How to stop the spread of HIV in Africa

While Ebola has attracted much of the world's attention recently, a severe HIV epidemic rages on around the world and in sub-Saharan Africa in particular. Globally, more than 34 million people are infected with HIV; in sub-Saharan Africa alone, 3 million new infections occur annually.

In an attempt to stop the spread of HIV, governments in the region are considering providing antiretroviral drugs to people who do not have the virus but are at risk for becoming infected. Such drugs are known as pre-exposure prophylaxis, or PrEP.

Although the conventional strategy -- attempting to attempt to distribute the drugs to people in every city and village -- might seem logical and equitable, researchers at UCLA have devised a plan they say would be much more effective in reducing HIV transmission.

The strategy, developed using a complex mathematical model, focuses on targeting "hot zones," areas where the risk of HIV infection is much higher than the national average. In South Africa, where 17 percent of the population is infected with HIV, the model predicted that targeting hot zones would prevent 40 percent more HIV infections than using the conventional strategy -- and would therefore be 40 percent more cost-effective.

"Stopping the HIV pandemic is one of the greatest challenges facing the global community," said Sally Blower, the paper's senior author and the director of the Center for Biomedical Modeling at the UCLA Semel Institute for Neuroscience and Human Behavior.

The report appears in the current online edition of Nature Communications.

"Since results from clinical trials have shown that antiretroviral drugs are effective in protecting individuals against HIV, the big question now is how best to use them," said David Gerberry, the study's first author and a former UCLA postdoctoral fellow who now is an assistant professor in mathematics at Xavier University.

To develop the strategy, UCLA researchers designed a computer model that calculated and mapped the incidence of HIV in South Africa and identified hot zones. The model featured three important components: the geographic dispersion of the population, the geographic variation in the severity of the HIV epidemic and the geographic variation in the level of risk behavior. The model revealed that two of South Africa's nine provinces are hot zones.

The researchers then used the model to predict where, and how many, new HIV infections would occur based on using either the conventional strategy or a strategy targeting hot zones for distributing the drugs.

"Our results are quite striking," Blower said. "Both strategies would provide PrEP to the same number of people, but using the hot zones plan would prevent 40 percent more HIV infections than using the conventional plan."

Gerberry said the team's strategy could be applied to other nations as well. "The methods we developed can be used to find hot zones in any other sub-Saharan countries that have geographic variation in the severity of their HIV epidemic, such as Lesotho, Botswana, Nigeria and Uganda," he said. "Once the hot zones have been found in these countries, our spatial optimization algorithm can be used to identify the geographic targeting strategy that would be the most cost-effective."

Blower said the study holds great significance for global health policy. "The findings show that, when interventions are rolled out, governments in sub-Saharan Africa will have to choose between maximizing equity in access to the drugs and minimizing transmission of HIV."

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Sophisticated HIV diagnostics adapted for remote areas

Diagnosing HIV and other infectious diseases presents unique challenges in remote locations that lack electric power, refrigeration, and appropriately trained health care staff. To address these issues, researchers funded by the National Institutes of Health (NIH) have developed a low-cost, electricity-free device capable of detecting the DNA of infectious pathogens, including HIV-1. The device uses a small scale chemical reaction, rather than electric power, to provide the heat needed to amplify and detect the DNA or RNA of pathogens present in blood samples obtained from potentially infected individuals.

"This highly creative technical solution brings sophisticated molecular diagnostics to underserved populations and represents a potentially groundbreaking advance in global health care for HIV as well as tuberculosis and malaria, which remain significant health challenges in many remote areas," said Roderic Pettigrew, Ph.D., M.D., director of the National Institute of Biomedical Imaging and Bioengineering (NIBIB) at NIH.

The work was performed by a team at the Seattle-based global health non-profit PATH, led by Paul LaBarre, senior technical officer, and is reported in the Nov. 26 issue of PLOS ONE. The core technology they developed and continue to improve is a system known as NINA, for non-instrumental nucleic acid amplification. The goal is to expand access to accurate diagnostics wherever they are needed, especially those areas that lack reliable electricity.

Early on-site diagnosis allows immediate treatment

LaBarre explains the problem their research endeavors to address. "In low-resource settings, the lack of on-site molecular diagnostic testing is a barrier to the control of infectious diseases. The need to transport the samples from local sites to a distant central diagnostic facility results in delays, lost results, and increased costs." One of the biggest problems, he says, is loss to follow-up, where individuals who have provided samples may fail to return to the local clinic, and therefore will not receive treatment if their test result indicates they are infected. Given these significant impediments to effective disease control, the goal of the NINA technology is to enable on-site point of care (POC) testing and subsequent treatment regardless of the available infrastructure.

A critical feature of the nucleic acid test is the ability to detect infection at very early stages. The currently available test sold over the counter is antibody-based, and cannot detect HIV until antibodies to the pathogen are produced by the body, which can take as long as several months after infection. The PATH method can detect HIV in the early stage of the disease, when the patient can be most infectious. Early detection is essential for POC medicine, where the goal is to diagnose infection and begin treatment in a single visit to the local clinic. For testing babies born to HIV-positive mothers, a nucleic acid-based test must be used because the mother's antibodies in the baby's blood can result in false positives.

Addressing the challenge one idea at a time

The amplification process involves extracting nucleic acids from an individual's blood sample, mixing it with a nucleic acid segment from the pathogen of interest, and using constant temperature heat in a process that makes many copies of (amplifies) pathogen nucleic acids present in the blood sample. The results of the test are highly accurate and easily visualized with a simple dipstick that reveals a colored band indicating the presence of the pathogen nucleic acids.

LaBarre and his team are developing the NINA system using an inexpensive insulated thermos where the source of heat is the chemical reaction. The newest version of the incubator produces heat using magnesium iron alloy (MgFe). MgFe was chosen because it costs just $0.06 per reaction and can be supplied in a self-contained packet. To start the heat-producing reaction, a technician simply adds saline solution to the packet at the bottom of the thermos.

Identifying high-performance, yet inexpensive materials

In this study, the researchers engineered each component of the incubator for maximum performance, ensuring that the amplification reaction that takes place in tiny test tubes maintains a constant temperature. To achieve this, the group identified a special compound that can store and regulate the heat created by the chemical reaction and can also be easily configured to the tube-holder design, guaranteeing uniform heating on each tube's surface. When designing the main body of the device, the research team used a thermal imaging camera to assess the performance of inexpensive materials, and eventually chose a reusable thermos and cover that minimize system heat loss.

Another critical factor is the setting in which the incubator must operate. Although a sophisticated diagnostic laboratory would have equipment operating at room temperature in a controlled environment, the device must operate in extreme ambient temperatures. The reaction inside the incubator must maintain a temperature of 140 degrees Fahrenheit for one hour. Therefore, the research team checked the ability of the NINA incubator to function properly over a range of ambient temperatures. The device maintained the required 140 degrees when tested in environments ranging from 50 to 90 degrees.

The group demonstrated that their amplification system provides sensitive and repeatable detection of HIV-1 in just 80 minutes. They are now working to pair their amplification system with a simple technique for preparing nucleic acids from blood samples in the field. LaBarre explains: "To complete this low-resource setting diagnostic, one remaining need is the integration of a simple method for isolating nucleic acids from patient blood samples before amplification. Current methods are expensive and technically difficult. Fortunately, there are several methods we are testing that look promising."

Because the NINA system can quickly determine whether an individual has an infectious disease, it is a critical technology that will enable POC health services, which combine testing and treatment in a single visit. This is an essential step toward the control and eventual eradication of infectious diseases across regions of small, isolated villages.

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Ability of HIV to cause AIDS is slowing, research suggests

The rapid evolution of HIV, which has allowed the virus to develop resistance to patients' natural immunity, is at the same time slowing the virus's ability to cause AIDS, according to new research funded by the Wellcome Trust.

The study also indicates that people infected by HIV are likely to progress to AIDS more slowly -- in other words the virus becomes less 'virulent' -- because of widespread access to antiretroviral therapy (ART).

Both processes make an important contribution to the overall goal of the control and eradication of the HIV epidemic. In 2013, there were a total of 35 million people living with HIV worldwide according to the World Health Organisation.

The study, published today in the journal Proceedings of the National Academy of Sciences (PNAS), was led by researchers at the University of Oxford, along with scientists from South Africa, Canada, Tokyo, Harvard University and Microsoft Research.

The research was carried out in Botswana and South Africa, two countries that have been worst affected by the HIV epidemic. Across those countries, researchers enrolled over 2000 women with chronic HIV infection to take part in the study.

The first part of the study looked at whether the interaction between the body's natural immune response and HIV leads to the virus becoming less virulent.

Central to this investigation are proteins in our blood called the human leukocyte antigens (HLA), which enable the immune system to differentiate between the human body's proteins and the proteins of pathogens. People with a gene that expresses a particular HLA protein called HLA-B*57, are known to benefit from a 'protective effect' to HIV. Infected patients with the HLA-B*57 gene progress more slowly than usual to AIDS.

This study showed that in Botswana, where HIV has evolved to adapt to HLA-B*57 more than in South Africa, patients no longer benefit from this gene's protective effect. However, the team's data show that the cost of this adaptation to HIV is that its ability to replicate is significantly reduced, therefore making the virus less virulent.

The authors show that viral adaptation to protective gene variants, such as HLA-B*57, is driving down the virulence of transmitted HIV and is thereby contributing to HIV elimination.

In the second part of the study the authors examined the impact of ART on HIV virulence. They developed a mathematical model, which concluded that selective treatment of people with low CD4 counts will accelerate the evolution of HIV variants with a weaker ability to replicate.

Lead scientist, Professor Phillip Goulder from the University of Oxford, said "This research highlights the fact that HIV adaptation to the most effective immune responses we can make against it comes at a significant cost to its ability to replicate. Anything we can do to increase the pressure on HIV in this way may allow scientists to reduce the destructive power of HIV over time."

Dr Mike Turner, Head of Infection and Immunobiology at the Wellcome Trust said "The widespread use of ART is an important step towards the control of HIV. This research is a good example of how further research into HIV and drug resistance can help scientists to eliminate HIV."

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