David Dunn

Risk of human immunodeficiency virus type 1 transmission through breastfeeding

Detection of human immunodeficiency virus type 1 (HIV-1) in breast milk by culture and polymerase chain reaction does not necessarily mean that breastfeeding is a route of transmission, although evidence from several case-reports points in that direction. We undertook a systematic review of published studies meeting criteria that allowed determination of quantitative risk of transmission via breastfeeding. Based on four studies in which mothers acquired HIV-1 postnatally, the estimated risk of transmission is 29% (95% Cl 16-42%). Analysis of five studies showed that when the mother was infected prenatally, the additional risk of transmission through breastfeeding, over and above transmission in utero or during delivery, is 14% (95% Cl 7-22%). Where there are safe alternatives to breastfeeding, universal named testing of pregnant women would provide an opportunity to advise more infected women not to breastfeed and might thereby reduce the number of vertically infected children. Since breastfeeding protects against infant deaths from infectious diseases, breastfeeding is still recommended where infectious diseases are a common cause of death in childhood, despite the additional risk of HIV transmission.

Current CD4 Cell Count and the Short-Term Risk of AIDS and Death before the Availability of Effective Antiretroviral Therapy in HIV-Infected Children and Adults

BACKGROUNDnCurrently, there are no comparable estimates of the short-term risk of disease progression in the absence of effective antiretroviral therapy for human immunodeficiency virus (HIV)-infected adults and children.nnnMETHODSnA joint analysis of 2 large studies of children with vertically acquired HIV infection (the HIV Paediatric Prognostic Markers Collaborative Study) and adults with seroconversion (the CASCADE [Concerted Action on Sero-Conversion to AIDS and Death in Europe] collaboration) was conducted. Follow-up was censored at the end of 1995, before the introduction of combination antiretroviral therapy. The incidence rates of death and AIDS or death (AIDS/death) were estimated on the basis of age and current CD4 cell count.nnnRESULTSnA total of 1260 deaths (over 20,500 person-years of follow-up) and 1894 initial AIDS events (over 17,200 person-years of follow-up) were observed among 6741 patients (3244 children [i.e., patients < or =15 years of age] and 3497 adults). Young children (age, <5 years) experienced high morbidity and mortality rates. After adjustment for the CD4 cell count, the effect of age on disease progression was not significant among older children, whereas the risk increased markedly in association with increasing age among adults. Death rates were similar among older children and adults aged approximately 20 years, as were the rates of progression to AIDS/death when cases of serious recurrent bacterial infection, which has a more restrictive case definition in adults, were excluded.nnnCONCLUSIONSnSimilar CD4 cell count criteria for initiation of antiretroviral therapy can be applied to adults and children > or = 5 years of age.

Risk factors for proliferative sickle retinopathy.

The prevalence, incidence, and risk factors associated with proliferative sickle retinopathy (PSR) were investigated in 786 patients with homozygous sickle cell (SS) disease and 533 patients with sickle cell haemoglobin C (SC) disease. PSR was more common in SC disease, in which there was a significant predominance of males, and it increased with age in both genotypes. In SC disease the risk of developing PSR was highest between 15 and 24 years in males, between 20 and 39 years in females, and in SS disease between 25 and 39 years in both sexes. PSR tended to be bilateral, especially in SC disease. There was no evidence of familial clustering of PSR in SC siblings, and insufficient numbers of SS siblings were available to test for clustering. Haematological risk factors associated with PSR in SS disease were a high haemoglobin in males and a low fetal haemoglobin in both sexes and in SC disease, a high mean cell volume, and a low fetal haemoglobin in females.

The haematology of homozygous sickle cell disease after the age of 40 years

Haematological indices have been studied in 181 patients with homozygous sickle cell (SS) disease aged 40–73 years. Cross‐sectional analyses in 5‐year age bands indicated age‐related decreases in HbF (males only), total haemoglobin and platelet counts. Longitudinal studies within individuals confirmed the downward age‐related trend in haemoglobin and platelets and also revealed a falling reticulocyte count, most significant when expressed as absolute values. Total nucleated cells also fell although the decline was significant only in females. These observations are consistent with a progressive bone marrow failure which is not explained by the commonly occurring renal impairment in older SS patients since the changes persisted in analyses confined to patients with normal creatinine levels. The mechanism of this bone marrow failure is currently unknown.

Genotypic resistance testing in routine clinical care

Purpose of reviewGenotypic resistance testing has become part of routine clinical management of HIV-infected patients. Focussing on observational studies, this review looks at recent advances in this area. Recent findingsTranslation of the nucleotide sequence generated by the resistance test into clinically useful information remains a major challenge. A recent key development is the availability of therapy optimization tools to predict regimens that are most likely to achieve virological suppression. Standard genotypic resistance testing only examines protease and part of reverse transcriptase; as drugs are licensed to further targets, it has become necessary to expand the repertoire for testing. Traditionally, genotypic testing has not been attempted at viral loads less than 1000 copies/ml, but recent studies indicate that major mutations are often detected at much lower levels. Similarly, various methods have been developed for the detection of minority variants including allele-specific PCR, single-genome sequencing, and ultra-deep sequencing. SummaryThe technology and interpretation of genotypic resistance tests is in a phase of rapid development. It remains uncertain which of these developments will become part of routine clinical practice.

Haematological risk factors for pregnancy outcome in Jamaican women with homozygous sickle cell disease

Objective To examine the association between fetal outcome and the steady state haematology of mothers with homozygous sickle cell disease.

Residual Activity of Two HIV Antiretroviral Regimens Prescribed without Virological Monitoring

ABSTRACT 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 log10(HIV RNA) at week 48 or 96 and week 0 and related to 50% inhibitory concentration (IC50) 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 log10 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.

HIV prevention trial design in an era of effective pre-exposure prophylaxis.

Pre-exposure prophylaxis (PrEP) has demonstrated remarkable effectiveness protecting at-risk individuals from HIV-1 infection. Despite this record of effectiveness, concerns persist about the diminished protective effect observed in women compared with men and the influence of adherence and risk behaviors on effectiveness in targeted subpopulations. Furthermore, the high prophylactic efficacy of the first PrEP agent, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), presents challenges for demonstrating the efficacy of new candidates. Trials of new agents would typically require use of non-inferiority (NI) designs in which acceptable efficacy for an experimental agent is determined using pre-defined margins based on the efficacy of the proven active comparator (i.e. TDF/FTC) in placebo-controlled trials. Setting NI margins is a critical step in designing registrational studies. Under- or over-estimation of the margin can call into question the utility of the study in the registration package. The dependence on previous placebo-controlled trials introduces the same issues as external/historical controls. These issues will need to be addressed using trial design features such as re-estimated NI margins, enrichment strategies, run-in periods, crossover between study arms, and adaptive re-estimation of sample sizes. These measures and other innovations can help to ensure that new PrEP agents are made available to the public using stringent standards of evidence.

Statistical issues in trials of preexposure prophylaxis

Purpose of reviewWe discuss selected statistical issues in the design and analysis of preexposure prophylaxis (PrEP) trials. The general principles may inform thinking for other interventions in HIV prevention. Recent findingsTo date, four different designs have been used to determine the effectiveness of PrEP: randomized, double-blind, placebo-controlled; randomized, open-label, immediate or delayed access; nonrandomized comparison of HIV incidence according to the level of drug detected; comparison of the observed HIV incidence to the expected rate using historical control data. Open-label trials of PrEP, which assess public health effectiveness, complement the placebo-controlled trials which established the biological efficacy of TDF/ FTC. Future trials of PrEP will be highly challenging to design since a no PrEP group is difficult to justify and the natural control regimen, TDF/FTC, is highly efficacious. SummaryStandard statistical paradigms for noninferiority trials should be reconsidered for evaluating alternative PrEP regimens.

MEASLES IN INDUSTRIALISED URBAN AREAS

Our data suggest that in developed, as in developing, countries, measles may occur at a very young age both in poor families living in crowded conditions in cities and in families referred to day-care centres. This age factor should be taken into account in mass vaccination programmes.