The paradoxical effects of using antiretroviral-based microbicides to control HIV epidemics.

Vaginal microbicides, designed to prevent HIV infection in women, are one of the most promising biomedical interventions. Clinical trials of second-generation microbicides have begun; if shown to be effective, they could be licensed within 5-10 years. Because these microbicides contain antiretrovirals (ARVs), they could be highly effective. However, there is concern that, if used by HIV-positive women, ARV resistance may evolve. By analyzing a mathematical model, we find that adherence could have both beneficial and detrimental effects on trial outcomes. Most importantly, we show that planned trial designs could mask resistance risks and therefore enable high-risk microbicides to pass clinical testing. We then parameterize a transmission model using epidemiological, clinical, and behavioral data to predict the consequences of wide-scale usage of high-risk microbicides in a heterosexual population. Surprisingly, we show that reducing a participant's risk of resistance during a trial could lead to unexpectedly high rates of resistance afterward when microbicides are used in public health interventions. We also find that, paradoxically, although microbicides will be used by women to protect themselves against infection, they could provide greater benefit to men. More infections in men than in women will be prevented if there is a high probability that ARVs are systemically absorbed, microbicides are less than approximately 50% effective, and/or adherence is less than approximately 60%. Men will always benefit more than women in terms of infections prevented per resistant case; but this advantage decreases as the relative fitness of drug-resistant strains increases. Interventions that use ARV-based microbicides could have surprising consequences.

Predicting the epidemiological impact of antiretroviral allocation strategies in KwaZulu-Natal: the effect of the urban-rural divide.

Antiretroviral therapy (ART) is becoming available in South Africa. Demand will exceed supply; thus, difficult decisions will have to be made in allocating ART. The majority of those treated for HIV are likely to be in cities, because health infrastructure and personnel are concentrated in urban centers. We predict the epidemiological impact of drug allocation strategies (DAS) by using a spatially explicit model that links urban and rural epidemics. We parameterize our model by using data from the KwaZulu-Natal province in South Africa. We model the South African government's treatment plan from 2004-2008, and we predict the consequences of one DAS that allocates drugs only to Durban and of two DAS that allocate drugs to both urban and rural areas. All three strategies would treat 500,000 people by 2008. Not surprisingly, the Durban-only DAS would prevent the greatest number of infections (an additional 15,000 infections by 2008). However, it may have been expected that this DAS would generate the highest levels of transmitted resistance, because it concentrates ART in one location. Paradoxically, we found that this DAS would generate the lowest levels of transmitted resistance. Concentrating treatment in Durban would also avert the greatest number of AIDS-related deaths. We discuss the difference between using the principle of treatment equity versus using the principle of utilitarianism/efficiency to allocate ART. Decisions about allocating scarce drugs should consider treatment equity as well as epidemiological consequences. Notably, a Durban-only DAS would lead to new disparities in healthcare between urban and rural areas in KwaZulu-Natal.

Predicting the potential public health impact of disease-modifying HIV vaccines in South Africa: the problem of subtypes.

Current HIV vaccines in development appear unlikely to prevent infection, but could provide benefits by increasing survival; such vaccines are described as disease-modifying vaccines. We review the current status of vaccines and modeling vaccines. We also predict the impact that disease-modifying vaccines could have in South Africa, where multiple subtypes are co-circulating. We model transmissibility/fitness differences among subtypes. We used uncertainty analyses to model vaccines with four characteristics: (i) take, (ii) duration of immunity, (iii) reduction in transmissibility/fitness, and (iv) increase in survival. We reconstructed, and forecasted, the South African epidemic from 1940 to 2140 (assuming no vaccination). We predict that: (i) incidence will peak in 2014, decline, and stabilize, (ii) prevalence will continue to rise, and (iii) the AIDS death rate curve will peak in 2022. Our predictions show that (over the next 135 years) the epidemic in South Africa will switch from a predominantly Subtype C epidemic to an epidemic driven by other subtypes. We predict that the epidemic could remain unchanged, even with mass vaccination with a vaccine that is equally effective against all co-circulating subtypes. However, if the non-C subtypes are less (or equally) transmissible as Subtype C then disease-modifying vaccines could result in eradication. Thus, in countries where multiple-subtypes are co-circulating it is critical to realize that small biological differences among subtypes will have dramatic consequences for the effectiveness of HIV vaccination campaigns. A slight difference in fitness will determine whether a disease-modifying vaccine has almost no impact on the epidemic or can achieve eradication.

Designing equitable antiretroviral allocation strategies in resource-constrained countries.

BACKGROUND: Recently, a global commitment has been made to expand access to antiretrovirals (ARVs) in the developing world. However, in many resource-constrained countries the number of individuals infected with HIV in need of treatment will far exceed the supply of ARVs, and only a limited number of health-care facilities (HCFs) will be available for ARV distribution. Deciding how to allocate the limited supply of ARVs among HCFs will be extremely difficult. Resource allocation decisions can be made on the basis of many epidemiological, ethical, or preferential treatment priority criteria. METHODS AND FINDINGS: Here we use operations research techniques, and we show how to determine the optimal strategy for allocating ARVs among HCFs in order to satisfy the equitable criterion that each individual infected with HIV has an equal chance of receiving ARVs. We present a novel spatial mathematical model that includes heterogeneity in treatment accessibility. We show how to use our theoretical framework, in conjunction with an equity objective function, to determine an optimal equitable allocation strategy (OEAS) for ARVs in resource-constrained regions. Our equity objective function enables us to apply the egalitarian principle of equity with respect to access to health care. We use data from the detailed ARV rollout plan designed by the government of South Africa to determine an OEAS for the province of KwaZulu-Natal. We determine the OEAS for KwaZulu-Natal, and we then compare this OEAS with two other ARV allocation strategies: (i) allocating ARVs only to Durban (the largest urban city in KwaZulu-Natal province) and (ii) allocating ARVs equally to all available HCFs. In addition, we compare the OEAS to the current allocation plan of the South African government (which is based upon allocating ARVs to 17 HCFs). We show that our OEAS significantly improves equity in treatment accessibility in comparison with these three ARV allocation strategies. We also quantify how the size of the catchment region surrounding each HCF, and the number of HCFs utilized for ARV distribution, alters the OEAS and the probability of achieving equity in treatment accessibility. We calculate that in order to achieve the greatest degree of treatment equity for individuals with HIV in KwaZulu-Natal, the ARVs should be allocated to 54 HCFs and each HCF should serve a catchment region of 40 to 60 km. CONCLUSION: Our OEAS would substantially improve equality in treatment accessibility in comparison with other allocation strategies. Furthermore, our OEAS is extremely different from the currently planned strategy. We suggest that our novel methodology be used to design optimal ARV allocation strategies for resource-constrained countries.

Evaluating the potential impact of vaginal microbicides to reduce the risk of acquiring HIV in female sex workers.

OBJECTIVES: The following questions were addressed: would the introduction of vaginal microbicides substantially reduce the risk of female sex workers (FSWs) acquiring HIV? Which factor would it be most important to maximize, microbicide efficacy or microbicide use? What level of microbicide efficacy and use would be necessary to counterbalance a possible reduction in condom use? DESIGN: Mathematical modeling, with parameter estimations from available literature. METHODS: Risk equations were developed and Monte Carlo simulations were performed to model a FSW's daily risk of HIV acquisition currently, and after, microbicide introduction. Uncertainty and sensitivity analyses were used as well as tornado plots for two ranges of microbicide efficacy (30-50%) and (50-80%). Risk was estimated for FSWs whose clients sometimes (10-50%) use condoms, and those whose clients never use condoms. An analytical threshold for which reducing condom use increases risk was estimated. RESULTS: For both groups of FSWs, daily risk would decrease by approximately 17% or approximately 28% using 30-50% or 50-80% effective microbicides, respectively. Increasing microbicide use would have greater impact on reducing risk than increasing microbicide efficacy. The microbicide efficacy and usage required to ensure that 'condom replacement' does not increase a FSW's risk of acquiring HIV was calculated. CONCLUSIONS: Microbicides could substantially reduce FSWs' risk of acquiring HIV; absolute decrease in risk would be greatest in high-prevalence regions. The public health impact of microbicides will depend upon usage and efficacy. Even if the microbicides that become available are only low-to-moderately effective, the probability that risk in FSWs will increase (due to replacing condoms with microbicides) is low.

Could disease-modifying HIV vaccines cause population-level perversity?

Most current candidate HIV vaccines seem to produce little protection against infection, but reduce viral load and slow the decline in CD4 lymphocyte numbers. Such disease-modifying vaccines could potentially provide important population-level benefits by reducing transmission, but could possibly also increase transmission. We address the following question: could disease-modifying HIV vaccines cause population-level perversity (ie, increase epidemic severity)? By analysing a mathematical model and defining a new quantity-the fitness ratio-we show that disease-modifying vaccines that provide only a low degree of protection against infection and/or generate high fitness ratios will have a high probability of making the epidemic worse. However, we show that if disease-modifying vaccines cause a 1.5 log(10) reduction in viral load (or greater) then perversity cannot occur (assuming risk behaviour does not increase). Finally, we determine threshold surfaces for risk behaviour change that determine the boundary between beneficial and perverse outcomes; the threshold surfaces are determined by the fitness ratio, the proportion of the population that are "successfully vaccinated", and the degree of change of risk behaviour in unvaccinated infected individuals. We discuss the implications of our results for designing optimal vaccination control strategies.

Modeling the emergence of the 'hot zones': tuberculosis and the amplification dynamics of drug resistance.

'Hot zones' are areas that have >5% prevalence (or incidence) of multidrug-resistant tuberculosis (MDRTB). We present a new mathematical model (the amplifier model) that tracks the emergence and evolution of multiple (pre-MDR, MDR and post-MDR) strains of drug-resistant Mycobacterium tuberculosis. We reconstruct possible evolutionary trajectories that generated hot zones over the past three decades, and identify the key causal factors. Results are consistent with recently reported World Health Organization (WHO) data. Our analyses yield three important insights. First, paradoxically we found that areas with programs that successfully reduced wild-type pansensitive strains often evolved into hot zones. Second, some hot zones emerged even when MDR strains were substantially less fit (and thus less transmissible) than wild-type pansensitive strains. Third, levels of MDR are driven by case-finding rates, cure rates and amplification probabilities. To effectively control MDRTB in the hot zones, it is essential that the WHO specify a goal for minimizing the amplification probability.

Predicting the emergence of drug-resistant HSV-2: new predictions.

BACKGROUND: Mathematical models can be used to predict the emergence and transmission of antiviral resistance. Previously it has been predicted that high usage of antivirals (in immunocompetent populations) to treat Herpes Simplex Virus type 2 (HSV-2) would only lead to fairly low levels of antiviral resistance. The HSV-2 predictions were based upon the assumption that drug-resistant strains of HSV-2 would be less infectious than drug-sensitive strains but that the drug-resistant strains would not be impaired in their ability to reactivate. Recent data suggest that some drug-resistant strains of HSV-2 are likely to be impaired in their ability to reactivate. OBJECTIVES: (1) To predict the effect of a high usage of antivirals on the prevalence of drug-resistant HSV-2 under the assumption that drug-resistant strains will be less infectious than drug-sensitive strains of HSV-2 and also have an impaired ability to reactivate. (2) To compare predictions with previous published predictions. METHODS: We generated theoretical drug-resistant HSV-2 strains that were attenuated (in comparison with drug-sensitive strains) in both infectivity and ability to reactivate. We then used a transmission model to predict the emergence and transmission of drug-resistant HSV-2 in the immunocompetent population assuming a high usage of antivirals. RESULTS: Our predictions are an order of magnitude lower than previous predictions; we predict that even after 25 years of high antiviral usage only 5 out of 10,000 immunocompetent individuals will be shedding drug-resistant virus. Furthermore, after 25 years, 52 cases of HSV-2 would have been prevented for each prevalent case of drug-resistant HSV-2. CONCLUSIONS: The predicted levels of drug-resistant HSV-2 for the immunocompetent population are so low that it seems unlikely that cases of drug-resistant HSV-2 will be detected.

Parasites detect host spatial pattern and density: a field experimental analysis.

A common assumption in mathematical models of parasitism is that the susceptibility to parasitism of an individual host increases both with host density and the degree of host spatial aggregation. To determine whether this assumption is correct in nature, we developed a factorial field experiment with the parasitic marine isopod Hemioniscus balani and its barnacle host Chthamalus dalli. Our factorial design enabled evaluation of the separate effects on parasitism of the two factors (host density and host spatial pattern) and also to assess the host density-spatial pattern interaction effect. Both host density and spatial aggregation were found to lead to increased parasitism, and the interaction effect was nonsignificant. These findings are the first experimental field demonstration that these processes occur in nature, as widely assumed in ecological theory.