Modelling the impact of social protection on tuberculosis: the S-PROTECT project.

BACKGROUND: Tackling the social determinants of Tuberculosis (TB) through social protection is a key element of the post-2015 End TB Strategy. However, evidence informing policies are still scarce. Mathematical modelling has the potential to contribute to fill this knowledge gap, but existing models are inadequate. The S-PROTECT consortium aimed to develop an innovative mathematical modelling approach to better understand the role of social protection to improve TB care, prevention and control. METHODS: S-PROTECT used a three-steps approach: 1) the development of a conceptual framework; 2) the extraction from this framework of three high-priority mechanistic pathways amenable for modelling; 3) the development of a revised version of a standard TB transmission model able to capture the structure of these pathways. As a test case we used the Bolsa Familia Programme (BFP), the Brazilian conditional cash transfer scheme. RESULTS: Assessing one of these pathways, we estimated that BFP can reduce TB prevalence by 4% by improving households income and thus their nutritional status. When looking at the direct impact via malnutrition (not income mediated) the impact was 33%. This variation was due to limited data availability, uncertainties on data transformation and the pathway approach taken. These results are preliminary and only aim to serve as illustrative example of the methodological challenges encountered in this first modelling attempt, nonetheless they suggest the potential added value of integrating TB standard of care with social protection strategies. CONCLUSIONS: Results are to be confirmed with further analysis. However, by developing a generalizable modelling framework, S-PROTECT proved that the modelling of social protection is complex, but doable and allowed to draw the research road map for the future in this field.

The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015.

Since the year 2000, a concerted campaign against malaria has led to unprecedented levels of intervention coverage across sub-Saharan Africa. Understanding the effect of this control effort is vital to inform future control planning. However, the effect of malaria interventions across the varied epidemiological settings of Africa remains poorly understood owing to the absence of reliable surveillance data and the simplistic approaches underlying current disease estimates. Here we link a large database of malaria field surveys with detailed reconstructions of changing intervention coverage to directly evaluate trends from 2000 to 2015, and quantify the attributable effect of malaria disease control efforts. We found that Plasmodium falciparum infection prevalence in endemic Africa halved and the incidence of clinical disease fell by 40% between 2000 and 2015. We estimate that interventions have averted 663 (542-753 credible interval) million clinical cases since 2000. Insecticide-treated nets, the most widespread intervention, were by far the largest contributor (68% of cases averted). Although still below target levels, current malaria interventions have substantially reduced malaria disease incidence across the continent. Increasing access to these interventions, and maintaining their effectiveness in the face of insecticide and drug resistance, should form a cornerstone of post-2015 control strategies.

How can mathematical models advance tuberculosis control in high HIV prevalence settings?

Existing approaches to tuberculosis (TB) control have been no more than partially successful in areas with high human immunodeficiency virus (HIV) prevalence. In the context of increasingly constrained resources, mathematical modelling can augment understanding and support policy for implementing those strategies that are most likely to bring public health and economic benefits. In this paper, we present an overview of past and recent contributions of TB modelling in this key area, and suggest a way forward through a modelling research agenda that supports a more effective response to the TB-HIV epidemic, based on expert discussions at a meeting convened by the TB Modelling and Analysis Consortium. The research agenda identified high-priority areas for future modelling efforts, including 1) the difficult diagnosis and high mortality of TB-HIV; 2) the high risk of disease progression; 3) TB health systems in high HIV prevalence settings; 4) uncertainty in the natural progression of TB-HIV; and 5) combined interventions for TB-HIV. Efficient and rapid progress towards completion of this modelling agenda will require co-ordination between the modelling community and key stakeholders, including advocates, health policy makers, donors and national or regional finance officials. A continuing dialogue will ensure that new results are effectively communicated and new policy-relevant questions are addressed swiftly.

On diffusion processes with variable drift rates as models for decision making during learning.

We investigate Ornstein-Uhlenbeck and diffusion processes with variable drift rates as models of evidence accumulation in a visual discrimination task. We derive power-law and exponential drift-rate models and characterize how parameters of these models affect the psychometric function describing performance accuracy as a function of stimulus strength and viewing time. We fit the models to psychophysical data from monkeys learning the task to identify parameters that best capture performance as it improves with training. The most informative parameter was the overall drift rate describing the signal-to-noise ratio of the sensory evidence used to form the decision, which increased steadily with training. In contrast, secondary parameters describing the time course of the drift during motion viewing did not exhibit steady trends. The results indicate that relatively simple versions of the diffusion model can fit behavior over the course of training, thereby giving a quantitative account of learning effects on the underlying decision process.

Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To compare the efficacy of combination therapy with methotrexate (MTX) and hydroxychloroquine (HCQ), MTX and sulfasalazine (SSZ), and MTX, HCQ, and SSZ in patients with rheumatoid arthritis (RA). METHODS: RA patients (n = 171) who had not previously been treated with combinations of the study medications were randomized to receive 1 of the 3 treatment combinations in this 2-year, double-blind, placebo-controlled protocol. HCQ was given at a dosage of 200 mg twice a day. The dosage of MTX was accelerated from 7.5 mg/week to 17.5 mg/week in all patients who were not in remission. Similarly, the dosage of SSZ was escalated from 500 mg twice a day to 1 gm twice a day in patients who were not in remission. The primary end point of the study was the percentage of patients who had a 20% response to therapy according to the American College of Rheumatology (ACR) criteria at 2 years. RESULTS: Intent-to-treat analysis revealed that patients receiving the triple combination responded best, with 78% achieving an ACR 20% response at 2 years, compared with 60% of those treated with MTX and HCQ (P = 0.05) and 49% of those treated with MTX and SSZ (P = 0.002). Similar trends were seen for the ACR 50% response, with 55%, 40%, and 29% of patients in the 3 treatment groups, respectively, achieving these results at 2 years (P = 0.005 for the triple combination group versus the MTX and SSZ group). All combination treatments were well-tolerated. Fourteen patients (evenly distributed among the 3 groups) withdrew from the protocol because of symptoms that were potentially related to the study medication. CONCLUSION: The triple combination of MTX, SSZ, and HCQ is well-tolerated, and its efficacy is superior to that of the double combination of MTX and SSZ and is marginally superior to that of the double combination of MTX and HCQ.

Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine.

OBJECTIVE: To compare the efficacy of minocycline with that of a conventional disease-modifying antirheumatic drug (DMARD), hydroxychloroquine, in patients with early seropositive rheumatoid arthritis (RA). METHODS: Sixty patients with seropositive RA of <1 year's duration who had not been previously treated with DMARDs were randomized to receive minocycline, 100 mg twice per day, or hydroxychloroquine, 200 mg twice per day, in a 2-year, double-blind protocol. All patients also received low-dose prednisone. The primary end points of the study were 1) the percentage of patients with an American College of Rheumatology (ACR) 50% improvement (ACR50) response at 2 years, and 2) the dosage of prednisone at 2 years. RESULTS: Minocycline-treated patients were more likely to achieve an ACR50 response at 2 years compared with hydroxychloroquine-treated patients (60% compared with 33%, respectively; P = 0.04). Minocycline-treated patients were also receiving less prednisone at 2 years compared with the hydroxychloroquine group (mean 0.81 mg/day compared with 3.21 mg/day, respectively; P < 0.01). In addition, patients treated with minocycline were more likely to have been completely tapered off prednisone (P = 0.03). Trends favoring the minocycline treatment group were seen when outcomes were assessed according to components of the ACR core criteria set, with the differences reaching statistical significance for patient's global assessment of disease activity (P = 0.004). CONCLUSION: Minocycline is an effective DMARD in patients with early seropositive RA. Patients treated with minocycline were more likely to achieve an ACR50 response and did so while receiving less prednisone. In addition, minocycline-treated patients were more likely to have discontinued treatment with prednisone at 2 years.

Treatment of early seropositive rheumatoid arthritis with minocycline: four-year followup of a double-blind, placebo-controlled trial.

OBJECTIVE: Rheumatoid arthritis (RA) causes substantial morbidity and mortality, and current treatments are suboptimal. Recent studies have demonstrated the short-term efficacy of minocycline in the treatment of patients with early RA. This study was undertaken to compare patients treated with conventional therapy in the early phase of their RA and those treated with minocycline, after 4 years of followup. METHODS: Forty-six patients with seropositive RA of <1 year's duration had been enrolled in a double-blind study of minocycline (100 mg twice daily) versus placebo. After the blinded portion of the study (3-6 months, depending upon response), all patients were treated with conventional therapy. This report compares those patients randomized to receive placebo for 3 months and then conventional therapy for the duration of 4 years versus those originally randomized to receive minocycline. RESULTS: Twenty of the 23 original minocycline-treated patients and 18 of the 23 original placebo-treated patients were available for followup (mean 4 years). At followup, RA was in remission (American College of Rheumatology criteria) without disease-modifying antirheumatic drug (DMARD) or steroid therapy in 8 of the patients originally treated with minocycline compared with 1 patient in the placebo group (P = 0.02). Ten patients in the minocycline group versus 16 in the original placebo group currently require DMARD therapy (P = 0.02). CONCLUSION: Among patients with seropositive RA, remissions are more frequent and the need for DMARD therapy is less in those treated early in the disease course with minocycline compared with those treated with conventional therapy delayed by an average of only 3 months. Minocycline appears to be an effective therapy for early RA; further investigation into its mechanism of action is needed.

HLA-DRB1 typing in rheumatoid arthritis: predicting response to specific treatments.

OBJECTIVE: To determine the predictive value of shared epitope alleles for response to treatment in patients with rheumatoid arthritis. METHODS: Patients from our previously published triple DMARD study were tested for the presence of shared epitope alleles (DRB1 *0401, 0404/0408, 0405, 0101, 1001, and 1402). Patients who were shared epitope positive were then compared with those who were negative to see if there was a differential effect on therapeutic response. RESULTS: Shared epitope positive patients were much more likely to achieve a 50% response if treated with methotrexate-sulphasalazine-hydroxychloroquine compared with methotrexate alone (94% responders versus 32%, p < 0.0001). In contrast shared epitope negative patients did equally well regardless of treatment (88% responders for methotrexate-sulphasalazine-hydroxychloroquine versus 83% for methotrexate). Additionally, a trend toward an inverse relation of the gene dose was seen for response to methotrexate treatment (p = 0.05). CONCLUSIONS: These data suggest that determining shared epitope status may provide clinical information useful in selecting among treatment options.

Treatment of early rheumatoid arthritis with minocycline or placebo: results of a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To determine if minocycline is an effective therapy for seropositive rheumatoid arthritis (RA) when used within the first year of disease. METHODS: The Rheumatoid Arthritis Investigational Network enrolled 46 patients with RA of <1 year duration into a 6-month study of minocycline (100 mg twice daily) versus placebo. All patients were rheumatoid factor positive. The primary end point of the study was successful completion of 6 months of treatment with no drug toxicity while maintaining 50% improvement in composite symptoms of arthritis. RESULTS: Eighteen of the 46 patients who were enrolled met 50% improvement criteria at 3 months, and maintained at least a 50% improvement for 6 months with no significant drug toxicity. Among them were 15 of the 23 patients (65%) treated with minocycline and 3 of 23 patients (13%) treated with placebo (P < 0.001). CONCLUSION: In patients with early seropositive RA, therapy with minocycline is superior to placebo.

Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications.

BACKGROUND: Rheumatoid arthritis is a common disease that causes substantial morbidity and mortality. The responses of patients with rheumatoid arthritis to treatment with a single so-called disease-modifying drug, such as methotrexate, are often suboptimal. Despite limited data, many patients are treated with combinations of these drugs. METHODS: We enrolled 102 patients with rheumatoid arthritis and poor responses to at least one disease-modifying drug in a two-year, double-blind, randomized study of treatment with methotrexate alone (7.5 to 17.5 mg per week), the combination of sulfasalazine (500 mg twice daily) and hydroxychloroquine (200 mg twice daily), or all three drugs. The dose of methotrexate was adjusted in an attempt to achieve remission in all patients. The primary and point of the study was the successful completion of two years of treatment with 50 percent improvement in composite symptoms of arthritis and no evidence of drug toxicity. RESULTS: Fifty of the 102 patients had 50 percent improvement at nine months and maintained at least that degree of improvement for two years without evidence of major drug toxicity. Among them were 24 of 31 patients treated with all three drugs (77 percent), 12 of 36 patients treated with methotrexate alone (33 percent, P < 0.001 for the comparison with the three-drug group), and 14 of 35 patients treated with sulfasalazine and hydroxychloroquine (40 percent), P = 0.003 for the comparison with the three-drug group). Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity. CONCLUSIONS: In patients with rheumatoid arthritis, combination therapy with methotrexate, sulfasalazine, and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine, and hydroxychloroquine.