The importance of local epidemic conditions in monitoring progress towards HIV epidemic control in Kenya: a modelling study.

INTRODUCTION: Setting and monitoring progress towards targets for HIV control is critical in ensuring responsive programmes. Here, we explore how to apply targets for reduction in HIV incidence to local settings and which indicators give the strongest signal of a change in incidence in the population and are therefore most important to monitor. METHODS: We use location-specific HIV transmission models, tailored to the epidemics in the counties and major cities in Kenya, to project a wide range of plausible future epidemic trajectories through varying behaviours, treatment coverage and prevention interventions. We look at the change in incidence across modelled scenarios in each location between 2015 and 2030 to inform local target setting. We also simulate the measurement of a library of potential indicators and assess which are most strongly associated with a change in incidence. RESULTS: Considerable variation was observed in the trajectory of the local epidemics under the plausible scenarios defined (only 10 of 48 locations saw a median reduction in incidence of greater than or equal to an 80% target by 2030). Indicators that provide strong signals in certain epidemic types may not perform consistently well in settings with different epidemiological features. Predicting changes in incidence is more challenging in advanced generalized epidemics compared to concentrated epidemics where changes in high-risk sub-populations track more closely to the population as a whole. Many indicators demonstrate only limited association with incidence (such as "condom use" or "pre-exposure prophylaxis coverage"). This is because many other factors (low effectiveness, impact of other interventions, countervailing changes in risk behaviours, etc.) can confound the relationship between interventions and their ultimate long-term impact, especially for an intervention with low expected coverage. The population prevalence of viral suppression shows the most consistent associations with long-term changes in incidence even in the largest generalized epidemics. CONCLUSIONS: Target setting should be appropriate for the local epidemic and what can feasibly be achieved. There is no one universally reliable indicator to predict future HIV incidence across settings. Thus, the signature of epidemic control must contain indications of success across a wide range of interventions and outcomes.

Patterns of uptake of HIV testing in sub-Saharan Africa in the pre-treatment era.

OBJECTIVES: To compare nationally representative trends in self-reported uptake of HIV testing and receipt of results in selected countries prior to treatment scale-up. METHODS: Demographic and Health Survey (DHS) data from 13 countries in sub-Saharan Africa were used to describe the pattern of uptake of testing for HIV among sexually active participants. Univariate and multivariate logistic regression were used to analyse the associations between socio-demographic and behavioural characteristics and the uptake of testing. RESULTS: Knowledge of serostatus ranged from 2.2% among women in Guinea (2005) to 27.4% among women in Rwanda (2005). Despite varied levels of testing, univariate analysis showed the profile of testers to be remarkably similar across countries, with respect to socio-demographic characteristics such as area of residence and socio-economic status. HIV-positive participants were more likely to have tested and received their results than HIV-negative participants, with the exception of women in Senegal and men in Guinea. Adjusted analyses indicate that a secondary or higher level of education was a key determinant of testing, and awareness that treatment exists was independently positively associated with testing, once other characteristics were taken into account. CONCLUSION: This work provides a baseline for monitoring trends in testing and exploring changes in the profile of those who get tested after the introduction and scale-up of treatment.

Sex with stitches: assessing the resumption of sexual activity during the postcircumcision wound-healing period.

OBJECTIVES: This study uses observational data collected as part of Zambia's male circumcision program to measure sexual behavior in the postsurgical healing period and to model its influence on HIV transmission for men and their partners. DESIGN/METHODS: From August to October 2010, 248 men about to undergo male circumcision were recruited to participate. Interviews were conducted at baseline and 6 weeks after circumcision, the recommended period of sexual abstinence for complete wound healing. Logistic and Poisson regression models were used to assess risk factors for early resumption of sex. A static-network deterministic transmission model was constructed to assess the impact of the program given early resumption of sex. RESULTS: Twenty-four percent of circumcised men reported resuming sex prior to 6 weeks after surgery. Of men having sex, 46% had sex in the first 3 weeks, 82% reported at least one unprotected sex act, and 37% reported sex with two or more partners. The model estimates that of the 61,000 men circumcised in 1 year, early resumption of sex leads to 69 extra HIV infections (32 among men, 37 among women), but it estimates a net effect of 230 fewer HIV infections in 1 year, predominantly among men. CONCLUSION: Prevalence of risky sexual behavior during wound healing is high and more likely among those reporting risky sexual behaviors at baseline. Nonetheless, the net effect of the male circumcision intervention is beneficial. The impact on women, however, is very sensitive to the prevalence of early resumption of sex.

The clinical interpretation of viral blips in HIV patients receiving antiviral treatment: are we ready to infer poor adherence?

OBJECTIVES: Viral blips may be an indication of poor adherence to antiretroviral treatment. This article studies how the variations of the definitions of viral blips and that of the choice of sampling frame in studies investigating viral blips may contribute to the uncertainty of the associations between viral blips and possible causes. DESIGN: Mathematical modeling study allows us to study the impact of different sampling frames and different definitions of blips upon study results that are usually not feasible in clinical settings. METHODS: Using a previously published mathematical model, scenarios of different drug adherence levels and viral blips, with different sampling frames, were modeled. RESULTS: In the case of viral blips as a result of nonadherence to combinational antiretroviral therapy, rather than calculating the incidence of blips directly from the number of blips observed in a given period of time, it is better to report the proportion of observations in a given period of time that are ≥50 copies per milliliter. Therefore, as the denominator, the number of observations in a given period of time is important. However, the proportion of blips is not very informative on the drug adherence level. CONCLUSIONS: We should standardize definitions of viral blips and the choice of sampling frame and to report the proportion of observations of a given sampling frame in a given period of time that are ≥50 copies per milliliter, so that comparable data can be generated across different populations.

Attitudes and acceptance of oral and parenteral HIV preexposure prophylaxis among potential user groups: a multinational study.

BACKGROUND: The use of antiviral medications by HIV negative people to prevent acquisition of HIV or pre-exposure prophylaxis (PrEP) has shown promising results in recent trials. To understand the potential impact of PrEP for HIV prevention, in addition to efficacy data, we need to understand both the acceptability of PrEP among members of potential user groups and the factors likely to determine uptake. METHODS AND FINDINGS: Surveys of willingness to use PrEP products were conducted with 1,790 members of potential user groups (FSWs, MSM, IDUs, SDCs and young women) in seven countries: Peru, Ukraine, India, Kenya, Botswana, Uganda and South Africa. Analyses of variance were used to assess levels of acceptance across different user groups and countries. Conjoint analysis was used to examine the attitudes and preferences towards hypothetical and known attributes of PrEP programs and medications. Overall, members of potential user groups were willing to consider taking PrEP (61% reported that they would definitely use PrEP). Current results demonstrate that key user groups in different countries perceived PrEP as giving them new possibilities in their lives and would consider using it as soon as it becomes available. These results were maintained when subjects were reminded of potential side effects, the need to combine condom use with PrEP, and for regular HIV testing. Across populations, route of administration was considered the most important attribute of the presented alternatives. CONCLUSIONS: Despite multiple conceivable barriers, there was a general willingness to adopt PrEP in key populations, which suggests that if efficacious and affordable, it could be a useful tool in HIV prevention. There would be a willingness to experience inconvenience and expense at the levels included in the survey. The results suggest that delivery in a long lasting injection would be a good target in drug development.

Mathematical models in the evaluation of health programmes.

Modelling is valuable in the planning and evaluation of interventions, especially when a controlled trial is ethically or logistically impossible. Models are often used to calculate the expected course of events in the absence of more formal assessments. They are also used to derive estimates of rare or future events from recorded intermediate points. When developing models, decisions are needed about the appropriate level of complexity to be represented and about model structure and assumptions. The degree of rigor in model development and assessment can vary greatly, and there is a danger that existing beliefs inappropriately influence judgments about model assumptions and results.

Did national HIV prevention programs contribute to HIV decline in Eastern Zimbabwe? Evidence from a prospective community survey.

OBJECTIVE: To add to the evidence on the impact of national HIV prevention programs in reducing HIV risk in sub-Saharan African countries. METHODS: Statistical analysis of prospective data on exposure to HIV prevention programs, relatives with AIDS and unemployment, and sexual behavior change and HIV incidence, in a population cohort of 4047 adults, collected over a period (1998-2003) when HIV prevalence and risk-behavior declined in eastern Zimbabwe. RESULTS: Exposure to HIV prevention programs and relatives with AIDS-but not unemployment-increased from 1998 to 2003. Men and women exposed to media campaigns and HIV/AIDS meetings had greater knowledge and self-efficacy, attributes that were concomitantly protective against HIV infection. Women attending community HIV/AIDS meetings before recruitment were more likely than other women to adopt lower-risk behavior (96.4% vs. 90.8%; adjusted odds ratio, 3.09; 95% confidence interval [CI], 1.27-7.49) and had lower HIV incidence (0.9% vs. 1.8%; adjusted incidence rate ratio, 0.63; 95% CI, 0.32-1.24) during the intersurvey period. Prior exposure to relatives with AIDS was not associated with differences in behavior change. More newly unemployed men as compared with employed men adopted lower-risk behavior (84.2% vs. 76.0%; adjusted odds ratio, 2.13; 95% CI, 0.98-4.59). CONCLUSIONS: Community-based HIV/AIDS meetings reduced risk-behavior amongst women who attended them, contributing to HIV decline in eastern Zimbabwe.

Chapter 18: Public health policy for cervical cancer prevention: the role of decision science, economic evaluation, and mathematical modeling.

Several factors are changing the landscape of cervical cancer control, including a better understanding of the natural history of human papillomavirus (HPV), reliable assays for detecting high-risk HPV infections, and a soon to be available HPV-16/18 vaccine. There are important differences in the relevant policy questions for different settings. By synthesizing and integrating the best available data, the use of modeling in a decision analytic framework can identify those factors most likely to influence outcomes, can guide the design of future clinical studies and operational research, can provide insight into the cost-effectiveness of different strategies, and can assist in early decision-making when considered with criteria such as equity, public preferences, and political and cultural constraints.

Chapter 21: Modelling the impact of HPV vaccines on cervical cancer and screening programmes.

The impact of human papillomavirus (HPV)-16/18 vaccination on the incidence of infection and disease can be explored in a range of different models. Here we explore the epidemiological and economic impact of vaccination where screening is absent and where it is well established. The importance for epidemiology of assumptions about naturally-acquired immunity and heterogeneity in risk behaviours are highlighted, as are the importance for health economic outcomes of vaccine costs and the ability to modify screening strategies. To date, model results are consistent in predicting a useful role for vaccine, but further epidemiological data are required to help test the validity of models.

Chapter 29: Knowledge gaps and priorities for research on prevention of HPV infection and cervical cancer.

The recognition that human papillomavirus (HPV) infection is the necessary cause of cervical cancer brought new prevention paradigms in screening and HPV immunization. We now face many questions about how to implement an ambitious evidence-based agenda for cervical cancer prevention. Much is known about the epidemiology and natural history of HPV infection but several key variables remain to be elucidated. Research on HPV transmission requires new study designs to provide useful insights into preventive strategies. HPV testing has carved a niche in clinical practice but to consolidate its role in screening still requires evidence of long-term benefit. The rapidly evolving field of HPV diagnostics has contributed useful information concerning the value of HPV typing. Other screening methods hold promise in specific settings. The decade-long process that brought HPV vaccines to the doorstep of public health application is over. Many questions remain concerning long-term efficacy, correlates of protection, age of vaccination, and delivery. As vaccination makes inroads as a cancer control strategy, screening practices must be reformulated to maximize the synergy between primary and secondary prevention. Research on how to achieve an efficient combination of these modalities is yet to begin, but mathematical models have provided a useful road map for field-testing of promising algorithms. Daunting questions loom large concerning delivery of vaccines to those populations that need it the most. The field of HPV and cervical cancer prevention has never been so multi-disciplinary. A new era has begun and the challenges are many.

Chapter 30: HPV vaccines and screening in the prevention of cervical cancer; conclusions from a 2006 workshop of international experts.

The finding that cervical cancer only occurs in women infected with specific, "high-risk" types of the human papillomavirus (HPV) has led to the development of novel, non-cytology-based cervical cancer prevention strategies. We now have sensitive molecular methods for detecting HPV that dramatically improve our ability to detect high-grade cervical cancer precursor lesions. Perhaps more importantly, prophylactic HPV vaccines have been developed that are protective against cervical cancer precursors caused by HPV 16 and 18. In the Spring of 2006, over 100 experts in HPV, cervical cancer screening, and vaccination worked together to define how best to incorporate HPV DNA testing and the HPV vaccines into cervical cancer prevention efforts. In this summary, we summarize the opinions of this expert group on how these advances can be introduced to provide the maximum benefit to women and to reduce the global burden of cervical cancer.

Role of herd immunity in determining the effect of vaccines against sexually transmitted disease.

BACKGROUND: Vaccination programs provide both direct protection to those immunized and herd immunity, which is indirect protection of those who remain susceptible, owing to a reduced prevalence of infections. METHODS: The well-understood impact of vaccination against ubiquitous childhood infections is compared with that of vaccination against sexually transmitted infections (STIs), and theoretical insights are derived from a review of mathematical modeling studies. RESULTS: Typically, a large fraction of cases of STIs are acquired by those with modest risk, and these cases could be prevented by low-efficacy vaccines. If coverage is good, vaccination of only one sex can protect the other sex. Candidate vaccines against human papillomavirus (HPV) and genital herpes are in the final stages of testing. The former is likely to be highly efficacious for a limited number of disease-causing HPV types, and the latter has provided protection against disease in women who initially were seronegative for both herpes simplex virus (HSV) type 1 and HSV-2, with 73% efficacy. In models, this vaccine had a substantial impact when infectiousness was assumed to be reduced along with incidence of disease. CONCLUSION: With such vaccines on the horizon, the requirements for vaccine delivery need to be considered, particularly who should be vaccinated and at what age.