxicity of different drugs . These changes cause pharmacokinetic alterations with consequent reduction of exposure to most of the drugs during the gestational period. However, it is not always necessary to adjust their dosages until the end of pregnancy .
The most frequent and significant maternal adverse effects studied are hematologic, hepatic and dermatologic alterations, metabolic disturbances like diabetes mellitus and dyslipidemia, pre-eclampsia and viral resistance [8, 22].
Our study demonstrated a global anemia rate of more than 50% in pregnant women exposed to ART, which is in accordance with the international and national literature. Recent study showed high anemia occurrence in Brazilian pregnant women . This adverse effect was not associated with any specific antiretroviral drug in our multivariate data analysis but was associated with the starting of ART during pregnancy, with the occurrence of infectious complications and with peripartum CD4 count lower than 200 cells/mm3.
It is known that anemia in pregnant women infected with HIV can be associated with other causes besides ART, such as advanced maternal disease, iron and folic acid deficiency, malnutrition, intestinal parasitosis, and increased intravascular volume (hemodilution); all significantly associated with increased risk for maternal mortality [24, 25].
The use of zidovudine is one of the causes of cytopenia in pregnant women infected with HIV. In general anemia occurs at the beginning of treatment, in the first 12 weeks of use, and it is frequently associated with low CD4 count and advanced disease [26,27,28], as demonstrated in our data.
Even when it is known that AZT is not the only cause of anemia in pregnancy, and that ART is linked to improved health, particularly in lower income countries, anemia is the most common adverse effect associated with AZT use in pregnancy, independently of the regimen [29,30,31]. A study with 1070 pregnant women in sub-Saharan Africa between 2005 and 2008 reported the same results . Many studies have been demonstrating high rates of anemia independently from the treatment regimen, as the one in South Africa with 408 pregnant women and 64.2% rate of anemia . Similarly, our multivariate analysis showed that low CD4 count is a risk factor associated with anemia.
Our data did not show a significant difference in the occurrence of anemia between pregnant women exposed to AZT or TDF regimens. We did not compare the use of monotherapy with AZT and combined ART because of the small number of cases using only AZT (23 cases). A clinical trial (PROMISE Trial) in six sub-Saharan African countries and India compared monotherapy with combined regimens (AZT/3TC/LPV/r or TDF/Emtricitabine/LPV/r) and demonstrated that maternal adverse effects were more frequent with combined regimens, although the difference was not significant .
A study with 117 pregnant women in 2011 demonstrated adverse hematologic and hepatic effects and gestational cholestasis particularly associated with nevirapine, zidovudine and nelfinavir use. The higher rates of discontinuation or substitution due to adverse effects or intolerance occurred with these same drugs, while only 1% of patients in use of lopinavir/ritonavir had the drugs changed . Our data also evidenced an increased risk of elevated hepatic enzymes with the use of combined ART. In the multivariate analysis, the use of nevirapine was associated with increased risk for hepatic alteration during pregnancy, although NFV and ATV were also associated with these adverse effects.
In our cohort, nevirapine was the most utilized NNRTI. It was associated with increased hepatic alterations and hypersensitivity skin reactions, in agreement with recently published researches. Using NVP in pregnant women, especially with CD4 count higher or equal to 250 cells/mm3 is debatable, due to elevated risk for hepatic toxicity and skin allergic reaction already demonstrated [36, 37]. However, an elevated risk for hepatic alteration and allergic reaction was not demonstrated in pregnant women exposed to nevirapine with CD4 > = 250 cells/mm3 in our cohort. This drug is considered an alternative, seldom recommended for pregnant women in Brazil .
Data from a 2006 Brazilian study evaluating NVP adverse effects in 197 pregnant women reported a 5.5% toxicity rate, 4.5% of exanthema with only one case of Stevens-Johnson Syndrome, and 1.5% of hepatotoxicity including one severe case . That study also described hepatitis C virus as the only risk factor for NVP toxicity, which was also demonstrated in recent studies [39, 40]. In our cohort, pregnant women co-infected with hepatitis C virus did not present higher hepatotoxicity due to ART use.
In our study, despite the low rates of maternal skin allergic reaction associated with NVP, there were three cases of Stevens-Johnson Syndrome with total recovery.
A clinical trial in Uganda compared LPV/r and efavirenz (EFV) use in 389 women infected with HIV during pregnancy and puerperium and found no difference in the adverse effects such as anemia and neutropenia related to the two drugs. On the other hand, the pregnant women exposed to EFV presented higher viral suppression at delivery compared to the ones in use of LPV/r, although this difference was extinguished one year after birth . In our study only four pregnant women were using EFV by pregnancy’s conclusion and only one of them used it continuously from the beginning to the end. Although for years EFV has been largely used in adults’ antiretroviral regimens due mainly to its highly potent effects and its simpler posology, only recently and after its security was demonstrate, was this drug suggested as the preferable regimen for pregnant women [6, 42]. For this reason, in 2015 the Brazilian Health Ministry recommended EFV as the chosen drug for initial treatment . Nevertheless, recent studies discussed its significant collateral effects, in special the neuropsychiatric one and the increased risk for suicide [44, 45], besides its lower potentiality when compared to the promising integrase strand inhibitors . Because of this, the most recent Brazilian recommendation is to use raltegravir as first choice to complete ART regimen in pregnancy .
Until 2015 the main recommended drug for pregnant women in Brazil was lopinavir/ritonavir (LPV/r). Atazanavir/ritonavir (ATV/r), which was highly recommended in international guidelines, was restricted in Brazil to first line PI intolerance cases and was associated with higher risk for elevated bilirubin, without clinical implications to the newborn. Bilirrubin elevation is a known adverse effect of atazanavir during pregnancy or anytime of use. It is known that protease inhibitors can cause lipid metabolic changes, metabolic syndrome, lipodystrophy, changes in the carbohydrate metabolism and increased cardiovascular risk in every HIV infected patient [47,48,49]. Some studies had demonstrated that during pregnancy women in use of PI also presented higher rates of dyslipidemia, metabolic syndrome, lipodystrophy, diabetes and pre-eclampsia [50,51,52], as some of our data also demonstrated.
When evaluating the different ART classes, PI use was associated with elevated risk for dyslipidemia and fasting glycemia alterations when compared to NVP use. In the multivariate analysis, LPV use was associated with elevated risk for alteration in fasting glycemia, demonstrating the need for its early evaluation and diagnosis in the pregnant women exposed to PI, and the need to revise the criteria for indicating PI to women with known risk factors for diabetes, such as obesity.
On carbohydrates metabolism, a study showed that some antiretroviral drugs increased the TNFα, IL-6 e IL-1β pro-inflammatory cytokines involved in changes of adipocytes function and in the decrease of adiponectin, a positive modulator for insulin sensitivity . A multi-center randomized clinical trial with 1407 women observed a general rate of gestational diabetes in 2.1%, higher with PI use (4.6%) .
Regarding birth outcomes, the authors used the same pregnant women’s cohort and their newborns to analyze neonatal adverse effects such as prematurity, low birth weight, small for gestational age week, neonatal anemia and hepatic alterations. The results on birth outcomes are described in another article which has just been published .
The high Caesarian section rate in this cohort occurred because from 2005 to 2015 most of pregnant women infected with HIV delivered by C-section following changes in the service’s protocol after the European Collaborative Group published their study . On the other hand, prematurity was not considered iatrogenic and was not associated with C-section as shown in the recently published article by the same authors .
Our study focus was on the evaluation of adverse effects to which we produced consistent data on a clinical cohort in use of ART following the Brazilian Health Ministry’s recommendations, using guidelines very similar to the international ones. Data collection based on information registered in the women’s and children’s clinical records might have contributed to a possible register bias. Another limitation was having no HIV negative controls. The authors did not compare adverse effects in HIV negative control women because some tests to evaluate toxicity (hepatic alterations and dyslipidemia) are done only when the pregnant woman is in use of specific medication such as ART.
Our data showed more than 700 evaluations of pregnant women infected with HIV followed in a specialized clinic showing that the ART choices recommended by the Brazilian Health Ministry were adequate, leading to low gravity adverse effects and reaching excellent rates of MTCT.