Efficacy and safety of lopinavir/ritonavir versus efavirenz-based antiretroviral therapy in HIV-infected pregnant Ugandan women.

OBJECTIVE: Combination antiretroviral therapy (ART) is now the global standard for HIV-infected pregnant and breastfeeding women at all CD4⁺ cell counts. We compared the efficacy and safety of an efavirenz versus lopinavir/ritonavir regimen for HIV-infected pregnant women initiating ART in rural Uganda. DESIGN: Randomized clinical trial. METHODS: We performed a planned secondary analysis comparing viral load suppression (HIV-1 RNA ≤400 copies/ml), safety, and HIV transmission to infants in a trial designed to test the hypothesis that lopinavir/ritonavir versus efavirenz-based ART would reduce placental malaria (PROMOTE, ClinicalTrials.gov, NCT00993031). HIV-infected, ART-naive pregnant women at 12-28 weeks gestation and any CD4⁺ cell count were randomized. ART was provided and participants were counseled to breastfeed for 1 year postpartum. RESULTS: The median age of the 389 study participants was 29 years; median CD4⁺ cell count was 370 cells/µl. At delivery, virologic suppression was 97.6% in the efavirenz arm and 86.0% in the lopinavir/ritonavir arm (P < 0.001). At 48 weeks postpartum, 91.0% of women on efavirenz and 88.4% on lopinavir/ritonavir had viral suppression (P = 0.49). Grade 1 or 2 gastrointestinal adverse events were higher among women on lopinavir/ritonavir versus efavirenz. Only two infants acquired HIV (both in the lopinavir/ritonavir arm), and HIV-free infant survival was similar between study arms: 92.9% (lopinavir/ritonavir) versus 97.2% (efavirenz) (P = 0.10). CONCLUSION: Virologic suppression at delivery was higher with an efavirenz versus lopinavir/ritonavir-based regimen. However, women in both arms achieved high levels of virologic suppression through 1 year postpartum and the risk of transmission to infants was low.

"I Have Remained Strong Because of That Food": Acceptability and Use of Lipid-Based Nutrient Supplements Among Pregnant HIV-Infected Ugandan Women Receiving Combination Antiretroviral Therapy.

We evaluated the acceptability and use of macronutrient supplementation among HIV-infected pregnant Ugandan women receiving antiretroviral therapy in a clinical study (NCT 00993031). We first conducted formative research among 56 pregnant and lactating women to select a supplement regimen. Acceptability and use of the supplementation regimen (35 sachets of lipid-based nutrient supplements (LNS) and 4 or 6 kg of instant soy porridge for the household provided monthly) were evaluated among 87 pregnant women. Organoleptic assessments of LNS were favorable. Participants reported consuming LNS a mean of 6.1 days per week, and adherence to recommended consumption behaviors (e.g. frequency, quantity, not sharing) was >80 %. Few women reported negative social consequences of supplementation. The majority of participants also consumed most of the porridge intended for the household. In sum, LNS was acceptable and used regularly. Larger studies to evaluate physical and psychosocial consequences of LNS during pregnancy among HIV-infected women are warranted.

Risk factors for preterm birth among HIV-infected pregnant Ugandan women randomized to lopinavir/ritonavir- or efavirenz-based antiretroviral therapy.

BACKGROUND: Protease inhibitor-based antiretroviral therapy (ART) has been associated with preterm birth in some studies. We examined risk factors for preterm birth among women randomized to lopinavir/ritonavir (LPV/r)- or efavirenz (EFV)-based ART. METHODS: This was a planned secondary analysis of the PROMOTE-Pregnant Women and Infants Study, an open-label, randomized controlled trial comparing the risk of placental malaria among HIV-infected, ART-naive pregnant Ugandan women assigned to initiate LPV/r- or EFV-based ART at 12-28 weeks gestation. Gestational age was determined based on last menstrual period and ultrasound biometry. All women received bednets and trimethoprim-sulfamethoxazole. Stillbirths, spontaneous abortions, and multiple gestations were excluded from the primary analysis. Potential risk factors for preterm birth (<37 weeks gestation) were evaluated by univariate and multivariate logistic regression. RESULTS: Three hundred fifty-six women were included in this analysis. At enrollment, median gestational age was 21 weeks and median CD4 cell count was 368 cells per cubic millimeter. 14.7% of deliveries in the EFV arm and 16.2% in the LPV/r arm were preterm. Preterm birth was associated with gestational weight gain below 0.1 kg/week versus 0.1 kg/week or more [odds ratio (OR) = 2.49; 95% confidence interval (CI): 1.38 to 4.47; P = 0.003]. Neither ART regimen of LPV/r versus EFV (OR = 1.12; 95% CI: 0.63 to 2.00; P = 0.69) nor placental malaria (OR = 0.74; 95% CI: 0.38 to 1.44; P = 0.37) was associated with preterm birth. CONCLUSIONS: LPV/r was not associated with an increased risk of preterm birth compared with EFV. However, interventions are needed to address modifiable risk factors for preterm birth, such as nutritional status (ClinicalTrials.gov, NCT00993031).

Lopinavir/ritonavir-based antiretroviral treatment (ART) versus efavirenz-based ART for the prevention of malaria among HIV-infected pregnant women.

BACKGROUND: Human immunodeficiency virus (HIV)-infected pregnant women are at increased risk of malaria and its complications. In vitro and in vivo data suggest that the HIV protease inhibitors lopinavir/ritonavir may have potent antimalarial activity. We sought to evaluate whether lopinavir/ritonavir-based antiretroviral therapy (ART) reduced the risk of placental malaria. METHODS: HIV-infected, ART-naive pregnant women were enrolled between gestational weeks 12 and 28 and randomly assigned to receive lopinavir/ritonavir-based or efavirenz-based ART. Women received daily trimethoprim-sulfamethoxazole prophylaxis and insecticide-treated bed nets at enrollment and were followed up to 1 year after delivery. The primary outcome was placental malaria, defined by the detection of malaria parasites, using microscopy or polymerase chain reaction (PCR) analysis of placental blood specimens. Secondary outcomes included placental malaria, defined by histopathologic results; adverse birth outcomes; incidence of malaria; and prevalence of asymptomatic parasitemia. Analyses were done using an intention-to-treat approach. RESULTS: Of 389 subjects randomly assigned to a treatment group, 377 were followed through to delivery. There was no significant difference in the risk of placental malaria, as defined by thick smear or PCR findings, between the lopinavir/ritonavir-based and efavirenz-based ART arms (7.4% vs 9.8%; P = .45). Similarly, there were no differences in secondary outcomes between the 2 treatment arms. CONCLUSIONS: Lopinavir/ritonavir-based ART did not reduce the risk of placental or maternal malaria or improve birth outcomes, compared with efavirenz-based ART. CLINICAL TRIALS REGISTRATION: NCT00993031.

Household food insecurity, maternal nutritional status, and infant feeding practices among HIV-infected Ugandan women receiving combination antiretroviral therapy.

Household food insecurity (HHFI) may be a barrier to both optimal maternal nutritional status and infant feeding practices, but few studies have tested this relationship quantitatively, and never among HIV-infected individuals. We therefore described the prevalence of HHFI and explored if it was associated with poorer maternal nutritional status, shorter duration of exclusive breastfeeding (EBF) and fewer animal-source complementary foods. We assessed these outcomes using bivariate and multivariate analyses among 178 HIV-infected pregnant and breastfeeding (BF) women receiving combination antiretroviral therapy in the PROMOTE trial (NCT00993031), a prospective, longitudinal cohort study in Tororo, Uganda. HHFI was common; the prevalence of severe, moderate, and little to no household hunger was 7.3, 39.9, and 52.8 %, respectively. Poor maternal nutritional status was common and women in households experiencing moderate to severe household hunger (MSHH) had statistically significantly lower body mass index (BMIs) at enrollment (21.3 vs. 22.5, p < 0.01) and prior to delivery (22.6 vs. 23.8, p < 0.01). BMI across time during pregnancy, but not gestational weight gain, was significantly lower for MSHH [adjusted beta (95 % CI) -0.79 (-1.56, -0.02), p = 0.04; -2.06 (-4.31, 0.19), p = 0.07], respectively. The prevalence (95 % CI) of EBF at 6 months was 67.2 % (59.7-73.5 %), and the proportion of women BF at 12 months was 80.4 % (73.3-85.7 %). MSHH was not associated with prevalence of EBF at 6 months or BF at 12 months. However, among those women still EBF at 4 months (81.4 % of population), those experiencing MSHH were significantly more likely to cease EBF between 4 and 6 months (aHR 2.38, 95 % CI 1.02-5.58). The prevalence of HHFI, maternal malnutrition, and suboptimal infant feeding practices are high and the causal relationships among these phenomena must be further explored.

Hair and plasma data show that lopinavir, ritonavir, and efavirenz all transfer from mother to infant in utero, but only efavirenz transfers via breastfeeding.

BACKGROUND: As efforts intensify to eliminate perinatal HIV transmission, understanding kinetics of maternal-to-child transfer of antiretrovirals during pregnancy and breastfeeding is critical. Antiretroviral levels in plasma, cord blood, and breastmilk reflect exposure over short intervals. Hair concentrations reflect cumulative exposure and can uniquely quantify in utero transfer of maternal medications to infants. We measured plasma and hair antiretroviral levels in HIV-infected Ugandan mothers and their infants at delivery and during breastfeeding to assess transfer. METHODS: HIV-infected pregnant women were randomized to lopinavir/ritonavir- or efavirenz-based therapy in a larger trial (the Prevention of Malaria and HIV disease in Tororo, PROMOTE). At 0, 8, and 12 weeks postpartum, plasma antiretroviral levels were measured in 117 mother-infant pairs; hair levels were assayed at 12 weeks. Ratios and correlations of infant:maternal concentrations were calculated. RESULTS: By 12 weeks, 90.4% of mothers reported exclusive breastfeeding. Hair and plasma levels over time suggest moderate (47%) to extensive (87%) in utero transfer of lopinavir and ritonavir, respectively, but negligible transfer of either via breastfeeding. Moderate transfer of efavirenz occurs during pregnancy and breastfeeding (40% cumulative; 15% during breastfeeding). Despite differences in exposure, no infant seroconversions or correlations between infant hair/plasma antiretroviral levels and adverse effects were observed. CONCLUSIONS: Using a unique approach combining hair and plasma data, we found that different antiretrovirals have distinct kinetics of mother-to-infant transfer. Efavirenz transfers during both pregnancy and breastfeeding, whereas lopinavir and ritonavir transfer only in utero. Further study of the degree and timing of maternal-to-child transfer by antiretroviral will help optimize strategies that protect infants and minimize toxicities during periods of risk.

Bioavailability of iron in geophagic earths and clay minerals, and their effect on dietary iron absorption using an in vitro digestion/Caco-2 cell model.

Geophagy, the deliberate consumption of earth, is strongly associated with iron (Fe) deficiency. It has been proposed that geophagy may be practiced as a means to improve Fe status by increasing Fe intakes and, conversely, that geophagy may cause Fe deficiency by inhibiting Fe absorption. We tested these hypotheses by measuring Fe concentration and relative bioavailable Fe content of 12 samples of geophagic earth and 4 samples of pure clay minerals. Further, we assessed the impact of these samples on the bioavailability of Fe from an Fe-rich test meal (cooked white beans, WB). Fe concentrations were measured with inductively coupled plasma atomic emission spectroscopy. Fe bioavailability was determined using an in vitro digestion/Caco-2 cell model in which ferritin formation was used as an index of Fe bioavailability. Geophagic earth and clay mineral samples were evaluated with this model, both alone and in combination with WB (1 : 16 ratio, sample : WB). Median Fe concentration of the geophagic earth was 3485 (IQR 2462, 14 ,571) µg g⁻¹ and mean Fe concentration in the clay minerals was 2791 (±1782) µg g⁻¹. All specimens had Fe concentrations significantly higher (p ≤ 0.005) than the Fe concentration of WB (77 µg g⁻¹). Ferritin formation (i.e. Fe uptake) in cells exposed to geophagic earths and clay minerals was significantly lower than in cells exposed to WB (p ≤ 0.05) and Fe uptake responses of 11 of the 16 samples were not significantly different from the blank, indicating no bioavailable Fe. When samples were combined with WB, 5 of 16 had mean ferritin levels that were significantly lower (p ≤ 0.05, one tail) than the WB alone, indicating that the samples inhibited Fe uptake from the WB. None of the ferritin responses of cells exposed to both WB and earth/clay were significantly higher than WB alone. Thus, although geophagic earths and mineral clays are high in total Fe, very little of this Fe is bioavailable. Further, some geophagic earth and clay mineral samples inhibit Fe absorption from foods. In vivo research is warranted to confirm these observations and to determine if geophagic earth samples can be a source of Fe and/or inhibit Fe absorption.