Background. The natural history of congenital cytomegalovirus (CMV) infection is scarcely known in populations with high maternal CMV seroprevalence.

The safety and efficacy of adding antiretroviral drugs to standard zidovudine prophylaxis in infants of mothers with human immunodeficiency virus (HIV) infection who did not receive antenatal antiretroviral therapy (ART) because of late identification are unclear. We evaluated three ART regimens in such infants. Within 48 hours after their birth, we randomly assigned formula-fed infants born to women with a peripartum diagnosis of HIV type 1 (HIV-1) infection to one of three regimens: zidovudine for 6 weeks (zidovudine-alone group), zidovudine for 6 weeks plus three doses of nevirapine during the first 8 days of life (two-drug group), or zidovudine for 6 weeks plus nelfinavir and lamivudine for 2 weeks (three-drug group). The primary outcome was HIV-1 infection at 3 months in infants uninfected at birth. A total of 1684 infants were enrolled in the Americas and South Africa (566 in the zidovudine-alone group, 562 in the two-drug group, and 556 in the three-drug group). The overall rate of in utero transmission of HIV-1 on the basis of Kaplan–Meier estimates was 5.7% (93 infants), with no significant differences among the groups. Intrapartum transmission occurred in 24 infants in the zidovudine-alone group (4.8%; 95% confidence interval [CI], 3.2 to 7.1), as compared with 11 infants in the two-drug group (2.2%; 95% CI, 1.2 to 3.9; P=0.046) and 12 in the three-drug group (2.4%; 95% CI, 1.4 to 4.3; P=0.046). The overall transmission rate was 8.5% (140 infants), with an increased rate in the zidovudine-alone group (P=0.03 for the comparisons with the two- and three-drug groups). On multivariate analysis, zidovudine monotherapy, a higher maternal viral load, and maternal use of illegal substances were significantly associated with transmission. The rate of neutropenia was significantly increased in the three-drug group (P<0.001 for both comparisons with the other groups). In neonates whose mothers did not receive ART during pregnancy, prophylaxis with a two- or three-drug ART regimen is superior to zidovudine alone for the prevention of intrapartum HIV transmission; the two-drug regimen has less toxicity than the three-drug regimen. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD] and others; ClinicalTrials.gov number, NCT00099359.)

Background: Antibodies to blood-stage Plasmodium falciparum antigens have been associated with protection against clinical malaria in some studies but not others. Many of these studies have not assessed whether high-titer antibodies are associated with protection and have not adjusted for differences in malaria exposure. Methods: The presence of high-titer antibodies to apical membrane antigen-1, erythrocyte-binding antigen-175 (EBA-175), and merozoite surface protein-1₁₉ (MSP-1₁₉) was assessed in 87 children living in a malaria holoendemic area of Kenya. The children were prospectively assessed during 1 year for clinical malaria. Results: In unadjusted analyses, high-titer antibodies to MSP-1₁₉, but not EBA-175 or apical membrane antigen-1, were associated with protection from clinical malaria. However, after adjustment for exposure, only high-titer antibodies to EBA-175 were associated with protection from clinical malaria (hazard ratio, 0.48; 95% confidence interval [CI], 0.24, 0.95; P = 0.03), and with reduced episodes of clinical malaria (incidence rate ratio, 0.50; 95% CI, 0.31, 0.81; P = 0.005). A trend toward increased protection from clinical malaria in children was seen with antibodies to both EBA-175 and MSP-1₁₉ (hazard ratio, 0.26; 95% CI, 0.03, 1.94; P = 0.18). Conclusions: High-titer antibodies to EBA-175 are associated with protection from clinical malaria in children in a malaria holoendemic area of Kenya. Accurate estimates of antibody-associated protection from clinical malaria require adjustment for malaria exposure.

Significance: Human cytomegalovirus (HCMV) is the leading cause of birth defects associated with infections and a leading cause of transplantation failure. This study reveals the patterns and limits of HCMV genomic diversity by performing a large-scale analysis of HCMV sequences sampled from human hosts, identifying the hot and cold spots of variability. We find that the diversity is unevenly distributed across three host compartments and show that HCMV populations of vascular compartments are genetically constrained while enriched for polymorphisms of glycoproteins and regulatory proteins. This work significantly advances our understanding of the genomic diversity of HCMV in humans and has clear implications for the development of therapeutics against HCMV.