Cell-free (RNA) and cell-associated (DNA) HIV-1 and postnatal transmission through breastfeeding

<p>Introduction - Transmission through breastfeeding remains important for mother-to-child transmission (MTCT) in resource-limited settings. We quantify the relationship between cell-free (RNA) and cell-associated (DNA) shedding of HIV-1 virus in breastmilk and the risk of postnatal HIV-1 transmission in the first 6 months postpartum.</p> <p>Materials and Methods - Thirty-six HIV-positive mothers who transmitted HIV-1 by breastfeeding were matched to 36 non-transmitting HIV-1 infected mothers in a case-control study nested in a cohort of HIV-infected women. RNA and DNA were quantified in the same breastmilk sample taken at 6 weeks and 6 months. Cox regression analysis assessed the association between cell-free and cell-associated virus levels and risk of postnatal HIV-1 transmission.</p> <p>Results - There were higher median levels of cell-free than cell-associated HIV-1 virus (per ml) in breastmilk at 6 weeks and 6 months. Multivariably, adjusting for antenatal CD4 count and maternal plasma viral load, at 6 weeks, each 10-fold increase in cell-free or cell-associated levels (per ml) was significantly associated with HIV-1 transmission but stronger for cell-associated than cell-free levels [2.47 (95% CI 1.33–4.59) vs. aHR 1.52 (95% CI, 1.17–1.96), respectively]. At 6 months, cell-free and cell-associated levels (per ml) in breastmilk remained significantly associated with HIV-1 transmission but was stronger for cell-free than cell-associated levels [aHR 2.53 (95% CI 1.64–3.92) vs. 1.73 (95% CI 0.94–3.19), respectively].</p> <p>Conclusions - The findings suggest that cell-associated virus level (per ml) is more important for early postpartum HIV-1 transmission (at 6 weeks) than cell-free virus. As cell-associated virus levels have been consistently detected in breastmilk despite antiretroviral therapy, this highlights a potential challenge for resource-limited settings to achieve the UNAIDS goal for 2015 of eliminating vertical transmission. More studies would further knowledge on mechanisms of HIV-1 transmission and help develop more effective drugs during lactation.</p&gt

Characteristics and management of HIV-1-infected pregnant women enrolled in a randomised trial: differences between Europe and the USA

<p>Abstract</p> <p>Background</p> <p>Rates of mother-to-child transmission of HIV-1 (MTCT) have historically been lower in European than in American cohort studies, possibly due to differences in population characteristics. The Pediatric AIDS Clinical Trials Group Protocol (PACTG) 316 trial evaluated the effectiveness of the addition of intrapartum/neonatal nevirapine in reducing MTCT in women already receiving antiretroviral prophylaxis. Participation of large numbers of pregnant HIV-infected women from the US and Western Europe enrolling in the same clinical trial provided the opportunity to identify and explore differences in their characteristics and in the use of non-study interventions to reduce MTCT.</p> <p>Methods</p> <p>In this secondary analysis, 1350 women were categorized according to enrollment in centres in the USA (n = 978) or in Europe (n = 372). Factors associated with receipt of highly active antiretroviral therapy and with elective caesarean delivery were identified with logistic regression.</p> <p>Results</p> <p>In Europe, women enrolled were more likely to be white and those of black race were mainly born in Sub-Saharan Africa. Women in the US were younger and more likely to have previous pregnancies and miscarriages and a history of sexually transmitted infections.</p> <p>More than 90% of women did not report symptoms of their HIV infection; however, more women from the US had symptoms (8%), compared to women from Europe (4%). Women in the US were less likely to have HIV RNA levels <400 copies/ml at delivery than women enrolling in Europe, and more likely to receive highly active antiretroviral therapy, and to start therapy earlier in pregnancy. The elective caesarean delivery rate in Europe was 61%, significantly higher than that in the US (22%). Overall, 1.48% of infants were infected and there was no significant difference in the rate of transmission between Europe and the US despite the different approaches to treatment and delivery.</p> <p>Conclusion</p> <p>These findings confirm that there are important historical differences between the HIV-infected pregnant populations in Western Europe and the USA, both in terms of the characteristics of the women and their obstetric and therapeutic management. Although highly active antiretroviral therapy predominates in pregnancy in both settings now, population differences are likely to remain.</p> <p>Trial registration</p> <p>NCT00000869</p

Progress in prevention of mother-to-child transmission of HIV infection in Ukraine: results from a birth cohort study

<p>Abstract</p> <p>Background</p> <p>Ukraine was the epicentre of the HIV epidemic in Eastern Europe, which has the most rapidly accelerating HIV epidemic world-wide today; national HIV prevalence is currently estimated at 1.6%. Our objective was to evaluate the uptake and effectiveness of interventions for prevention of mother-to-child transmission (PMTCT) over an eight year period within operational settings in Ukraine, within the context of an ongoing birth cohort study.</p> <p>Methods</p> <p>The European Collaborative Study (ECS) is an ongoing birth cohort study in which HIV-infected pregnant women identified before or during pregnancy or at delivery were enrolled and their infants prospectively followed. Three centres in Ukraine started enrolling in 2000, with a further three joining in September 2006.</p> <p>Results</p> <p>Of the 3356 women enrolled, 21% (689) reported current or past injecting drug use (IDU). Most women were diagnosed antenatally and of those, the proportion diagnosed in the first/second trimester increased from 47% in 2000/01 (83/178) to 73% (776/1060) in 2006/07 (p < 0.001); intrapartum diagnosis was associated with IDU (Adjusted odds ratio 4.38; 95%CI 3.19–6.02). The percentage of women not receiving any antiretroviral prophylaxis declined from 18% (36/205) in 2001 to 7% in 2007 (61/843) (p < 0.001). Use of sdNVP alone substantially declined after 2003, with a concomitant increase in zidovudine prophylaxis. Median antenatal zidovudine prophylaxis duration increased from 24 to 72 days between 2000 and 2007. Elective caesarean section (CS) rates were relatively stable over time and 34% overall. Mother-to-child transmission (MTCT) rates decreased from 15.2% in 2001 (95%CI 10.2–21.4) to 7.0% in 2006 (95%CI 2.6–14.6). In adjusted analysis, MTCT risk was reduced by 43% with elective CS versus vaginal delivery and by 75% with zidovudine versus no prophylaxis.</p> <p>Conclusion</p> <p>There have been substantial improvements in use of PMTCT interventions in Ukraine, including earlier diagnosis of HIV-infected pregnant women and increasing coverage with antiretroviral prophylaxis and the initial MTCT rate has more than halved. Future research should focus on hard-to-reach populations such as IDU and on missed opportunities for further reducing the MTCT rate.</p

High prevalence of herpes simplex virus (HSV)- type 2 co-infection among HIV-positive women in Ukraine, but no increased HIV mother-to-child transmission risk.

BACKGROUND Over 3500 HIV-positive women give birth annually in Ukraine, a setting with high prevalence of sexually transmitted infections. Herpes simplex virus Type 2 (HSV-2) co-infection may increase HIV mother-to-child transmission (MTCT) risk. We explored factors associated with HSV-2 seropositivity among HIV-positive women in Ukraine, and its impact on HIV MTCT. METHODS Data on 1513 HIV-positive women enrolled in the Ukraine European Collaborative Study from 2007 to 2012 were analysed. Poisson and logistic regression models respectively were fit to investigate factors associated with HSV-2 seropositivity and HIV MTCT. RESULTS Median maternal age was 27 years (IQR 24-31), 53% (796/1513) had been diagnosed with HIV during their most recent pregnancy and 20% had a history of injecting drugs. Median antenatal CD4 count was 430 cells/mm(3) (IQR 290-580). Ninety-six percent had received antiretroviral therapy antenatally. HSV-2 seroprevalence was 68% (1026/1513). In adjusted analyses, factors associated with HSV-2 antibodies were history of pregnancy termination (APR 1.30 (95% CI 1.18-1.43) for ≥ 2 vs. 0), having an HIV-positive partner (APR 1.15 (95% CI 1.05-1.26) vs partner's HIV status unknown) and HCV seropositivity (APR 1.23 (95 % CI 1.13-1.35)). The overall HIV MTCT rate was 2.80% (95% CI 1.98-3.84); no increased HIV MTCT risk was detected among HSV-2 seropositive women after adjusting for known risk factors (AOR 1.43 (95% CI 0.54-3.77). CONCLUSION No increased risk of HIV MTCT was detected among the 68% of HIV-positive women with antibodies to HSV-2, in this population with an overall HIV MTCT rate of 2.8%. Markers of ongoing sexual risk among HIV-positive HSV-2 seronegative women indicate the importance of interventions to prevent primary HSV-2 infection during pregnancy in this high-risk group

Treatment and disease progression in a birth cohort of vertically HIV-1 infected children in Ukraine

Background: Ukraine has the highest HIV prevalence (1.6%) and is facing the fastest growing epidemic in Europe. Our objective was to describe the clinical, immunological and virological characteristics, treatment and response in vertically HIV-infected children living in Ukraine and followed from birth.Methods: The European Collaborative Study (ECS) is an ongoing cohort study, in which HIV-1 infected pregnant women are enrolled and followed in pregnancy, and their children prospectively followed from birth. ECS enrolment in Ukraine started in 2000 initially with three sites, increasing to seven sites by 2009.Results: A total of 245 infected children were included in the cohort by April 2009, with a median age of 23 months at most recent follow-up; 33% (n = 77) had injecting drug using mothers and 85% (n = 209) were infected despite some use of antiretroviral prophylaxis for prevention of mother-to-child transmission. Fifty-five (22%) children had developed AIDS, at a median age of 10 months (IQR = 6-19). The most prevalent AIDS indicator disease was Pneumocystis jiroveci pneumonia (PCP). Twenty-seven (11%) children had died (median age, 6.2 months). Overall, 108 (44%) children had started highly active antiretroviral treatment (HAART), at a median 18 months of age; median HAART duration was 6.6 months to date. No child discontinued HAART and 92% (100/108) remained on their first-line HAART regimen to date. Among children with moderate/severe immunosuppression, 36% had not yet started HAART. Among children on HAART, 71% (69/97) had no evidence of immunosuppression at their most recent visit; the median reduction in HIV RNA was 4.69 log10 copies/mL over a median of 10 months treatment. From survival analysis, an estimated 94%, 84% and 81% of children will be alive and AIDS-free at 6, 12 and 18 months of age, respectively. However, survival increased significantly over time: estimated survival rates to 12 months of age were 87% for children born in 2000/03 versus 96% for those born in 2004/08.Conclusion: One in five children had AIDS and one in ten had died. The half of children who received HAART has responded well and survival has significantly improved over time. Earlier diagnosis and prompt initiation of HAART remain key challenges

Mother-to-child transmission of human immunodeficiency virus in aten years period

<p>Abstract</p> <p>Objectives</p> <p>to evaluate mother-to-child transmission (MTCT) rates and related factors in HIV-infected pregnant women from a tertiary hospital between 2000 and 2009.</p> <p>Subjects and method</p> <p>cohort of 452 HIV-infected pregnant women and their newborns. Data was collected from recorded files and undiagnosed children were enrolled for investigation. Statistical analysis: qui-square test, Fisher exact test, Student <it>t </it>test, Mann-Whitney test, ANOVA, risk ratio and confidence intervals.</p> <p>Results</p> <p>MTCT occurred in 3.74%. The study population displayed a mean age of 27 years; 86.5% were found to have acquired HIV through sexual contact; 55% were aware of the diagnosis prior to the pregnancy; 62% were not using HAART. Mean CD4 cell-count was 474 cells/ml and 70.3% had undetectable viral loads in the third trimester. HAART included nevirapine in 35% of cases and protease inhibitors in 55%; Zidovudine monotherapy was used in 7.3%. Mean gestational age at delivery was 37.2 weeks and in 92% by caesarian section; 97.2% received intravenous zidovudine. Use of AZT to newborn occurred in 100% of them. Factors identified as associated to MTCT were: low CD4 cell counts, elevated viral loads, maternal AIDS, shorter periods receiving HAART, other conditions (anemia, IUGR (intra uterine growth restriction), oligohydramnium), coinfecctions (CMV and toxoplasmosis) and the occurrence of labor. Use of HAART for longer periods, caesarian and oral zidovudine for the newborns were associated with a decreased risk. Poor adhesion to treatment was present in 13 of the 15 cases of transmission; in 7, coinfecctions were diagnosed (CMV and toxoplasmosis).</p> <p>Conclusion</p> <p>Use of HAART and caesarian delivery are protective factors for mother-to-child transmission of HIV. Maternal coinfecctions and other conditions were risk factors for MTCT.</p

Maternal characteristics during pregnancy and risk factors for positive HIV RNA at delivery: a single-cohort observational study (Brescia, Northern Italy)

<p>Abstract</p> <p>Background</p> <p>Detectable HIV RNA in mothers at delivery is an important risk factor for HIV transmission to newborns. Our hypothesis was that, in migrant women, the risk of detectable HIV RNA at delivery is greater owing to late HIV diagnosis. Therefore, we examined pregnant women by regional provenance and measured variables that could be associated with detectable HIV RNA at delivery.</p> <p>Methods</p> <p>A observational retrospective study was conducted from January 1999 to May 2008. Univariate and multivariable regression analyses (generalized linear models) were used, with detectable HIV RNA at delivery as dependent variable.</p> <p>Results</p> <p>The overall population comprised 154 women (46.8% migrants). Presentation was later in migrant women than Italians, as assessed by CD4-T-cell count at first contact (mean 417/mm³versus 545/mm³, respectively; p = 0.003). Likewise, HIV diagnosis was made before pregnancy and HAART was already prescribed at the time of pregnancy in more Italians (91% and 75%, respectively) than migrants (61% and 42.8%, respectively). A subgroup of women with available HIV RNA close to term (i.e., ≤30 days before labour) was studied for risk factors of detectable HIV RNA (≥50 copies/ml) at delivery. Among 93 women, 25 (26.9%) had detectable HIV RNA. A trend toward an association between non-Italian nationality and detectable HIV RNA at delivery was demonstrated by univariate analysis (relative risk, RR = 1.86; p = 0.099). However, by multivariable regression analysis, the following factors appeared to be more important: lack of stable (i.e., ≥14 days) antiretroviral therapy at the time of HIV RNA testing (RR = 4.3; p < 0.0001), and higher CD4+ T-cell count at pregnancy (per 50/mm³, RR = 0.94; p = 0.038).</p> <p>Conclusions</p> <p>These results reinforce the importance of extensive screening for HIV infection, earlier initiation of antiretroviral therapy and stricter monitoring of pregnant women to reduce the risk of detectable HIV RNA at delivery. Public health interventions should be particularly targeted to migrant women who are frequently unaware of their HIV status at the time of pregnancy.</p

The role of neutralizing antibodies in prevention of HIV-1 infection: what can we learn from the mother-to-child transmission context?

International audienceIn most viral infections, protection through existing vaccines is linked to the presence of vaccine-induced neutralizing antibodies (NAbs). However, more than 30 years after the identification of AIDS, the design of an immunogen able to induce antibodies that would neutralize the highly diverse HIV-1 variants remains one of the most puzzling challenges of the human microbiology. The role of antibodies in protection against HIV-1 can be studied in a natural situation that is the mother-to-child transmission (MTCT) context. Indeed, at least at the end of pregnancy, maternal antibodies of the IgG class are passively transferred to the fetus protecting the neonate from new infections during the first weeks or months of life. During the last few years, strong data, presented in this review, have suggested that some NAbs might confer protection toward neonatal HIV-1 infection. In cases of transmission, it has been shown that the viral population that is transmitted from the mother to the infant is usually homogeneous, genetically restricted and resistant to the maternal HIV-1-specific antibodies. Although the breath of neutralization was not associated with protection, it has not been excluded that NAbs toward specific HIV-1 strains might be associated with a lower rate of MTCT. A better identification of the antibody specificities that could mediate protection toward MTCT of HIV-1 would provide important insights into the antibody responses that would be useful for vaccine development. The most convincing data suggesting that NAbs migh confer protection against HIV-1 infection have been obtained by experiments of passive immunization of newborn macaques with the first generation of human monoclonal broadly neutralizing antibodies (HuMoNAbs). However, these studies, which included only a few selected subtype B challenge viruses, provide data limited to protection against a very restricted number of isolates and therefore have limitations in addressing the hypervariability of HIV-1. The recent identification of highly potent second-generation cross-clade HuMoNAbs provides a new opportunity to evaluate the efficacy of passive immunization to prevent MTCT of HIV-1

Serum S100B in primary progressive multiple sclerosis patients treated with interferon-beta-1a

S100B belongs to a family of calcium-binding proteins implicated in intracellular and extracellular regulatory activities. This study of serum S100B in primary progressive multiple sclerosis (PPMS) is based on data obtained from a randomized, controlled trial of Interferon β-1a in subjects with PPMS. The key questions were whether S100B levels were associated with either disability or MRI findings in primary progressive MS and whether Interferon β-1a has an effect on their S100B levels. Serial serum S100B levels were measured using an ELISA method. The results demonstrated that serum S100B is not related to either disease progression or MRI findings in subjects with primary progressive MS given Interferon β-1a. Furthermore there is no correlation between S100B levels and the primary and secondary outcome measures