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

Abstract 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 ≥ 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.

Use of total lymphocyte count for informing when to start antiretroviral therapy in HIV-infected children : a meta-analysis of longitudinal data

Background Total lymphocyte count has been proposed as an alternative to the percentage of CD4+ T-cells to indicate when antiretroviral therapy should be started in children with HIV in resource-poor settings. We aimed to assess thresholds of total lymphocyte count at which antiretroviral therapy should be considered, and compared monitoring of total lymphocyte count with monitoring of CD4-cell percentage.Methods Longitudinal data on 3917 children with HIV infection were pooled from observational and randomised studies in Europe and the USA. The 12-month risks of death and AIDS by most recent total lymphocyte count and age were estimated by parametric survival models, based on measurements before antiretroviral therapy or during zidovudine monotherapy. Risks were derived and compared at thresholds of total lymphocyte count and CD4-cell percentage for starting antiretroviral therapy recommended in WHO 2003 guidelines.Findings Total lymphocyte count was a powerful predictor of the risk of disease progression despite a weak correlation with CD4-cell percentage (r=0.08-0.19 dependent on age). For children older than 2 years, the 12-month risk of death and AIDS increased sharply at values less than 1500-2000 cells per mu L, with little trend at higher values. Younger children had higher risks and total lymphocyte count was less prognostic. Mortality risk was substantially higher at thresholds of total lymphocyte count recommended by WHO than at corresponding thresholds of CD4-cell percentage. When the markers were compared at the threshold values at which mortality risks were about equal, total lymphocyte count was as effective as CD4-cell percentage for identifying children before death, but resulted in an earlier start of antiretroviral therapy.Interpretation In this population, total lymphocyte count was a strong predictor of short-term disease progression, being only marginally less predictive than CD4-cell percentage. Confirmatory studies in resource-poor settings are needed to identify the most cost-effective markers to guide initiation of antiretroviral therapy.BACKGROUND Total lymphocyte count has been proposed as an alternative to the percentage of CD4+ T-cells to indicate when antiretroviral therapy should be started in children with HIV in resource-poor settings. We aimed to assess thresholds of total lymphocyte count at which antiretroviral therapy should be considered, and compared monitoring of total lymphocyte count with monitoring of CD4-cell percentage. METHODS Longitudinal data on 3917 children with HIV infection were pooled from observational and randomised studies in Europe and the USA. The 12-month risks of death and AIDS by most recent total lymphocyte count and age were estimated by parametric survival models, based on measurements before antiretroviral therapy or during zidovudine monotherapy. Risks were derived and compared at thresholds of total lymphocyte count and CD4-cell percentage for starting antiretroviral therapy recommended in WHO 2003 guidelines. FINDINGS Total lymphocyte count was a powerful predictor of the risk of disease progression despite a weak correlation with CD4-cell percentage (r=0.08-0.19 dependent on age). For children older than 2 years, the 12-month risk of death and AIDS increased sharply at values less than 1500-2000 cells per muL, with little trend at higher values. Younger children had higher risks and total lymphocyte count was less prognostic. Mortality risk was substantially higher at thresholds of total lymphocyte count recommended by WHO than at corresponding thresholds of CD4-cell percentage. When the markers were compared at the threshold values at which mortality risks were about equal, total lymphocyte count was as effective as CD4-cell percentage for identifying children before death, but resulted in an earlier start of antiretroviral therapy. INTERPRETATION In this population, total lymphocyte count was a strong predictor of short-term disease progression, being only marginally less predictive than CD4-cell percentage. Confirmatory studies in resource-poor settings are needed to identify the most cost-effective markers to guide initiation of antiretroviral therapy.

Discordance between CD4 cell count and CD4 cell percentage : implications for when to start antiretroviral therapy in HIV-1 infected children

Objective:Antiretroviral therapy (ART) guidelines for HIV-1-infected children specify both absolute CD4 cell count and CD4 percentage thresholds at which consideration should be given to initiating ART. This leads to clinical dilemma when one marker is below the threshold, whereas the other is above. Design:Data were obtained on a large group of children followed longitudinally in trials and cohort studies in Europe and the USA. Follow-up was censored 6 months after the start of any antiretroviral drug other than zidovudine monotherapy. Methods:Discordance between CD4 cell count and percentage was defined in relation to ART initiation thresholds in World Health Organization (WHO) and European paediatric treatment guidelines. The relative prognostic value of CD4 cell count and percentage for progression to AIDS/death was investigated using time-updated Cox proportional hazards models, stratified by age. Results:Among 3345 children, with a total of 21 815 pairs of CD4 measurements analysed, 980 developed AIDS and/or died after a median follow-up of 1.7 years. Over one-half of children had discordant values of CD4 cell markers at the first visit when one or both treatment thresholds were crossed and approximately one-third had the same pattern of discordance at a subsequent measurement. Models suggested that CD4 percentage had little or no prognostic value over and above that contained in CD4 cell count, irrespective of age. Conclusions:More emphasis should be placed on CD4 cell count than on CD4 percentage in deciding when to start ART in HIV-1-infected children.

Quality-of-life outcomes from the Prostate Adenocarcinoma: TransCutaneous Hormones (PATCH) trial evaluating luteinising hormone-releasing hormone agonists versus transdermal oestradiol for androgen suppression in advanced prostate cancer

To compare quality‐of‐life (QoL) outcomes at 6 months between men with advanced prostate cancer receiving either transdermal oestradiol (tE2) or luteinising hormone‐releasing hormone agonists (LHRHa) for androgen‐deprivation therapy (ADT).

A Randomised Comparison Evaluating Changes in Bone Mineral Density in Advanced Prostate Cancer: Luteinising Hormone-releasing Hormone Agonists Versus Transdermal Oestradiol

Background Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa. Objective To compare BMD change in men receiving either LHRHa or oestradiol patches (OP). Design, setting, and participants Men with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006–2011; 1:1, thereafter) were recruited into a BMD study (2006–2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr. Interventions LHRHa as per local practice, OP (FemSeven 100 μg/24 h patches). Outcome measurements and statistical analysis The primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance. Results and limitations A total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was −0.021 g/cm3 for patients randomised to the LHRHa arm (mean percentage change −1.4%) and +0.069 g/cm3 for the OP arm (+6.0%; p < 0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa −3.0% and OP +7.9% (p < 0.001). Conclusions Transdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial. Patient summary This study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial. Trial registration ISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784).

Androgen Deprivation Therapy and the Re-emergence of Parenteral Estrogen in Prostate Cancer

Androgen deprivation therapy (ADT) resulting in testosterone suppression is central to the management of prostate cancer (PC). As PC incidence increases, ADT is more frequently prescribed, and for longer periods of time as survival improves. Initial approaches to ADT included orchiectomy or oral estrogen (diethylstilbestrol [DES]). DES reduces PC-specific mortality, but causes substantial cardiovascular (CV) toxicity. Currently, luteinizing hormone-releasing hormone agonists (LHRHa) are mainly used; they produce low levels of both testosterone and estrogen (as estrogen in men results from the aromatization of testosterone), and many toxicities including osteoporosis, fractures, hot flashes, erectile dysfunction, muscle weakness, increased risk for diabetes, changes in body composition, and CV toxicity. An alternative approach is parenteral estrogen, it suppresses testosterone, appears to mitigate the CV complications of oral estrogen by avoiding first-pass hepatic metabolism, and avoids complications caused by estrogen deprivation. Recent research on the toxicity of ADT and the rationale for revisiting parenteral estrogen is discussed.

Outcomes after viral load rebound on first-line antiretroviral treatment in children with HIV in the UK and Ireland: an observational cohort study

BACKGROUND About a third of children with HIV have virological failure within 2 years of beginning antiretroviral treatment (ART). We assessed the probability of switch to second-line ART or virological re-suppression without switch in children who had virological rebound on first-line ART in the UK and Ireland. METHODS In this study, we used data reported to the Collaborative HIV Paediatric Study (CHIPS), a national multicentre observational cohort. We included children with virological rebound (confirmed viral load>400 copies per mL after suppression<400 copies per mL) on first-line ART. We did a competing-risk analysis to estimate the probability of switch to second-line treatment, confirmed resuppression (two consecutive viral load measurments<400 copies per mL) without switch, and continued viral load above 400 copies per mL without switch. We also assessed factors that predicted a faster time to switch. FINDINGS Of the 900 children starting first-line ART who had a viral load below 400 copies per mL within a year of starting treatment, 170 (19%) had virological rebound by a median of 20·6 months (IQR 9·7–40·5). At rebound, median age was 10·6 years (5·6–13·4), median viral load was 3·6 log10 copies per mL (3·1–4·2), and median CD4% was 24% (17–32). 89 patients (52%) switched to second-line ART at a median of 4·9 months (1·7–13·4) after virological rebound, 53 (31%) resuppressed without switch (19 [61%] of 31 patients on a first-line regimen that included a protease inhibitor and 31 [24%] of 127 patients on a first-line regimen that included a non-nucleoside reverse transcriptase inhibitor; NNRTI), and 28 (16%) neither resuppressed nor switched. At 12 months after rebound, the estimated probability of switch was 38% (95% CI 30–45) and of resuppression was 27% (21–34). Faster time to switch was associated with a higher viral load (p<0·0001), later calendar year at virological rebound (p=0·02), and being on an NNRTI-based or triple nucleoside reverse transcriptase inhibitor-based versus protease-inhibitor-based first-line regimen (p=0·001). INTERPRETATION A third of children with virological rebound resuppressed without switch. Clinicians should consider the possibility of resuppression with adherence support before switching treatment in children with HIV. FUNDING NHS England (London Specialised Commissioning Group).

Parenteral oestrogen: Effective and safer than both oral oestrogen and contemporary androgen deprivation therapy for prostate cancer?

MRC Clinical TrialsUnit, London, UKDear Editor,In this era of emerging novel, complex prostatecancer treatments, it was refreshing to review a his-torical perspective of the merits of oestrogen, the firstpharmacological agent used as androgen deprivationtherapy (ADT), i.e. suppression of testosterone byabout 95% to castrate levels [1]. Prescribed for oraluse as diethylstilboestrol, it had to be discontinuedbecause of the resulting high cardiovascular toxicityand deaths, despite evidence of greater efficacy thanorchiectomy as a prostate cancer treatment [2].Although oestrogen suppresses testosterone primarilythrough the hypothalamic–pituitary–gonadal axis,additional mechanisms similar to those of some ofthe newest therapies under investigation may accountfor this greater efficacy, e.g. inhibition of 17,20-lyaseand consequent extragonadal steroid synthesis, anabiraterone-like action [1].ADT was subsequently achieved by replacing oraloestrogenwithluteinizinghormone-releasinghormoneagonist (LHRHa), which also suppresses testosteronetocastratelevels.Therateoftestosteronesuppressioniseven more marked with an LHRH antagonist [3].However, this reduction in testosterone also results insuppression of the endogenously produced oestrogenby about 80%. Oestrogen in men is derived fromaromatization of testosterone [4,5]. The resulting iat-rogenic hypogonadism (of both male and female sexhormones) causes unwanted side-effects includingsarcopenia, anaemia and erectile dysfunction (fromtestosterone depletion), and osteoporosis (with a highrisk of fractures), hot flushes and, probably, cognitiveimpairment (from oestrogen depletion) [6].Can the potential benefits of oestrogen berealized without the cardiovascular andhypogonadal risks of the oral route?Parenteraloestrogenadministration(intramuscularaspolyoestradiolphosphateortransdermalasoestradiol)avoids first pass through the liver and the consequenthepatic overexpression of proteins, includingthose affecting coagulation, thereby diminishingcardiovascular toxicity substantially [7,8]. Exogenousoestrogen also replaces suppressed endogenousoestrogen, potentially diminishing the oestrogendepletion-relatedtoxicityofLHRHa.Thus,parenteraloestrogen as single-agent therapy offers potential ben-efits over either oral diethylstilboestrol or LHRHathrough (i) treating the cancer, by suppressing testos-terone to castrate levels, (ii) reducing the risk ofcardiovascular hazards of oral oestrogen, and (iii)possiblyavoidingsomeoftheadverseeffectsofLHRHaby maintaining endogenous levels of oestrogen.The Prostate Adenocarcinoma TransCutaneousHormones (PATCH) study, funded by CancerResearch UK, is a randomized phase II trial compar-ing LHRHa with transdermal oestrogen patches inmen with locally advanced or metastatic prostatecancer. Stage 1 of this study (n = 254) specificallyaddressed cardiovascular toxicity as the primary out-come, and data showed similar rates of cardiovascular

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

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

Discordance between CD4 cell count and CD4 cell percentage

Objective:Antiretroviral therapy (ART) guidelines for HIV-1-infected children specify both absolute CD4 cell count and CD4 percentage thresholds at which consideration should be given to initiating ART. This leads to clinical dilemma when one marker is below the threshold, whereas the other is above. Design:Data were obtained on a large group of children followed longitudinally in trials and cohort studies in Europe and the USA. Follow-up was censored 6 months after the start of any antiretroviral drug other than zidovudine monotherapy. Methods:Discordance between CD4 cell count and percentage was defined in relation to ART initiation thresholds in World Health Organization (WHO) and European paediatric treatment guidelines. The relative prognostic value of CD4 cell count and percentage for progression to AIDS/death was investigated using time-updated Cox proportional hazards models, stratified by age. Results:Among 3345 children, with a total of 21 815 pairs of CD4 measurements analysed, 980 developed AIDS and/or died after a median follow-up of 1.7 years. Over one-half of children had discordant values of CD4 cell markers at the first visit when one or both treatment thresholds were crossed and approximately one-third had the same pattern of discordance at a subsequent measurement. Models suggested that CD4 percentage had little or no prognostic value over and above that contained in CD4 cell count, irrespective of age. Conclusions:More emphasis should be placed on CD4 cell count than on CD4 percentage in deciding when to start ART in HIV-1-infected children.