Experts discuss new design of the Phase IIb PAVE 100 trial



Jorge Sampaio, the United Nations (UN) Secretary-General’s Special Envoy to Stop Tuberculosis (TB), convened a meeting on June 9 in New York City at which activists and researchers called for integrated health services for people infected with HIV and TB in order to prevent TB from undermining the advances made in providing life-saving antiretroviral (ARV) treatment to more HIV-infected people, especially in Africa. Representatives at the meeting issued a “call for action” to the global community to better prevent, diagnose, and treat TB in HIV-infected individuals. 
HIV and TB are a deadly combination (see Deadly Duo: Joining forces to fight TB and HIV, IAVI Report, Nov.-Dec. 2006). TB is the number one cause of death among HIV-infected individuals in Africa. This bacterial infection also contributes to the death of one-third of the people who die of AIDS in low- and middle-income countries, said Kevin De Cock, director of the World Health Organization’s (WHO) HIV/AIDS department.

This HIV/TB meeting preceded a UN General Assembly High-Level Meeting on HIV/AIDS, which was held on June 10-11, also in New York City. The focus of this meeting was to review progress toward reaching the goal of achieving universal access to HIV prevention and treatment by 2010. On that front, UN Secretary-General Ban Ki-moon reported significant progress. At the end of 2007, three million people in low- and middle-income countries were receiving ARV therapy, a 42% increase over the previous year.

But even with this progress, there is still a long way to go in meeting the goal of universal access—only one-third of individuals currently in need are now receiving ARV therapy, according to the Secretary-General’s report on progress in the response to HIV. “There must be better access to prevention, treatment, and support services, especially for those populations at most risk,” said H.E. Srgjan Kerim, President of the UN General Assembly, in his closing statement to the High-Level Meeting. “We must not lose the momentum of our global response. For every two people that begin HIV treatment there are five new HIV/AIDS infections,” he added.

De Cock said progress toward universal access to ARV therapy should also involve access to TB prevention, treatment, and care since even individuals on ARV therapy are more vulnerable to TB. This requires successfully diagnosing TB in HIV-infected people, said Lucy Chesire, an HIV/TB activist. “We need to ensure that every person with HIV [is] screened for TB,” added Chesire. “We know that that’s not the case now. That’s why we [had] over 700,000 new HIV-associated TB cases in the last year.”

There are already examples of how coordinated HIV/TB efforts can make a difference, according to Mario Raviglione, director of the WHO’s Stop TB Department. In Kenya, for example, only 19% of individuals diagnosed with TB were also tested for HIV in 2004. This went up to 70% in 2007, he said, largely due to funding from the US President’s Emergency Plan for AIDS Relief (PEPFAR). “These are very good signs that this funding is being used properly to implement activities,” added Raviglione.

The “call for action” issued at the HIV/TB meeting requests that the global community mobilize an estimated US$19 billion to halve, by 2015, the number of HIV-infected people who die each year of TB, compared with 1990 levels. Of this, $14 billion would be spent on TB prevention and $5 billion on research, said Chesire. Part of the funding for research would go into developing better treatments for TB. There is an urgent need for better tools, such as drugs, said Raviglione. —Andreas von Bubnoff


What can AIDS vaccine researchers learn from live-attenuated SIV vaccines?

Researchers have drawn on a number of different strategies in the pursuit of a safe and effective AIDS vaccine. Among the approaches that have been tested are using non-infectious viruses such as the cold virus as vectors to transport HIV fragments into cells to try to induce immune responses against HIV that will subsequently protect against infection. This was the strategy tested in Merck’s recently conducted STEP and Phambili trials.

But one approach used in many modern-day vaccines remains off limits to AIDS vaccine developers—using a weakened or attenuated version of HIV to stimulate protective immunity. This strategy has been used to develop several existing vaccines that are highly efficacious at preventing disease, including the measles and yellow fever vaccines. Although still a major killer of children in developing countries, measles deaths have dropped 91% in Africa and 68% globally, according to the World Health Organization, following introduction of the live-attenuated vaccine.

This strategy remains on the sidelines of AIDS vaccine development, however, because researchers are worried that live-attenuated HIV will revert to a disease-causing or pathogenic strain once inside the body, which could cause an HIV infection in the very people the vaccine is designed to protect.

Safety concerns

These safety concerns with live-attenuated HIV vaccines are not unfounded. A group of individuals in Australia were inadvertently infected with HIV after receiving tainted blood and, as researchers later discovered, the HIV they were exposed to was a live-attenuated version of the normally circulating virus. This group, which came to be known as the Sydney Blood Bank Cohort, was infected with HIV that lacked a critical gene known as nef that plays a key role in the virus’s ability to replicate in human cells. The nef gene is also responsible for shutting down a class of molecules that would normally summon the immune system’s killer T cells to attack and destroy HIV-infected cells. Despite being infected with an attenuated strain of HIV, several of the long-term survivors of this cohort have now developed damage to their immune systems. After living without any signs or symptoms for nearly two decades, three of the seven survivors now have declining CD4+ T-cell counts, the key marker for progression of HIV infection and development of AIDS.

Researchers believe the nef-deficient HIV strain, which infected the individuals in the Sydney cohort, mutated to regain its ability to replicate rapidly, and therefore became pathogenic. For this reason, live-attenuated HIV vaccines are considered by many to be unsafe for study in humans.

Protection by live-attenuated vaccines

Live-attenuated vaccines are prepared by purposely removing critical pieces of the virus’s genetic material that would normally allow them to wage war on their hosts. The attenuated virus strains are no longer pathogenic but they still pack enough punch to produce a strong immune response against the virus. Neutralizing antibodies, which bind to viruses and prevent them from infecting cells, are thought to be an important component of the protection generated by many of the currently available live-attenuated vaccines, including polio and measles.

In most situations where live-attenuated vaccines are employed, there is also ample evidence of natural immunity to support using an attenuated version of the actual disease-causing pathogen as a vaccine. Consider polio. Despite the recurring images of helpless victims in iron lungs, about 95% of people infected with polio either never get sick or display only mild symptoms. The live-attenuated polio vaccine merely replicated what occurred naturally. The opposite applies with HIV. Without treatment, over 95% of HIV-infected people will ultimately develop AIDS. An AIDS vaccine must therefore accomplish something that largely does not occur in natural infection.

Developing live-attenuated SIV vaccines

While safety concerns prevent the testing of live-attenuated HIV vaccines, the study of live-attenuated simian immunodeficiency virus (SIV) vaccines in nonhuman primates remains an important area of research. Although SIV is a different virus, nonhuman primate studies with SIV are the closest approximation researchers have for studying HIV. Experimental data collected from the study of SIV in non-human primate models can shed light on the development of future AIDS vaccine candidates.

To study the protection afforded by live-attenuated SIV vaccines in nonhuman primates researchers purposely handicap the virus by removing pieces of SIV’s genetic material. One strain of live-attenuated SIV is developed by removing part of the virus’s nef gene. There are also several other versions of live-attenuated SIV vaccines that are currently being studied in nonhuman primates. Generally, the virus becomes more compromised in its ability to replicate and cause an infection when more of its genetic material is removed. But as more genes or parts of genes are removed from SIV, the less effective the live-attenuated vaccine becomes at protecting against infection. Researchers must therefore develop an attenuated SIV strain that does not infect the animals, but is still close enough to the natural form to induce strong immune responses.

The crippled SIV strains are grown in a laboratory and are then used to vaccinate nonhuman primates. These animals are then purposely exposed to a naturally-circulating version of SIV so that researchers can see how well the immune responses induced by the vaccine are able to protect against infection.

Modeling protection

The live-attenuated SIV vaccine strategy has elicited some of the most impressive and consistent protection to date in nonhuman primate studies and can provide researchers with unique insights into the types of immune responses that might also provide some level of partial protection against HIV. Researchers are now developing a better understanding of how the spectrum of SIV-specific CD8+ T-cell, CD4+ T-cell, and antibody responses work together to provide protection against SIV.