Immune Activation and Microbial Translocation Markers in HIV-Exposed Uninfected Malawian Infants in the First Year of Life.

BACKGROUND: HIV-exposed uninfected (HEU) infants show a high rate of morbidity. We aimed to investigate on biomarkers of immune activation/microbial translocation in HEU infants, evaluating the impact that infections/malnutrition can have on biomarker levels during the first year of life. METHODS: Clinical data of 72 Malawian infants were recorded monthly and correlated with levels of soluble CD14 (sCD14), lipopolysaccharide-binding protein (LBP) and intestinal fatty acid-binding protein (I-FABP), analyzed longitudinally. RESULTS: Levels of sCD14 and LBP showed a significant age-related increase. Higher levels of LBP (19.4 vs. 15.2 µg/ml) were associated with stunting, affecting 30% of the infants. The association remained statistically significant after adjusting for cytomegalovirus acquisition, malaria and respiratory infections (p = 0.031). I-FABP levels were significantly increased in infants experiencing gastrointestinal infections (1442.8 vs. 860.0 pg/ml, p = 0.018). CONCLUSION: We provide evidence that stunting is associated with an enhanced inflammatory response to microbial products in HEU children, suggesting that malnutrition status should be taken into consideration to better understand the alteration of the immune profile of HEU infants living in poor socioeconomic settings.

A multivariate genetic analysis confirms rs5010528 in the human leucocyte antigen-C locus as a significant contributor to Stevens-Johnson syndrome/toxic epidermal necrolysis susceptibility in a Mozambique HIV population treated with nevirapine.

Objectives: Nevirapine is used in developing countries for the treatment of HIV infection, but its use is associated with rare serious adverse reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Recently, an association between rs5010528 in the human leucocyte antigen (HLA)-C locus and SJS/TEN susceptibility has been described in sub-Saharan populations. Our aim was to verify this association in a population of nevirapine-treated patients from Mozambique. Methods: The rs5010528 SNP was analysed by direct sequencing in 27 patients who had developed SJS/TEN and 75 patients who did not develop adverse reactions after nevirapine treatment. A case-control association study was conducted. A multivariate analysis was performed in order to evaluate the role of HLA-C also in relation to other susceptibility genetic factors (CYP2B6, TRAF3IP2, HCP5, PSORS1C1 and GSTM1 genes). Results: rs5010528 was significantly associated with a higher risk of developing SJS/TEN; the variant allele was more frequent in cases than in controls, conferring a high risk of developing this adverse reaction in carriers (OR = 5.72 and P = 0.0002 at genotype level, OR = 3.51 and P = 0.0002 at allelic level). The multivariate analysis showed that the HLA-C SNP, CYP2B6 (rs28399499), TRAF3IP2 (rs76228616) and GSTM1 (null genotype) can explain 25% of the susceptibility to this reaction, with the HLA-C SNP as the most significant contributor (P = 0.02 and OR = 5.64). Conclusions: Our study confirmed the association of the rs5010528 SNP in the HLA-C region with susceptibility to developing SJS/TEN in a population from Mozambique, suggesting that it could be a good genomic biomarker for SJS/TEN susceptibility in different sub-Saharan populations.

Antibody response to hepatitis B vaccine in HIV-exposed infants in Malawi and correlation with HBV infection acquisition.

The aim of this study was to assess the immune response to HBV vaccine in HIV-exposed infants and to correlate it to HBV infection acquisition. Protective anti-HBs levels (>10 mIU/mL) were found in 54/58 (93.2%) infants at 6 months, 126/144 (87.5%) at 12 months and 141/176 (80.1%) children at 24 months. HBV infection (seven children were HBsAg + at Month 24) occurred also in the presence of levels above 10 mIU/mL. Our findings indicate limited impact of HIV exposure on anti-HBV immune response, but suggest that levels >10 mIU/mL may be required to confer protection in this context.

Deficit of IgG2 in HIV-positive pregnant women is responsible of inadequate IgG2 levels in their HIV-uninfected children in Malawi.

BACKGROUND: Transplacental passage of IgGs is impaired in HIV + pregnant women, possibly determining an inadequate immunological protection in their children. We aimed to determine the impact of maternal immunological IgG profile and immunoactivation status on the efficiency of transplacental passage of IgG subclasses in HIV + mothers. METHODS: 16 mother/infants pairs were studied in Malawi. Mothers received antiretroviral therapy (ART) from the third trimester of pregnancy. Determinations of pre-ART levels of maternal sCD14, of IgG subclasses in mothers at delivery and in their 1-month-old infants, were performed using commercial ELISA kits. RESULTS: At delivery, after a median of 10 weeks of ART, 12/16 mothers were hypergammaglobulinemic, with IgG levels (20.5 mg/ml, 95% CI:18.8-26.8) directly correlated to the plasmatic levels of sCD14 (r = 0.640, p = 0.014). IgG1 levels (17.9 mg/ml) accounted for 82% of IgG, IgG3 and IgG4 levels were in the normal range. A profound deficit of IgG2 was observed both in mothers (0.60 mg/ml) and in infants (0.14 mg/ml). Placental transfer ratio (range 0.16-0.42) did not show a selective impairment between the different IgG subclasses. The transplacental passage of all IgG subclasses was decreased in the presence of maternal IgG over 16 mg/ml (significantly for IgG1, p = 0.031) and of high levels of sCD14 (p = 0.063). CONCLUSIONS: Transplacental passage was reduced for all IgG subclasses and inversely correlated to high levels of maternal IgGs and to the degree of immunoactivation. The profound depression of IgG2 in mothers suggests that IgG2 neonatal levels mostly reflect the maternal deficit rather than a selective impairment of IgG2 transfer.

Frailty as a predictor of mortality and hospital services use in older adults: a cluster analysis in a cohort study.

Background: Lowering mortality and hospitalization of older adults is one of the main goals of public health to improve both health systems' sustainability and older adults' quality of life. The aim of this study is to identify the determinants associated with mortality and the use of hospital services in the population older than 64 years of age. Methods: A randomized sample from the population of the Lazio region (Italy) above the age of 64 was enrolled in 2014 by the administration of a questionnaire to assess frailty; the rates of use of hospital services and mortality in the year following the enrolment have been retrieved by the regional database. Univariable and multivariable analyses addressed the association of health status, social and economic variables with health outcomes. Results: One thousand two hundred and eighty persons were recruited; 52 deaths were reported at 1 year of follow-up (robust 1.8%, frail 10.1% and very frail 19.1%, P < 0.001). The mean rate of use of hospital services was 692.2 per 1000 observation/year (robust 589.5, frail 1191.1 and very frail 848.4, P < 0.001). In the multivariate analysis, the higher rate of use of hospital services was independently associated with functional status, social support, psychological/psychiatric discomfort, availability of home care services and physical health. Conclusions: Frailty, as a multidimensional issue, is also a strong predictor of survival in the short term. The use of the hospital services by older adults is associated mainly with functional status, social resources, psycho-physical status and health service organization factors.

[The progressive patient care program as a model of field training of public health practitioners: the experience of the Roman Public Health Academy]. / L'ospedale ad Intensità di cura come modello di formazione condivisa sul campo: l'esperienza dell'Accademia Romana di Sanità Pubblica.

The management of healthcare facilities has become increasingly complex in recent years, leading to a greater demand for public health physicians in Italy. Public Health physicians are responsible for evaluating community needs, with particular attention to health determinants and, at the same time, to final user feedback. During their training, they must acquire the competencies to manage a wide range of problems. The Roman Public Health Academy (ARSP) was developed to motivate young residents in Public Health to acquire the knowhow, skills and abilities required of a public health practitioner. It therefore implemented a special training program offering different educational opportunities for residents. In particular, the program offers a team of three young residents field training opportunities, allowing them to become engaged in solving complex technical and management problems. In this paper we describe the methods through which, following a specific request by the director of a hospital in Rome, the team supported a project involving the reorganization of several hospital wards. The aim of the reorganization was to enhance the performance and efficiency of the wards, according to the Progressive Patients Care program.

Tuberculosis Case Finding With Combined Rapid Point-of-Care Assays (Xpert MTB/RIF and Determine TB LAM) in HIV-Positive Individuals Starting Antiretroviral Therapy in Mozambique.

BACKGROUND: Tuberculosis is a major health concern in several countries, and effective diagnostic algorithms for use in human immunodeficiency virus (HIV)-positive patients are urgently needed. METHODS: At prescription of antiretroviral therapy, all patients in 3 Mozambican health centers were screened for tuberculosis, with a combined approach: World Health Organization (WHO) 4-symptom screening (fever, cough, night sweats, and weight loss), a rapid test detecting mycobacterial lipoarabinomannan in urine (Determine TB LAM), and a molecular assay performed on a sputum sample (Xpert MTB/RIF; repeated if first result was negative). Patients with positive LAM or Xpert MTB/RIF results were referred for tuberculosis treatment. RESULTS: Among 972 patients with a complete diagnostic algorithm (58.5% female; median CD4 cell count, 278/µL; WHO HIV stage I, 66.8%), 98 (10.1%) tested positive with Xpert (90, 9.3%) or LAM (34, 3.5%) assays. Compared with a single-test Xpert strategy, dual Xpert tests improved case finding by 21.6%, LAM testing alone improved it by 13.5%, and dual Xpert tests plus LAM testing improved it by 32.4%. Rifampicin resistance in Xpert-positive patients was infrequent (2.5%). Among patients with positive results, 22 of 98 (22.4%) had no symptoms at WHO 4-symptom screening. Patients with tuberculosis diagnosed had significantly lower CD4 cell counts and hemoglobin levels, more advanced WHO stage, and higher HIV RNA levels. Fifteen (15.3%) did not start tuberculosis treatment, mostly owing to rapidly deteriorating clinical conditions or logistical constraints. The median interval between start of the diagnostic algorithm and start of tuberculosis treatment was 7 days. CONCLUSIONS: The prevalence of tuberculosis among Mozambican HIV-positive patients starting antiretroviral therapy was 10%, with limited rifampicin resistance. Use of combined point-of-care tests increased case finding, with a short time to treatment. Interventions are needed to remove logistical barriers and prevent presentation in very advanced HIV/tuberculosis disease.

CMV infection in a cohort of HIV-exposed infants born to mothers receiving antiretroviral therapy during pregnancy and breastfeeding.

Antiretroviral therapy has been shown to reduce rates of congenital CMV infection. Little information is available on the possible impact of antiretroviral therapy on postnatal breastfeeding-associated CMV infection acquisition. A cohort of 89 HIV-infected mothers and their children was studied. Women received antiretroviral therapy from week 25 of gestation until 6 months postpartum or indefinitely if meeting the criteria for treatment. All women were evaluated for CMV IgG presence and CMV DNA in breast milk. Children were tested for CMV infection by either the presence of IgM or the presence of CMV DNA in plasma at 1, 6 and 12 months and by the presence of IgG at 24 months. All mothers had high titers of CMV DNA in breast milk (5.7 log at Month 1 and 5.1 log at Month 6). Cumulative CMV infection rates were 60.3 % at Month 6, 69 % at Month 12 and 96.4 % at Month 24. There was a significant negative correlation between the duration of antiretroviral treatment during pregnancy and levels of CMV DNA in breast milk at Month 1 (P = 0.033). There was a trend for a correlation between high titers of CMV DNA in breast milk at 6 months and CMV infection at 6 months (P = 0.069). In this cohort, more than 95 % of the children had acquired CMV infection by 2 years of age. Besides breastfeeding, which played a major role, also horizontal transmission between 1 and 2 years was certainly relevant in determining CMV infection acquisition.

Accumulation of HIV-1 drug resistance in patients on a standard thymidine analogue-based first line antiretroviral therapy after virological failure: implications for the activity of next-line regimens from a longitudinal study in Mozambique.

BACKGROUND: We describe the accumulation of HIV-1 drug resistance and its effect on the activity of next-line components in patients with virological failure (HIV-1 RNA >1000 copies/mL) after 1 year (t1) of first-line antiretroviral therapy (ART) not switching to second-line drugs for one additional year (t2) in low-middle income countries (LMIC). METHODS AND RESULTS: We selected 48 patients from the DREAM cohort (Maputo, Mozambique); their median pre-ART CD4+ cell count was 165 cells/µl. At t1 patients were receiving ART since a median of 12.2 months (mainly zidovudine/lamivudine/nevirapine), their median HIV RNA was 3.8 log10 copies/mL, 43 (89.6%) presented at least one resistance-associated mutation (RAM), most frequently for lamivudine/emtricitabine, nevirapine and efavirenz. Resistance to tenofovir, was 10% at 1 year and higher than 20% at 2 years, while projection at 3 years was >30%. At t2, 42 (89.4%) had a predicted low-level or higher resistance to at least 1 s-line drug. At t1, the frequency of RAM in patients with a lower adherence to pharmacy appointments (<95%) was significantly lower (12/20, 60% for NRTI and 14/20, 70% for NNRTI) than in those with a better adherence (26/28, 92.8% for NRTI and 25/28, 89.3% for NNRTI) (OR 0.12, 95% CI 0.02-0.63, p = 0.012 and OR 0.28, 95% CI 0.06-1.29, p = 0.103, respectively). Overall thymidine analogue mutations (TAMs) accumulation rate was 0.32/year, 0.50/year in the subgroup with HIV RNA >10,000 copies/mL; NNRTI RAM accumulation rate was 0.15/year, 0.40/year in the subgroup with HIV RNA >10,000 copies/mL. CONCLUSIONS: While the activity of NNRTIs is compromised early during failure, tenofovir and zidovudine activity are reduced more frequently after 1 year of documented virological failure of thymidine analogue-based first-line ART, with RAMs accumulating faster in patients with higher viral loads. The present observation may help informing decisions on when to switch to a second line ART in patients on virological failure in LMIC.

Impact of glutathione transferases genes polymorphisms in nevirapine adverse reactions: a possible role for GSTM1 in SJS/TEN susceptibility.

PURPOSE: Nevirapine (NVP) is used in developing countries as first-line treatment of HIV infection. Unfortunately, its use is associated with common serious adverse drug reactions, such as liver toxicity and the most severe and rare Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). GSTT1 and GSTM1 genes code for enzymes involved in the metabolism of a wide range of drugs. We hypothesized that this gene variability could be implicated in NVP adverse reactions. METHODS: We analyzed the GSTM1 and GSTT1 null genotypes by multiplex PCR in a population of 181 patients from Mozambique, treated with NVP. A case/control association study was performed. We also counted the number of risk alleles in SJS/TEN patients and in controls, including the GSTM1 null genotype and four previously identified risk alleles in CYP2B6, HCP5, and TRAF3IP2 genes. RESULTS: Among patients, 27 had developed SJS/TEN and 76 had developed hepatotoxicity during the treatment. The GSTM1 null genotype was more frequent in the cases with SJS/TEN than in the controls (OR = 2.94, P = 0.027). This association is also observed when other risk factors are taken into account, by a multivariate analysis (P = 0.024 and OR = 3.58). The risk allele counting analysis revealed a significantly higher risk for SJS/TEN in patients carrying three or four risk alleles. Moreover, all subjects with five or six risk alleles developed SJS/TEN, while subjects without any risk alleles were present only in the control group. CONCLUSIONS: We observed an association between GSTM1 and SJS/TEN susceptibility. Moreover, GSTM1 contributes to the definition of a genetic risk profile for SJS/TEN susceptibility.

Concentrations of tenofovir, lamivudine and efavirenz in mothers and children enrolled under the Option B-Plus approach in Malawi.

OBJECTIVES: To evaluate antiretroviral drug concentrations in mothers and infants enrolled under the Option B-Plus approach for the prevention of HIV mother-to-child transmission in Malawi and to assess the maternal virological response after 1 year of treatment. PATIENTS AND METHODS: Forty-seven women and 25 children were studied. Mothers were administered during pregnancy a combination of tenofovir, lamivudine and efavirenz and continued it during breastfeeding (up to 2 years) and thereafter. Drug concentrations were evaluated in mothers (plasma and breast milk) at 1 and 12 months post-partum and in infants (plasma) at 6 and 12 months of age. Drug concentrations were determined using an LC-MS/MS validated methodology. RESULTS: In breast milk, tenofovir concentrations were very low (breast milk/maternal plasma ratio = 0.08), while lamivudine was concentrated (breast milk/plasma ratio = 3) and efavirenz levels were 80% of those found in plasma. In infants, median levels at 6 months were 24 ng/mL tenofovir, 2.5 ng/mL lamivudine and 86.4 ng/mL efavirenz. At month 12, median levels were below the limit of quantification for the three drugs. No correlation was found between drug concentrations and laboratory parameters or indices of growth. HIV-RNA >1000 copies/mL was seen at month 1 in 15% of the women and at month 12 in 8.5%. Resistance was found in half of the women with detectable viral load. CONCLUSIONS: Breastfeeding infants under Option B-Plus are exposed to low concentrations of antiretroviral drugs. With this strategy, mothers had a good virological response 1 year after delivery.

Levels of bone markers in a population of infants exposed in utero and during breastfeeding to tenofovir within an Option B+ programme in Malawi.

OBJECTIVES: No data are available on bone metabolism in infants exposed to tenofovir during breastfeeding. We investigated bone metabolism markers in the first year of life in infants from mothers who received tenofovir, lamivudine and efavirenz during pregnancy and 12 months of breastfeeding in a national Option B+ programme in Malawi. METHODS: Serum samples collected at 6 and 12 months in tenofovir-exposed infants and in a small sample of tenofovir-unexposed infants from the same clinical centre were analysed in batches for levels of bone-specific alkaline phosphatase (BAP; marker of bone formation) and of C-terminal telopeptide of type I collagen (CTX; marker of bone resorption). RESULTS: Overall, 136 tenofovir-exposed infants were evaluated. No infant had at either timepoint CTX values above the upper normal limit, while most of them had at 6 and 12 months levels of BAP above the upper normal limit for the age range. Levels of bone markers showed no differences by gender and no association with growth parameters. Tenofovir-unexposed and -exposed children had similar mean levels of bone markers at 6 months (CTX: 0.62 versus 0.55 ng/mL, P = 0.122; BAP: 384 versus 362 U/L, P = 0.631). CONCLUSIONS: No significant association between treatment with tenofovir and CTX or BAP levels was found. The high levels of BAP, coupled to the normal levels observed for CTX, might reflect primarily skeletal growth. Potential negative effects of prolonged exposure to tenofovir through breastfeeding cannot however be excluded and longitudinal studies that evaluate bone mineralization status in children enrolled in Option B+ programmes are warranted.

[What are the competencies that public health physician should have today? A proposal for a shared training program at three Hygiene and Preventive Medicine residency training schools in Rome (Italy)]. / Quali sono le competenze che al giorno d'oggi un professionista medico di sanità pubblica deve possedere? Risultati di un'analisi di formazione condivisa fra le Scuole di Specializzazione mediche in Igiene e Medicina Preventiva di Roma.

To acquire essential knowledge and skills for Public Health practice, residents in Hygiene and Preventive Medicine programs should be provided with excellent training. On behalf of the Roman Public Health Academy (ARSP), the authors, representing the three Hygiene and Preventive Medicine residency training programs in Rome (Italy) aimed to propose a training program to be shared by the above three schools. Firstly, they performed a scientific literature review to identify the core competencies that a public health specialist should have acquired at the end of training. Ten areas (macro-areas or domains) relevant to Public Health practice were defined. The authors then identified the main characteristics that the proposed training program should have, which include: enhancement of community healthcare services and optimization of local resources to create/strengthen exchange and cooperation networks; possibility to adapt the training proposal to an international setting; adoption of a training approach that can respond effectively to a changing health system; customization of training on the basis of residents' individual abilities and motivations, so that their individual strengths can be enhanced; achievement of educational excellence, in compliance with ethical requirements.

Drug resistance mutations 18 months after discontinuation of nevirapine-based ART for prevention of mother-to-child transmission of HIV in Malawi.

OBJECTIVES: The objective of this study was to determine the prevalence of drug resistance mutations among HIV-positive women in Malawi 18 months after discontinuing nevirapine-based ART for the prevention of mother-to-child transmission. PATIENTS AND METHODS: HIV-infected antiretroviral-naive (except for single-dose nevirapine) pregnant Malawian women receiving a nevirapine-based triple antiretroviral regimen from Week 25 of gestation until 6 months of breastfeeding were included in this analysis. Drug resistance was assessed in HIV-DNA 24 months post-partum and at baseline (before the initiation of treatment). In patients with resistance, the presence of mutations was also evaluated in the corresponding plasma samples. RESULTS: Seven out of 42 (16.7%) women studied had archived drug resistance at Month 24 [six cases had NNRTI-associated mutations and two cases the M184I mutation]. In four cases, resistance mutations were already present at baseline (all NNRTI mutations). In three cases, there was an emergence of 'new' resistance (also present in the plasma in one case). Of the 35 women without resistance mutations at Month 24, only one subject had resistance mutations at baseline. Baseline resistance was significantly more common among women with mutations at 24 months compared with those harbouring a WT virus (4/7 versus 1/35, P < 0.001). CONCLUSIONS: Among women who had discontinued drugs 6 months post-partum, only 3/42 (7.1%) had accumulated new resistance mutations in HIV-DNA 2 years after delivery. These findings are reassuring in terms of the safety of the Option B strategy for the prevention of HIV mother-to-child transmission.

Laboratory confirmation of clinically diagnosed malaria in a cohort of HIV-infected mothers and their children in Malawi.

To avoid overdiagnosis, accuracy in the identification of true malaria cases is of critical importance. Samples (either whole blood, dried blood spots or plasma/serum) collected at the time of clinically diagnosed malaria episodes in a cohort of Malawian HIV-infected mothers and their children were retrospectively tested with the enzyme-linked immunosorbent assay (ELISA) for HRP-2 (histidine-rich protein 2) detection. There were 55 and 56 clinically diagnosed cases of malaria in mothers and children, respectively, with samples available for testing. Rates of laboratory-confirmed episodes were 20% (11 of 55) in mothers and 16.1% (9 of 56) in children. Hemoglobin was lower in children with confirmed malaria compared to those with clinical malaria diagnosis. The results of our study support the widespread use of rapid diagnostic tests.

A pharmacogenetics study in Mozambican patients treated with nevirapine: full resequencing of TRAF3IP2 gene shows a novel association with SJS/TEN susceptibility.

Steven-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are severe adverse drug reactions, characterized by extensive epidermal detachment and erosions of mucous membrane. SJS/TEN is one of the most serious adverse reactions to Nevirapine (NVP) treatment, commonly used in developing countries as first-line treatment of human immunodeficiency virus infection. In the last years TRAF3IP2 gene variants had been described as associated with susceptibility to several diseases such as psoriasis and psoriatic arthritis. We hypothesized that this gene, involved in immune response and in NF-κB activation, could also be implicated in the SJS/TEN susceptibility. We performed a full resequencing of TRAF3IP2 gene in a population of patients treated with NVP. Twenty-seven patients with NVP-induced SJS/TEN and 78 controls, all from Mozambique, were enrolled. We identified eight exonic and three intronic already described variants. The case/control association analysis highlighted an association between the rs76228616 SNP in exon 2 and the SJS/TEN susceptibility. In particular, the variant allele (C) resulted significantly associated with a higher risk to develop SJS/TEN (p = 0.012 and OR = 3.65 (95% CI 1.33-10.01)). A multivariate analysis by logistic regression confirmed its significant contribution (p = 0.027, OR = 4.39 (95% CI 1.19-16.23)). In conclusion, our study suggests that a variant in TRAF3IP2 gene could be involved in susceptibility to SJS/TEN.

Malnutrition decreases the odds of attaining motor milestones in HIV exposed children: results from a paediatric DREAM cohort.

OBJECTIVE: HIV and malnutrition are the two major causes of infant mortality in Sub-Saharan Africa. The study describes the impact of malnutrition on motor milestone development in HIV-exposed children. DESIGN: Randomized community intervention trial (SMAC, Safe Milk for African Children). SETTING AND PARTICIPANTS: Growth, motor development, and malnutrition were assessed in a sample of 76 HIV-exposed children, aged 0-24 months, at the Blantyre Dream Centre in Malawi. MAIN OUTCOME MEASURES: We assessed growth and selected motor milestone achievement in agreement with WHO/UNICEF criteria. Odds ratios and 95%confidence intervals were calculated according to motor milestones and malnutrition indices. Multivariable logistic regression was performed with 18 months data. RESULTS: High rates of malnutrition were observed. Underweight increased by 6.7/9.2 and 3.2/5.5 the odds of not standing alone and not walking alone at 15 and 18 months. Stunting increased by 9.7 the odds of not standing alone at 11 months and by 6.1 the odds of not walking alone at 18 months. Wasting increased by 5.5/10.3 the odds for not walking with assistance at 12 and 18 months. Low weight for age was associated with delay in walking at 18 months (HR=2.9). CONCLUSION: Malnutrition in HIV-exposed children decreases the likelihood of adequate development.

Viro-immunological response and emergence of resistance in HIV-infected women receiving combination antiretroviral regimens for the prevention of mother-to-child transmission in Malawi.

OBJECTIVES: To identify factors associated with detectable viral load and the emergence of drug resistance in a cohort of HIV-infected pregnant women in Malawi receiving antiretroviral combination regimens for the prevention of mother-to-infant transmission. METHODS: The study included 260 treatment-naive women who had received a three-drug nevirapine-based regimen from week 25 of gestational age until 6 months after delivery. HIV RNA was determined at month 6 and drug resistance was assessed if viral load was >50 copies/mL. Attendance at the scheduled follow-up visits was used as an indirect measure of treatment adherence. RESULTS: The rate of detectable HIV RNA at 6 months was 9.6% (25/260). The only significant predictor of this occurrence was the presence of ≥1 missed visit during follow-up (P = 0.012). Resistance was assessed in 19 of these women: 7 (37%) had a wild-type virus and the other 12 (63%) had resistance-associated mutations (nucleoside reverse transcriptase inhibitor, 7/12; non-nucleoside reverse transcriptase inhibitor, 11/12). Three of 12 cases (25%) in which mutations were detected had a viral load <1000 copies/mL. The emergence of resistance was not correlated with the presence of baseline mutations in either plasma or archived DNA. CONCLUSIONS: In this cohort of women, detectable HIV RNA 6 months post-partum was infrequent and associated with low adherence to the treatment programme. Mutations were present in 63% of the women with detectable viral load at 6 months who had samples available for resistance testing. The impact of resistance on treatment re-initiation in women discontinuing drugs after the risk of transmission has ceased can be limited.

The impact of HBV or HCV infection in a cohort of HIV-infected pregnant women receiving a nevirapine-based antiretroviral regimen in Malawi.

BACKGROUND: Coinfection with the hepatitis viruses is common in the HIV population in sub-Saharan Africa. The aim of this study was to assess, in a cohort of HIV-infected pregnant women receiving antiretroviral drugs (ARVs), the prevalence of HBV and HCV infections and to determine the impact of these infections on the occurrence of liver toxicity and on the viro-immunological response. METHODS: Women were screened for HBsAg and HCV-RNA before starting, at week 25 of gestational age, an antiretroviral regimen consisting of lamivudine and nevirapine plus either stavudine or zidovudine. Women with CD4+ < 350/mm3 continued ARVs indefinitely, while the other women interrupted treatment 6 months postpartum (end of breastfeeding period). Both groups were followed for 2 years after delivery. Liver function was monitored by alanine aminotransferase (ALT) measurement. The Cox proportional hazards model was used to identify factors associated with the emergence of liver toxicity. RESULTS: A total of 28 women out of the 309 enrolled in the study (9.1%) were coinfected with HBV (n. 27), or HCV (n. 1). During follow-up 125 women (40.4%) developed a grade ≥ 1 ALT elevation, 28 (9.1%) a grade ≥ 2 and 6 (1.9%) an elevation defining grade 3 toxicity. In a multivariate model including age, baseline CD4+ count and hemoglobin level, the presence of either HBV or HCV infection was significantly associated with the development of an ALT increase of any grade (P = 0.035). Moderate or severe liver laboratory toxicity (grade ≥ 2) was more frequent among women with baseline CD4+ > 250/mm3 (P = 0.030). In HBV-infected women a baseline HBV-DNA level above 10,000 IU/ml was significantly associated to the development of liver toxicity of grade ≥ 1 (P = 0.040). Coinfections had no impact on the immunological and virological response to antiretroviral drugs up to 2 years after delivery. CONCLUSIONS: In this cohort of nevirapine-treated women the presence of HBV or HCV was associated only to the development of mild liver toxicity, while the occurrence of moderate or severe hepatoxicity was correlated to a baseline CD4+ count > 250/mm3. No statistically significant effect of the coinfections was observed on the efficacy of antiretroviral therapy.

HCP5 genetic variant (RS3099844) contributes to Nevirapine-induced Stevens Johnsons Syndrome/Toxic Epidermal Necrolysis susceptibility in a population from Mozambique.

PURPOSE: Nevirapine (NVP) is an anti-retroviral drug used for the treatment of HIV infection, that may cause several severe adverse events, including Stevens Johnsons Syndrome/Toxic Epidermal Necrolysis (SJS/TEN). A recent whole genome association study highlighted a strong association with allopurinol-induced SJS/TEN within the HCP5 and PSORS1C1 genes in the Japanese population. Our aim was to verify the contribution of these two genes in the susceptibility to NVP-induced SJS/TEN in a population from Mozambique. METHODS: Genotyping of PSORS1C1 rs2233945 and HCP5 rs3099844 SNPs was performed in a sample of 27 patients with SJS/TEN and 76 controls. A case-control and a haplotype analysis were performed. RESULTS: The HCP5 rs3099844 variant allele was significantly associated with the SJS/TEN susceptibility (OR = 2.03 and P = 0.039). The TA haplotype, carrying both the variant alleles of the two genes, showed a higher risk for developing SJS/TEN (OR = 3.44and P = 0.003). The regression analysis confirmed the contribution of HCP5 rs3099844 SNP (OR = 2.05, P = 0.047). By a log-linear model, we also investigated for interaction between HCP5 rs309844 and PSORS1C1 rs2233945 SNPs with respect to SJS/TEN risk, and we observed a strong interaction between the two SNPs (P = 0.005). CONCLUSIONS: We confirmed the association of HCP5 with the SJS/TEN susceptibility in a population from Mozambique treated with NVP.