Luminita Ene

Use of combination neonatal prophylaxis for the prevention of mother-to-child transmission of HIV infection in European high-risk infants

Objectives:To evaluate use of combination neonatal prophylaxis (CNP) in infants at high risk for mother-to-child transmission (MTCT) of HIV in Europe and investigate whether CNP is more effective in preventing MTCT than single drug neonatal prophylaxis (SNP). Design:Individual patient-data meta-analysis across eight observational studies. Methods:Factors associated with CNP receipt and with MTCT were explored by logistic regression using data from nonbreastfed infants, born between 1996 and 2010 and at high risk for MTCT. Results:In 5285 mother–infant pairs, 1463 (27.7%) had no antenatal or intrapartum antiretroviral prophylaxis, 915 (17.3%) had only intrapartum prophylaxis and 2907 (55.0%) mothers had detectable delivery viral load despite receiving antenatal antiretroviral therapy. Any neonatal prophylaxis was administered to 4623 (87.5%) infants altogether; 1105 (23.9%) received CNP. Factors significantly associated with the receipt of CNP were later calendar birth year, no elective caesarean section, maternal CD4 cell count less than 200 cells/&mgr;l, maternal delivery viral load more than 1000 copies/ml, no antenatal antiretroviral therapy, receipt of intrapartum single-dose nevirapine and cohort. After adjustment, absence of neonatal prophylaxis was associated with higher risk of MTCT compared to neonatal prophylaxis [adjusted odds ratio (aOR) 2.29; 95% confidence interval (95% CI) 1.46–2.59; P < 0.0001]. Further, there was no association between CNP and MTCT compared to SNP (aOR 1.41; 95% CI 0.97–2.5; P = 0.07). Conclusion:In this European population, CNP use is increasing and associated with presence of MTCT risk factors. The finding of no observed difference in MTCT risk between one drug and CNP may reflect residual confounding or the fact that CNP may be effective only in a subgroup of infants rather than the whole population of high-risk infants.

Transmitted HIV drug resistance in treatment-naive Romanian patients.

Transmitted HIV drug resistance (TDR) remains an important concern for individuals unexposed to antiretroviral treatment. Data on the prevalence of TDR, available mainly for HIV‐1 subtype B, are now also emerging for other subtypes. In Romania, a steady predominance of subtype F was reported among both long‐term survivor children and newly infected adults. The pol gene of 61 drug‐naïve patients infected with HIV, diagnosed between 1997 and 2011 was sequenced in order to analyze the prevalence of primary resistance mutations and to correlate these with the infecting genotype. Only 5/61 specimens were classified as infected recently using the BED‐Capture Enzyme Immunoassay. Subtype F1 was prevalent (80.3%), however, other HIV‐1 clades are increasingly identified, especially in the group of subjects infected recently. An HIV transmission cluster, associated to injecting drug use was identified by phylogenetic analysis. The overall prevalence of TDR was 14.75%, mainly associated with NRTI resistance (13.11%), TAMs and M184V being the most common mutations. A declining trend of TDR was recorded from 26.08% in 1997–2004 to 7.89% in 2005–2011. No primary resistance was identified among recent seroconvertors. All HIV‐1 strains had minor mutations in the protease and RT genes, often detected at polymorphic positions. The declining rates of TDR might be related to the high efficacy of HAART and to the increasing number of treated patients with virological success who have a low risk of transmission. The recent increase of HIV‐1 infections which involve other subtypes impose a continuous surveillance of the genetic composition of the epidemic. J. Med. Virol. 85:1139–1147, 2013.

Early vs deferred highly active antiretroviral therapy in HIV infected infants: a European Collaborative Cohort Study

Without antiretroviral therapy (ART), approximately 20% of HIV-1 vertically infected infants develop severe disease manifestations before the age of 1 year [1] and surrogate markers poorly predict infants at higher risk of rapid disease progression. Several small prospective and retrospective studies in developed countries have suggested that ART initiated early in life could prevent this rapid clinical and immunologic deterioration [2-6].

miR-29a associates with viro-immunological markers of HIV infection in treatment experienced patients.

MicroRNAs (miRNAs) are small, non‐coding RNA species essential for the post‐translational regulation of gene expression. Several miRNA have been proposed to contribute to Human immunodeficiency virus‐1 (HIV‐1) infection establishment, progression and latency. Among them, miR‐29a seems to be of particular interest. The aim of this study was to investigate the association between miR‐29a expression and immunologic and virologic markers of HIV infection progression in long‐term antiretroviral‐treated individuals. In a homogenous group of 165 young adults, with chronic HIV infection, parenterally acquired during childhood, the expression level of miR‐29a was found to be inversely correlated with HIV viral load and the degree of immunosuppression, expressed by both CD4 cell count and the CD4/CD8 ratio. There was a significant difference in miR‐29a expression according to the patients response to treatment, with the lowest levels expressed by patients with treatment failure, defined as detectable viremia and CD4 < 350 cells/mm3. No significant correlation was found between miRNA level and the nadir CD4 count or zenith HIV viral load. This study establishes the association between miR‐29a expression and markers of HIV infection in long‐term survivors, treatment‐experienced patients, suggesting its potential use as an indicator for the on‐treatment disease evolution. J. Med. Virol. 88:2132–2137, 2016.

Immunoassay and molecular methods to investigate DNA methylation changes in peripheral blood mononuclear cells in HIV infected patients on cART

ABSTRACT This study aimed to investigate the influence of antiretroviral therapy on methylation markers, in a group of HIV infected, heavily treated patients. Immune and molecular methods were used to investigate potential changes in methylation profile in DNA isolated from peripheral blood mononuclear cells collected from antiretroviral-experienced HIV infected patients and healthy controls. The percentage of 5-methylcytosine was inversely correlated with proviral DNA and active replication while DNMT1 (p = 0.01) and DNMT3A (p = 0.004) independently correlated with active viral replication. DNMT3A expression increased with total treatment duration (p = 0.03), number of antiretroviral drugs ever used (p = 0.003), and cumulative exposure to protease inhibitors (p = 0.02) even in currently HIV undetectable patients.

Cervical HPV infection in Romanian women infected with HIV during early childhood.

Human papillomavirus (HPV) is the most common cause of cervical cancer worldwide, and Romania has the highest rate of cervical cancer in Europe. Sixty-five young Romanian women infected with HIV during early childhood and 25 control subjects were evaluated for the presence of cervical HPV infection and for cytologic abnormalities. HPV infection was evaluated longitudinally in 42 HIV-infected individuals. Overall 28/65 (43.1%) of HIV-infected and 8/25 (32.0%) of uninfected subjects were infected with HPV, and 21/65 (32.3%) and 6/25 (24%) had high-risk subtypes, respectively. In HIV-infected women, those maintaining or acquiring a new subtype in follow-up were more likely to have a lower nadir (p = 0.04) and current (p = 0.01) CD4 cell counts. The incidence rate for HPV acquisition events was 0.69 per subject per year, and 0.52 for high-risk subtypes. In the HIV-infected group, 9/13 (69.2%) individuals with abnormal cytology progressed at follow-up. Although HPV prevalence was similar to controls, the rate of Pap smear abnormalities was much higher, possibly due to the decreased ability to mount new immune responses. Given the high rate of incident detection of vaccine preventable strains and cytologic progression in this cohort, HPV vaccination may be beneficial at any age in co-infected women.

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis

Background Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in “real-life” settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. Methods and findings Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5–5.2) years for the total cohort and 6.4 (3.6–8.0) years in Europe, 3.7 (2.0–5.4) years in North America, 2.5 (1.2–4.4) years in South and Southeast Asia, 5.0 (2.7–7.5) years in South America and the Caribbean, and 2.1 (0.9–3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3–2.1) years in North America to 7.1 (5.3–8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4–2.6) years in North America to 7.9 (6.0–9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%–2.8%), 15.6% (15.1%–16.0%), and 11.3% (10.9%–11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%–1.1%]) and highest in South America and the Caribbean (4.4% [3.1%–6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%–6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%–13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. Conclusion To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.

Sex based differences in neurocognitive functioning in HIV infected young adults

Introduction: Sex differences in cognition of HIV positive (HIV+) patients are controversial. We aimed to investigate the relationship between cognition, HIV status, and sex, in a highly homogenous cohort of young Romanians parenterally infected during early childhood. Methods: In total, 250 HIV+ participants were compared with age-matched HIV negative (HIV−) controls (n = 72) in a cross-sectional study. After standardized neurocognitive, psychological testing and medical evaluation, linear regression was used to assess the effect of sex and HIV on neurocognitive outcomes. Results: Study participants were on average 23 years old with balanced sex distribution (% women = 52% vs. 43%). HIV− were more educated (12.7 vs. 11.6 years, P = 0.002). HIV+ status was associated with a lower global performance (&bgr; = −0.22, P < 0.001), after controlling for age and education. HIV+ women had better previous and current HIV-associated markers. The effect of HIV on global cognition did not differ between sexes in most cognitive domains (&bgr; = 0.07, P = 0.14). An interaction between sex, HIV status, and cognitive functioning was found in the psychomotor domain. HIV+ women had worse motor skills than HIV− women (&bgr; = −0.32, P < 0.001) suggesting a specific effect of HIV on motor functioning in women only. Moreover, current CD4+ less than 200 cells/&mgr;l (P = 0.013) and longer time lived with CD4+ less than 200 cells/&mgr;l (P = 0.023) were negatively correlated with the motor scaled score in women (&bgr; = −0.22, P = 0.034). Conclusion: Despite less advanced disease in women, long-term HIV infection has an equally detrimental effect on cognitive performances of both sexes, in all cognitive domains, except the psychomotor domain where women are preferentially affected.

Safety of darunavir and atazanavir in HIV-infected children in Europe and Thailand

BACKGROUND Surveillance for mid- and long-term antiretroviral therapy (ART) toxicity in children is important for informing treatment guidelines. We assessed the safety of darunavir (DRV) and atazanavir (ATV), commonly used as second-line protease inhibitors following lopinavir/ritonavir, in Europe and Thailand. METHODS Cohorts contributed individual patient data on adverse events (AE) in those aged <18 years taking DRV and ATV, respectively, to 02/2014. Rates of Division of AIDS (DAIDS) grade ≥3 laboratory AEs were calculated. RESULTS Of 431 patients on DRV and 372 on ATV, 317 (74%) and 301 (81%), respectively, had weight and dose data available, of whom 56 (18%) and 33 (9%) took the drugs at a non-approved age or dose. Median age at DRV and ATV start was 14.8 years (IQR 12.8-16.1) and 13.5 years (11.4-15.2); 43% and 26% had received ≥8 ART drugs previously. Overall rates of grade ≥3 AEs for absolute neutrophils, total cholesterol, triglycerides, pancreatic amylase, lipase and alanine aminotransferase (ALT) were ≤3/100 person-years (PY) on approved doses of both drugs, but 66/100 PY (95% CI 52, 84) for bilirubin after <12 months on ATV declining to 32/100 PY (95% CI 23, 44) after >24 months. Five serious drug-related clinical AEs were reported in four patients on ATV (one discontinued) and three in three patients on DRV (all discontinued), and did not substantially differ in those on approved compared to non-approved doses. Proportions on the drugs at last follow-up were 89% (383/431) for DRV and 81% (301/372) for ATV (including 73/92 with grade ≥3 hyperbilirubinaemia). CONCLUSIONS AEs were few in number and comparable for the two drugs, with the exception of high rates of hyperbilirubinaemia for ATV; few patients discontinued due to toxicity.

Post-licensing safety of fosamprenavir in HIV-infected children in Europe.

Fosamprenavir, combined with low‐dose ritonavir (FPV/r), is indicated for treatment of HIV‐infected children aged ≥6 years in Europe. Our purpose was to assess the safety of licensed use of FPV/r in HIV‐infected children reported to six cohorts in the European Pregnancy and Paediatric HIV Cohort Collaboration.