Continuation of emtricitabine/lamivudine within combination antiretroviral therapy following detection of the M184V/I HIV-1 resistance mutation.

OBJECTIVES: The aim of the study was to investigate whether lamivudine (3TC) or emtricitabine (FTC) use following detection of M184V/I is associated with better virological outcomes. METHODS: We identified people with viruses harbouring the M184V/I mutation in UK multicentre data sets who had treatment change/initiation within 1 year. We analysed outcomes of viral suppression (< 200 HIV-1 RNA copies/mL) and appearance of new major drug resistance mutations (DRMs) using Cox and Poisson models, with stratification by new drug regimen (excluding 3TC/FTC) and Bayesian implementation, and estimated the effect of 3TC/FTC adjusted for individual and viral characteristics. RESULTS: We included 2597 people with the M184V/I resistance mutation, of whom 665 (25.6%) were on 3TC and 458 (17.6%) on FTC. We found a negative adjusted association between 3TC/FTC use and viral suppression [hazard ratio (HR) 0.84; 95% credibility interval (CrI) 0.71-0.98]. On subgroup analysis of individual drugs, there was no evidence of an association with viral suppression for 3TC (n = 184; HR 0.94; 95% CrI 0.73-1.15) or FTC (n = 454; HR 0.99; 95% CrI 0.80-1.19) amongst those on tenofovir-containing regimens, but we estimated a reduced rate of viral suppression for people on 3TC amongst those without tenofovir use (n = 481; HR 0.71; 95% CrI 0.54-0.90). We found no association between 3TC/FTC and detection of any new DRM (overall HR 0.92; 95% CrI 0.64-1.18), but found inconclusive evidence of a lower incidence rate of new DRMs (overall incidence rate ratio 0.69; 95% CrI 0.34-1.11). CONCLUSIONS: We did not find evidence that 3TC or FTC use is associated with an increase in viral suppression, but it may reduce the appearance of additional DRMs in people with M184V/I. 3TC was associated with reduced viral suppression amongst people on regimens without tenofovir.

HIV self-testing intervention experiences and kit usability: results from a qualitative study among men who have sex with men in the SELPHI (Self-Testing Public Health Intervention) randomized controlled trial in England and Wales.

OBJECTIVES: SELPHI (HIV Self-Testing Public Health Intervention) is the largest randomized controlled trial (RCT) of HIV self-testing (HIVST) in a high-income setting to date, and has recruited 10 000 men who have sex with men (cis- and transgender) and transgender women who have sex with men. This qualitative substudy aimed to explore how those utilizing self-tests experience HIVST and the implications for further intervention development and scale-up. This is the first qualitative study in Europe investigating experiences of HIVST among intervention users, and the first globally examining the experience of using blood-based HIVST. METHODS: Thirty-seven cisgender MSM SELPHI participants from across England and Wales were purposively recruited to the substudy, in which semi-structured interviews were used to explore testing history, HIVST experiences and intervention preferences. Interviews were audio-recorded, transcribed and analysed through a framework analysis. RESULTS: Men accessed the intervention because HIVST reduced barriers related to convenience, stigma and privacy concerns. Emotional responses had direct links to acceptability. Supportive intervention components increased engagement with testing and addressed supportive concerns. HIVST facilitated more frequent testing, with the potential to reduce sexually transmitted infection (STI) screening frequency. Substudy participants with an HIV-positive result (n = 2) linked to care promptly and reported very high acceptability. Minor adverse outcomes (n = 2; relationship discord and fainting) did not reduce acceptability. Ease of use difficulties were with the lancet and the test processing stage. CONCLUSIONS: Intervention components shaped acceptability, particularly in relation to overcoming a perceived lack of support. The intervention was broadly acceptable and usable; participants expressed an unexpected degree of enthusiasm for HIVST, including those with HIV-positive results and individuals with minor adverse outcomes.

Phenotypic and genotypic analyses to guide selection of reverse transcriptase inhibitors in second-line HIV therapy following extended virological failure in Uganda.

OBJECTIVES: We investigated phenotypic and genotypic resistance after 2 years of first-line therapy with two HIV treatment regimens in the absence of virological monitoring. METHODS: NORA [Nevirapine OR Abacavir study, a sub-study of the Development of AntiRetroviral Therapy in Africa (DART) trial] randomized 600 symptomatic HIV-infected Ugandan adults (CD4 cell count <200 cells/mm(3)) to receive zidovudine/lamivudine plus abacavir (cABC arm) or nevirapine (cNVP arm). All virological tests were performed retrospectively, including resistance tests on week 96 plasma samples with HIV RNA levels ≥1000 copies/mL. Phenotypic resistance was expressed as fold-change in IC(50) (FC) relative to wild-type virus. RESULTS: HIV-1 RNA viral load ≥1000 copies/mL at week 96 was seen in 58/204 (28.4%) cABC participants and 21/159 (13.2%) cNVP participants. Resistance results were available in 35 cABC and 17 cNVP participants; 31 (89%) cABC and 16 (94%) cNVP isolates had a week 96 FC below the biological cut-off for tenofovir (2.2). In the cNVP arm, 16/17 participants had resistance mutations synonymous with high-level resistance to nevirapine and efavirenz; FC values for etravirine were above the biological cut-off in 9 (53%) isolates. In multivariate regression models, K65R, Y115F and the presence of thymidine analogue-associated mutations were associated with increased susceptibility to etravirine in the cABC arm. CONCLUSIONS: Our data support the use of tenofovir following failure of a first-line zidovudine-containing regimen and shed further light on non-nucleoside reverse transcriptase inhibitor hypersusceptibility.

Residual activity of two HIV antiretroviral regimens prescribed without virological monitoring.

Virological residual activity (VRA) denotes the degree of HIV RNA suppression achieved by antiretroviral therapy in the presence of resistant virus. This concept is particularly important in resource-limited settings, where rapid switching after detection of virological failure may not be feasible. Using data from the NORA trial, we estimated VRA for two regimens-zidovudine-lamivudine-abacavir (ZDV-3TC-ABC) and zidovudine-lamivudine-nevirapine (ZDV-3TC-NVP)-and related this to the phenotypic drug sensitivity of the component drugs in the two regimens. Plasma samples at weeks 0, 48, and 96 were retrospectively assayed for HIV-1 RNA, and genotypic/phenotypic resistance testing was performed if HIV-1 RNA exceeded 1,000 copies/ml. Virological residual activity (VRA) was defined as the difference between log(10)(HIV RNA) at week 48 or 96 and week 0 and related to 50% inhibitory concentration (IC(50)) relative to wild-type virus for ZDV and ABC (fold change [FC]). Twenty-seven samples in the ZDV-3TC-NVP group and 56 in the ZDV-3TC-ABC group contributed to the analysis. Mean VRA was significantly higher in the ZDV-3TC-ABC group than in the ZDV-3TC-NVP at week 48 (1.62 versus 0.90) and week 96 (1.29 versus 0.78). There was a weak and nonsignificant relationship between VRA and ZDV FC, with VRA decreasing by 0.1 log(10) copies/ml per 2-fold increase in ZDV. The association with ABC FC was much stronger, with a marked reduction in VRA occurring at ABC FC values greater than approximately 2. This information should be considered in future treatment guidelines relevant to resource-poor settings.

Modelling the association between patient characteristics and the change over time in a disease measure using observational cohort data.

In observational cohort studies we may wish to examine the associations between fixed patient characteristics and the longitudinal changes from baseline in a repeated outcome measure. Many biological and other outcome measures are known to be subject to measurement error and biological variation. In an initial analysis we may fit a regression model to all outcome measurements, accounting for all the identified sources of variability, and see how the characteristics are linked to the change for typical patients. However, the characteristics may also be linked to different distributions of the underlying outcome value at baseline, which itself may be correlated with the change over time. Therefore, if we wish to examine the change over time for patients of different characteristics but with the same underlying baseline value then the initial approach is confounded by the baseline values. Furthermore, if we attempt to remove this confounding by including the observed baseline measure as a covariate in a model for later measurements, then this may provide an approximate solution but is likely to introduce some bias. We propose a method based on first following the initial approach but then, applying a correction to the parameter estimates. This allows the predicted trajectories to be plotted and valid significance tests of association with characteristics. Our approach is compared with other methods and illustrated through a simulation study and an analysis of the association between HIV-1 subtype and immunological response after starting antiretroviral therapy.

What is the risk of mortality following diagnosis of multidrug-resistant HIV-1?

OBJECTIVES To estimate the risk of death and examine the predictors of death and virological/immunological response, following diagnosis of multidrug-resistant (MDR) HIV-1 in a UK multicentre cohort of HIV-infected individuals. METHODS Five hundred and seventy-two patients were identified with MDR HIV-1 between 1997 and 2004. Factors associated with survival and virological/immunological response 24-48 weeks after MDR diagnosis were determined by the Poisson and linear regression, respectively. RESULTS Patient characteristics: 86% males; median age 39 years; median CD4 and viral load (VL) at MDR diagnosis 230 cells/mm3 and 4.2 log10 copies/mL; median number of antiretroviral drugs previously exposed to 8. Sixty patients died over a median follow-up of 31 months (IQR: 17-50), giving an estimated mortality rate of 3.7 deaths per 100 person-years (95% CI 2.9-4.7) following MDR diagnosis. In adjusted analysis, higher CD4 count, lower VL, more recent calendar year, lower number of antiretroviral drugs previously exposed to and greater age at MDR diagnosis were associated with an increased chance of survival. There was some evidence of a better virological response at 24-48 weeks after MDR diagnosis in patients who changed regimen compared with patients who did not change regimen. CONCLUSIONS The risk of death following MDR diagnosis may be at least 3-fold the risk observed overall in HIV-infected individuals. Changing antiretroviral therapy following emergence of MDR HIV-1 may be associated with improved short-term virological response.

The painful crisis of homozygous sickle cell disease. A study of the risk factors.

Some epidemiologic features of the painful crisis in homozygous sickle cell disease were examined in a retrospective study of 995 painful crises. Previously reported associations with cold weather and pregnancy were confirmed. There was a striking increase in painful crises in male patients between the ages of 15 and 25 years, whereas female patients showed little age-related change. The frequency of painful crises correlated positively with hemoglobin levels and reticulocyte counts in both sexes and negatively with mean corpuscular volume in female patients. There was a striking increase in painful crises in male patients with hemoglobin levels above 8.5 g/dL (greater than 85 g/L). High hemoglobin levels appear to be an important risk factor for painful crises.

Breastfeeding, genetic, obstetric and other risk factors associated with mother-to-child transmission of HIV-1 in Sao Paulo State, Brazil. Sao Paulo Collaborative Study for Vertical Transmission of HIV-1.

OBJECTIVES: To evaluate the effect of maternal, obstetric, neonatal and post-natal factors on the risk of vertical transmission of HIV-1. DESIGN: Multicentre retrospective cohort study. SETTING: Obstetric and paediatric clinics in four cities in Sao Paulo State, Brazil. MAIN OUTCOME: Child's HIV-1 infection status. METHODS: Data were collected by standardized record abstraction and interview on 553 children born to women identified as HIV-1-infected before or at delivery. Paediatric infection was determined by immunoglobulin G anti-HIV-1 tests at age 18 months or by AIDS diagnosis at any age. Multivariate logistic regression was used to assess the effect of potential risk factors on vertical transmission of HIV-1. RESULTS: HIV-1 infection status was determined for 434 children (follow-up rate of 78%); 69 were classified as HIV-1-infected [transmission risk, 16%; 95% confidence interval (CI), 13-20%]. In multivariate analysis, advanced maternal HIV-1 disease [odds ratio (OR), 4.5; 95% CI, 2.1-9.5], ever breastfed (OR, 2.2; 95% CI, 1.2-4.2), child's negative Rhesus blood group (OR, 2.5; 95% CI, 1.2-5.5), third trimester amniocentesis (OR, 4.1; 95% CI, 1.2-13.5) and black racial group (OR, 0.3; 95% CI, 0.1-0.9) were independently and significantly associated with mother-to-child transmission of HIV-1. Transmission was increased marginally with prematurity, more than 10 lifetime sexual partners and prolonged duration of membrane rupture. No association was found between child's HIV-1 infection and mode of delivery or serological evidence of syphilis during pregnancy. CONCLUSION: These findings support the importance of severity of maternal HIV-1 disease in the risk of vertical transmission of HIV-1, indicate measures to reduce transmission by avoiding amniocentesis and breastfeeding and suggest that race and Rhesus blood type may be markers for genetic susceptibility to infection.

Vertical transmission of HIV-1: maternal immune status and obstetric factors. The European Collaborative Study.

OBJECTIVE: To estimate the effect of maternal factors and events around the time of delivery on HIV-1 vertical transmission risk. DESIGN: Prospective study. SETTING: Twenty-two obstetric and paediatric clinics in seven European countries. PATIENTS OR OTHER PARTICIPANTS: Mothers identified as HIV-infected before or at delivery and their children. MAIN OUTCOME MEASURE: Paediatric HIV infection. RESULTS: By November 1995, 1846 mothers with 1945 children had been enrolled. The vertical transmission rate was 16.4% (95% confidence interval, 14.5-18.3). Parity, maternal age, race, mode of HIV acquisition, injecting drug use and sex of infant were not statistically significantly associated with risk of transmission. Children delivered vaginally were more likely to be infected than those delivered by Caesarean section. However, in vaginal deliveries the procedures used, duration of ruptured membranes or length of second-stage labour were not related to transmission. Transmission increased almost linearly with decreasing CD4 cell count, but there was no such trend for CD8 cell count. Women with CD4 cell counts below 200 x 10(6)/l were significantly more likely to deliver early (chi 2 for trend, 14.02; P < 0.001). Very premature infants were at increased risk of infection, but after about 35 weeks gestation the transmission rate remained stable, with no increase in late pregnancy. This trend was confirmed after allowing for maternal CD4 cell count. CONCLUSIONS: The rate of vertical transmission increases linearly with decreasing maternal CD4 cell count. Women with fewer than 200 x 10(6) CD4 cells/l have an increased risk of premature delivery, which would affect timing of interventions. The stable transmission rate after 35 weeks gestation suggests little acquisition of infection during late pregnancy.

Mother-to-child transmission of HIV: implications of variation in maternal infectivity.

OBJECTIVES: To examine the implications of variation in maternal infectivity on the timing of mother-to-child HIV transmission through breastfeeding. DESIGN AND METHODS: A mathematical model of mother-to-child HIV transmission was developed that incorporates two main features: (i) the fetus/child potentially experiences a series of exposures (in utero, intrapartum, and via breastmilk) to HIV; and (ii) variation in maternal infectivity. The model was estimated from different sources of epidemiological data: a retrospective cohort study of children born to HIV-1-infected women in Sao Paulo State, Brazil, the International Registry of HIV-Exposed Twins, and the AIDS Clinical Trials Group 076 trial, which assessed the effectiveness of zidovudine in preventing mother-to-child HIV transmission. RESULTS: Variation in maternal infectivity results in higher average risk of breastfeeding-related transmission in the early stages of breastfeeding than in the late stages, even in the absence of a direct relationship between transmission risk and the age of the child. However, the available data were unable to resolve the quantitative importance of this mechanism. CONCLUSIONS: Our model has helped identify a previously unrecognized determinant of the timing of breastfeeding-related HIV transmission, which may have adverse implications for the effectiveness of certain interventions to reduce mother-to-child HIV transmission such as maternal antiretroviral therapy in breastfeeding populations and the early cessation of breastfeeding.

PIP: By 2000, an estimated 5 million children will have been infected with HIV, the majority of them in sub-Saharan Africa. 30-50% of such infections could be the result of mother-to-child viral transmission through breast-feeding. Findings are presented from a study conducted to examine the implications of variation in maternal infectivity upon the timing of mother-to-child HIV transmission through breast-feeding. A mathematical model of mother-to-child HIV transmission was developed which incorporates the possibility of the fetus/child being exposed to HIV in utero, during the intrapartum period, and through breast milk; and variation in maternal infectivity. The model was estimated from epidemiological data drawn from a retrospective cohort study of children born to HIV-1-infected women in Sao Paulo State, Brazil, the International Registry of HIV-Exposed Twins, and the AIDS Clinical Trials Group 076 trial, which assessed the effectiveness of zidovudine in preventing mother-to-child HIV transmission. The effect of duration of breast-feeding upon the overall probability of mother-to-child HIV transmission, and therefore the age-specific risk of breast-feeding-related transmission, is highly sensitive to the degree of variation in infectivity. When substantial, the average risk of breast-feeding-related transmission declines rapidly with age and most infections occur in the early stages of breast-feeding. When the variation is less, infections attributable to breast-feeding are more evenly spread across the period of exposure to breast milk, although an imbalance towards early transmission remains.

The sensitivity of HIV-1 DNA polymerase chain reaction in the neonatal period and the relative contributions of intra-uterine and intra-partum transmission.

OBJECTIVE: To derive reliable estimates of the sensitivity of HIV-1 DNA polymerase chain reaction (PCR) in the neonatal period and to quantify the relative contributions of intra-uterine and intra-partum transmission. METHODS: After reviewing studies on the early diagnosis of HIV-1 infection, investigators were asked to provide published and unpublished PCR test results on prospectively followed, non-breastfed, vertically infected children. Age-specific estimates of the sensitivity of PCR were derived using distribution-free methods for interval-censored data. RESULTS: Data on 271 infected children were combined for analysis. PCR detected HIV-1 DNA in an estimated 38% [90% confidence interval (CI), 29-46] of HIV-infected children tested on the day of, or day after, birth. Sensitivity was observed to rise rapidly in the second week of life, reaching 93% (90% CI, 76-97) by 14 days of age. CONCLUSION: The sensitivity of PCR in the neonatal period is higher than previously reported. This affects the clinical interpretation of an early negative test result and encourages the use of PCR as an endpoint for trials to evaluate interventions to reduce vertical transmission in non-breastfed populations. Approximately one-third of vertically acquired HIV-1 infection could be attributable to intra-uterine transmission.

Interventions to prevent vertical transmission of HIV-1: effect on viral detection rate in early infant samples.

OBJECTIVE: To determine whether mode of delivery or the use of maternal or neonatal antiretroviral prophylaxis influence the age when HIV-1 can first be detected in infected infants, particularly the probability of detection at birth. METHODS: In a collaboration between four multicentre studies, data on 422 HIV-1 infected infants who were assessed by HIV-1 DNA PCR or cell culture before 14 days of age were analysed. Weibull mixture models were used to estimate the cumulative proportion of infants with detectable levels of HIV-1 according to use of maternal/neonatal antiretroviral therapy (mainly zidovudine monotherapy) and mode of delivery. RESULTS: HIV-1 was detected in 162 infants (38%) when they were first tested, at a median age of 2 days. At birth, it was estimated that 36% [95% confidence interval (CI), 31-41%] of infants have levels of virus that can be detected by DNA PCR or cell culture. This percentage was not associated with either mode of delivery (35% for vaginal delivery versus 40% for cesarean section delivery; P = 0.4) or the use of maternal or neonatal antiretroviral prophylaxis. Among infants with undetectable levels of HIV-1 at birth, the median time to viral detectability was estimated to be 14.8 days (95% CI, 12.9-16.8 days). This time was increased by 15% (95% CI, -11 to 48%; P = 0.3) among infants who were exposed to antiretroviral therapy postnatally compared with infants who were not exposed. No effect was observed for mode of delivery. CONCLUSIONS: The outcome of an early virological test for HIV-1 is thought to be related directly to the timing of transmission and cesarean section delivery primarily reduces the risk of intrapartum transmission. The absence of an association between mode of delivery and viral detectability at birth was therefore unexpected. There was no evidence that foetal or neonatal exposure to prophylactic zidovudine delays substantially the diagnosis of infection, although this cannot be inferred for combination antiretroviral therapy.

Timing and interpretation of tests for diagnosing perinatally acquired hepatitis C virus infection.

The diagnosis of hepatitis C virus (HCV) infection in children born to HCV-infected women is based on serologic assays and HCV RNA measurement by PCR. Interpretation of the results of these tests is hampered by uncertainty about the age distribution of loss of maternal antibody and the sensitivity and specificity of PCR at different ages. On the basis of findings from a recent vertical transmission study, we estimated the posttest probability of a child's being infected or uninfected under several test result scenarios. These estimates may assist clinicians in assessing the likelihood of infection in an individual child and in using the currently available assays cost effectively.

Salivary testing for human immunodeficiency virus type 1 infection in children born to infected mothers in Sao Paulo, Brazil. The Sao Paulo Collaborative Study for Vertical Transmission of HIV-1.

OBJECTIVE: To validate a method for salivary testing for HIV infection in children older than 12 months. METHODS: Oral fluid samples were collected via sponge foam swabs from children born to HIV-positive mothers and were tested for antibodies to HIV-1 and HIV-2 with an IgG antibody capture enzyme-linked immunosorbent assay and a modified Western blot for confirmation. In each child serum antibody status was the standard used to validate the salivary antibody test. RESULTS: We obtained 331 oral fluid samples from children born to HIV-positive mothers. The specificity and sensitivity of salivary testing compared with results on sera were both 100% (297 of 297 (95% confidence interval 98.8 to 100%) and 34 of 34 (95% confidence interval 89.7 to 100%), respectively). Compliance in the study population increased from 91% to 97% when mothers were offered the opportunity to provide oral fluid from their children instead of blood specimens. CONCLUSION: Salivary testing provides an accurate and acceptable noninvasive method for assessing the HIV infection status of children born to infected mothers by using IgG antibody capture enzyme-linked immunosorbent assay alone with a strategy of duplicate retesting of reactive specimens.

A review of statistical methods for estimating the risk of vertical human immunodeficiency virus transmission.

BACKGROUND: Estimation of the risk of vertical transmission of human immunodeficiency virus (HIV) has been complicated by the lack of a reliable diagnostic test for paediatric HIV infection. METHODS: A literature search was conducted to identify all statistical methods that have been used to estimate HIV vertical transmission risk. Although the focus of this article is the analysis of birth cohort studies, ad hoc studies are also reviewed. CONCLUSIONS: The standard method for estimating HIV vertical transmission risk is biased and inefficient. Various alternative analytical approaches have been proposed but all involve simplifying assumptions and some are difficult to implement. However, early diagnosis/exclusion of infection is now possible because of improvements in polymerase chain reaction technology and complex estimation methods should no longer be required. The best way to analyse studies conducted in breastfeeding populations is still unclear and deserves attention in view of the many intervention studies being planned or conducted in developing countries.

Effect of prenatal treatment on the risk of intracranial and ocular lesions in children with congenital toxoplasmosis.

BACKGROUND: Hydrocephalus, intracranial calcification and retinochoroiditis are the most common manifestations of tissue damage due to congenital toxoplasmosis, but the effect of prenatal treatment on these outcomes is unclear. We aimed to determine the effect of prenatal treatment for toxoplasmosis on the risk of intracranial and ocular lesions in congenitally infected children at 3 years of age. METHODS: A cohort of mothers identified during pregnancy with toxoplasma infection and their 181 liveborn children with confirmed congenital toxoplasmosis was retrospectively analysed to determine the presence of intracranial and ocular lesions. As few women are not treated, we compared the effects of the treatment potency (pyrimethamine-sulfadiazine versus spiramycin or no treatment), and the timing of treatment, on the risks of intracranial lesions, time to detection of ocular lesions, and detection of any lesions (intracranial or ocular) by 3 years of age. Analyses took account of the gestation at maternal seroconversion. RESULTS: There was no evidence for an effect of pyrimethamine-sulfadiazine on intracranial, ocular or any lesions by 3 years: odds ratio (OR) for any lesions 0.89 (95% CI : 0.41, 1.88). There was no evidence of an effect of delayed treatment on ocular lesions (hazard ratio = 0.69, 95% CI : 0.28, 1.68) or any lesions by 3 years of age (OR = 0.44, 95% CI : 0.16, 1.19). CONCLUSIONS: Our study failed to detect a beneficial effect of early or more potent anti toxoplasma treatment on the risks of intracranial or ocular lesions in children with congenital toxoplasmosis. However, larger, prospective studies, which determine the effect of prenatal treatment on long-term developmental outcomes are required to justify changes in clinical practice.

Effect of prenatal treatment on mother to child transmission of Toxoplasma gondii: retrospective cohort study of 554 mother-child pairs in Lyon, France.

BACKGROUND: The aim of prenatal serological screening for toxoplasmosis is to identify and treat maternal infection as soon as possible in order to prevent transmission of the parasite to the fetus. However, despite widespread provision of prenatal toxoplasma screening across Europe, the effectiveness of prenatal treatment is uncertain. The study aimed to determine the effect of the timing and type of prenatal treatment on mother to child transmission of Toxoplasma gondii. METHOD: A cohort of 554 infected pregnant women were identified in Lyon, France between 1987 and 1995 and their children were followed to determine congenital infection status. We determined the effect of prenatal treatment on transmission by examining the effect of the delay between maternal seroconversion and start of treatment. We also compared the effect of the type of treatment and no treatment on the risk of mother to child transmission. Analyses were adjusted for gestation at maternal seroconversion. RESULTS: Compared to treatment within 4 weeks from seroconversion, the adjusted odds ratios (OR) for mother to child transmission after a treatment delay of 4-7 weeks was 1.29 (95% CI : 0.61, 2.73) and after more than 8 weeks, 1.44 (95% CI : 0.60, 3.31). The adjusted OR associated with spiramycin alone compared with pyrimethamine-sulfadiazine treatment was 0.91 (95% CI : 0.45, 1.84) and the OR for no treatment compared with pyrimethamine-sulfadiazine treatment was 1.06 (95% CI : 0.37, 3.03). CONCLUSIONS: The authors hypothesize that the absence of an effect of prenatal treatment is due to transmission before the start of treatment.

Suppressed peripheral and placental blood lymphoproliferative responses in first pregnancies: relevance to malaria.

An understanding of processes that predispose pregnant women, and in particular primigravidae, to malaria infection is essential to improve malaria management in pregnancy. Lymphoproliferative responses to malaria-specific (F32, 190L, and 190N) as well as other antigens (Candida and purified protein derivative [PPD]) were examined in the peripheral and placental blood of 102 Gambian women at the time of delivery. The lymphoproliferative responses of placental cells were poor to all antigens compared with those of peripheral blood (Candida P < 0.001, PPD P < 0.001, F32 P = 0.008, 190L P = 0.003, and 190N P = 0.10). Reduced proliferative capacity of placental mononuclear cells may contribute to heavy parasite colonization of this organ. Proliferation to malarial and PPD but not Candida antigens was selectively suppressed in peripheral and placental blood of primiparae relative to multiparae (F32 P = 0.07, 190L P = 0.09, 190N P = 0.007, PPD P = 0.09). Autologous plasma contained factors that suppressed lymphoproliferative responses to the same series of antigens to which the primiparae responded poorly (F32 P < 0.001, 190L P < 0.001, 190N P < 0.001, PPD P = 0.03). Malarial antibody levels were comparable among women of different parities and between peripheral and placental blood. Primigravidae may be more susceptible to malaria because of unique physiologic factors, such as higher levels of circulating immunosuppressive corticosteroids (P < 0.001), rather than differences in levels of acquired immunity.

Comparison of five assays for the heat-labile enterotoxin of Escherichia coli.

Enzyme-linked immunosorbent assay (ELISA), DNA-DNA hybridisation, Vero cell assay, the Biken test and a new membrane-filter method were compared in the detection of heat-labile enterotoxin (LT) of Escherichia coli. Six subcultures of each of 50 strains of E. coli from the Biken collection were evaluated "blind" in the laboratory. The combined results of the most reproducible tests (ELISA and DNA-DNA hybridisation) were used to calculate the sensitivity and specificity of the other assays. The Vero-cell assay had a high sensitivity (98%) but a lower specificity (91%). The Biken and membrane-filter assays had sensitivities of 58-71% and 77-84% respectively, depending on the type of antiserum used. Only one false positive result was obtained with the Biken test; specificity of the membrane-filter assay was 94-95%. The membrane-filter assay, with anti-cholera toxin, is specific and reasonably sensitive. It has particular advantages over DNA-DNA hybridisation and the Biken test, and it may prove suitable for screening large numbers of E. coli isolates in epidemiological studies in developing countries.

Nutritional status and risk of morbidity among young Gambian children allowing for social and environmental factors.

A prospective study of the relationship between anthropometric indices and subsequent morbidity was conducted during 2 seasons in young children in an urban Gambian community. Children with low height-for-age at the beginning of the rainy season had a significantly higher prevalence of diarrhoea and fever during the next 4 months, even after controlling for the possible confounding effects of a range of social, economic and environmental factors. The association was weaker in the dry season. This indicates that the increased prevalence of symptoms among stunted children is not solely attributable to environmental factors, and suggests that impaired growth is associated with impaired host response to infection.