Grace C. John

Correlates of Mother-to-Child Human Immunodeficiency Virus Type 1 (HIV-1) Transmission: Association with Maternal Plasma HIV-1 RNA Load, Genital HIV-1 DNA Shedding, and Breast Infections

To determine the effects of plasma, genital, and breast milk human immunodeficiency virus type 1 (HIV-1) and breast infections on perinatal HIV-1 transmission, a nested case-control study was conducted within a randomized clinical trial of breast-feeding and formula feeding among HIV-1-seropositive mothers in Nairobi, Kenya. In analyses comparing 92 infected infants with 187 infants who were uninfected at 2 years, maternal viral RNA levels >43,000 copies/mL (cohort median) were associated with a 4-fold increase in risk of transmission (95% confidence interval [CI], 2.2-7.2). Maternal cervical HIV-1 DNA (odds ratio [OR], 2.4; 95% CI, 1.3-4.4), vaginal HIV-1 DNA (OR, 2.3; 95% CI, 1.1-4.7), and cervical or vaginal ulcers (OR, 2.7; 95% CI, 1.2-5.8) were significantly associated with infant infection, independent of plasma virus load. Breast-feeding (OR, 1.7; 95% CI, 1.0-2.9) and mastitis (relative risk [RR], 3.9; 95% CI, 1.2-12.7) were associated with increased transmission overall, and mastitis (RR, 21.8; 95% CI, 2.3-211.0) and breast abscess (RR, 51.6; 95% CI, 4.7-571.0) were associated with late transmission (occurring >2 months postpartum). Use of methods that decrease infant exposure to HIV-1 in maternal genital secretions or breast milk may enhance currently recommended perinatal HIV-1 interventions.

Cell-Free Human Immunodeficiency Virus Type 1 in Breast Milk

Breast-feeding may be an important route of human immunodeficiency virus type 1 (HIV-1) vertical transmission in settings where it is routinely practiced. To define the prevalence and quantity of HIV-1 in cell-free breast milk, samples from HIV-1-seropositive women were analyzed by quantitative competitive reverse transcription-polymerase chain reaction (QC-RT-PCR). HIV-1 RNA was detected in 29 (39%) of 75 specimens tested. Of these 29 specimens, 16 (55%) had levels that were near the detection limit of the assay (240 copies/mL), while 6 (21%) had >900 copies/mL. The maximum concentration of HIV-1 RNA detected was 8100 copies/mL. The prevalence of cell-free HIV-1 was higher in mature milk (47%) than in colostrum (27%, P = 0.1). Because mature milk is consumed in large quantities, these data suggest that cell-free HIV-1 in breast milk may contribute to vertical transmission of HIV-1.

Maternal SDF1 3'A polymorphism is associated with increased perinatal human immunodeficiency virus type 1 transmission.

ABSTRACT Genetic polymorphisms in chemokine and chemokine receptor genes influence susceptibility to human immunodeficiency virus type 1 (HIV-1) infection and disease progression, but little is known regarding the association between these allelic variations and the ability of the host to transmit virus. In this study, we show that the maternal heterozygous SDF1 genotype (SDF1 3′A/wt) is associated with perinatal transmission of HIV-1 (risk ratio [RR], 1.8; 95% confidence interval [CI], 1.0 to 3.3) and particularly postnatal breastmilk transmission (RR, 3.1; 95% CI, 1.1 to 8.6). In contrast, the infant SDF1 genotype had no effect on mother-to-infant transmission. These data suggest that SDF1, which is a ligand for the T-tropic HIV-1 coreceptor CXCR4, may affect the ability of a mother to transmit the virus to her infant. This suggests that a genetic polymorphism in a gene encoding a chemokine receptor ligand may be associated with increased infectivity of the index case and highlights the importance of considering transmission as well as clinical outcome in designing chemokine-based therapies for HIV-1.

Partner Notification by HIV-1 Seropositive Pregnant Women: Association With Infant Feeding Decisions

Many countries in sub-Saharan Africa are in the process of integrating antenatal voluntary HIV-1 counseling and testing (VCT), antiretroviral prophylaxis, and counseling regarding infant feeding into routine maternal and child health services.1 Even with greater availability of interventions to protect infants from HIV-1 acquisition, many women choose not to receive their HIV-1 test results, and many who learn that they are HIV infected do not implement interventions to prevent vertical or sexual transmission. In both research and non-research settings, <75% of HIV-infected pregnant women who are tested learn their HIV-1 status2,3 and <50% of these women obtain antiretrovirals to prevent mother-to-child HIV-1 transmission2,4–6 or use condoms postpartum.7,8 Not disclosing HIV-1 test results to a sexual partner may impede a woman’s access to interventions to prevent vertical and sexual HIV-1 transmission. There is evidence that lack of partner support is associated with poor uptake of antiretroviral medication and the inability to modify infant feeding practices.9,10 Sexual abstinence and condom use have also been shown to be more common among postpartum women who reveal HIV-positive results to partners.7 These associations between partner involvement and uptake of interventions underscore the importance of involving the male partner in HIV-1 prevention efforts initiated in the antenatal setting. Antenatal VCT involves counseling and testing the woman alone, with the expectation that she will disclose results to her partner. Using this model, the majority of pregnant women in stable relationships who are tested as part of routine care do not inform their partner of positive HIV-1 results, fearing domestic violence, abandonment, or stigmatization.7,11,12 We hypothesized that conducting VCT for pregnant women together with partners could facilitate notification and increase partner participation in the decision-making process. This could in turn improve maternal access to mother-to-child HIV-1 prevention interventions. Studies among discordant couples in nonantenatal settings support this hypothesis and demonstrate that couple counseling is associated with significant behavior change, including sustainable increases in condom use.13–15 In addition, when comparing couple counseling and individual counseling, provision of counseling to couples appears to be more cost-effective in averting HIV-1 infections.16 To examine whether couple counseling in the antenatal setting could be used as a strategy to increase use of interventions to prevent perinatal and sexual HIV-1 transmission, we introduced couple VCT into a Nairobi antenatal clinic and determined the prevalence and correlates of partner participation and couple counseling. The study’s primary aim was to assess the impact of partner involvement, specifically being counseled as a couple, on perinatal intervention uptake and condom use.

CCR5 Promoter Polymorphisms in a Kenyan Perinatal Human Immunodeficiency Virus Type 1 Cohort: Association with Increased 2-Year Maternal Mortality

The CCR5 chemokine receptor acts as a coreceptor with CD4 to permit infection by primary macrophage-tropic human immunodeficiency virus type 1 (HIV-1) strains. The CCR5Delta32 mutation, which is associated with resistance to infection in homozygous individuals and delayed disease progression in heterozygous individuals, is rare in Africa, where the HIV-1 epidemic is growing rapidly. Several polymorphisms in the promoter region of CCR5 have been identified, the clinical and functional relevance of which remain poorly defined. We evaluated the effect of 4 CCR5 promoter mutations on systemic and mucosal HIV-1 replication, disease progression, and perinatal transmission in a cohort of 276 HIV-1-seropositive women in Nairobi, Kenya. Mutations at positions 59353, 59402, and 59029 were not associated with effects on mortality, virus load, genital shedding, or transmission in this cohort. However, women with the 59356 C/T genotype had a 3.1-fold increased risk of death during the 2-year follow-up period (95% confidence interval [CI], 1.0-9.5) and a significant increase in vaginal shedding of HIV-1-infected cells (odds ratio, 2.1; 95% CI, 1.0-4.3), compared with women with the 59356 C/C genotype.

Studies of human immunodeficiency virus type 1 mucosal viral shedding and transmission in Kenya

If human immunodeficiency virus type 1 (HIV-1) vaccines are to be highly effective, it is essential to understand the virologic factors that contribute to HIV-1 transmission. It is likely that transmission is determined, in part, by the genotype or phenotype (or both) of infectious virus present in the index case, which in turn will influence the quantity of virus that may be exchanged during sexual contact. Transmission may also depend on the fitness of the virus for replication in the exposed individual, which may be influenced by whether a virus encounters a target cell that is susceptible to infection by that specific variant. Of interest, our data suggest that the complexity of the virus that is transmitted may be different in female and male sexual exposures.

comparison of Techniques for Hiv-1 Rna Detection and Quantitation in Cervicovaginal Secretions

Principles: HIV‐1 in female genital secretions has been measured using swabs, Sno Strips (Akorn, Inc., Buffalo Grove, IL), and cervicovaginal lavage (CVL), but little is known regarding the comparability of these collection techniques. Methods: We compared HIV‐1 RNA detection and quantity in specimens obtained from HIV‐1‐seropositive women in Kenya using three sample collection techniques and three storage techniques and evaluated reproducibility in samples collected 5 days apart. Specimens were stored in no medium, freezing medium, or TRI Reagent (Molecular Research Center, Cincinnati, OH) for 2 to 15 months. Results: HIV‐1 RNA assays were conducted on 640 specimens from 20 antiretroviral naive women. Storage in TRI Reagent significantly enhanced detection of genital HIV‐1 and yielded significantly higher mean log10 RNA levels than specimens collected in either no or freezing medium. The prevalence of HIV‐1 RNA detection in TRI Reagent ranged from 50% to 80% depending on collection method and was highest in cervical swabs. Mean log10 HIV‐1 RNA levels were 3.1 log10 copies/cervical swab, 2.6 log10 copies/cervical Sno Strip, 2.5 log10 copies/vaginal swab, 2.4 log10 copies/ vaginal Sno Strip, 2.9 log10 copies/ml for cervicovaginal lavage (CVL) cell pellet, and 2.1 log10 copies/ml in CVL supernatant. Comparing specimens from days 1 and 6, there was significant concordance of HIV‐1 RNA detection and correlation of HIV‐1 RNA levels for cervical swabs, vaginal swabs, vaginal Sno Strips, and CVL cell pellets (&khgr;, 0.5‐0.9; r, 0.5‐0.9), but not for cervical Sno Strips or CVL supernatants. Conclusions: Cervical or vaginal swab, vaginal Sno Strip, and CVL collection led to reproducible measurement of genital HIV‐1 RNA, despite storage for several months and international transport. Collection using swabs was simpler than Sno Strips or cervicovaginal lavage, and yielded the highest prevalence of HIV‐1 RNA detection and reproducibility.

Morbidity and mortality in breastfed and formula-fed infants of HIV-1-infected women : A randomized clinical trial

There is evidence that breast-feeding by women with human immunodeficiency virus-1 (HIV-1) infection carries a substantial risk of viral transmission. In a resource-poor setting however formula feeding might lead to an increase in infectious infant morbidity and mortality. This randomized trial undertaken at four antenatal clinics in Nairobi Kenya during 1992-1998 compared outcomes in breast-fed and formula-fed infants of HIV-infected women. Participating were 371 live-born singleton (or first-born twin) infants of seropositive mothers. The parturients were randomly assigned to use formula (N = 186) or to breast-feed their infants (N = 185). Ninety-two infants acquired HIV-1 infection. Cumulative rates after 2 years of follow-up were 37% in the breast-fed group and 21% in the formula-fed group. Mortality rates did not differ significantly at either 1 or 2 years of follow-up. Among infants who became infected during the study 40% of those fed formula and 46% of breast-fed infants died within 2 years. Hazard ratios did not differ significantly. Mortality was however much increased for infants infected in the first 2 months of life compared with those infected later (63% vs. 9%). Women assigned to breast-feeding had 3-fold higher mortality than those assigned to formula feeding during the 2 years of follow-up. Moreover maternal deaths were associated with a higher risk of subsequent infant death. Considering HIV infection and death together as adverse outcomes formula feeding conferred protection amounting to 28%. Diarrheal illness and pneumonia occurred at similar rates despite the mode of feeding. HIV-infected children were about twice as likely to be malnourished at some time if fed formula than if breast-fed. (excerpt)

Effect of Breastfeeding and Formula Feeding on Transmission of HIV-1: A Randomized Clinical Trial

CONTEXT Transmission of human immunodeficiency virus type 1 (HIV-1) is known to occur through breastfeeding, but the magnitude of risk has not been precisely defined. Whether breast milk HIV-1 transmission risk exceeds the potential risk of formula-associated diarrheal mortality in developing countries is unknown. OBJECTIVES To determine the frequency of breast milk transmission of HIV-1 and to compare mortality rates and HIV-1-free survival in breastfed and formula-fed infants. DESIGN AND SETTING Randomized clinical trial conducted from November 1992 to July 1998 in antenatal clinics in Nairobi, Kenya, with a median follow-up period of 24 months. PARTICIPANTS Of 425 HIV-1-seropositive, antiretroviral-naive pregnant women enrolled, 401 mother-infant pairs were included in the analysis of trial end points. INTERVENTIONS Mother-infant pairs were randomized to breastfeeding (n = 212) vs formula feeding arms (n = 213). MAIN OUTCOME MEASURES Infant HIV-1 infection and death during the first 2 years of life, compared between the 2 intervention groups. RESULTS Compliance with the assigned feeding modality was 96% in the breastfeeding arm and 70% in the formula arm (P<.001). Median duration of breastfeeding was 17 months. Of the 401 infants included in the analysis, 94% were followed up to HIV-1 infection or mortality end points: 83% for the HIV-1 infection end point and 93% to the mortality end point. The cumulative probability of HIV-1 infection at 24 months was 36.7% (95% confidence interval [CI], 29.4%-44.0%) in the breastfeeding arm and 20.5% (95% CI, 14.0%-27.0%) in the formula arm (P = .001). The estimated rate of breast milk transmission was 16.2% (95% CI, 6.5%-25.9%). Forty-four percent of HIV-1 infection in the breastfeeding arm was attributable to breast milk. Most breast milk transmission occurred early, with 75% of the risk difference between the 2 arms occurring by 6 months, although transmission continued throughout the duration of exposure. The 2-year mortality rates in both arms were similar (breastfeeding arm, 24.4% [95% CI, 18.2%-30.7%] vs formula feeding arm, 20.0% [95% CI, 14.4%-25.6%]; P = .30). The rate of HIV-1-free survival at 2 years was significantly lower in the breastfeeding arm than in the formula feeding arm (58.0% vs 70.0%, respectively; P = .02). CONCLUSIONS The frequency of breast milk transmission of HIV-1 was 16.2% in this randomized clinical trial, and the majority of infections occurred early during breastfeeding. The use of breast milk substitutes prevented 44% of infant infections and was associated with significantly improved HIV-1-free survival.