Peter J. Dodd

Examining the promise of HIV elimination by 'test and treat' in hyperendemic settings.

Background:It has been suggested that a new strategy for HIV prevention, ‘Universal Test and Treat’, whereby everyone is tested for HIV once a year and treated immediately with antiretroviral therapy (ART) if they are infected, could ‘eliminate’ the epidemic and reduce ART costs in the long term. Methods:We investigated the impact of test-and-treat interventions under a variety of assumptions about the epidemic using a deterministic mathematical model. Results:Our model shows that such an intervention can substantially reduce HIV transmission, but that impact depends crucially on the epidemiological context; in some situations, less aggressive interventions achieve the same results, whereas in others, the proposed intervention reduces HIV by much less. It follows that testing every year and treating immediately is not necessarily the most cost-efficient strategy. We also show that a test-and-treat intervention that does not reach full implementation or coverage could, perversely, increase long-term ART costs. Conclusion:Interventions that prevent new infections through ART scale-up may hold substantial promise. However, as plans move forward, careful consideration should be given to the nature of the epidemic and the potential for perverse outcomes.

The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling.

Background The existing estimate of the global burden of latent TB infection (LTBI) as “one-third” of the world population is nearly 20 y old. Given the importance of controlling LTBI as part of the End TB Strategy for eliminating TB by 2050, changes in demography and scientific understanding, and progress in TB control, it is important to re-assess the global burden of LTBI. Methods and Findings We constructed trends in annual risk in infection (ARI) for countries between 1934 and 2014 using a combination of direct estimates of ARI from LTBI surveys (131 surveys from 1950 to 2011) and indirect estimates of ARI calculated from World Health Organisation (WHO) estimates of smear positive TB prevalence from 1990 to 2014. Gaussian process regression was used to generate ARIs for country-years without data and to represent uncertainty. Estimated ARI time-series were applied to the demography in each country to calculate the number and proportions of individuals infected, recently infected (infected within 2 y), and recently infected with isoniazid (INH)-resistant strains. Resulting estimates were aggregated by WHO region. We estimated the contribution of existing infections to TB incidence in 2035 and 2050. In 2014, the global burden of LTBI was 23.0% (95% uncertainty interval [UI]: 20.4%–26.4%), amounting to approximately 1.7 billion people. WHO South-East Asia, Western-Pacific, and Africa regions had the highest prevalence and accounted for around 80% of those with LTBI. Prevalence of recent infection was 0.8% (95% UI: 0.7%–0.9%) of the global population, amounting to 55.5 (95% UI: 48.2–63.8) million individuals currently at high risk of TB disease, of which 10.9% (95% UI:10.2%–11.8%) was isoniazid-resistant. Current LTBI alone, assuming no additional infections from 2015 onwards, would be expected to generate TB incidences in the region of 16.5 per 100,000 per year in 2035 and 8.3 per 100,000 per year in 2050. Limitations included the quantity and methodological heterogeneity of direct ARI data, and limited evidence to inform on potential clearance of LTBI. Conclusions We estimate that approximately 1.7 billion individuals were latently infected with Mycobacterium tuberculosis (M.tb) globally in 2014, just under a quarter of the global population. Investment in new tools to improve diagnosis and treatment of those with LTBI at risk of progressing to disease is urgently needed to address this latent reservoir if the 2050 target of eliminating TB is to be reached.

Burden of childhood tuberculosis in 22 high-burden countries: a mathematical modelling study

BACKGROUND Confirmation of a diagnosis of tuberculosis in children (aged <15 years) is challenging; under-reporting can result even when children do present to health services. Direct incidence estimates are unavailable, and WHO estimates build on paediatric notifications, with adjustment for incomplete surveillance by the same factor as adult notifications. We aimed to estimate the incidence of infection and disease in children, the prevalence of infection, and household exposure in the 22 countries with a high burden of the disease. METHODS Within a mechanistic mathematical model, we combined estimates of adult tuberculosis prevalence in 2010, with aspects of the natural history of paediatric tuberculosis. In a household model, we estimated household exposure and infection. We accounted for the effects of age, BCG vaccination, and HIV infection. Additionally, we tested sensitivity to key structural assumptions by repeating all analyses without variation in BCG efficacy by latitude. FINDINGS The median number of children estimated to be sharing a household with an individual with infectious tuberculosis in 2010 was 15,319,701 (IQR 13,766,297-17,061,821). In 2010, the median number of Mycobacterium tuberculosis infections in children was 7,591,759 (5,800,053-9,969,780), and 650,977 children (424,871-983,118) developed disease. Cumulative exposure meant that the median number of children with latent infection in 2010 was 53,234,854 (41,111,669-68,959,804). The model suggests that 35% (23-54) of paediatric cases of tuberculosis in the 15 countries reporting notifications by age in 2010 were detected. India is predicted to account for 27% (22-33) of the total burden of paediatric tuberculosis in the 22 countries. The predicted proportion of tuberculosis burden in children for each country correlated with incidence, varying between 4% and 21%. INTERPRETATION Our model has shown that the incidence of paediatric tuberculosis is higher than the number of notifications, particularly in young children. Estimates of current household exposure and cumulative infection suggest an enormous opportunity for preventive treatment. FUNDING UNITAID and the US Agency for International Development.

Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models.

BACKGROUND New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per μL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage. METHODS We used several independent mathematical models in four settings-South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)-to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per μL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per μL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US

Reconstructing disease outbreaks from genetic data: a graph approach

) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the countrys 2012 per-head gross domestic product (GDP; South Africa:

Global burden of drug-resistant tuberculosis in children: a mathematical modelling study

8040; Zambia:

The potential effects of changing HIV treatment policy on tuberculosis outcomes in South Africa: results from three tuberculosis-HIV transmission models

1425; India:

The global burden of tuberculosis mortality in children: a mathematical modelling study

1489; Vietnam:

Age- and Sex-Specific Social Contact Patterns and Incidence of Mycobacterium tuberculosis Infection

1407) and cost effective if the cost per DALY averted was less than three times the per-head GDP. FINDINGS In South Africa, the cost per DALY averted of extending eligibility for antiretroviral therapy to adult patients with CD4 counts of 500 cells per μL or less ranged from

Counting children with tuberculosis: why numbers matter.

237 to