Impact of elevated maternal HIV viral load at delivery on T-cell populations in HIV exposed uninfected infants in Mozambique.

BACKGROUND: HIV-uninfected infants born to HIV-infected mothers (HIV-exposed uninfected, HEU) have been described to have immune alterations as compared to unexposed infants. This study sought to characterize T-cell populations after birth in HEU infants and unexposed infants living in a semirural area in southern Mozambique. METHODS: Between August 2008 and June 2009 mother-infant pairs were enrolled at the Manhiça District Hospital at delivery into a prospective observational analysis of immunological and health outcomes in HEU infants. Infants were invited to return at one month of age for a clinical examination, HIV DNA-PCR, and immunophenotypic analyses. The primary analysis sought to assess immunological differences between HEU and unexposed groups, whereas the secondary analysis assessed the impact of maternal HIV RNA viral load in the HEU group. Infants who had a positive HIV DNA-PCR test were not included in the analysis. RESULTS: At one month of age, the 74 HEU and the 56 unexposed infants had similar median levels of naïve, memory and activated CD8 and CD4 T-cells. Infant naïve and activated CD8 T-cells were found to be associated with maternal HIV-RNA load at delivery. HEU infants born to women with HIV-RNA loads above 5 log10 copies/mL had lower median levels of naïve CD8 T-cells (p = 0.04), and higher median levels of memory CD8 T-cells, (p = 0.014). CONCLUSIONS: This study suggests that exposure to elevated maternal HIV-RNA puts the infant at higher risk of having early T-cell abnormalities. Improving prophylaxis of mother to child HIV programs such that more women have undetectable viral load is crucial to decrease vertical transmission of HIV, but may also be important to reduce the consequences of HIV virus exposure in HEU infants.

Impact of HIV exposure on health outcomes in HIV-negative infants born to HIV-positive mothers in Sub-Saharan Africa.

BACKGROUND: Up to 30% of infants may be HIV-exposed noninfected (ENI) in countries with high HIV prevalence, but the impact of maternal HIV on the child's health remains unclear. METHODS: One hundred fifty-eight HIV ENI and 160 unexposed (UE) Mozambican infants were evaluated at 1, 3, 9, and 12 months postdelivery. At each visit, a questionnaire was administered, and HIV DNA polymerase chain reaction and hematologic and CD4/CD8 determinations were measured. Linear mixed models were used to evaluate differences in hematologic parameters and T-cell counts between the study groups. All outpatient visits and admissions were registered. ENI infants received cotrimoxazol prophylaxis (CTXP). Negative binomial regression models were estimated to compare incidence rates of outpatient visits and admissions. RESULTS: Hematocrit was lower in ENI than in UE infants at 1, 3, and 9 months of age (P = 0.024, 0.025, and 0.012, respectively). Percentage of CD4 T cells was 3% lower (95% confidence interval: 0.86 to 5.15; P = 0.006) and percentage of CD8 T cells 1.15 times higher (95% confidence interval: 1.06 to 1.25; P = 0.001) in ENI vs. UE infants. ENI infants had a lower weight-for-age Z score (P = 0.049) but reduced incidence of outpatient visits, overall (P = 0.042), diarrhea (P = 0.001), and respiratory conditions (P = 0.042). CONCLUSIONS: ENI children were more frequently anemic, had poorer nutritional status, and alterations in some immunologic profiles compared with UE children. CTXP may explain their reduced mild morbidity. These findings may reinforce continuation of CTXP and the need to understand the consequences of maternal HIV exposure in this vulnerable group of children.

Recent HIV-1 infection: identification of individuals with high viral load setpoint in a voluntary counselling and testing centre in rural Mozambique.

BACKGROUND: Identification of recent HIV-infections is important for describing the HIV epidemic and compiling HIV-RNA-setpoint data for future HIV intervention trials. We conducted a study to characterize recent infections, and HIV-RNA-setpoint within the adult population presenting at a voluntary counselling and testing centre (VCT) in southern Mozambique. METHODS: All adults attending the Manhiça District-Hospital VCT between April and October 2009 were recruited if they had at least one positive rapid HIV-serology test. Patients were screened for recent HIV-1 infection by BED-CEIA HIV-incidence test. Clinical examination, assessment of HIV-RNA and CD4 cell counts were performed at enrollment, 4 and 10 months. RESULTS: Of the 492 participants included in this study, the prevalence of recent infections as defined by BED-CEIA test, CD4 counts >200 cells/µl and HIV-RNA >400 copies/mL, was 11.58% (57/492; 95% CI 8.89-14.74). Due to heterogeneity in HIV-RNA levels in recently infected patients, individuals were categorized as having "high" HIV-RNA load if their HIV-RNA level was above the median (4.98 log(10) copies/mL) at diagnosis. The "high" HIV-RNA group sustained a significantly higher HIV-viral load at all visits with a median HIV-RNA setpoint of 5.22 log(10) copies/mL (IQR 5.18-5.47) as compared to the median of 4.15 log(10) copies/ml (IQR 3.37-4.43) for the other patients (p = 0.0001). CONCLUSION: The low proportion of recent HIV-infections among HIV-seropositive VCT clients suggests that most of this population attends the VCT at later stages of HIV/AIDS. Characterization of HIV-RNA-setpoint may serve to identify recently infected individuals maintaining HIV viral load>5 log10 copies/mL as candidates for antiretroviral treatment as prevention interventions.

Impact of CCR5delta32 host genetic background and disease progression on HIV-1 intrahost evolutionary processes: efficient hypothesis testing through hierarchical phylogenetic models.

The interplay between C-C chemokine receptor type 5 (CCR5) host genetic background, disease progression, and intrahost HIV-1 evolutionary dynamics remains unclear because differences in viral evolution between hosts limit the ability to draw conclusions across hosts stratified into clinically relevant populations. Similar inference problems are proliferating across many measurably evolving pathogens for which intrahost sequence samples are readily available. To this end, we propose novel hierarchical phylogenetic models (HPMs) that incorporate fixed effects to test for differences in dynamics across host populations in a formal statistical framework employing stochastic search variable selection and model averaging. To clarify the role of CCR5 host genetic background and disease progression on viral evolutionary patterns, we obtain gp120 envelope sequences from clonal HIV-1 variants isolated at multiple time points in the course of infection from populations of HIV-1-infected individuals who only harbored CCR5-using HIV-1 variants at all time points. Presence or absence of a CCR5 wt/Δ32 genotype and progressive or long-term nonprogressive course of infection stratify the clinical populations in a two-way design. As compared with the standard approach of analyzing sequences from each patient independently, the HPM provides more efficient estimation of evolutionary parameters such as nucleotide substitution rates and d(N)/d(S) rate ratios, as shown by significant shrinkage of the estimator variance. The fixed effects also correct for nonindependence of data between populations and results in even further shrinkage of individual patient estimates. Model selection suggests an association between nucleotide substitution rate and disease progression, but a role for CCR5 genotype remains elusive. Given the absence of clear d(N)/d(S) differences between patient groups, delayed onset of AIDS symptoms appears to be solely associated with lower viral replication rates rather than with differences in selection on amino acid fixation.

High prevalence of symptomatic acute HIV infection in an outpatient ward in southern Mozambique: identification and follow-up

To determine the prevalence of acute HIV infection (AHI) within the HIV-seronegative adult population presenting with reported fever in a district hospital in southern Mozambique and evaluate clinical, immunological and virological parameters of AHI. Design: This is a prospective observational study. Methods: Three hundred and forty-six adults presenting with reported fever at an outpatient ward at the Manhiça District Hospital in Mozambique were screened for AHI by HIV rapid serology testing, followed by HIV-RNA testing in HIV-seronegative individuals. Plasma from HIV-seronegative patients was pooled in the ratio of 1: 5 for HIV-RNA testing. Whole blood was used for Plasmodium falciparum rapid test determination at screening visit. Follow-up visits at day 7, 4 and 10 months included clinical examination, HIV serotesting and assessment of HIV-RNA, CD4 cell counts and percentage of activated CD8 T cells. Results: HIV serotesting revealed that 37.8% (95% confidence interval 32.7­43.2) of the adults had previously undiagnosed established HIV infection. Among the HIV-seronegative patients, 3.3% (95% confidence interval 1.3­6.7) were found to have AHI as demonstrated by positive HIV-1 RNA testing. Median HIV-1 RNA levels at diagnosis of AHI were 6.21 log10 copies/ml (interquartile range 5.92­6.41) and significantly higher than median HIV-RNA load at 4 months. At day 7 after screening, patients showed a median CD4 cell count of 384 cells/µl (interquartile range 239­441) and a median percentage of activated CD8 T cells of 68.4% (interquartile range 59.6­87.8). Conclusion: Of patients reporting with fever, 3.3% were shown to be potentially due to AHI. High prevalence of AHI in southern African populations may warrant investigation of tools and target populations for AHI screening as a novel way to address HIV prevention.

High prevalence of symptomatic acute HIV infection in an outpatient ward in southern Mozambique: identification and follow-up.

OBJECTIVES: To determine the prevalence of acute HIV infection (AHI) within the HIV-seronegative adult population presenting with reported fever in a district hospital in southern Mozambique and evaluate clinical, immunological and virological parameters of AHI. DESIGN: This is a prospective observational study. METHODS: Three hundred and forty-six adults presenting with reported fever at an outpatient ward at the Manhiça District Hospital in Mozambique were screened for AHI by HIV rapid serology testing, followed by HIV-RNA testing in HIV-seronegative individuals. Plasma from HIV-seronegative patients was pooled in the ratio of 1: 5 for HIV-RNA testing. Whole blood was used for Plasmodium falciparum rapid test determination at screening visit. Follow-up visits at day 7, 4 and 10 months included clinical examination, HIV serotesting and assessment of HIV-RNA, CD4 cell counts and percentage of activated CD8 T cells. RESULTS: HIV serotesting revealed that 37.8% (95% confidence interval 32.7-43.2) of the adults had previously undiagnosed established HIV infection. Among the HIV-seronegative patients, 3.3% (95% confidence interval 1.3-6.7) were found to have AHI as demonstrated by positive HIV-1 RNA testing. Median HIV-1 RNA levels at diagnosis of AHI were 6.21 log10 copies/ml (interquartile range 5.92-6.41) and significantly higher than median HIV-RNA load at 4 months. At day 7 after screening, patients showed a median CD4 cell count of 384 cells/microl (interquartile range 239-441) and a median percentage of activated CD8 T cells of 68.4% (interquartile range 59.6-87.8). CONCLUSION: Of patients reporting with fever, 3.3% were shown to be potentially due to AHI. High prevalence of AHI in southern African populations may warrant investigation of tools and target populations for AHI screening as a novel way to address HIV prevention.

Impact of elevated maternal HIV viral load at delivery on T-cell populations in HIV exposed uninfected infants in Mozambique

: HIV-uninfected infants born to HIV-infected mothers (HIV-exposed uninfected, HEU) have been described to have immune alterations as compared to unexposed infants. This study sought to characterize T-cell populations after birth in HEU infants and unexposed infants living in a semirural area in southern Mozambique. Methods: Between August 2008 and June 2009 mother-infant pairs were enrolled at the Manhiça District Hospital at delivery into a prospective observational analysis of immunological and health outcomes in HEU infants. Infants were invited to return at one month of age for a clinical examination, HIV DNA-PCR, and immunophenotypic analyses. The primary analysis sought to assess immunological differences between HEU and unexposed groups, whereas the secondary analysis assessed the impact of maternal HIV RNA viral load in the HEU group. Infants who had a positive HIV DNA-PCR test were not included in the analysis. Results: At one month of age, the 74 HEU and the 56 unexposed infants had similar median levels of naïve, memory and activated CD8 and CD4 T-cells. Infant naïve and activated CD8 T-cells were found to be associated with maternal HIV-RNA load at delivery. HEU infants born to women with HIV-RNA loads above 5 log10 copies/mL had lower median levels of naïve CD8 T-cells (p = 0.04), and higher median levels of memory CD8 T-cells, (p = 0.014). Conclusions: This study suggests that exposure to elevated maternal HIV-RNA puts the infant at higher risk of having early T-cell abnormalities. Improving prophylaxis of mother to child HIV programs such that more women have undetectable viral load is crucial to decrease vertical transmission of HIV, but may also be important to reduce the consequences of HIV virus exposure in HEU infants.