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

Antigen-driven T-cell turnover.

A mathematical model is developed to characterize the distribution of cell turnover rates within a population of T lymphocytes. Previous models of T-cell dynamics have assumed a constant uniform turnover rate; here we consider turnover in a cell pool subject to clonal proliferation in response to diverse and repeated antigenic stimulation. A basic framework is defined for T-cell proliferation in response to antigen, which explicitly describes the cell cycle during antigenic stimulation and subsequent cell division. The distribution of T-cell turnover rates is then calculated based on the history of random exposures to antigens. This distribution is found to be bimodal, with peaks in cell frequencies in the slow turnover (quiescent) and rapid turnover (activated) states. This distribution can be used to calculate the overall turnover for the cell pool, as well as individual contributions to turnover from quiescent and activated cells. The impact of heterogeneous turnover on the dynamics of CD4(+) T-cell infection by HIV is explored. We show that our model can resolve the paradox of high levels of viral replication occurring while only a small fraction of cells are infected

Estimating the risk of HIV transmission from homosexual men receiving treatment to their HIV-uninfected partners

Objective To determine how the risk of HIV transmission from homosexual men receiving antiretroviral treatment is related to patterns of patient monitoring and condom use. Methods A stochastic mathematical simulation model was developed of cohorts of men in the Netherlands who have sex with men (MSM), defining the parameters of the model using observational cohort data. The model incorporates viral load trends during first-line treatment, patient monitoring and different scenarios for the way in which condom use may depend on recent viral load measurements. The model does not include the effect of sexually transmitted infections on HIV transmission. Results For MSM receiving treatment, the risk of transmitting HIV to their long-term partner is 22% (uncertainty interval: 9-37%) if condoms are never used. With incomplete use (in 30% of sex acts) the risk is reduced slightly, to 17% (7-29%). However, the risk is as low as 3% (0.2-8%) when men receiving treatment use condoms only 6 months beyond their last undetectable viral load measurement. The risk is further reduced when 3 months is the time period beyond which condoms are used. Conclusions When condom use by HIV-infected men receiving combination treatment with antiretroviral agents is based on their last viral load measurement, the transmission risk is much lower than with incomplete condom use. The key message for patients is that although always using condoms during treatment is the best way to protect partners from the risk of HIV transmission, when such use cannot be achieved, the second best strategy is to use condoms whenever the last undetectable viral load was measured more than 3 months ag

Transmission of HIV-1 infection in sub-Saharan Africa and effect of elimination of unsafe injections

During the past year, a group has argued that unsafe injections are a major if not the main mode of HIV-1 transmission\ud in sub-Saharan Africa. We review the main arguments used to question the epidemiological interpretations on the lead\ud role of unsafe sex in HIV-1 transmission, and conclude there is no compelling evidence that unsafe injections are a\ud predominant mode of HIV-1 transmission in sub-Saharan Africa. Conversely, though there is a clear need to eliminate\ud all unsafe injections, epidemiological evidence indicates that sexual transmission continues to be by far the major\ud mode of spread of HIV-1 in the region. Increased efforts are needed to reduce sexual transmission of HIV-1

Individual Level Injection History: A Lack of Association with HIV Incidence in Rural Zimbabwe

BACKGROUND: It has recently been argued that unsafe medical injections are a major transmission route of HIV infection in the generalised epidemics of sub-Saharan Africa. METHODS AND FINDINGS: We have analysed the pattern of injections in relation to HIV incidence in a population cohort in Manicaland in a rural area of Zimbabwe. In Poisson regression models, injections were not found to be associated with HIV in males (rate ratio = 0.33; 95% confidence interval: 0.07 to 1.46) or females (rate ratio = 1.04; 95% confidence interval: 0.59 to 1.85). CONCLUSION: It is important that unsafe medical injections can be confidently excluded as a major source of HIV infection. In rural Zimbabwe the evidence is that they can

Epidemiology of HPV 16 and Cervical Cancer in Finland and the Potential Impact of Vaccination: Mathematical Modelling Analyses

BACKGROUND: Candidate human papillomavirus (HPV) vaccines have demonstrated almost 90%-100% efficacy in preventing persistent, type-specific HPV infection over 18 mo in clinical trials. If these vaccines go on to demonstrate prevention of precancerous lesions in phase III clinical trials, they will be licensed for public use in the near future. How these vaccines will be used in countries with national cervical cancer screening programmes is an important question. METHODS AND FINDINGS: We developed a transmission model of HPV 16 infection and progression to cervical cancer and calibrated it to Finnish HPV 16 seroprevalence over time. The model was used to estimate the transmission probability of the virus, to look at the effect of changes in patterns of sexual behaviour and smoking on age-specific trends in cancer incidence, and to explore the impact of HPV 16 vaccination. We estimated a high per-partnership transmission probability of HPV 16, of 0.6. The modelling analyses showed that changes in sexual behaviour and smoking accounted, in part, for the increase seen in cervical cancer incidence in 35- to 39-y-old women from 1990 to 1999. At both low (10% in opportunistic immunisation) and high (90% in a national immunisation programme) coverage of the adolescent population, vaccinating women and men had little benefit over vaccinating women alone. We estimate that vaccinating 90% of young women before sexual debut has the potential to decrease HPV type-specific (e.g., type 16) cervical cancer incidence by 91%. If older women are more likely to have persistent infections and progress to cancer, then vaccination with a duration of protection of less than 15 y could result in an older susceptible cohort and no decrease in cancer incidence. While vaccination has the potential to significantly reduce type-specific cancer incidence, its combination with screening further improves cancer prevention. CONCLUSIONS: HPV vaccination has the potential to significantly decrease HPV type-specific cervical cancer incidence. High vaccine coverage of women alone, sustained over many decades, with a long duration of vaccine-conferred protection, would have the greatest impact on type-specific cancer incidence. This level of coverage could be achieved through national coordinated programmes, with surveillance to detect cancers caused by nonvaccine oncogenic HPV types