Optimal CD4 count for treatment initiation in HIV-infection: impact of CD4 observation frequency and grace periods, and performance of dynamic marginal structural models, in realistic scenarios

Background: In HIV infection, dynamic marginal structural models have estimated the optimal CD4 for treatment initiation to minimize AIDS/death. The impact of CD4 observation frequency and grace periods (permitted delay to initiation) on the optimal regimen has not been investigated nor has the performance of dynamic marginal structural models in moderately sized data sets—two issues that are relevant to many applications. Methods: To determine optimal regimens, we simulated 31,000,000 HIV-infected persons randomized at CD4 500–550 cells/mm3 to regimens “initiate treatment within a grace period following observed CD4 first <x cells/mm3,” x = 200, 210, …, 500. Natural history and treatment response were simulated using previous model estimates from CASCADE data. Optimal treatment regimens for the observation frequencies and grace periods were defined by highest 10-year AIDS-free survival. To evaluate the performance of dynamic marginal structural models, we simulated 1000 observational studies (n = 3,000) with CD4-dependent treatment initiation. Results: Decreasing the frequency of CD4 measurements from monthly to every 3, 6, and 12 months increased the optimal regimen from a CD4 level of 350 (10-year AIDS-free survival, 0.8657) to 410 (0.8650), 460 (0.8634), and 490 (0.8564), respectively. Under a regimen defined by x = 350 with annual CD4s, 10-year AIDS-free survival dropped to 0.8304. Extending the grace period from 1 to 3 or 6 months, with 3-monthly CD4s, maintained the optimal regimen at 410 for 3 months and increased it to 460 for 6 months. In observational studies with 3-monthly CD4s, the mean (SE) estimated optimal regimen was 402 (76), 424 (66), and 430 (63) with 1-, 3-, and 6-month grace periods; 24%, 15%, and 14% of estimated optimal regimens resulted in >0.5% lower AIDS-free survival compared with the true optimal regimen. Conclusions: The optimal regimen is strongly influenced by CD4 frequency and less by grace period length. Dynamic marginal structural models lack precision at moderate sample sizes

Promoting help-seeking in response to symptoms amongst primary care patients at high risk of lung cancer: a mixed method study

Background: Lung cancer symptoms are vague and difficult to detect. Interventions are needed to promote early diagnosis, however health services are already pressurised. This study explored symptomology and help-seeking behaviours of primary care patients at ‘high-risk’ of lung cancer (≥50 years old, recent smoking history), to inform targeted interventions. Methods: Mixed method study with patients at eight general practitioner (GP) practices across south England. Study incorporated: postal symptom questionnaire; clinical records review of participant consultation behaviour 12 months pre- and post-questionnaire; qualitative participant interviews (n = 38) with a purposive sample. Results: A small, clinically relevant group (n = 61/908, 6.7%) of primary care patients was identified who, despite reporting potential symptoms of lung cancer in questionnaires, had not consulted a GP ≥12 months. Of nine symptoms associated with lung cancer, 53.4% (629/1172) of total respondents reported ≥1, and 35% (411/1172) reported ≥2. Most participants (77.3%, n = 686/908) had comorbid conditions; 47.8%, (n = 414/908) associated with chest and respiratory symptoms. Participant consulting behaviour significantly increased in the 3-month period following questionnaire completion compared with the previous 3-month period (p = .002), indicating questionnaires impacted upon consulting behaviour. Symptomatic non-consulters were predominantly younger, employed, with higher multiple deprivation scores than their GP practice mean. Of symptomatic non-consulters, 30% (18/61) consulted ≤1 month post-questionnaire, with comorbidities subsequently diagnosed for five participants. Interviews (n = 39) indicated three overarching differences between the views of consulting and non-consulting participants: concern over wasting their own as well as GP time; high tolerance threshold for symptoms; a greater tendency to self-manage symptoms. Conclusions: This first study to examine symptoms and consulting behaviour amongst a primary care population at ‘high- risk’ of lung cancer, found symptomatic patients who rarely consult GPs, might respond to a targeted symptom elicitation intervention. Such GP-based interventions may promote early diagnosis of lung cancer or other comorbidities, without burdening already pressurised services

Nevirapine concentrations in HIV-infected children treated with divided fixed-dose combination antiretroviral tablets in Malawi and Zambia.

OBJECTIVE: To investigate nevirapine concentrations in African HIV-infected children receiving divided Triomune tablets (stavudine+lamivudine+nevirapine). DESIGN: Cross-sectional study. METHODS: Steady-state plasma nevirapine concentrations were determined in Malawian and Zambian children aged 8 months to 18 years receiving Triomune in routine outpatient settings. Predictors from height-for-age, body mass index (BMI)-for-age, age, sex, post-dose sampling time and dose/m2/day were investigated using centre-stratified regression with backwards elimination (P or =300 mg/m2/day nevirapine had subtherapeutic concentrations (<3 mg/l) compared with 22 (23%) of those prescribed <300 mg/m2/day; most children with subtherapeutic nevirapine concentrations were taking half or quarter Triomune tablets. Lower nevirapine concentrations were independently associated with lower height-for-age (indicating stunting) (0.37 mg/l per unit higher [95% confidence interval (CI): -0.003, +0.74]; P=0.05), lower prescribed dose/m2 (+0.89 mg/l per 50 mg/m2 higher [95% CI: 0.32, 1.46]; P=0.002) and higher BMI-for-age (indicating lack of wasting) (-0.42 mg/l per unit higher [95% CI: -0.80, -0.04]; P=0.03). CONCLUSIONS: Currently available adult fixed-dose combination tablets are not well suited to children, particularly at younger ages: Triomune 30 is preferable to Triomune 40 because of the higher dose of nevirapine relative to stavudine. Further research is required to confirm that concentrations are reduced in stunted children but increased in wasted children. Development of appropriate paediatric fixed-dose combination tablets is essential if antiretroviral therapy is to be made widely available to children in resource-limited settings

The risk of AIDS-defining events is decreasing over time in the German HIV-1 Seroconverter Cohort

<p>Abstract</p> <p>Background</p> <p>With ageing of the HIV-infected population, long-term exposure to treatment, varying adherence, emerging resistance and complications to therapies, effectiveness of Highly Active Antiretroviral Therapy (HAART) needs to be monitored continuously at the population level. The German HIV-1 Seroconverter Cohort is a multi-centre, open, long-term observational cohort including patients with a known or reliably estimated date of HIV-infection i.e. last negative and first positive HIV antibody test within a maximum three-year interval or laboratory evidence of seroconversion. Our study aims to investigate survival improvements and changes in AIDS risk over calendar periods in the German HIV-1 Seroconverter Cohort.</p> <p>Methods</p> <p>Retrospective (for the pre-1997 period) and prospective (since 1997) data from the German HIV-1 Seroconverter Cohort were used. Time from seroconversion to first AIDS-defining event over calendar periods was analysed by using Cox models adjusting for age at seroconversion, sex, transmission groups and short HIV test interval. Kaplan-Meier methods were used to determine expected survival (remaining AIDS-free) by calendar period.</p> <p>Results</p> <p>2162 seroconverters with 8976 person-years of observation were included in our analysis (up to 31.12.2010). A total of 196 first AIDSdefining events were reported. Two periods i.e. 19972000 and 2007-2010 were statistically associated with a reduction in the risk of AIDS, accounting for an overall reduction of 80%. Compared to1997-2000, hazard ratios were 2.6 (95%CI, 1.6-4.8; p=0.000) in pre-1997 and 0.5 (95%CI, 0.3-0.8; p=0.007) in 20072010. Independent risk factor for AIDS progression was age at seroconversion (HR, 1.3 per 10year-increase; p=0.001).</p> <p>Conclusion</p> <p>HAART effectiveness has improved in the German HIV-1-Seroconverter Cohort. The risk to develop AIDS decreased significantly in 19972000 and in 20072010. However, elderly may require particular monitoring in view of their faster progression to AIDS.</p