The epidemiological impact of antiretroviral use predicted by mathematical models: a review

This review summarises theoretical studies attempting to assess the population impact of antiretroviral therapy (ART) use on mortality and HIV incidence. We describe the key parameters that determine the impact of therapy, and argue that mathematical models of disease transmission are the natural framework within which to explore the interaction between antiviral use and the dynamics of an HIV epidemic. Our review focuses on the potential effects of ART in resource-poor settings. We discuss choice of model type and structure, the potential for risk behaviour change following widespread introduction of ART, the importance of the stage of HIV infection at which treatment is initiated, and the potential for spread of drug resistance. These issues are illustrated with results from models of HIV transmission. We demonstrate that HIV transmission models predicting the impact of ART use should incorporate a realistic progression through stages of HIV infection in order to capture the effect of the timing of treatment initiation on disease spread. The realism of existing models falls short of properly reproducing patterns of diagnosis timing, incorporating heterogeneity in sexual behaviour, and describing the evolution and transmission of drug resistance. The uncertainty surrounding certain effects of ART, such as changes in sexual behaviour and transmission of ART-resistant HIV strains, demands exploration of best and worst case scenarios in modelling, but this must be complemented by surveillance and behavioural surveys to quantify such effects in settings where ART is implemented

Modelling the impact of antiretroviral use in resource-poor settings.

BACKGROUND: The anticipated scale-up of antiretroviral therapy (ART) in high-prevalence, resource-constrained settings requires operational research to guide policy on the design of treatment programmes. Mathematical models can explore the potential impacts of various treatment strategies, including timing of treatment initiation and provision of laboratory monitoring facilities, to complement evidence from pilot programmes. METHODS AND FINDINGS: A deterministic model of HIV transmission incorporating ART and stratifying infection progression into stages was constructed. The impact of ART was evaluated for various scenarios and treatment strategies, with different levels of coverage, patient eligibility, and other parameter values. These strategies included the provision of laboratory facilities that perform CD4 counts and viral load testing, and the timing of the stage of infection at which treatment is initiated. In our analysis, unlimited ART provision initiated at late-stage infection (AIDS) increased prevalence of HIV infection. The effect of additionally treating pre-AIDS patients depended on the behaviour change of treated patients. Different coverage levels for ART do not affect benefits such as life-years gained per person-year of treatment and have minimal effect on infections averted when treating AIDS patients only. Scaling up treatment of pre-AIDS patients resulted in more infections being averted per person-year of treatment, but the absolute number of infections averted remained small. As coverage increased in the models, the emergence and risk of spread of drug resistance increased. Withdrawal of failing treatment (clinical resurgence of symptoms), immunologic (CD4 count decline), or virologic failure (viral rebound) increased the number of infected individuals who could benefit from ART, but effectiveness per person is compromised. Only withdrawal at a very early stage of treatment failure, soon after viral rebound, would have a substantial impact on emergence of drug resistance. CONCLUSIONS: Our analysis found that ART cannot be seen as a direct transmission prevention measure, regardless of the degree of coverage. Counselling of patients to promote safe sexual practices is essential and must aim to effect long-term change. The chief aims of an ART programme, such as maximised number of patients treated or optimised treatment per patient, will determine which treatment strategy is most effective

Patient population with multiple myeloma and transitions across different lines of therapy in the USA: an epidemiologic model.

PURPOSE: Multiple myeloma (MM) is a progressive, malignant neoplasia with a worldwide, age-standardized annual incidence of 1.5 per 100 000 individuals and 5-year prevalence around 230 000 patients. Main favorable prognostic factors are younger age, low/standard cytogenetic risk, and undergoing stem cell transplantation. Our aim was to estimate the size of the patient population with MM eligible to receive a new MM therapy at different lines of therapy in the USA. METHODS: We constructed a compartmental, differential equation model representing the flow of MM patients from diagnosis to death, via two possible treatment pathways and distinguished in four groups based on prognostic factors. Parameters were obtained from published references, available statistics, and assumptions. The model was used to estimate number of diagnosed MM patients and number of patient transitions from one line of therapy to the next over 1 year. Model output included 95% credible intervals from probabilistic sensitivity analyses. RESULTS: The base-case estimates were 80 219 patients living with MM, including 70 375 on treatment, 780 symptomatic untreated patients, and 9064 asymptomatic untreated patients. Over a 1-year period, the number of MM patients on treatment line 1 was estimated at 23 629 (credible intervals 22 236-25 029), and the number of transitions from treatment line 1 to treatment line 2 was estimated at 14 423. CONCLUSIONS: The size of the patient population with MM on different lines of therapy and in patient subgroups of interest estimated from this epidemiologic model can be used to assess the number of patients who could benefit from new MM therapies and their corresponding budgetary impact. Copyright © 2016 John Wiley & Sons, Ltd

Modelling HIV epidemics in the antiretroviral era: the UNAIDS Estimation and Projection package 2009

OBJECTIVE: The UNAIDS Estimation and Projection Package (EPP) is a tool for country-level estimation and short-term projection of HIV/AIDS epidemics based on fitting observed HIV surveillance data on prevalence. This paper describes the adaptations made in EPP 2009, the latest version of this tool, as new issues have arisen in the global response, in particular the global expansion of antiretroviral therapy (ART). RESULTS: By December 2008 over 4 million people globally were receiving ART, substantially improving their survival. EPP 2009 required modifications to correctly adjust for the effects of ART on incidence and the resulting increases in HIV prevalence in populations with high ART coverage. Because changing incidence is a better indicator of program impact, the 2009 series of UNAIDS tools also focuses on calculating incidence alongside prevalence. Other changes made in EPP 2009 include: an improved procedure, incremental mixture importance sampling, for efficiently generating more accurate uncertainty estimates; provisions to vary the urban/rural population ratios in generalised epidemics over time; introduction of a modified epidemic model that accommodates behaviour change in low incidence settings; and improved procedures for calibrating models. This paper describes these changes in detail, and discusses anticipated future changes in the next version of EPP

Estimating the public health impact of the effect of herpes simplex virus suppressive therapy on plasma HIV-1 viral load.

OBJECTIVE: Trials of herpes simplex virus (HSV) suppressive therapy among HSV-2/HIV-1-infected individuals have reported an impact on plasma HIV-1 viral loads (PVLs). Our aim was to estimate the population-level impact of suppressive therapy on female-to-male HIV-1 sexual transmission. DESIGN AND METHODS: By comparing prerandomization and postrandomization individual-level PVL data from the first two HSV suppressive therapy randomized controlled trials in sub-Saharan Africa, we estimated the effect of treatment on duration of asymptomatic infection and number of HIV-1 transmission events for each trial. RESULTS: Assuming that a reduction in PVL is accompanied by an increased duration of HIV-1 asymptomatic infection, 4-6 years of HSV suppressive therapy produce a 1-year increase in the duration of this stage. To avert one HIV-1 transmission requires 8.8 [95% confidence interval (CI), 5.9-14.9] and 11.4 (95% CI, 7.8-27.5) women to be treated from halfway through their HIV-1 asymptomatic period, using results from Burkina Faso and South African trials, respectively. Regardless of the timing of treatment initiation, 51.6 (95% CI, 30.4-137.0) and 66.5 (95% CI, 36.7-222.6) treatment-years are required to avert one HIV-1 infection. Distributions of set-point PVL values from sub-Saharan African populations suggest that unintended adverse consequences of therapy at the population level (i.e. increased HIV-1 transmission due to increased duration of infection) are unlikely to occur in these settings. CONCLUSION: HSV suppressive therapy may avert relatively few HIV-1 transmission events per person-year of treatment. Its use as a prevention intervention may be limited; however, further research into its effect on rate of CD4 cell count decline and the impact of higher dosing schedules is warranted

Heterosexual HIV-1 infectiousness and antiretroviral use : systematic review of prospective studies of discordant couples

Background: Recent studies have estimated the reduction in HIV-1 infectiousness with antiretroviral therapy (ART), but high-quality studies such as randomized controlled trials, accompanied by rigorous adherence counseling, are likely to overestimate the effectiveness of treatment-as-prevention in real-life settings. Methods: We attempted to summarize the effect of ART on HIV transmission by undertaking a systematic review and meta-analysis of HIV-1 infectiousness per heterosexual partnership (incidence rate and cumulative incidence over study follow-up) estimated from prospective studies of discordant couples. We used random-effects Poisson regression models to obtain summary estimates. When possible, the analyses were further stratified by direction of transmission (man-to-woman or woman-to-man) and economic setting (high- or low-income countries). Potential causes of heterogeneity of estimates were explored through subgroup analyses. Results: Fifty publications were included. Nine allowed comparison between ART and non-ART users within studies (ART-stratified studies), in which summary incidence rates were 3.6/100 person-years (95% confidence interval = 2.0-6.5) and 0.2/100 person-years (0.07-0.7) for non-ART- and ART-using couples, respectively (P < 0.001), constituting a 91% (79-96%) reduction in per-partner HIV-1 incidence rate with ART use. The 41 studies that did not stratify by ART use provided estimates with high levels of heterogeneity (I2 statistic) and few reported levels of ART use, making interpretation difficult. Nevertheless, estimates tended to be lower with ART use. Infectiousness tended to be higher for low-income than high-income settings, but there was no clear pattern by direction of transmission (man-to-woman and woman-to-man). Conclusions: ART substantially reduces HIV-1 infectiousness within discordant couples, based on observational studies, and could play a major part in HIV-1 prevention efforts. However, the non-zero risk from partners receiving ART demonstrates that appropriate counseling and other risk-reduction strategies for discordant couples are still required. Additional estimates of ART effectiveness by adherence level from real-life settings will be important, especially for persons starting treatment early without symptoms