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.

Patterns and predictors of the use of different antiretroviral drug regimens at treatment initiation in the UK.

BACKGROUND: We describe the patterns of antiretroviral drug use at treatment initiation from 1996 to 2005 in a large UK multicentre cohort. METHODS: We examined trends over time and across 10 clinical sites in stage of disease and type of antiretroviral therapy (ART). Multivariable regression was used to identify factors associated with the CD4 cell count at ART initiation, and with the choice of a protease inhibitor (PI) over a nonnucleoside reverse transcriptase inhibitor (NNRTI), and use of nevirapine over efavirenz. RESULTS: A total of 14 252 patients initiated ART, of whom 54% had a CD4 count <200 cells/microL. The most important predictors of starting ART at a lower CD4 cell count were being male, nonwhite, and heterosexual or an injecting drug user (P<0.0001). Among those starting ART, the use of highly active ART increased from 23% in 1996 to >96% from 2000 onwards. There were differences over time and across the clinics in the use of PIs vs. NNRTIs, in the choice of specific PIs, NNRTIs and nucleoside reverse transcriptase inhibitor (NRTI) backbone, and in the rate at which prescribing practices changed. CONCLUSIONS: Clinic site and calendar year were important determinants of choice of drug at ART initiation, whereas clinical and demographic characteristics were more important in influencing the CD4 cell count at initiation of ART.

Emergence of the H208Y mutation in the reverse transcriptase (RT) of HIV-1 in association with nucleoside RT inhibitor therapy.

OBJECTIVES: The aim of the study was to determine whether mutations at RT codon 208 are associated with nucleoside RT inhibitor (NRTI) exposure, NRTI resistance patterns and HIV-1 subtype. METHODS: Six thousand three hundred and fifty two genotypic resistance tests linked to a clinical database were analysed. RESULTS: The prevalence of mutations at codon 208 was 6/2347 (0.3%) in treatment-naive and 165/4005 (4.1%) in treatment-experienced persons. H208Y was the most common mutation in both groups (0.2% and 3.8%, respectively) and occurred in 4.5% of treatment-experienced persons with Subtype B, 1.7% of those with Subtype C and 0.7% of those with other non-B subtypes (P=0.001). The association with subtypes was independent of treatment experience. H208Y showed a strong association with NRTI experience, which persisted after adjusting for subtype [odds ratio (OR) 19.34; 95% confidence interval (CI) 7.87-47.54; P=0.0001]. The prevalence of H208Y was highest in genotypes harbouring M184V and the thymidine analogue mutations (TAMs) M41L, D67N, L210W and T215Y. The median number of TAMs was 4 and 0 in genotypes with and without H208Y, respectively (P=0.0001). The prevalence of H208Y declined over time, being highest in 1998 (9.9%) and lowest in 2003 (0.9%) (P=0.0001). CONCLUSIONS: There is a strong association between H208Y and NRTI experience, particularly in persons with Subtype B harbouring multiple NRTI resistance mutations. These findings indicate an accessory role for H208Y in NRTI resistance.

A randomized controlled trial of the value of phenotypic testing in addition to genotypic testing for HIV drug resistance: evaluation of resistance assays (ERA) trial investigators.

OBJECTIVES: To assess the clinical utility of phenotypic resistance testing in addition to genotypic resistance testing among HIV-1-infected patients experiencing virologic failure and with limited therapeutic options. DESIGN: Multicenter randomized trial. METHODS: Patients were eligible if a decision had been made to switch antiretroviral therapy, the most recent HIV-1 RNA plasma viral load (VL) exceeded 2000 copies/mL, and the clinician was unable to select a potent regimen of 3 or more drugs without access to a resistance test. Subjects were randomized to genotypic resistance testing alone (G arm) or to genotypic plus phenotypic testing (G + P arm). Patients had access to resistance testing at any time during follow-up (minimum of 1 year) according to the original allocation. The primary end point was change in plasma VL from baseline at 12 months. RESULTS: Three hundred eleven patients were recruited between February 2000 and July 2001. At baseline, mean VL and CD4 count were 4.23 log10 copies/mL and 275 cells/mm, respectively, and subjects had previous exposure to a mean of 7.7 antiretroviral drugs. There was no appreciable difference between the study arms in the drug regimens prescribed after randomization. Mean reduction in VL load at 12 months was similar in the 2 arms (G: 1.37 log10 reduction, G + P: 1.28 log10 reduction; P = 0.77), as was the proportion of subjects with VL <50 copies/mL (G: 35%, G + P: 27%). CONCLUSION: The study did not demonstrate added value of phenotypic resistance testing in conjunction with genotypic resistance testing in patients with limited therapeutic options.

A prospective multicentre study of discontinuing prophylaxis for opportunistic infections after effective antiretroviral therapy.

OBJECTIVE: To assess the medium-term safety of discontinuing prophylaxis (primary or secondary) for opportunistic infections following an effective response to antiretroviral therapy. METHODS: Participating clinical sites prospectively identified patients in whom the discontinuation of prophylaxis for any opportunistic infection was considered to be clinically indicated, although CD4 levels were not predefined. A follow-up report was subsequently sent every 6 months requesting information on changes in prophylaxis, antiretroviral drugs, new AIDS-defining events, and CD4 cell count results. RESULTS: Prophylaxis for Pneumocystis carinii pneumonia (PCP) was withdrawn in 524 patients (426 primary and 98 secondary prophylaxis), prophylaxis for Mycobacterium avium complex (MAC) was withdrawn in 28 patients (13 primary and 15 secondary), and prophylaxis for cytomegalovirus (CMV) retinitis was withdrawn in 10 patients. CD4 counts were generally maintained above accepted prophylaxis threshold levels during the period of follow up (95-98% of the time). Total follow up to last report or re-continuation of prophylaxis was 680 and 144 person-years for patients discontinuing primary and secondary PCP prophylaxis, respectively. No cases of PCP were reported, giving incidence rates of 0.0 (upper 95% confidence limit 0.4) and 0.0 (2.1) per 100 person-years. No cases of MAC were reported, but one patient had a recurrence of CMV retinitis. PCP prophylaxis was restarted in 30 patients; no patients restarted MAC or CMV prophylaxis. CONCLUSIONS: Previous studies have demonstrated a low risk of PCP in the short term following the withdrawal of prophylaxis in patients who have responded well to antiretroviral therapy. The present study suggests a continuing low level of risk with extended follow up, provided adequate CD4 count levels are maintained. The case of recurrent CMV retinitis in a patient with impressive immunological and virological response indicates the need for close monitoring of patients previously diagnosed with this condition.

Decline in mortality, AIDS, and hospital admissions in perinatally HIV-1 infected children in the United Kingdom and Ireland.

OBJECTIVE: To describe changes in demographic factors, disease progression, hospital admissions, and use of antiretroviral therapy in children with HIV. DESIGN: Active surveillance through the national study of HIV in pregnancy and childhood (NSHPC) and additional data from a subset of children in the collaborative HIV paediatric study (CHIPS). SETTING: United Kingdom and Ireland. PARTICIPANTS: 944 children with perinatally acquired HIV-1 under clinical care. MAIN OUTCOME MEASURES: Changes over time in progression to AIDS and death, hospital admission rates, and use of antiretroviral therapy. RESULTS: 944 children with perinatally acquired HIV were reported in the United Kingdom and Ireland by October 2002; 628 (67%) were black African, 205 (22%) were aged > or = 10 years at last follow up, 193 (20%) are known to have died. The proportion of children presenting who were born abroad increased from 20% in 1994-5 to 60% during 2000-2. Mortality was stable before 1997 at 9.3 per 100 child years at risk but fell to 2.0 in 2001-2 (trend P < 0.001). Progression to AIDS also declined (P < 0.001). From 1997 onwards the proportion of children on three or four drug antiretroviral therapy increased. Hospital admission rates declined by 80%, but with more children in follow up the absolute number of admissions fell by only 26%. CONCLUSION: In children with HIV infection, mortality, AIDS, and hospital admission rates have declined substantially since the introduction of three or four drug antiretroviral therapy in 1997. As infected children in the United Kingdom and Ireland are living longer, there is an increasing need to address their medical, social, and psychological needs as they enter adolescence and adult life.

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.

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.

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.

Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission.

BACKGROUND: Little information is available about the timing of mother-to-child transmission of hepatitis C virus (HCV), and no interventions to decrease transmission rates have been identified. We examined the effect of risk factors, including mode of delivery, on the vertical transmission rate. METHODS: Data from HCV-infected women and their infants from three hospitals in Ireland and from a British Paediatric Surveillance Unit study of infants born to HCV-infected mothers were used to estimate the vertical transmission rate and risk factors for transmission. We used a probabilistic model using methods that simultaneously estimated the time to HCV-antibody loss in uninfected infants and the diagnostic accuracy of PCR tests for HCV RNA. FINDINGS: 441 mother-child pairs from the UK (227) and Ireland (214) were included. 50% of uninfected children became HCV-antibody negative by 8 months and 95% by 13 months. The estimated specificity of PCR for HCV RNA was 97% (95% CI 96-99) and was unrelated to age; sensitivity was only 22% (7-46) in the first month but rose sharply to 97% (85-100) thereafter. The vertical transmission rate was 6.7% (4.1-10.2) overall, and 3.8 times higher in HIV coinfected (n=22) than in HIV-negative women after adjustment for other factors (p=0.06). No effect of breastfeeding on transmission was observed, although only 59 women breastfed. However, delivery by elective caesarean section before membrane rupture was associated with a lower transmission risk than vaginal or emergency caesarean-section delivery (odds ratio 0 [0-0.87], p=0.04, after adjustment for other factors). INTERPRETATION: The low sensitivity of HCV RNA soon after birth and the finding of a lower transmission rate after delivery by elective caesarean section suggest that HCV transmission occurs predominantly around the time of delivery. If the findings on elective caesarean section are confirmed in other studies, the case for antenatal HCV testing should be reconsidered.

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.

Sources of toxoplasma infection in pregnant women: European multicentre case-control study. European Research Network on Congenital Toxoplasmosis.

OBJECTIVE: To determine the odds ratio and population attributable fraction associated with food and environmental risk factors for acute toxoplasmosis in pregnancy. DESIGN: Case-control study. SETTING: Six large European cities. PARTICIPANTS: Pregnant women with acute infection (cases) detected by seroconversion or positive for anti-Toxoplasma gondii IgM were compared with pregnant women seronegative for toxoplasma (controls). MAIN OUTCOME MEASURES: Odds ratios for acute infection adjusted for confounding variables; the population attributable fraction for risk factors. RESULTS: Risk factors most strongly predictive of acute infection in pregnant women were eating undercooked lamb, beef, or game, contact with soil, and travel outside Europe and the United States and Canada. Contact with cats was not a risk factor. Between 30% and 63% of infections in different centres were attributed to consumption of undercooked or cured meat products and 6% to 17% to soil contact. CONCLUSIONS: Inadequately cooked or cured meat is the main risk factor for infection with toxoplasma in all centres. Preventive strategies should aim to reduce prevalence of infection in meat, improve labelling of meat according to farming and processing methods, and improve the quality and consistency of health information given to pregnant women.

Incidence of symptomatic toxoplasma eye disease: aetiology and public health implications.

Ocular disease is the commonest disabling consequence of toxoplasma infection. Incidence and lifetime risk of ocular symptoms were determined by ascertaining affected patients in a population-based, active reporting study involving ophthalmologists serving a population of 7.4 million. Eighty-seven symptomatic episodes were attributed to toxoplasma infection. Bilateral visual acuity of 6/12 or less was found in seven episodes (8%) and was likely to have been transient in most cases. Black people born in West Africa had a 100-fold higher incidence of symptoms than white people born in Britain. Only two patients reported symptoms before 10 years of age. The estimated lifetime risk of symptoms in British born individuals (52% of all episodes) was 18/100000 (95% confidence interval: 10.8-25.2). The low risk and mild symptoms in an unscreened British population indicate limited potential benefits of prenatal or postnatal screening. The late age at presentation suggests a mixed aetiology of postnatally acquired and congenital infection for which primary prevention may be appropriate, particularly among West Africans.

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.