This paper describes a targeted maximum likelihood estimator (TMLE) for the parameters of longitudinal static and dynamic marginal structural models. We consider a longitudinal data structure consisting of baseline covariates, time-dependent intervention nodes, intermediate timedependent covariates, and a possibly time-dependent outcome. The intervention nodes at each time point can include a binary treatment as well as a right-censoring indicator. Given a class of dynamic or static interventions, a marginal structural model is used to model the mean of the intervention-specific counterfactual outcome as a function of the intervention, time point, and possibly a subset of baseline covariates. Because the true shape of this function is rarely known, the marginal structural model is used as a working model. The causal quantity of interest is defined as the projection of the true function onto this working model. Iterated conditional expectation double robust estimators for marginal structural model parameters were previously proposed by Robins ( , 2002 and Bang and Robins (2005). Here we build on this work and present a pooled TMLE for the parameters of marginal structural working models. We compare this pooled estimator to a stratified TMLE (Schnitzer et al. 2014) that is based on estimating the intervention-specific mean separately for each intervention of interest. The performance of the pooled TMLE is compared to the performance of the stratified TMLE and the performance of Correspondence to: Maya Petersen, mayaliv@berkeley.edu. HHS Public Access

Objectives To determine magnitude and reasons of loss to programme and poor antiretroviral prophylaxis coverage in prevention of mother-to-child transmission (PMTCT) programmes in sub-Saharan Africa. Design Systematic review and meta-analysis. Methods We searched PubMed and Embase databases for PMTCT studies in sub-Saharan Africa published between January 2002 and March 2012. Outcomes were the percentage of pregnant women (i) tested for HIV, (ii) initiating antiretroviral prophylaxis, (iii) having a CD4 cell count measured, and (iv) initiating antiretroviral combination therapy (cART) if eligible. In children outcomes were (v) early infant diagnosis for HIV, and (vi) cART initiation. We combined data using random-effects meta-analysis and identified predictors of uptake of interventions. Results Forty-four studies from 15 countries including 75,172 HIV-infected pregnant women were analyzed. HIV-testing uptake at antenatal care services was 94% (95% confidence intervals [CI] 92-95%) for opt-out and 58% (95% CI 40-75%) for opt-in testing. Coverage with any antiretroviral prophylaxis was 70% (95% CI 64-76%) and 62% (95% CI 50-73%) of pregnant women eligible for cART received treatment. Sixty-four percent (95% CI 48-81%) of HIV exposed infants had early diagnosis performed and 55% (95% CI 36-74%) were tested between 12 and 18 months. Uptake of PMTCT interventions was improved if cART was provided at the antenatal clinic and if the male partner was involved. Conclusions In sub-Saharan Africa, uptake of PMTCT interventions and early infant diagnosis is unsatisfactory. An integrated family-centered approach seems to improve retention.

Background-The number of patients in need of second-line antiretroviral drugs is increasing in sub-Saharan Africa. We aimed to project the need of second-line antiretroviral therapy (ART) in adults in sub-Saharan Africa up to 2030.

Objectives HIV ‘treatment as prevention’ (TasP) describes early treatment of HIV-infected patients intended to reduce viral load (VL) and transmission. Crucial assumptions for estimating TasP's effectiveness are the underlying estimates of transmission risk. We aimed to determine transmission risk during primary infection, and of the relation of HIV transmission risk to VL. Design Systematic review and meta-analysis. Methods We searched PubMed and Embase databases for studies that established a relationship between VL and transmission risk, or primary infection and transmission risk, in serodiscordant couples. We analyzed assumptions about the relationship between VL and transmission risk, and between duration of primary infection and transmission risk. Results We found 36 eligible articles, based on six different study populations. Studies consistently found that larger VLs lead to higher HIV transmission rates, but assumptions about the shape of this increase varied from exponential increase to saturation. The assumed duration of primary infection ranged from 1.5 to 12 months; for each additional month, the log10 transmission rate ratio between primary and asymptomatic infection decreased by 0.40. Conclusions Assumptions and estimates of the relationship between VL and transmission risk, and the relationship between primary infection and transmission risk, vary substantially and predictions of TasP's effectiveness should take this uncertainty into account.

Background Monitoring of HIV viral load in patients on combination antiretroviral therapy (ART) is not generally available in resource-limited settings. We examined the cost-effectiveness of qualitative point-of-care viral load tests (POC-VL) in sub-Saharan Africa. Design Mathematical model based on longitudinal data from the Gugulethu and Khayelitsha township ART programmes in Cape Town, South Africa. Methods Cohorts of patients on ART monitored by POC-VL, CD4 cell count or clinically were simulated. Scenario A considered the more accurate detection of treatment failure with POC-VL only, Scenario B also considered the effect on HIV transmission. Scenario C further assumed that the risk of virologic failure is halved with POC-VL due to improved adherence. We estimated the change in costs per quality-adjusted life-year gained (incremental cost-effectiveness ratios, ICER) of POC-VL compared to CD4 and clinical monitoring. Results POC-VL tests with detection limits <1000 copies/ml increased costs due to unnecessary switches to second-line ART, without improving survival. Assuming POC-VL unit costs between US$5–US$20 and detection limits between 1000 and 10000 copies/ml, the ICER of POC-VL was US$4010–US$9230 compared to clinical and US$5960–US$25540 compared to CD4 monitoring. In Scenario B the corresponding ICERs were US$2450–US$5830 and US$2230–US$10380. In Scenario C the ICER ranged between US$960–US$2500 compared to clinical monitoring and between cost-saving and US$2460 compared to CD4 monitoring. Conclusions The cost-effectiveness of POC-VL for monitoring ART is improved by a higher detection limit, by taking the reduction in new HIV infections into account and when assuming that failure of first-line ART is reduced due to targeted adherence counselling.

Background The WHO’s 2013 revisions to its Consolidated Guidelines on ARVs will recommend routine viral load monitoring (VLM), rather than clinical or immunological monitoring, as the preferred monitoring approach on the basis of clinical evidence. However, HIV programmes in resource-limited settings require guidance on the most cost-effective use of resources given other competing priorities, including expansion of ART coverage. Here we assess the cost-effectiveness of alternative patient monitoring strategies. Methods A range of monitoring strategies was evaluated, including clinical, CD4 and viral load monitoring alone and together at different frequencies and with different criteria for switching to second-line therapies. Three independently-constructed and validated models were analysed simultaneously. Costs were estimated based on resource use projected in the models and associated unit costs; impact was quantified as disability-adjusted life years (DALYs) averted. Alternatives were compared using incremental cost-effectiveness analysis. Results All models show that clinical monitoring delivers significant benefit compared to a hypothetical baseline scenario with no monitoring or switching. Regular CD4 cell count monitoring confers a benefit over clinical monitoring alone, at an incremental cost that makes it affordable in more settings than VLM, which is currently more expensive. VLM without CD4 every six to 12 months provides the greatest reductions in morbidity and mortality, but incurs a high cost per DALY averted, resulting in lost opportunities to generate health gains if implemented instead of increasing ART coverage or expanding ART eligibility. Interpretation The priority for HIV programmes should be to expand ART coverage, firstly at CD4 <350 cells and then at CD4 <500, using lower-cost clinical or CD4 monitoring. At current costs, VLM should be considered only after high ART coverage has been achieved. Point-of-care technologies and other factors reducing costs may make VLM more affordable in future. Funding The HIV Modelling Consortium is funded by the Bill and Melinda Gates Foundation. Funding for this work was also provided by the World Health Organization.

Background Tuberculosis (TB) is the leading cause of death in South Africa. The burden of disease varies by age, with peaks in TB notification rates in the HIV-negative population at ages 0-5, 20-24 and 45-49 years. There is little variation between age groups in the rates in the HIV-positive population. The drivers of this age pattern remain unknown. Methods We developed an age-structured simulation model of Mycobacterium tuberculosis (Mtb) transmission in Cape Town, South Africa. We considered five states of TB progression: susceptible, infected (latent TB), active TB, treated TB and treatment default. Latently infected individuals could be re-infected; a previous Mtb infection slowed progression to active disease. We further considered three states of HIV progression: HIV negative, HIV positive, on antiretroviral therapy. To parameterize the model, we analysed treatment outcomes from the Cape Town electronic TB register, social mixing patterns from a Cape Town community and literature estimates for other parameters. To investigate the main drivers behind the age patterns, we conducted sensitivity analyses on all parameters related to the age structure. Results The model replicated the age patterns in HIV-negative TB notification rates of Cape Town in 2009. Simulated TB notification rate in HIV-negative patients was 1,000/100,000 person-years (pyrs) in children aged < 5 years and decreased to 51/100,000 in children 5-15 years. The peak in early adulthood occurred at 25-29 years (463/100,000 pyrs). After a subsequent decline, simulated TB notification rates gradually increased from the age of 30 years. Sensitivity analyses showed that the dip after the early adult peak was due to the protective effect of latent TB and that retreatment TB was mainly responsible for the rise in TB notification rates from the age of 30 years. Conclusion The protective effect of a first latent infection on subsequent infections and the faster progression in previously treated patients are the key determinants of the age-structure of TB notification rates in Cape Town.

Aberrant pro-survival signaling is a hallmark of cancer cells, but the response to chemotherapy is poorly understood. In this study, we investigate the initial signaling response to standard induction chemotherapy in a cohort of 32 acute myeloid leukemia (AML) patients, using 36-dimensional mass cytometry. Through supervised and unsupervised machine learning approaches, we find that reduction of extracellular-signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK) phosphorylation in the myeloid cell compartment 24 h post-chemotherapy is a significant predictor of patient 5-year overall survival in this cohort. Validation by RNA sequencing shows induction of MAPK target gene expression in patients with high phospho-ERK1/2 24 h post-chemotherapy, while proteomics confirm an increase of the p38 prime target MAPK activated protein kinase 2 (MAPKAPK2). In this study, we demonstrate that mass cytometry can be a valuable tool for early response evaluation in AML and elucidate the potential of functional signaling analyses in precision oncology diagnostics.