Modelling the relative cost-effectiveness of the RTS,S/AS01 malaria vaccine compared to investment in vector control or chemoprophylaxis.

BACKGROUND: The World Health Organization has recommended a 4-dose schedule of the RTS,S/AS01 (RTS,S) vaccine for children in regions of moderate to high P. falciparum transmission. Faced with limited supply and finite resources, global funders and domestic malaria control programs will need to examine the relative cost-effectiveness of RTS,S and identify target areas for vaccine implementation relative to scale-up of existing interventions. METHODS: Using an individual-based mathematical model of P. falciparum, we modelled the cost-effectiveness of RTS,S across a range of settings in sub-Saharan Africa, incorporating various rainfall patterns, insecticide-treated net (ITN) use, treatment coverage, and parasite prevalence bands. We compare age-based and seasonal RTS,S administration to increasing ITN usage, switching to next generation ITNs in settings experiencing insecticide-resistance, and introduction of seasonal malaria chemoprevention (SMC) in areas of seasonal transmission. RESULTS: For RTS,S to be the most cost-effective intervention option considered, the maximum cost per dose was less than $9.30 USD in 90.9% of scenarios. Nearly all (89.8%) values at or above $9.30 USD per dose were in settings with 60% established bed net use and / or with established SMC, and 76.3% were in the highest PfPR2-10 band modelled (40%). Addition of RTS,S to strategies involving 60% ITN use, increased ITN usage or a switch to PBO nets, and SMC, if eligible, still led to significant marginal case reductions, with a median of 2,653 (IQR: 1,741 to 3,966) cases averted per 100,000 people annually, and 82,270 (IQR: 54,034 to 123,105) cases averted per 100,000 fully vaccinated children (receiving at least three doses). CONCLUSIONS: Use of RTS,S results in reductions in malaria cases and deaths even when layered upon existing interventions. When comparing relative cost-effectiveness, scale up of ITNs, introduction of SMC, and switching to new technology nets should be prioritized in eligible settings.

Seasonal use case for the RTS,S/AS01 malaria vaccine: a mathematical modelling study.

BACKGROUND: A 2021 clinical trial of seasonal RTS,S/AS01E (RTS,S) vaccination showed that vaccination was non-inferior to seasonal malaria chemoprevention (SMC) in preventing clinical malaria. The combination of these two interventions provided significant additional protection against clinical and severe malaria outcomes. Projections of the effect of this novel approach to RTS,S vaccination in seasonal transmission settings for extended timeframes and across a range of epidemiological settings are needed to inform policy recommendations. METHODS: We used a mathematical, individual-based model of malaria transmission that was fitted to data on the relationship between entomological inoculation rate and parasite prevalence, clinical disease, severe disease, and deaths from multiple sites across Africa. The model was validated with results from a phase 3b trial assessing the effect of SV-RTS,S in Mali and Burkina Faso. We developed three intervention efficacy models with varying degrees and durations of protection for our population-level modelling analysis to assess the potential effect of an RTS,S vaccination schedule based on age (doses were delivered to children aged 6 months, 7·5 months, and 9 months for the first three doses, and at 27 months of age for the fourth dose) or season (children aged 5-17 months at the time of first vaccination received the first three doses in the 3 months preceding the transmission season, with any subsequent doses up to five doses delivered annually) in seasonal transmission settings both in the absence and presence of SMC with sulfadoxine-pyrimethamine plus amodiaquine. This is modelled as a full therapeutic course delivered every month for four or five months of the peak in transmission season. Estimates of cases and deaths averted in a population of 100 000 children aged 0-5 years were calculated over a 15-year time period for a range of levels of malaria transmission intensity (Plasmodium falciparum parasite prevalence in children aged 2-10 years between 10% and 65%) and over two west Africa seasonality archetypes. FINDINGS: Seasonally targeting RTS,S resulted in greater absolute reductions in malaria cases and deaths compared with an age-based strategy, averting an additional 14 000-47 000 cases per 100 000 children aged 5 years and younger over 15 years, dependent on seasonality and transmission intensity. We predicted that adding seasonally targeted RTS,S to SMC would reduce clinical incidence by up to an additional 42 000-67 000 cases per 100 000 children aged 5 years and younger over 15 years compared with SMC alone. Transmission season duration was a key determinant of intervention effect, with the advantage of adding RTS,S to SMC predicted to be smaller with shorter transmission seasons. INTERPRETATION: RTS,S vaccination in seasonal settings could be a valuable additional tool to existing interventions, with seasonal delivery maximising the effect relative to an age-based approach. Decisions surrounding deployment strategies of RTS,S in such settings will need to consider the local and regional variations in seasonality, current rates of other interventions, and potential achievable RTS,S coverage. FUNDING: UK Medical Research Council, UK Foreign Commonwealth & Development Office, The Wellcome Trust, and The Royal society.

The J-IDEA Pandemic Planner: A Framework for Implementing Hospital Provision Interventions During the COVID-19 Pandemic.

BACKGROUND: Planning for extreme surges in demand for hospital care of patients requiring urgent life-saving treatment for coronavirus disease 2019 (COVID-19), while retaining capacity for other emergency conditions, is one of the most challenging tasks faced by health care providers and policymakers during the pandemic. Health systems must be well-prepared to cope with large and sudden changes in demand by implementing interventions to ensure adequate access to care. We developed the first planning tool for the COVID-19 pandemic to account for how hospital provision interventions (such as cancelling elective surgery, setting up field hospitals, or hiring retired staff) will affect the capacity of hospitals to provide life-saving care. METHODS: We conducted a review of interventions implemented or considered in 12 European countries in March to April 2020, an evaluation of their impact on capacity, and a review of key parameters in the care of COVID-19 patients. This information was used to develop a planner capable of estimating the impact of specific interventions on doctors, nurses, beds, and respiratory support equipment. We applied this to a scenario-based case study of 1 intervention, the set-up of field hospitals in England, under varying levels of COVID-19 patients. RESULTS: The Abdul Latif Jameel Institute for Disease and Emergency Analytics pandemic planner is a hospital planning tool that allows hospital administrators, policymakers, and other decision-makers to calculate the amount of capacity in terms of beds, staff, and crucial medical equipment obtained by implementing the interventions. Flexible assumptions on baseline capacity, the number of hospitalizations, staff-to-beds ratios, and staff absences due to COVID-19 make the planner adaptable to multiple settings. The results of the case study show that while field hospitals alleviate the burden on the number of beds available, this intervention is futile unless the deficit of critical care nurses is addressed first. DISCUSSION: The tool supports decision-makers in delivering a fast and effective response to the pandemic. The unique contribution of the planner is that it allows users to compare the impact of interventions that change some or all inputs.

Adapting hospital capacity to meet changing demands during the COVID-19 pandemic.

BACKGROUND: To calculate hospital surge capacity, achieved via hospital provision interventions implemented for the emergency treatment of coronavirus disease 2019 (COVID-19) and other patients through March to May 2020; to evaluate the conditions for admitting patients for elective surgery under varying admission levels of COVID-19 patients. METHODS: We analysed National Health Service (NHS) datasets and literature reviews to estimate hospital care capacity before the pandemic (pre-pandemic baseline) and to quantify the impact of interventions (cancellation of elective surgery, field hospitals, use of private hospitals, deployment of former medical staff and deployment of newly qualified medical staff) for treatment of adult COVID-19 patients, focusing on general and acute (G&A) and critical care (CC) beds, staff and ventilators. RESULTS: NHS England would not have had sufficient capacity to treat all COVID-19 and other patients in March and April 2020 without the hospital provision interventions, which alleviated significant shortfalls in CC nurses, CC and G&A beds and CC junior doctors. All elective surgery can be conducted at normal pre-pandemic levels provided the other interventions are sustained, but only if the daily number of COVID-19 patients occupying CC beds is not greater than 1550 in the whole of England. If the other interventions are not maintained, then elective surgery can only be conducted if the number of COVID-19 patients occupying CC beds is not greater than 320. However, there is greater national capacity to treat G&A patients: without interventions, it takes almost 10,000 G&A COVID-19 patients before any G&A elective patients would be unable to be accommodated. CONCLUSIONS: Unless COVID-19 hospitalisations drop to low levels, there is a continued need to enhance critical care capacity in England with field hospitals, use of private hospitals or deployment of former and newly qualified medical staff to allow some or all elective surgery to take place.

Modelling the incremental benefit of introducing malaria screening strategies to antenatal care in Africa.

Plasmodium falciparum in pregnancy is a major cause of adverse pregnancy outcomes. We combine performance estimates of standard rapid diagnostic tests (RDT) from trials of intermittent screening and treatment in pregnancy (ISTp) with modelling to assess whether screening at antenatal visits improves upon current intermittent preventative therapy with sulphadoxine-pyrimethamine (IPTp-SP). We estimate that RDTs in primigravidae at first antenatal visit are substantially more sensitive than in non-pregnant adults (OR = 17.2, 95% Cr.I. 13.8-21.6), and that sensitivity declines in subsequent visits and with gravidity, likely driven by declining susceptibility to placental infection. Monthly ISTp with standard RDTs, even with highly effective drugs, is not superior to monthly IPTp-SP. However, a hybrid strategy, recently adopted in Tanzania, combining testing and treatment at first visit with IPTp-SP may offer benefit, especially in areas with high-grade SP resistance. Screening and treatment in the first trimester, when IPTp-SP is contraindicated, could substantially improve pregnancy outcomes.

The duration of chemoprophylaxis against malaria after treatment with artesunate-amodiaquine and artemether-lumefantrine and the effects of pfmdr1 86Y and pfcrt 76T: a meta-analysis of individual patient data.

BACKGROUND: The majority of Plasmodium falciparum malaria cases in Africa are treated with the artemisinin combination therapies artemether-lumefantrine (AL) and artesunate-amodiaquine (AS-AQ), with amodiaquine being also widely used as part of seasonal malaria chemoprevention programs combined with sulfadoxine-pyrimethamine. While artemisinin derivatives have a short half-life, lumefantrine and amodiaquine may give rise to differing durations of post-treatment prophylaxis, an important additional benefit to patients in higher transmission areas. METHODS: We analyzed individual patient data from 8 clinical trials of AL versus AS-AQ in 12 sites in Africa (n = 4214 individuals). The time to PCR-confirmed reinfection after treatment was used to estimate the duration of post-treatment protection, accounting for variation in transmission intensity between settings using hidden semi-Markov models. Accelerated failure-time models were used to identify potential effects of covariates on the time to reinfection. The estimated duration of chemoprophylaxis was then used in a mathematical model of malaria transmission to determine the potential public health impact of each drug when used for first-line treatment. RESULTS: We estimated a mean duration of post-treatment protection of 13.0 days (95% CI 10.7-15.7) for AL and 15.2 days (95% CI 12.8-18.4) for AS-AQ overall. However, the duration varied significantly between trial sites, from 8.7-18.6 days for AL and 10.2-18.7 days for AS-AQ. Significant predictors of time to reinfection in multivariable models were transmission intensity, age, drug, and parasite genotype. Where wild type pfmdr1 and pfcrt parasite genotypes predominated (<=20% 86Y and 76T mutants, respectively), AS-AQ provided ~ 2-fold longer protection than AL. Conversely, at a higher prevalence of 86Y and 76T mutant parasites (> 80%), AL provided up to 1.5-fold longer protection than AS-AQ. Our simulations found that these differences in the duration of protection could alter population-level clinical incidence of malaria by up to 14% in under-5-year-old children when the drugs were used as first-line treatments in areas with high, seasonal transmission. CONCLUSION: Choosing a first-line treatment which provides optimal post-treatment prophylaxis given the local prevalence of resistance-associated markers could make a significant contribution to reducing malaria morbidity.

Ivermectin as a novel complementary malaria control tool to reduce incidence and prevalence: a modelling study.

BACKGROUND: Ivermectin is a potential new vector control tool to reduce malaria transmission. Mosquitoes feeding on a bloodmeal containing ivermectin have a reduced lifespan, meaning they are less likely to live long enough to complete sporogony and become infectious. We aimed to estimate the effect of ivermectin on malaria transmission in various scenarios of use. METHODS: We validated an existing population-level mathematical model of the effect of ivermectin mass drug administration (MDA) on the mosquito population and malaria transmission against two datasets: clinical data from a cluster- randomised trial done in Burkina Faso in 2015 wherein ivermectin was given to individuals taller than 90 cm and entomological data from a study of mosquito outcomes after ivermectin MDA for onchocerciasis or lymphatic filariasis in Burkina Faso, Senegal, and Liberia between 2008 and 2013. We extended the existing model to include a range of complementary malaria interventions (seasonal malaria chemoprevention and MDA with dihydroartemisinin-piperaquine) and to incorporate new data on higher doses of ivermectin with a longer mosquitocidal effect. We consider two ivermectin regimens: a single dose of 400 µg/kg (1 × 400 µg/kg) and three consecutive daily doses of 300 µg/kg per day (3 × 300 µg/kg). We simulated the effect of these two doses in a range of usage scenarios in different transmission settings (highly seasonal, seasonal, and perennial). We report percentage reductions in clinical incidence and slide prevalence. FINDINGS: We estimate that MDA with ivermectin will reduce prevalence and incidence and is most effective in areas with highly seasonal transmission. In a highly seasonal moderate transmission setting, three rounds of ivermectin only MDA at 3 × 300 µg/kg (rounds spaced 1 month apart) and 70% coverage is predicted to reduce clinical incidence by 71% and prevalence by 34%. We predict that adding ivermectin MDA to seasonal malaria chemoprevention in this setting would reduce clinical incidence by an additional 77% in children younger than 5 years compared with seasonal malaria chemoprevention alone; adding ivermectin MDA to MDA with dihydroartemisinin-piperaquine in this setting would reduce incidence by an additional 75% and prevalence by an additional 64% (all ages) compared with MDA with dihydroartemisinin-piperaquine alone. INTERPRETATION: Our modelling predictions suggest that ivermectin could be a valuable addition to the malaria control toolbox, both in areas with persistently high transmission where existing interventions are insufficient and in areas approaching elimination to prevent resurgence. FUNDING: Imperial College Junior Research Fellowship.

Prioritizing the scale-up of interventions for malaria control and elimination.

BACKGROUND: A core set of intervention and treatment options are recommended by the World Health Organization for use against falciparum malaria. These are treatment, long-lasting insecticide-treated bed nets, indoor residual spraying, and chemoprevention options. Both domestic and foreign aid funding for these tools is limited. When faced with budget restrictions, the introduction and scale-up of intervention and treatment options must be prioritized. METHODS: Estimates of the cost and impact of different interventions were combined with a mathematical model of malaria transmission to estimate the most cost-effective prioritization of interventions. The incremental cost effectiveness ratio was used to select between scaling coverage of current interventions or the introduction of an additional intervention tool. RESULTS: Prevention, in the form of vector control, is highly cost effective and scale-up is prioritized in all scenarios. Prevention reduces malaria burden and therefore allows treatment to be implemented in a more cost-effective manner by reducing the strain on the health system. The chemoprevention measures (seasonal malaria chemoprevention and intermittent preventive treatment in infants) are additional tools that, provided sufficient funding, are implemented alongside treatment scale-up. Future tools, such as RTS,S vaccine, have impact in areas of higher transmission but were introduced later than core interventions. CONCLUSIONS: In a programme that is budget restricted, it is essential that investment in available tools be effectively prioritized to maximize impact for a given investment. The cornerstones of malaria control: vector control and treatment, remain vital, but questions of when to scale and when to introduce other interventions must be rigorously assessed. This quantitative analysis considers the scale-up or core interventions to inform decision making in this area.

Modelling the cost-effectiveness of introducing the RTS,S malaria vaccine relative to scaling up other malaria interventions in sub-Saharan Africa.

OBJECTIVES: To evaluate the relative cost-effectiveness of introducing the RTS,S malaria vaccine in sub-Saharan Africa compared with further scale-up of existing interventions. DESIGN: A mathematical modelling and cost-effectiveness study. SETTING: Sub-Saharan Africa. PARTICIPANTS: People of all ages. INTERVENTIONS: The analysis considers the introduction and scale-up of the RTS,S malaria vaccine and the scale-up of long-lasting insecticide-treated bed nets (LLINs), indoor residual spraying (IRS) and seasonal malaria chemoprevention (SMC). MAIN OUTCOME MEASURE: The number of Plasmodium falciparum cases averted in all age groups over a 10-year period. RESULTS: Assuming access to treatment remains constant, increasing coverage of LLINs was consistently the most cost-effective intervention across a range of transmission settings and was found to occur early in the cost-effectiveness scale-up pathway. IRS, RTS,S and SMC entered the cost-effective pathway once LLIN coverage had been maximised. If non-linear production functions are included to capture the cost of reaching very high coverage, the resulting pathways become more complex and result in selection of multiple interventions. CONCLUSIONS: RTS,S was consistently implemented later in the cost-effectiveness pathway than the LLINs, IRS and SMC but was still of value as a fourth intervention in many settings to reduce burden to the levels set out in the international goals.

Mathematical Modelling to Guide Drug Development for Malaria Elimination.

Mathematical models of the dynamics of a drug within the host are now frequently used to guide drug development. These generally focus on assessing the efficacy and duration of response to guide patient therapy. Increasingly, antimalarial drugs are used at the population level, to clear infections, provide chemoprevention, and to reduce onward transmission of infection. However, there is less clarity on the extent to which different drug properties are important for these different uses. In addition, the emergence of drug resistance poses new threats to longer-term use and highlights the need for rational drug development. Here, we argue that integrating within-host pharmacokinetic and pharmacodynamic (PK/PD) models with mathematical models for the population-level transmission of malaria is key to guiding optimal drug design to aid malaria elimination.

Estimating the most efficient allocation of interventions to achieve reductions in Plasmodium falciparum malaria burden and transmission in Africa: a modelling study.

BACKGROUND: Reducing the burden of malaria is a global priority, but financial constraints mean that available resources must be allocated rationally to maximise their effect. We aimed to develop a model to estimate the most efficient (ie, minimum cost) ordering of interventions to reduce malaria burden and transmission. We also aimed to estimate the efficiency of different spatial scales of implementation. METHODS: We combined a dynamic model capturing heterogeneity in malaria transmission across Africa with financial unit cost data for key malaria interventions. We combined estimates of patterns of malaria endemicity, seasonality in rainfall, and mosquito composition to map optimum packages of these interventions across Africa. Using non-linear optimisation methods, we examined how these optimum packages vary when control measures are deployed and assessed at national, subnational first administrative (provincial), or fine-scale (5 km(2) pixel) spatial scales. FINDINGS: The most efficient package in a given setting varies depending on whether disease reduction or elimination is the target. Long-lasting insecticide-treated nets are generally the most cost-effective first intervention to achieve either goal, with seasonal malaria chemoprevention or indoor residual spraying added second depending on seasonality and vector species. These interventions are estimated to reduce malaria transmission to less than one case per 1000 people per year in 43·4% (95% CI 40·0-49·0) of the population at risk in Africa. Adding three rounds of mass drug administration per year is estimated to increase this proportion to 90·9% (95% CI 86·9-94·6). Further optimisation can be achieved by targeting policies at the provincial level, achieving an estimated 32·1% (95% CI 29·6-34·5) cost saving relative to adopting country-wide policies. Nevertheless, we predict that only 26 (95% CI 22-29) of 41 countries could reduce transmission to these levels with these approaches. INTERPRETATION: These results highlight the cost-benefits of carefully tailoring malaria interventions to the ecological landscape of different areas. However, novel interventions are necessary if malaria eradication is to be achieved. FUNDING: Bill & Melinda Gates Foundation, UK Medical Research Council.

Potential for reduction of burden and local elimination of malaria by reducing Plasmodium falciparum malaria transmission: a mathematical modelling study.

BACKGROUND: Rapid declines in malaria prevalence, cases, and deaths have been achieved globally during the past 15 years because of improved access to first-line treatment and vector control. We aimed to assess the intervention coverage needed to achieve further gains over the next 15 years. METHODS: We used a mathematical model of the transmission of Plasmodium falciparum malaria to explore the potential effect on case incidence and malaria mortality rates from 2015 to 2030 of five different intervention scenarios: remaining at the intervention coverage levels of 2011-13 (Sustain), for which coverage comprises vector control and access to treatment; two scenarios of increased coverage to 80% (Accelerate 1) and 90% (Accelerate 2), with a switch from quinine to injectable artesunate for management of severe disease and seasonal malaria chemoprevention where recommended for both Accelerate scenarios, and rectal artesunate for pre-referral treatment at the community level added to Accelerate 2; a near-term innovation scenario (Innovate), which included longer-lasting insecticidal nets and expansion of seasonal malaria chemoprevention; and a reduction in coverage to 2006-08 levels (Reverse). We did the model simulations at the first administrative level (ie, state or province) for the 80 countries with sustained stable malaria transmission in 2010, accounting for variations in baseline endemicity, seasonality in transmission, vector species, and existing intervention coverage. To calculate the cases and deaths averted, we compared the total number of each under the five scenarios between 2015 and 2030 with the predicted number in 2015, accounting for population growth. FINDINGS: With an increase to 80% coverage, we predicted a reduction in case incidence of 21% (95% credible intervals [CrI] 19-29) and a reduction in mortality rates of 40% (27-61) by 2030 compared with 2015 levels. Acceleration to 90% coverage and expansion of treatment at the community level was predicted to reduce case incidence by 59% (Crl 56-64) and mortality rates by 74% (67-82); with additional near-term innovation, incidence was predicted to decline by 74% (70-77) and mortality rates by 81% (76-87). These scenarios were predicted to lead to local elimination in 13 countries under the Accelerate 1 scenario, 20 under Accelerate 2, and 22 under Innovate by 2030, reducing the proportion of the population living in at-risk areas by 36% if elimination is defined at the first administrative unit. However, failing to maintain coverage levels of 2011-13 is predicted to raise case incidence by 76% (Crl 71-80) and mortality rates by 46% (39-51) by 2020. INTERPRETATION: Our findings show that decreases in malaria transmission and burden can be accelerated over the next 15 years if the coverage of key interventions is increased. FUNDING: UK Medical Research Council, UK Department for International Development, the Bill & Melinda Gates Foundation, the Swiss Development Agency, and the US Agency for International Development.

Estimating the potential public health impact of seasonal malaria chemoprevention in African children.

Seasonal malaria chemoprevention, previously known as intermittent preventive treatment in children, is highly effective in areas with a short malaria transmission season. Here we assess seasonality in malaria incidence data and define a predictor of seasonality based on rainfall. We then use spatial rainfall, malaria endemicity and population data to identify areas likely to have highly seasonal malaria incidence, and estimate the population at risk and malaria burden in areas where seasonal malaria chemoprevention would be appropriate. We estimate that in areas suitable for seasonal malaria chemoprevention, there are 39 million children under 5 years of age, who experience 33.7 million malaria episodes and 152,000 childhood deaths from malaria each year. The majority of this burden occurs in the Sahelian or sub-Sahelian regions of Africa. Our data suggest that seasonal malaria chemoprevention has the potential to avert several million malaria cases and tens of thousands of childhood deaths each year if successfully delivered to the populations at risk.

Comparison of the risks of atherosclerotic events versus death from other causes associated with antiretroviral use.

BACKGROUND: Studies considering the risk of atherosclerotic disease (AtD) associated with the use of HAART have reported inconsistent results. METHODS: Data on antiretroviral therapy (ART) use, risk factors for cardiovascular disease (CVD), AtD and death from other causes in 18 603 HIV-infected patients from two established cohorts were evaluated. The relative hazards of AtD and death from other causes were calculated using a proportional hazards competing risks framework. The impact of protease inhibitor (PI)-containing, non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing or PI + NNRTI-containing regimens on these outcomes were compared to nucleoside reverse transcriptase inhibitor (NRTI)-only regimens or stopping therapy, adjusting for known CVD risk factors. RESULTS: In 77 480 person-years of follow-up (median duration 3.49 years) there were 318 AtD events including 92 myocardial infarctions and 2044 deaths. Older age, hypertension, diabetes mellitus, having smoked and HIV disease stage were significantly associated with increased risk of AtD. PI- and NNRTI-containing regimens significantly reduced the joint risk of either AtD or death from other causes compared to NRTI-only or stopping therapy [hazard ratio (HR) for PI-containing ART, 0.76, 95% confidence interval (CI), 0.73-0.78, P< 0.001; NNRTI-containing ART, 0.69, 95% CI, 0.65-0.74; P< 0.001). PI-containing ART was associated with a borderline significant increased risk of myocardial infarction (cause-specific HR for PI-containing ART 1.19, 95% CI, 1.01-1.40, P = 0.04) but not with increased risk of AtD compared to NRTI-only regimens or stopping therapy (cause-specific HR for PI-containing ART, 1.03, 95% CI, 0.95-1.13, P = 0.44). CONCLUSIONS: Overall benefits of PI- and NNRTI-based ART in reducing mortality significantly outweigh any risks of AtD in the "short-term" follow-up of this study. Traditional cardiac risk factors play an important role in determining AtD risk status.