HIV Research Funding

It is often said that we know more about HIV than any other virus, and it’s likely to be true. In the 1980’s a staggering amount of scientific research regarding the genome, viral receptors, transmission of HIV, and drug development – including the FDA’s approval of AZT was accomplished. Scientists were hopeful that a vaccine could be developed within a few years, and it seemed that HIV might soon become a problem of the past. However, there is still much to be learned about the virus – and we have yet to see a successful vaccine. Since the 1980’s billions of dollars have been allocated for HIV/AIDS research and drug development. For 2007 alone, 2.6 billion dollars was allocated by the federal government for research on HIV.

Funding for HIV research is higher than for any other virus. But is it in the right places?
Image coutesy of the National Institutes of Health

Most of the funding for HIV research today can be categorized as either marketable and cure-finding, or non-marketable. Marketable research includes research to find a vaccine, drug development, and microbicides. These can be called marketable because they include research that has a potentially huge payback in the form of drug sales or scientific reputation. Global vaccine funding in 2006 was a whopping 933 million dollars, with significant contributions from the NIH (around 600 million), the European Commission, and the Gates foundation. Drug development still takes the largest chunk of the NIH’s HIV research budget at a little over 620 million dollars. Global funding for microbicide development in 2006 was roughly 222 million dollars – significantly less, but still an extremely substantial proportion of HIV research in total. Alone, vaccine and microbicide development take the great majority of research funding both globally and domestically, leaving little for other, less marketable research. Research concerning prevention for at-risk populations and highly impacted communities (especially those in poor nations) remains lacking as compared to budget increases for microbicide development. Without the potential payback that drug sales and vaccine development present, research is much harder to fund and therefore, less gets done. Even though HIV is the most researched virus by any measure, there are still aspects of its actions that are both poorly understood and poorly funded.

2.6 billion dollars is a huge sum of money for research, and not all of it is used by labs operated by the government. The NIH awards some of their allocated budget to other laboratories (often academic laboratories), thereby increasing the amount of researchers involved in HIV science. What can we do with our budget? Recently researchers have experienced a huge setback in vaccine development, as the most advanced vaccine in drug trials was scrapped because test subjects with the vaccine were contracting AIDS at the same rate as a placebo group. With the failure of the most promising vaccine so far, researchers are less hopeful that a vaccine can even be developed. Microbicides are a more recent addition to the field and have become popular recently as an alternative to traditional vaccines, as they are meant to be applied before intercourse to prevent the virus from taking hold. In their proposed budget for 2008 (which differs little from the 2.9 billion dollar budget of 2007), the NIH notes microbicides as an exciting field of research that will receive the most increased funding of any area of research. No matter what the immediate outcome, it seems that we’ll be spending many more billions of dollars before research rewards us with a solution to the AIDS crisis.

Merck announces failure of V520 HIV vaccine candidate

On September 21, 2007, Merck announced the disappointing news that the Phase IIb testing of it’s V520 as an HIV vaccine candidate would be cut short per recommendations of the study’s Data Safety and Monitoring Board. The National Institute of Health and the National Institutes of Allergy and Infectious Diseases worked with Merck in a clinical trial that began in 2004 named the Step Study involving 3,000 HIV-negative, but “high-risk” individuals in North America, South America and Australia. During a preliminary review of data, the DSMB found 24 of the 751 volunteers who received one dose of V520, and 19 of the 672 who received two doses became infected with HIV. They found nearly identical rates of infection in those who had received placebo. Moreover, those who became infected after being vaccinated with V520 did not show significantly reduced viral loads, indicating that the vaccine did not have the desired therapeutic effects.

Also put on hold was a study of the same vaccine candidate in South Africa. The so called Phambili study (from the Xhosa word for ‘moving forward’) began in February 2007 and involved around 800 candidates. V520 had been developed against the B subtype of HIV that is more common in the Americas, but smaller trials had shown that the vaccine had the potential to produce cross-clade immunogenicity to the C subtype that is prevalent in South Africa. The Phambili study also differed from the Step study in that in was aimed primarily at heterosexuals at high risk for infection, while the Step study centered on homosexuals. No more volunteers in either group will receive vaccinations, but those who have already been vaccinated will continue to be monitored.


Most previous vaccine attempts focused on the stimulation of production of antibodies capable of neutralizing the virus before infection is able to occur. This tactic makes successful vaccination difficult because of the high level of diversity that exists in HIV envelope proteins. The highly conserved portion of gp120 that binds with CD4 is not easily accessible to antibodies and so far current vaccination methods have not been able to produce a high enough titer of antibodies to provide immunity. In the V520 vaccine, Merck followed a different approach, aiming not for the production of neutralizing antibodies, but for a strong cytotoxic response capable of killing HIV-infected cells.

V520 is a modified adenovirus, the class of virus often responsible for the common cold. It was altered to display three synthetic HIV genes, gag, pol, and nef. The virus was changed in such a way that it was unable to replicate, and did not contain other HIV genetic information, so there was no chance of accidental infection. Gag, pol, and nef, code for HIV viral core proteins, enzymes necessary for replication and integration, and transcription regulatory proteins. By infecting human cells with a virus coding for these internal proteins of HIV, Merck sought to prime a cytotoxic T cell response directed against cells displaying these more conserved antigens, rather than trying to stimulate antibodies to HIV surface proteins. The vaccine was designed to stimulate the replication of enough cytotoxic T cells specific to gag, pol, and nef antigens that should HIV enter the body, infected cells would be killed before the virus spread to other cells. It was thought that if infection was still viable after vaccination, then the primed cytotoxic response might at least slow the rate of viral replication. Unfortunately, neither of these outcomes occurred.

While the failure of the vaccine was a disappointing setback in the quest for a cure, the study may still provide a useful example for future vaccine candidate trials. In most cases, the efficacy of a vaccine is not put to the test until phase III studies. These studies generally require around 10,000 volunteers and can cost more than $100 million to conduct. The Step study was what is often referred to as phase IIb, or a ‘test of concept’ study. While not in itself sufficient to license a vaccine, test of concept studies provide a less costly intermediate between phase II and phase III studies that allow researchers a relatively quick way of determining if it is worth it to proceed to phase III testing.

Despite this setback, other HIV vaccine research is still proceeding as planned. Sanofi-Aventis currently has a potential vaccine in a phase III trial in Thailand. The vaccine is also aimed at generating a cytotoxic response, but uses a modified canarypox virus as the vector and contains additional gene insertions. Sanofi-Aventis is expected to release data from the study in 2009.

I'm Andrew Johnson. Thanks for listening.

Cognitive Dissonance Theory & HIV/AIDS Prevention

Welcome to The AIDS Pandemic, a podcast hosted by Dr. David Wessner from the Department of Biology at Davidson College. I'm Ali Cundari.

Beyond the obvious physical symptoms associated with AIDS, there are many psychological and social implications surrounding this debilitating disease that we don’t often consider. Mass media efforts and expensive awareness campaigns have done a good job at spreading information to the general public, however, these programs have not been highly successful in reducing risky sexual behavior. Talking about sexuality and proper protection is a topic very uncomfortable to many people, even in today’s world, and this is the reason why many people fail to practice safe sex despite the vast knowledge about how this disease is transmitted. Additionally, a perplexing phenomenon exists among individuals outwardly preaching safe sex, but in reality, not using protection in their own sex lives. This type of insensible behavior is particularly prevalent among sexually active college students, who are aware of the risks and severity of AIDS, but proportionately, very few of them actually use condoms. Recently, several social psychologists have examined this hypocrisy by researching the effects of cognitive dissonance theory on safer sex practices.

Cognitive dissonance theory has been an integral component of social psychology for nearly 50 years, and according to this theory, dissonance arises when a person possesses two contradictory beliefs, or when a person’s attitude conflicts with an action that they chose to perform. This clash between attitude and behavior results in feelings of discomfort, and subsequently the conflicted individual strives to change either their beliefs or behavior to reduce this tension. Hypocrisy is considered a special type of cognitive dissonance, produced when a person decides to promote a behavior that in actuality, they do not practice. Several experiments have been conducted in an attempt to apply this theory to AIDS prevention.

Elliot Aronson was the major contributor to this field of research, and his original study (1991) placed young college students in the role of a HIV prevention educator, who is asked to advocate condom-use to others, but hypocritically does not use condoms in their own sex life. Half the students were asked to compile a list of their past failures to use condoms, when they had deemed it to be too awkward or impossible to do so. Each subject was then asked to compose a speech about the dangers of AIDS and the importance of using condoms for every sexual encounter. The students were quite willing to take on this role, believing it was a good idea to encourage sexually active people to use protection. Then, some of the students recited their speech in front of a video camera, after being informed that this tape would be played in a high-school sex-education class. This produced a high level of dissonance in the subjects. They were now preaching condom-use to others, but hypocritically had failed to practice this at earlier points in their lives. In order to remove this dissonance, the subjects would have to change their attitude to bring it in line with the position they were advocating. Essentially, they’d have to start practicing what they preached. Sure enough, Aronson’s results supported this hypothesis, and after the conclusion of the experiment, the students were far more likely to purchase condoms, which were available on a display table outside the experimental room. Several months later, Aronson followed up with these same students, and they reported that they were regularly using condoms and practicing safer sex.

Many further studies have been conducted, all producing results quite similar to Aronson’s findings. The results of these experiments could have a profound impact on the future of AIDS education and risk reduction efforts, forcing people out of a state of denial and into safer sex practices. Although almost everybody today would agree that AIDS is a huge danger and using condoms is important, the reality is very few of these people actually use condoms themselves. Aronson suggests that the solution to this problem is relatively simple. Society attempts to insulate themselves from a state of dissonance through denial, so in order to cut through this denial, we must directly confront people with their own hypocrisy. Whether it’s through personal and direct surveys or questionnaires, we need to make people realize their past failures and strive to regularly practice safer sex. People need to realize that AIDS is not just a problem for other people, but they themselves are at risk as well. Overall, cognitive dissonance seems to have a strong impact on human behavior, and we can hope to use such theories to encourage safer sex and address the growing social problem that is AIDS.

Thanks for listening. Until next time, this is Ali Cundari.

Testing and Treatment of HIV/AIDS in Children

According to a 2006 UNAIDS/WHO AIDS Epidemic Update, there are approximately 39.5 million people living with HIV/AIDS throughout the world. Of those infected, 2.3 million are aged 15 or younger. Approximately 90% of children infected with HIV acquire the virus perinatally, meaning it is transmitted from a mother to her child during pregnancy, labor, delivery or through breastfeeding. According to the CDC, the prevalence of mother-to-child transmission of AIDS in the US has dropped significantly due to effective testing of pregnant women and treatment of those found to be infected; in resource poor settings, however, the testing and treatment of infected women is far less common. In 2005, the UNAIDS/WHO AIDS Epidemic Update found that only 9% of pregnant women in resource poor countries were offered any sort of prevention services, leading to a higher prevalence of pediatric HIV/AIDS infection in less developed countries. As the prevalence of women of childbearing age who are infected with HIV increases in resource poor settings, it can be expected that the number of babies infected from mother-to-child transmission will likewise increase.

Children infected with HIV/AIDS are confronted with an extremely high rate of illness and death. The World Health Organization has found that because of their unique metabolic and immunologic circumstances, HIV progresses rapidly in children, with an estimated one third of infants dying by the time they reach their first birthday and half dying by their second birthday. Although in most developed countries identification and treatment of HIV infected babies is quite successful, which allows those children to lead healthier and longer lives, the situation is quite different in resource poor countries where testing, much less treatment of infants and children is relatively unavailable. To begin with, testing may be unavailable to individuals in developing countries due to the distance, expense and impracticality of reaching those hospitals and clinics that provide testing. Even when testing is locally available, parents may be unwilling to test their babies for fear of stigma and prejudice associated with an HIV positive status. Furthermore, testing of infants in developing countries can require far more time than in developed countries. PCR tests are among the fastest and most effective ways to diagnose infants as they can be done within 48 hours of birth and results are available to the mother within 6 weeks of the completion of the test. PCR tests are rarely accessible and prohibitively expensive in resource poor settings where antibody tests are the norm. These antibody tests only begin to give accurate results 18 months after birth, and so babies in developing countries are oftentimes diagnosed far later than in developed countries, if they are diagnosed at all.

Aside from the difficulties in testing infants and children for HIV in resource poor settings, there continues to be a dearth of treatment for children found to be positive for the virus. Although both prophylaxis and HAART or highly active antiretroviral therapy can be extremely effective in treating HIV/AIDS and preventing opportunistic infections in children, the unique difficulties associated with treating children in resource poor settings mean that these therapies are widely underused. UNAIDS found in 2006 that “an estimated 380,000 children died of AIDS-related causes” and that, “the vast majority of these deaths could have been prevented either by treating opportunistic infections or providing HAART.” Similarly, a UNAIDS/WHO report found that nearly 90% of children who could benefit from ARV treatments are not currently receiving it. This lack of treatment can be attributed to several factors.

In many resource poor settings, antiretroviral treatment may simply be unavailable. Those countries where the HIV/AIDS burden is greatest such as in Sub-Saharan Africa are oftentimes the least able to provide treatment, and so a lack of resources oftentimes translates into a lack of prophylaxis and/or antiretrovirals. Prophylaxis has been found to be extremely effective in staving off opportunistic infections in HIV positive children and is useful in delaying the need for HAART in pediatric populations. Although prophylactic drugs are widely available and relatively cheap, a UNAIDS/WHO study has found that currently nearly 4 million children who could benefit from such treatment are not receiving it. This is probably the result of lack of available treatment sites and infrastructure in resource poor settings. This dearth of available treatment translates to ARVs as well as prophylactic treatments. Even in areas where adult ARV treatment is present, there is rarely a comparable pediatric treatment site. This is due to the fact that suitable pediatric drug formulations are oftentimes prohibitively expensive and impractical. Little research had been conducted in the area of pediatric dosages because in the developed world effective mother to child prevention had limited the need for pediatric ARVs. Because so few drugs are available in pediatric dosages, and those that are available tend to be far more expensive than those made for adults, most caregivers in resource poor settings are limited to providing either expensive and unpleasant tasting syrup formulas or cutting and crushing adult tablets to provide ARVs for their pediatric patients. Crushing the pills provides an inexact measure of the amount of medication that is administered. Since under dosage can result in resistance of the virus to the drugs, and over dosage can result in amplified side-effects, the lack of correct dosages inherent in using adult drugs for pediatric patients means this mode of drug administration is far from ideal.

Important steps have been taken to begin to provide better treatment for pediatric AIDS patients. In August of 2007 the US Food and Drug Administration (FDA) approved a special tablet for children with HIV that combines three antiretroviral drugs into one pill. The tablet can be dissolved in water for ease of administration which is required only twice a day. The drug is produced by the manufacturer Cipla Limited, a generic pharmaceutical company based in India. Though unapproved for use in the US, the drug has been authorized for use in developing countries where the need and demand is greatest. Despite the enormous implications for successful treatment of pediatric AIDS that this drug will bring, there are still substantial obstacles to be overcome before pediatric care and treatment of AIDS is fully complete. Mother-to-child transmission must be diminished in resource poor settings. In situations where prevention of mother-to-child transmission is not achieved, suitable infrastructure for administration of prophylactic and antiretroviral drugs to pediatric patients must be established. Movements and groups such as the “Stop AIDS in Children” campaign are working towards prevention of mother-to-child transmission and improvement of treatment for infected children. With support of both developed and resource poor countries, the relatively ignored problem of HIV/AIDS in children can be successfully addressed.

Until next time, this is Dominique Maietta for the AIDS Pandemic Podcast.

PRODUCT(RED): Philanthropy or Exploitation?

Product(RED)



An earlier installment of this podcast from a year ago called attention to the launch of PRODUCT(RED) in the United States. Since the brand’s introduction, (RED) watches, sunglasses, t-shirts, cell phones, and iPods have been extensively marketed and sold, with some of the revenues going to support the fight against AIDS in Africa. Nevertheless, the (RED) brand has been a target of criticism for its commercial approach to a philanthropic endeavor. In this installment, I intend to take a close look at PRODUCT(RED) and its impact on the AIDS pandemic.

(RED)’s business model embodies the strategy of cause marketing, where for-profit companies and non-profit organizations collaborate in a joint initiative for their mutual benefit. (RED) currently has partnerships with several distinctive consumer goods companies, including Motorola, The Gap, Converse, Apple, and Emporio Armani. PRODUCT(RED) gives its partners permission to brand certain products as (RED), and in return the partners send a share of their profits from those products to the Global Fund to Fight AIDS, Tuberculosis, and Malaria. Hip, humanitarian, and business-savvy, PRODUCT(RED) panders simultaneously to Americans’ munificence and to their conspicuous consumption.

According to the PRODUCT(RED) website, as of September 2007 the sale of (RED) products has generated more than $45 million for the Global Fund. This money has been directed toward AIDS treatment and prevention programs for women and children in Ghana, Swaziland, and Rwanda. (RED) points out that its contribution to the Global Fund will be a steady, constant stream of revenue rather than a one-time lump sum donation, ensuring that the brand will have a sustained impact on its beneficiaries.

Most criticism against the brand has centered on the belief that its partners are taking advantage of the AIDS problem in order to turn a profit. Early detractors of the brand encouraged consumers to donate their money directly to charity and thereby bypass the middle-men (RED) partners siphoning off most of the revenues. Later, a particularly scathing article in the magazine Advertising Age cited the disproportionately large amount of money spent by the brand’s partners promoting their (RED) products compared to the amount the partners actually raised for the Global Fund from the product sales. More recently, Ben Davis, creator of a parody campaign called BUY(LESS), has written an open letter to (RED) CEO Bobby Shriver requesting both more transparency in the distribution of profits from (RED) products and a more direct way for consumers to contribute directly to the Global Fund without having to buy (RED)-branded products.

In the end, it is important to consider what PRODUCT(RED) really is. It is not a charity, but “an economic initiative”, according to its website. Accordingly, its partners’ financial interest in the (RED) brand gives them an incentive to ensure its continued success. So what if the amount of money spent by the partners promoting their (RED) products exceeds the amount they turn over to the Global Fund? The money is already designated for their advertising budgets and would be spent anyway. This way, it at least goes toward publicizing a good cause. And besides, strictly fiscal measurements of PRODUCT(RED)’s impact (in terms of dollars alone) understate the heightened general awareness that the brand engenders among consumers.

Debating whether (RED) is more philanthropic or exploitative in nature misses the point. Even its most ardent critics would agree that the brand is making a positive contribution to the fight against AIDS. The question is, could PRODUCT(RED) do more to achieve its stated goal to “expand opportunities for the people of Africa”? I think it could.

Thanks for listening. I’m Bill Stokes.


References:
Bennett, J. Does Shopping for a Good Cause Really Help?. Newsweek. 14 March 2007.
Davis, B. Buy (Less), Give More. accessed 09 October 2007.
Kim, R. Africa’s Poor Had the Best Week Ever. The Nation. 15 October 2006.
The Persuaders, LLC. 2006. (RED). accessed 09 October 2007.
Vallely, P. The Big Question: Does the RED campaign help big Western brands more than Africa?. The Independent. 09 March 2007.

Integrase Inhibitors: A New Hope

I’m Bevin English.

On October 12th, the Food and Drug Administration (the FDA) announced that it had approved a New Drug Application for a completely new kind of medication in the fight against AIDS. This drug, called IsentressTM, is the first integrase inhibitor and comes in 400 mg tablets that are taken twice daily. Produced by Merck & Co., Inc., Isentress, whose generic name is raltegravir and whose in-development name was MK-0518, has impressed many leading AIDS researchers, including Dr. Amneris Luque, medical director of the AIDS Center at the University of Rochester, who called the new drug “the road to hope for people who have failed all other AIDS medications.”

Before raltegravir’s approval, there were three oral anti-retroviral drug classes approved by the FDA: nucleoside reverse transcriptase inhibitors (also called NRTIs), non-nucleoside reverse transcriptase inhibitors (also called NNRTIs), and protease inhibitors (also called PIs). These drugs block two of HIV’s three enzymes that are necessary for infection: reverse transcriptase and protease. When HIV infects a cell, reverse transcriptase converts the viral genetic information from RNA to DNA. Integrase then inserts this viral DNA into the host cell’s genome. After the viral DNA has been translated by the host cell, protease cleaves the proteins into the functional units that come together to form protein coats for new viruses. These three classes of drugs have been used to treat HIV positive patients for many years. Nucleoside reverse transcriptase inhibitors have been used since 1987, when the FDA approved AZT. One of the most prominent non-nucleoside reverse transcriptase inhibitors, efavirenz, has been in use since 1998. And three common protease inhibitors, saquinavir, indinavir, and ritonavir, were approved by the FDA in 1996.

In Phase III clinical trials, raltegravir was administered to over 600 people who had viral loads greater than 1000 copies/mL and resistance to at least one drug in each of the three oral antiretroviral classes. In all trial groups, patients receiving raltegravir tended to have lower viral loads and higher CD4 cell counts than the control group, which consisted of patients receiving optimized background therapy (OBT) and a placebo. OBT is a personalized combination of different antiretroviral drugs that will most effectively increase an individual’s CD4 count and decrease his or her viral load; OBT is based on the patient’s history, current viral load and CD4 count, and any resistance tests. In raltegravir’s Phase III trial, the most dramatic result was seen when the drug was combined with one or two other active drugs, with 98% of patients’ viral loads below 400 copies/mL after 16 weeks. Data from on-going Phase II clinical trials show that raltegravir in combination with OBT maintains low viral loads over an extended period of time, with 64-71% of individuals achieving loads below 400 copies/mL and 46-64% of patients having loads less than 50 copies/mL after 48 weeks of the therapy.

Side effects of raltegravir were generally reported as mild to moderate and caused fewer than 2% of participants to discontinue therapy; nausea, headache, and diarrhea were the most common. Currently, there are no known drug interactions, although further studies must be conducted to investigate any possible drug interaction issues. Because of raltegravir’s efficacy, safety, and tolerability, the FDA gave this new drug priority review status, meaning that the Administration promised to review the drug within six months of their reception of the New Drug Application because it could potentially help with unmet medical needs.

However, it is important to note that “[t]he fight will not end with raltegravir,” as AIDS activist and participant in raltegravir clinical trials Matt Sharp stated to the FDA. One problem is that the drug simply has not been around long enough for scientists to understand its long-term effects in vivo. It has been less than four years since the drug was first used in humans and less than three years since it was first used in HIV positive individuals. During clinical trials, researchers observed more cases of different cancers, including lymphoma, squamous cell carcinoma, and hepatocellular cancer, among individuals who received raltegravir. Upon analysis, researchers claimed that the increase in the occurrence of cancers was not significant. However, any patient receiving raltegravir must be observed for the long-term to ensure that the drug does not lead to an increased risk of cancer.

Another important issue that must be taken into consideration is viral resistance to the new drug. In vitro data has shown that HIV can become resistant to raltegravir, but resistance generally occurs after serial passage in cell culture for several months. During clinical trials, 16% of patients were virological failures in the raltegravir group after 24 weeks. However, researchers remain hopeful that second-generation integrase inhibitors, such as Gilead’s elvitegravir, which is currently undergoing Phase II clinical trials, may help overcome resistance.

Despite the uncertainty of raltegravir’s long-term effects in vivo and the possibility of resistance, this breakthrough drug marks a milestone in AIDS treatment. The first integrase inhibitor, raltegravir, in combination with other drugs, has shown to be extremely effective in reducing viral loads and increasing CD4 counts, even in patients whose treatment options are severely limited by multi-class resistance.

Integrase Inhibitor Isentress Provides a New Way to Treat AIDS Patients

Welcome to this installment of The AIDS Pandemic, a podcast hosted by Dr. David Wessner from the Department of Biology at Davidson College. I’m Mike Neri.

In this podcast, I will talk about the optimism surrounding the recently FDA approved AIDS drug Isentress, including how it works, what step in the HIV replication cycle it affects, and what preliminary data show about the drug’s effectiveness and side effects. Ever since the discovery of HIV as the causative agent of AIDS, scientists have searched for weaknesses in its life cycle that they can exploit. As early as 1990, scientists had identified 13 pathways in the life cycle of HIV where the virus was susceptible to treatment. Unfortunately, due to the years of trial and error necessary to produce safe and effective drugs, new AIDS medications are developed slowly, and often have many side effects.




But optimism is high after the new drug Isentress showed very promising results when acting on a novel pathway to inhibit HIV replication. Isentress, also called Raltegravir, was developed by the Merck Corporation. It’s the first drug in a new line of AIDS medications called integrase inhibitors. As the name suggests, these drugs target an enzyme called integrase that the virus brings with it into an infected cell. Integrase, along with two other enzymes called reverse transcriptase and protease, is essential for HIV’s replication within the host. Therefore, scientists believe that if they can find a compound that stops integrase, they may be able to stop HIV from replicating.

After HIV has entered the cell by fusing with the membrane of its target cell, the virus dumps its genetic material and enzymes inside. It then makes copies of its own genetic material and uses integrase to insert them into the DNA of its host. This allows the virus to replicate its genome using the host’s machinery, and essentially take over the infected cell for its own reproductive purposes. The goal of integrase inhibitors is to prevent integrase from working correctly, therefore keeping the HIV genetic material out of the host’s genome and hindering viral replication. Previously, there had been only four pathways that drugs target in the HIV life cycle, and none of them had targeted integrase. However, integrase is an attractive target molecule for drug development for a number of reasons. First of all, integrase does not resemble any known human proteins, meaning the chances of side effects are reduced. In addition, by going after a new viral pathway for infection, doctors can combine integrase inhibitors with drugs targeting different pathways, which prevent the virus from becoming resistant to an entire class of drugs.

Scientists have long wanted to develop an integrase inhibitor, but the road to creating an effective drug and gaining FDA approval for it is a long one. According to Merck’s website, research into integrase inhibitors began in 1993 and eventually resulted in the identification of a class of compounds that could impede the function of the enzyme. These compounds work by binding to the active site of the integrase, thus preventing it from binding and cutting the host DNA, which prevents the viral genome from being inserted. After this discovery, researchers worked with these compounds in the lab to create the best integrase inhibitor, and tested it in virus cultures and animals. The use of animals allowed them to get an idea of the severity of the side effects and an approximate idea of the appropriate drug dosage. The final product of this drug testing was named Isentress. After emerging from the laboratory phase, Isentress was put through three phases of clinical studies involving groups of healthy and sick people. Results from the studies of Isentress given with a combination of other AIDS drugs were compared to a placebo given with the same drugs. From these data, researchers were able to get an idea of the effectiveness of the drug in treating the virus and fine-tune dosage information, all while closely monitoring side effects. At the end of this process, Merck submitted the data from all of the tests and clinical studies to the FDA for it to decide whether the drug was safe to be offered on the market. And on October 12, 2007, Isentress was officially approved by the FDA for treatment in AIDS patients, specifically those with HIV strains resistant to all other drugs. Most of the optimism surrounding the approval and release of the drug comes from the data obtained in the clinical studies. In the later phases of these trials, Isentress and a standard combination of other drugs were given to the most drug-resistant patients and compared to a placebo group. After 16 weeks, the Isentress treatment reduced the viral load to almost undetectable amounts in nearly 80% of patients, compared to only 43% in the placebo group.

While questions concerning Isentress still remain, such as whether the drug will work over longer periods of time and what the long term side effects might be, the preliminary results suggest that Isentress will have a significant impact on the treatment of AIDS immediately. As mentioned before, Isentress is initially expected to be used in patients who have exhausted all other drug treatment options. However, the overwhelming success of the drug so far has medical professionals wondering whether it can eventually be used as a front-line treatment against HIV. The true impact of Isentress cannot be known until it has been used by all types of AIDS patients over long periods of time. Nevertheless, the approval of Isentress is a sure sign for optimism in the AIDS community and a great success for the drug and pharmaceutical companies that have spent years producing and testing it.

I’m Mike Neri, and thanks for listening.

HIV/AIDS: The Brazilian Response

In the arena of HIV/AIDS prevention and treatment, Brazil has become a beacon of hope, particularly among developing countries. Countries around the globe are now looking towards their system of universal AIDS care for guidance.

In the early 90’s it was estimated that within a decade, the number of HIV+ people in Brazil would be near 1.2 million. Instead, recent estimates suggest that only half that amount (about 660,000 people) are infected. How have they been so successful in limiting the spread of this deadly disease? With a three pronged government program focusing on prevention, treatment, and reducing the stigma associated with AIDS patients.

The first aspect of Brazil’s plan hopes to prevent the spread of HIV, particularly among the highest risk groups. After a brief stint of abstinence education failed early in the epidemic, the government looked towards other alternatives. Surprisingly, even in a country that is dominated by the Catholic Church, promoting condoms has proven very effective. The government has plans to distribute millions of condoms through local clinics, particularly to those involved in the commercial sex industry. Condom distribution is intensified during Carnival, a lively celebration before Lent where “free condoms are passed out like candy.” They have even encouraged the adult films industry to incorporate condoms into their films, and have produced prime time TV ads promoting condom usage in homosexuals. Additionally, a government funded needle exchange program hopes to slow down the spread among IV drug users.

A particularly intriguing aspect of Brazil’s treatment program has been their ability to supply anti-retroviral drugs to any AIDS patient needing them. As of September 2005, over 170,000 patients who required treatment were receiving it for free from the government. On a recent visit, the head of Uganda’s Parliamentary Committee on HIV/AIDS affirmed that “being able to provide the same standards of care to all citizens irrespective of their status in society is something to emulate.” This program, which began in 1997 as the first of its kind in the developing world, has lead Brazil to seek cheaper prices in order to keep costs down. A government sponsored company produces generic forms for many of the most widely used drugs. They have even broke patents on some of the newer drugs as costs have continued to skyrocket. Under fear that the Brazilian government will bypass the patent system, many companies have opted to cooperate and lower their prices. Even still, treatment makes up about 80% of their AIDS budget.

Contrary to many aspects of the US AIDS program, the Brazilian government has worked to gain the support of many of the most at risk groups. In 2005, Brazil rejected over $40 million from the United States because they would have had to pledge that they oppose commercial sex work; having the support of the sex industry has been integral in their fight against AIDS. Additionally, focusing on treatment instead of solely on prevention has encouraged testing and reduced stigma for those suffering with AIDS.

The model system that Brazil has implemented is envied by many countries around the world. Even the United States could learn from Brazil’s focus on condom distribution and treatment, as well as their support for constructive dialogue about the disease.

For more information about the current status of HIV/AIDS in Brazil, go to Brazil’s page of the UNAIDS website.

I’m Ben Young, thanks for listening.

The AIDS Pandemic - Your Thoughts

Welcome to this installment of The AIDS Pandemic. I’m Dave Wessner.

Last week, I was invited to speak about this blog and podcast at the annual meeting of the American Society for Virology in Corvallis Oregon. Based on questions and comments I received, I’d like to try something a little different with this installment. I’d like to ask for your opinion of this project.

Before getting your feedback, though, I’d like to remind everyone about the genesis of this podcast. I began it during the summer of 2006, just over a year ago. Throughout the fall, students enrolled in my course on HIV/AIDS at Davidson College developed and recorded installments, which we then posted throughout the academic year. Beginning in September, a new group of students will continue this project, recording and posting more interesting installments. My goals for this class assignment were two-fold. First, I hoped that the creation of podcast installments would provide a good learning experience for my students. It would give them an opportunity to explore in detail some aspect of the pandemic – scientific, social, political – that truly interested them. Second, I hoped that the podcast itself would be some benefit to the outside world and, in some small way, increase public understanding of HIV/AIDS.

I can assess the impact of this class assignment on my students. And I am convinced that it is a worthwhile exercise. But I’m less sure how to assess the broader impact of this podcast and blog. That’s where you come in. I’d appreciate feedback from you. Please tell me if you listen to the podcast and/or read the blog. How did you first hear about it? How regularly do you listen/read? What topics have you found most interesting? Is it a worthwhile source of information? Are there things we could do better? Have you ever looked at our AIDS and pop culture website? Is it a worthwhile source of information?

You can email your responses to dawessner@davidson.edu.

Thanks for your input.

National HIV Testing Day

Welcome to this install of The AIDS Pandemic, a podcast hosted by Dr. David Wessner of Davidson College. I’m Dave Wessner.

June 27 is the 15th annual National HIV Testing Day, an event sponsored by the National Association of People with AIDS to encourage people to get tested and learn their HIV status. Today, I had the pleasure of participating in a Webinar hosted by the Department of Health and Human Services and the Centers for Disease Control and Prevention about this important event.

During this Webinar, we were reminded of the CDC’s new recommendations about HIV testing – all individuals between the ages of 13 and 64 should be tested routinely on an opt-out basis. In other words, testing for HIV should be included in normal health care, unless a person specifically asks not to be tested. The reasons for this recommendation are several-fold. Most importantly, a majority of new infections result from transmission of the virus from an individual who does not know his or her HIV status and studies have shown that if people know their status, they tend to modify their behavior to reduce the risk of transmission. So increased testing should lead to decreased transmission rates.

Of course, there are important issues that need to be addressed. How can we reach underserved populations, including the homeless and uninsured? How can we reach young people? How will the costs of the test and necessary follow-up counseling be absorbed by our health care system? Despite these obstacles, though, the goal of universal, routine testing is admirable. I encourage everyone to get tested.

More information about National HIV Testing Day can be found at www.hivtest.org. This site contains information about HIV testing and has an easy to use test center finder. Simply type in your zip code and a list of local testing sites will be provided.

As the CDC testing campaign slogan states: Take the Test. Take Control.

Until next time, I’m Dave Wessner

Bush advocates $30B for PEPFAR

Welcome to this installment of The AIDS Pandemic, a podcast hosted by Dr. David Wessner from Davidson College. I’m Dave Wessner.

Yesterday, President Bush implored Congress to extend PEPFAR, the President’s Emergency Plan for AIDS Relief, for an additional 5 years and allocate an additional $30 billion to the program. Initially proposed in the President’s 2003 State of the Union address, PEPFAR targets HIV/AIDS treatment in 15 countries with high HIV/AIDS burdens.

As President Bush noted, the $15 billion allocated to PEPFAR thus far has resulted in antiretroviral drugs for 1.1 million people in these resource limited countries and the increased funding could result in treatment for as many as 2.5 million people. This drug therapy, obviously, will extend and improve the lives of these lucky individuals. Arguably, then, PEPFAR is changing the HIV/AIDS landscape.

The plan cannot, however, be considered an unqualified success. Approximately 30 million people in sub-Saharan Africa alone are HIV positive. Providing treatment to 2.5 million of them is not enough. Until all people, in all countries, have access to the life-saving antiretroviral drugs, we can not be satisfied with any existing plan.

More importantly, we need to examine the restrictions associated with PEPFAR funds. One third of allocated funds must be spent on abstinence programs, despite the clear evidence that condoms are the most effective means of preventing the sexual spread of HIV. No funds can be spent on clean needle exchange programs, despite the clear evidence that needle exchange programs prevent the transmission of HIV and do not lead to increased injection drug use. The $15 billion currently allocated to PEPFAR has made a difference. And the additional $30 billion proposed by President Bush will make an even greater impact on the pandemic. President Bush should be commended for this initiative and his leadership. But President Bush also should be admonished for ignoring the scientific evidence. When it comes to the AIDS pandemic, decisions need to be based on evidence, not one person’s faith-based morality.

Until next time, I’m Dave Wessner

True Colors Tour for the Human Rights Campaign

Welcome to this installment of The AIDS Pandemic, a podcast hosted by Dr. David Wessner from Davidson College. I’m Dave Wessner.

We opened this installment with a short segment from True Colors, by Cyndi Lauper, the iconic voice of ‘80s pop. Long supported by and a supporter of the gay, lesbian, bisexual, and transgender communities, Lauper recently announced her plans for this summer’s True Colors tour in support of the Human Rights Campaign. Along with Debbie Harry, the Dresden Dolls, Erasure, and others, Cyndi Lauper will headline this tour that opens June 8th in Las Vegas. A portion of all tickets sales will go to the Human Rights Campaign.

Throughout its 25-year history, HIV/AIDS has been inextricably linked to human rights issues. Sexual violence against women, stigma associated with men who have sex with men, young girls forced into prostitution – all of these human rights violations have contributed to the spread of HIV/AIDS. The Human Rights Campaign fights tirelessly to rid the world of these injustices. You certainly can help by becoming a member of the HRC and contributing to them directly. And this summer, you also can help simply by attending a great concert.

As Cyndi Lauper states on the Tue Colors Tour web site, “We should all have the right to live with the same dignity, opportunity and safety. It shouldn’t matter what anyone’s sexual orientation is.”

Until next time, I’m Dave Wessner.

Microbicides: Empowering women

Current global AIDS statistics are staggering, to say the least. Approximately 40 million people worldwide are living with the disease, while 14,000 new infections occur each day. Women make up almost 50% of adult infections, but this figure is higher in sub-Saharan Africa, where women are 30% more likely to be HIV-positive than men. Due to physiological differences, women are twice as likely as men to contract HIV from an infected partner, but many lack the necessary tools for protection. Even if the tools are available, poverty and inequality can make it impossible for women to have control over their sexual interactions. The ABCs of prevention (abstain, be faithful, and use condoms) are useless without male cooperation. The ABCs are even more ineffective for married women with non-monogamous husbands because, as Melinda Gates states, “abstinence is unrealistic, being faithful is insufficient, and the use of condoms if not under their control.”
Microbicides are a new and important HIV prevention method that can put the power of protection in the hands of women. Microbicides are formulated as gels, creams, suppositories, or films that can kill or neutralize viruses when applied before sexual intercourse, thus preventing infection. Because women could apply the microbicide without the cooperation or awareness of their partners, they would have more control over preventing an HIV infection. Ideal microbicides would also protect against other STDs that can facilitate HIV transmission and come in spermicidal or non-spermicidal formulations that allow pregnancy while still offering protection. An ideal microbicide should be active upon application, remain active for an extended period of time, and be tasteless, odorless, and invisible in order to prevent detection and interference with sexual activity. Finally, for distribution and accessibility, an ideal microbicide must be cheap and easy to store.
There are three major approaches a microbicide can use to prevent infection. Some microbicides act as physical barriers that prevent HIV from entering tissue. They are liquid at room temperature, but become gel-like inside the body and work like a condom. Others contain molecules that inhibit the virus itself. They might create an acidic environment in which the virus cannot survive, or contain known anti-HIV drugs, such as AZT. Still others prevent infection by interfering with viral surface proteins, therefore preventing attachment. Researchers hope that multiple methods of prevention will be combined into one microbicide to increase effectiveness.
While no microbicides have been approved for general use, twelve versions are currently undergoing various phases of clinical trials. However, there are several important issues that stand between microbicide development and widespread use. Most microbicides are developed by small biotech companies and educational research institutions. Only 1% of federal research funding goes toward microbicide research, and pharmaceutical companies are unwilling to invest because the women who need their products will be unable to pay for them. Once microbicides are developed, they must go through a series of clinical trials. International support to build the necessary infrastructure for trials in developing countries is crucial so testing can occur in the locations where products will be most used. Microbicide producers are concerned about the low efficacy of first-generation microbicides and the potential for increased risk behavior, such as condom substitution. However, most agree that since condom use is rarely consistent, microbicides can provide better protection than nothing at all. Finally, only 20% of the population at high risk of infection currently has access HIV prevention methods. Even a 100% effective product does little good if it cannot be distributed to those who need it most.
While microbicide development is currently facing many challenges, there is no doubt that microbicides are a powerful HIV prevention tool. By giving women more control over HIV protection we can drastically reduce the number of new infections each year and save millions of lives.

I'm Page Bomar. Thanks for lsitening.

VIRIP: A new anti-HIV compound?

Welcome to this installment of The AIDS Pandemic. I’m Dave Wessner.

Could our own bodies be producing potent inhibitors of HIV? According to research published in today’s issue of Cell, the answer may be ‘Yes.’ And these interesting findings eventually may lead to the development of new anti-retroviral drugs.

Since the isolation of HIV in 1983, numerous naturally occurring human factors have been postulated to have anti-HIV properties. Today, a group of researchers in Germany have added another factor to this list. By studying hundreds of small molecules isolated from human blood, the researchers identified a short peptide, or protein fragment, that effectively blocked HIV from infecting cells. Termed Virus-Inhibitory Peptide, or VIRIP, this peptide represents a small piece of a larger protein normally found in our blood – alpha1-anti-trypsin.

To demonstrate the inhibitory effects of VIRIP, the researchers infected cell lines with HIV-1, added VIRIP to the cells, and then determined how many additional cells subsequently became infected. VIRIP decreased the infection rate in a dose-dependent manner. In other words, when higher concentrations of VIRIP were used, the effect was greater. The effect also was very specific for HIV; the peptide did not block the infectivity of other types of viruses. Interestingly, the researchers showed that if they altered the VIRIP peptide slightly, it’s inhibitory properties increased dramatically. Finally, VIRIP was equally effective against strains of HIV that were resistant to other anti-retroviral drugs, yet resistance to VIRIP was not observed.

Mechanistically, it appears that VIRIP blocks HIV infection by binding to the viral protein gp41 and preventing fusion between the viral envelope and the cell membrane. An existing drug, T20, or Fuzeon, works in a similar manner.

The path from an initial discovery like this and a marketable drug is a long and winding path, filled with potholes. Promising candidate molecules rarely become FDA-approved drugs. So, the odds are against VIRIP. But, based on this report, it’s certainly worth keeping our eye on it.

Until next time, I’m Dave Wessner.

Kiva: Using microfinancing to help people in developing countries

Paul Farmer, one of the founders of Partners in Health, describes the ‘great epi divide,’ the epidemiological divide that exists between developed countries and developing countries, between affluent neighborhoods and less well-off neighborhoods, between the haves and the have-nots. Morbidity and mortality associated with infectious diseases, Farmer notes, correlate well with economic disparities.

HIV/AIDS is no exception. Certainly, HIV can, and does, infect people of all walks of life. Increasingly, though, the HIV burden is highest among developing countries and the poor within developed countries. The reasons for this correlation are many. In economically challenged areas, medical care and treatment often are unavailable or unaffordable. In these areas, access to education may be limited. The list goes on.

One could argue, then, that improving the economic independence of people is the ultimate weapon against the spread of HIV. One group addressing the issue of economic independence in developing countries is KIVA. Kiva, Swahili for ‘agreement,’ is a non-profit organization designed to help people gain economic independence through microfinancing. Individuals can search the Kiva web site for people in Africa, central Asia, eastern Europe, and other parts of the world, who have great ideas, but need some initial capital. Through Kiva, one can make small, interest-free loans to these individuals. In some cases, a few hundred dollars may be all that a person needs to open a small bakery or expand a pottery shop.

The loans aren’t guaranteed; as a donor, you may never be repaid. But the results could be transformative. A little seed money may be all a person needs to become self-sufficient and cross the great epi divide.

Find out more about Kiva and help someone make their dreams a reality.

Until next time, I’m Dave Wessner.

Refrigeration and HIV Meds in Resource-limited Settings

I'm Charlie Raver.

One of the distinguishing characteristics between the AIDS epidemic in the developed world and that in Africa and the developing world is a simple lack of the infrastructure to deal with the disease. Infrastructure includes everything from roads to electricity to hospitals. One example that most of us rarely think of as a gift, couldn’t dream of walking into a home and not finding, and would be lost without is something to which many in the developing world do not have access. What am I talking about? Refrigeration. Without this amazing piece of technology we would not be able to easily enjoy fresh meats, fish, dairy, and many simple nutritional luxuries that we as Americans take for granted. In addition to problems with food preservation, hospitals and health clinics would be unable to store blood, vaccines, heat intolerant medicines, and many laboratory supplies.

For many in the developing world that is exactly the problem. Without refrigeration they have no means to store many of the supplies necessary for maintaining a health clinic. Without this infrastructure, access to basic care, essential for the treatment of AIDS, is extremely limited. Recently, the WHO recommended the use of a ritonavir boosted protease inhibitor as part of the drug regimen. Aside from being able to obtain the drug, one problem is that ritonavir requires refrigeration in hot climates. Currently only one of the ritonavir boosted PIs is available in a heat stable form which, obviously puts a huge constraint on the availability of the drug in the developing world. A confounding issue is the high rates of coinfection of diseases such as tuberculosis and malaria in these resource poor areas. In addition to proper care, access to testing for HIV and TB has been cited as one of the first obstacles to fighting the epidemic. The WHO estimates that less than 10% of people living with HIV/AIDS in parts of Sub-Saharan Africa are aware of their HIV status.

In addition to poor access to health care, the epidemic is only made worse by the staggering rates of malnutrition. In their recommendations for antiretroviral therapy, the WHO emphasized the importance of nutrition not just for the overall health of the affected individuals but also because of the link between nutrition and the effectiveness of ART. However, in some parts of Sub-Saharan Africa, it is estimated that as much as 50% of the population is malnourished. Many Africans do not even have the means to buy or grow the most basic foods. This problem is again only made worse by the lack of refrigeration. Some form of food preservation could allow rural communities and individuals to grow crops in excess and store the surplus to either sell and trade with other communities or even just maintain a supply during the non-productive parts of the year. However, when you consider that over 500 million people in Sub-Saharan Africa do not have access to electricity the idea of refrigeration is a long shot.

Unfortunately providing those in rural Africa with electricity is a problem unto itself. Without economic stability there is little room for expansion and improvement of infrastructure whether it is roads, electricity or health care. These lacks in infrastructure only make the AIDS epidemic harder to fight which further hinders economic growth. However, small improvements like access to refrigeration could be a catalyst for change.

One type of refrigeration that requires no electricity is sorption refrigeration. This form of refrigeration works by having two chambers connected by some type of tube. One chamber, the hot side, contains an absorbent material. The other chamber, the cold side, contains a refrigerant. The tube connecting the two would be filled with refrigerant vapor. The vapor in the tube is then absorbed on the hot side causing a drop in pressure in the connecting tube. This causes evaporation of the refrigerant which in the process absorbs heat and causes cooling on the cold side. This continues until all the refrigerant has vaporized and been absorbed on the hot side. To restart the cooling process, the hot side must be heated gently to drive the refrigerant vapor out of the absorbent material and back to the cold side. In the late 1920s, Powell Crosley Jr. developed a commercial version using ammonia and water that was used throughout the rural United States prior to wide-spread access to electricity. Although this is by no means a large scale solution to the infrastructure problem, adaptation of these ideas for use in the developing world could provide one of the basic necessities for health care and food preservation.

AIDS Orphans in Sub-Saharan Africa

I'm Christie Brough

According to the AIDS Epidemic Update of December 2006, about 25 million people are living with HIV in sub-Saharan Africa, comprising 63 percent of all individuals with HIV globally. Approximately 13.3 million, or 59 percent, of these individuals are women, most of whom have children. Although considerable efforts have been made to provide these individuals increased access to antiretroviral therapy, 2.1 million Africans died in 2006, resulting in an increased number of AIDS orphans.

In 2001, 14 million children had already lost one or both of their parents to AIDS. Because of the difficulty of obtaining antiretroviral therapy, many more children will be affected. In fact, one estimate projects that the number of AIDS orphans will increase by approximately 150 percent by the year 2010, leaving 20 million children to raise themselves.

As children watch their parents succumb to AIDS, they often suffer psychological and emotional harm. Once a parent becomes too sick to work, children are forced to work themselves in order to raise money for their families or to take care of younger siblings, causing them to drop out of school. Another factor forcing children to drop out of school is their inability to pay for required items, like school uniforms, pencils, textbooks, and exam fees, which they no longer can afford. If they do not have these items for school every day, they may be sent home and told not to return until they have the proper materials. Children that continue to attend school despite their parent’s illness often display a lack of attention or inappropriate behavior in the classroom, which is thought to result from emotional stress. Academic performance is also negatively affected by child malnutrition. Malnutrition is common in AIDS-related poverty since most of the family’s resources must be spent on medication for the ill parent. As a result, school enrollment rates in sub-Saharan Africa are dropping as the death toll from AIDS continues to rise.

Children that grow up without parents and without an education are “trapped in a social and pedagogical vacuum.” These children are not only more vulnerable to contract HIV/AIDS, but they are also at higher risk of unemployment, exploitation, and other forms of social inequalities. In order to change the outlook for AIDS orphans in sub-Saharan Africa, international and national agencies must aid in providing greater access to antiretroviral treatment. One relatively successful example is the World Heath Organization’s 3-by-5 program. The 3-by-5 plan aimed at providing 3 million individuals worldwide antiretroviral treatment by 2005. Although the program did not meet its goal of treating 3 million HIV positive individuals in the 2-year period, the program successfully provided access to many individuals who were not receiving treatment before. According to the World Health Organization, the number of individuals receiving treatment in sub-Saharan Africa increased by more than 800 percent, increasing the distribution of antiretroviral drugs from 100,000 individuals to 810,000 individuals.

Although the success of the 3-by-5 program will decrease the number of AIDS orphans in future generations, programs must be implemented to save current AIDS orphans. One option is the development of vocational training programs, which could help orphans stay off the streets (especially, young girls who are forced into sex work). If funds from debt relief programs are channeled directly into schools, school enrollment might increase. Another option is to offer government subsidies to extended families, which might help children stay out of work and stay in school. Additionally, providing government subsidies would maintain a family structure for children, keeping them out of orphanages. While these appear to be wonderful programs, the effectiveness of these programs would be difficult to monitor. Thus, before any programs are employed, local, national, and international governments and agencies want to ensure their success. However, it is imperative that these agencies act quickly before it is too late.

Stigma in the Lives of HIV+ Healthcare Workers

I'm Pete Levandoski

Advances in HIV related pharmacology have given HIV patients extended lifetimes, turning them from dead men walking to living individuals with a debilitating condition. In treating any patient, HIV status not withstanding, the American Dental Association states that dentists should practice, “high ethical standards which have the benefit of the patient as their primary goal” (Rhode Island Dental Association, 2006). If the maxim is adhered to, dentists should have no problems treating HIV positive individuals who come to them seeking care. The fear of exposure to the virus however, has led some dentists to refuse treatment. In these instances, the Supreme Court has stepped in, ordering treatment and protecting the rights of patients. However, in jumping to the aid of patients, the High Court may have inadvertently aided efforts to discriminate against those living with HIV.

A landmark case for HIV patients was the 1998 affirmation of the ruling in Abbott vs. Bragdon. Sidney Abbott, an HIV positive individual, successfully argued that in refusing to treat him because he was HIV positive, Dr. Rondon Bragdon had violated the Americans with Disabilities Act. Bragdon’s unsuccessful defense was that Abbott’s HIV represented a “direct threat” to his own health (Sfikas, 2002).

In May of 2002, the “direct threat” defense was again used, this time in the case of Waddell vs. Valley Forge. The Court ruled that Spencer Waddell, an HIV positive dental hygienist, could be removed from his job because his disease was a “direct threat” to the health of his patients (Sfikas, 2002). The sum of these two decisions is that the idea of “direct threat” can legally be used to protect patients but not to protect dentists.

The same code of ethics that puts patients first also claims that this goal has lead to, “…society affording to the profession the privilege and obligation of self-government” (Rhode Island Dental Association, 2006). Above all, dentists want to retain autonomy and self regulation. In the process of trying to protect patients, these two court decisions have reduced the autonomy of dentists. Decisions in the cases of Waddell and Abbott should have been made by dental professionals, argues Peter Sfikas in his article in the March 2002 Journal of the American Dental Association (Sfikas, 2002).

In the Abbott case, the procedure being performed was a cavity filling, which involves little to no blood. In the Waddell case, root planning, which involves a large amount of blood, was being done. The courts made the correct decision in siding with the patient when looking at the evidence in each specific case (Sfikas, 2002). However, instead of maintaining a case by case system, the courts have set precedents which issue blanket statements without regard for case specifics. This has lead to the reality that the only way a dentist can refuse treatment is by preemptively providing evidence of a “direct threat” to his or her health from the patient (Sfikas, 2002).

These two court cases have gone a long way to advancing the rights of HIV positive patients. The Supreme Court stepped in and set a precedent to prevent HIV positive individuals from being denied healthcare. The Waddell case however, could be spun to deny rights to HIV positive individuals (Sfikas, 2002). The Court gave Spencer Waddell’s employer the right to fire him because he was HIV positive. In trying to protect the rights of patients, the court system has set a legal precedent which discriminates against HIV positive workers if they pose a “direct threat” to the health of their customers (Sfikas, 2002).
Waddell’s case was denied writ of certiorari by the Supreme Court, so it will be up to future cases to decide whether or not firing an employee because they have HIV is legal (Waddell v. Valley Forge Dental Assocs. 2002). Whatever decisions are made in future cases; these two examples highlight the complex interplay between human rights and stigma that HIV positive individuals still face in the United States today.


Sources
Sfikas PM. “HIV and discrimination: A review of the Waddell case and its implications for health care professionals”. The Journal of the American Dental Association. Vol. 133, March 2002. (pp. 372-374).
Rhode Island Dental Association. “Principles of Ethics & Code of Professional Conduct”. 2006.< http://www.ridental.com/ethics.cfm>. (29 November 2006).
Waddell v. Valley Forge Dental Assocs. 535 U.S. 1096. US Supreme Court. 2002.

AIDS dementia: Current findings

Welcome to The AIDS Pandemic, a podcast hosted by Dr. David Wessner from the Department of Biology at Davidson College. I'm Steve Halliday.

One of my most striking memories from my time spent in the hospital in Mwandi was towards the end of my stay when I saw a woman suffering from AIDS dementia who was in the courtyard screaming at the top of her lungs. I asked one of the hospital employees what was going on, and he responded “oh, she is confused.” Since that moment I’ve been interested in this symptom of late stage AIDS, and in today’s installment I am going to look at a paper that examines one possible cause of AIDS dementia, titled HIV-1 Promotes Quiescence in Human Neural Progenitor Cells by Krathwohl and Kaiser.

AIDS dementia is a purely clinical diagnosis, based on observations of cognitive decline and motor dysfunction, and occurs in approximately 6-15% of AIDS patients. The pathology of AIDS dementia remains elusive, however, and this article represents only one theory of how it is caused.

The article examines the possibility that HIV could inhibit the activity of recently discovered neural progenitor cells. These cells have been found to be capable of differentiating into new astrocytes and neurons, which are thought to then form synaptic connections with other neurons, increasing memory and replacing lost neurons in the hippocampus.
These progenitor cells exist in quiescent states until they are needed, and it has been found that these cells can be forced into quiescence by chemokines, which can be mediated by CXCR4 or CCR3. Because HIV-1 uses chemokine coreceptors it is thought that it may inhibit proliferation of progenitor cells and force them into quiescence.

To test whether HIV-1 could induce quiescence, the researchers used purified recombinant coat proteins from several stains of HIV-1 using proteins that signal through either CXCR4 or CCR3. They found that two strains caused plated progenitor cells to enter a quiescent state, reducing proliferation by 67 and 74%, while a third strain had no visible effect. They also discovered that by washing the plates the cells were able to begin differentiating again. The researchers went on to determine that the coat proteins of the effective strains induced expression of cyclin-dependent kinase inhibitors p21 and p27.

The researchers then sought to prove the HIV-1 coat proteins were mediated by chemokine receptor binding. They found that by adding pertussis toxin, which affects the G-proteins linked to chemokine receptors, the inhibitory effects of both effective strains were blocked, suggesting the suppressive effects of HIV-1 are mediated by chemokine receptors.
In addition to direct inhibition, HIV-1 was found to suppress phosphorylation of ERK, which stimulates neural progenitor cells. The two effective strains of HIV-1 were found on to inhibit ERK by 34 nad 77%. This was also shown to occur by signaling through chemokine receptors.

Having established that HIV-1 can inhibit neural progenitor cell differentiation, the researchers examined CerebroSpinal Fluid from patients suffering from AIDS dementia, and discovered that the CSF from patients suffering from dementia was able to suppress progenitor cells by 67% whereas CSF from patients without dementia showed no inhibitor effect.
They also determined that gp120 was responsible for this inhibition. Furthermore they determined that viral load for patients with and without dementia was similar, and presence or absence of antiretroviral therapy had no effect on the inhibitory effect of the CerebroSpinal Fluid.

The researchers then proved that both the HIV-1 coat proteins and the CSF from patients with dementia could reduce neural cell proliferation in human hippocampal tissue in vitro, and that autopsied hippocampal tissue from patients with dementia was found to contain 75% fewer neural progenitor cells than in patients without dementia.

This paper provides seemingly very conclusive evidence for the role of neural progenitor cells in AIDS dementia, but this is by no means the only area of research going on in AIDS dementia. Another paper, Pharmacological frontiers in the treatment of AIDS dementia by McGuire and Marder, discusses possibilities that reactants to viral products and macrophages may cause neuronal cell death, leading to dementia via a more direct route.

The pathology of AIDS dementia is complex and not easily deciphered, but hopefully with this continuing research an effective treatment can be found for this devastating AIDS related illness.

This is Steve Halliday signing off.

HIV/AIDS in Prisons

Welcome to this installment of the AIDS Pandemic, a podcast hosted by Dave Wessner of the Department of Biology at Davidson College. I am Justin Fried.

Prisons have become a fertile ground for the HIV epidemic in the United States. In fact the Joint United Nation Programme on AIDS (UNAIDS) listed prisoners as one of the four "major at-risk and neglected populations" in the HIV/AIDS pandemic (2006 Report on the Global AIDS Epidemic). The other three categories included men who have sex with men, injection drug users, and sex workers (2006 Report on the Global AIDS Epidemic). Recent figures show that 2.3 percent of state prison inmates, and 1.0 percent of federal prison inmates in the United States are HIV positive, and an estimated 20 to 26 percent of people living with HIV have spent time in the correctional system (2006 Report on the Global AIDS Epidemic and Kantor 2006). The overcrowded and typically understaffed prisons in the United States are ideal breeding grounds for HIV. HIV is transmitted through bodily fluids with sharing needles and unprotected sex being the leading causes of virus transmission. Despite strict regulations against drugs in prisons, intravenous drug use still occurs. Clean needles are almost impossible to find and needles or improvised injection devices are often shared by inmates. These needles may also be shared for tattooing, another common practice in prisons. In addition to drugs, many inmates turn to sex to escape the boredom of prison life. Because distribution of condoms is prohibited in most penal institutions across the United States, safe sex is not even an option for most inmates. Sexual assault and rape, which are common intimidation tactics used by inmates, are also potential sources of transmission of HIV in correctional facilities (2006 Report on the Global AIDS Epidemic).

While high risk behaviors common to prisons put inmates at a higher risk for HIV infection while incarcerated, most HIV positive prisoners were infected before being sent to prison (HIV/AIDS Prevention). Indeed, the populations most vulnerable to the HIV infection are the same communities at high risk for criminalization and incarceration (HIV/AIDS Prevention). Fear of discrimination deters prisoners from accessing the voluntary HIV testing available in most prisons. Test result confidentiality is a major issue in a prison environment where even the suspicion of a positive test result can lead to stigmatization, bringing social isolation and violence from other inmates and sometimes even prison staff. The fear of stigmatization also discourages many inmates living with HIV from seeking medical services and treatment. Prison conditions also undermine the dosing schedules that are important for the effectiveness of antiretroviral therapy. Transfers of inmates to different correctional institutions or to and from courthouses can cause gaps in treatment. Searches for contraband may also result in medicine confiscation (Kantor 2006).

Addressing the problem of HIV and AIDS in prisons requires a multifaceted approach. UNAIDS believes that it is essential that prisoners be allowed access to prevention materials, including condoms, safer-sex supplies, and bleach kits for cleaning needles (HIV/AIDS Prevention). Increasing HIV and AIDS awareness through prisoner health education programs is crucial to decreasing the stigmatization of HIV inside prisons that prevents many inmates from seeking testing or treatment. For inmates living with HIV, provisions must be taken to ensure the regular interruptions of a prisoner’s life do not interrupt his or her antiretroviral therapy.

The Hampden County Correctional Facility in Massachusetts is a prison which is taking steps towards providing preventive education and effective health care to its inmates. This prison has adopted a health care program based on a public health model that provides inmates with a community-based standard of care (Kahn 2000). This program is based around five basic tenets: detection, effective and prompt treatment, education, prevention, and continuity of care. Prisoners undergo a three-day orientation upon admission and are given a full physical exam including tests for common communicable diseases. After attending an intensive peer-led educational session on HIV and AIDS, new inmates are encouraged to take an HIV test. Inmates that test positive for HIV then undergo additional tests to determine how best to proceed with treatment. Doctors, nurses, and case managers from the community are brought into the jail to deliver services to inmates. After the prisoners are released they have the option of continuing with the same primary care providers through a comprehensive discharge plan that includes Medicaid benefits and other supportive services (Kahn 2000).

The Hampden County Correctional facility is taking steps in the right direction, but fighting HIV in prisons is an uphill battle that will require revolutionizing prison health care. For changes to be made, Americans must first recognize that prisons are not isolated from the world, and that most inmates will eventually be released and infections acquired inside prison walls can be transmitted to the society outside. Preventing and treating HIV in prisons will benefit society as a whole and is important in the fight against AIDS.

Until next time, I am Justin Fried.
References

At Risk and Neglected: Four Key Populations. 2006 Report on the Global AIDS Epidemic. Joint United Nation Programme on AIDS. 2006. Retrieved Dec 2, 2006 from http://data.unaids.org/pub/GlobalReport/2006/2006_GR_CH05_en.pdf

HIV/AIDS Prevention, Care, and Treatment in Prison Settings: A Framework for an Effective National Response. Health Organization and Joint United Nation Programme on AIDS. 2006. Retrieved Dec 2, 2006 from
http://data.unaids.org/pub/Report/2006/20060701_HIV-AIDS_prisons_en.pdf.

Kahn, Stanya. Fire in the belly: A model program stresses community involvement. AIDS Info NYC. January 2000. Retrieved Dec 2, 2006 from http://www.aidsinfonyc.org/hivplus/issue6/report/model.html.

Kantor, Elizabeth. HIV Transmission and Prevention in Prisons. HIV Insight. April 2006. Retrieved Dec 2, 2006 from http://hivinsite.ucsf.edu/InSite?page=kb-07-04-13

A Dual Epidemic: HIV/AIDS and Injection Drug Use in Russia

I'm Meredith Prasse.


Before 1995, the total number of HIV infections in the entire region of central and Eastern Europe, with over 450 million inhabitants, was less than 30,000. The World Health Organization reported an estimated 0.6-1.9% prevalence, between 420,000 and 1.4 million cases, of HIV/AIDS in Russia in 2003. Between 1996 and 1998 alone, Russia experienced a 100-fold increase in new HIV infections, demonstrating the rapid onset of the epidemic in this region. Well over 70% of all HIV cases in Russia occur in injection drug users (IDUs), demonstrating the widespread exercise of unsafe drug-using practices among the IDU population in Russia. Sadly, only 10% of HIV-infected Russian IDUs currently receive HIV combination therapy, and only 15% of HIV-positive Russians receiving therapy are IDUs.

An epidemic of drug use is occurring alongside the HIV/AIDS epidemic in Russia. While the epidemic of injection drug use in Russia cannot be attributed to a single factor, there was a significant rise in drug use following the collapse of the Soviet Union. WHO estimates that between 1.5 and 3.5 million Russians are IDUs, and the prevalence of HIV in the drug-using population approaches 65% in some Russian cities, further demonstrating the connection between drug use and HIV in Russia. Between 1990 and 2002, the number of first-time drug users referred to treatment centers increased 6.5-fold, while the number of drug-associated deaths increased 5-fold between 1999 and 2000.

The challenges facing the Russian HIV/AIDS epidemic are multifaceted. An estimated 30-40% of IDUs in Russia use non-sterile needles or share needles, demonstrating the widespread unsafe drug use in Russia. Many IDUs reportedly re-fill their syringes by front-loading from the dealers’ syringes, and many dealers are IDUs themselves who inject from that very supply. During the drug preparation process, dealers in several different Russian cities have also reported adding blood to the drug solution as a ‘cleansing’ process, believing that the blood neutralizes toxic substances used to produce the drugs.
There are also significant legal and political dilemmas which complicate the Russian HIV/AIDS epidemic in IDUs. A combination of harsh drug policies and regular harassment by the police force pushes IDUs underground and decreases their chances of accessing preventive resources or care in drug treatment facilities. The synonymously corrupt Russian police arrests IDUs for possession of minimal amounts of narcotics in order to fill quotas. As a result, drug users refrain from seeking treatment or accessing clean needles in fear of incarceration or simply being registered as a drug user. IDUs that access formal treatment centers are officially registered and monitored by that facility for five years, and this official registration can have further negative repercussions such as restrictions on employment, drivers’ licenses, and military service. While treatment for drug dependence is an effective way to both eliminate drug dependence and decrease the risk of contracting HIV, the distrust in drug treatment services has resulted in low utilization of these resources by IDUs. Another legal dilemma for IDUs is that methadone, a common substitution for heroine users and an important part of HIV prevention for heroine users elsewhere, is banned for treatment in Russia.

While IDUs comprise the majority of the at-risk population in Russia, the threat to non-IDUs is on the rise. A majority of IDUs in Russia are young heterosexual men. These men have the potential to spread HIV to their partners: commercial sex workers, girlfriends, wives, etc., many who do not have the power or awareness to demand condom usage. In addition, commercial sex work is on the rise in numerous Russian cities, and the overlap between injection drug use and commercial sex work is high. It is estimated that between 15 and 50% of female IDUs practice commercial sex work, and many of them do so as a means of obtaining drugs. HIV transmission from sex workers to their clients is high, and these male clients may subsequently infect their non-IDU sex partners. Thus, IDUs and sex workers act as a bridge for sexual HIV transmission between IDUs and non-IDUs in Russia, facilitating a more widespread epidemic.

In the face of the continually increasing rates of drug use and HIV infection, the Russian government needs to implement policy changes to slow these increasing rates. This dual epidemic can be fought on many different fronts. Primarily, the government must increase support for safe needle exchange programs to reduce the spread of HIV among the IDU population. In addition, the ban on methadone-substitution therapy for heroine users should be lifted to encourage treatment options and reduce needle use. More generally, the government needs to put more focus on drug prevention programs. Future HIV prevention strategies targeting IDUs should include sexual risk reduction to reduce the potential spread between the IDU and non-IDU populations. With such alarmingly high rates of HIV infection among the IDU population, this problem cannot be ignored. The longer it is disregarded, the more this epidemic will seep into the non-IDU sectors of Russian society, facilitating an epidemic with a wider scope and greater force.


Works Cited
Bobrova, Natalia, Tim Rhodes, Robert Power, Ron Alcorn, Elena Neifeld, Nikolai Krasiukov, Natalia Latyshevskaia, and Svetlana Maksimova. “Barriers to accessing drug treatment in Russia: a qualitative study among injecting drug users in two cities.” Drug and Alcohol Dependence 82 (2006): S57-S63.
Dehne, Karl L., Lev Khodakevich, Francoise F. Hamers, and Bernhard Schwartlander. “The HIV/AIDS epidemic in eastern Europe: recent patterns and trends and their implications for policy-making.” AIDS 13 (1999): 741-749.
Human Rights Watch. “Russia: harsh drug policies fuel AIDS epidemic.” Available at http://hrw.org/english/docs/2004/04/27/russia8497_txt.htm. Accessed on 16 November 2006. Human Rights Watch: 28 April 2004.
Kalichman, Seth C., Jeffrey A. Kelly, Kathleen J. Koslov, P Andrei, Alla Shaboltas, and Juliana Granskaya. “The emerging AIDS crisis in Russia: review of enabling factors and prevention needs.” International Journal of STD & AIDS 11 (February 2000): 71-75.
Lowndes, Catherine M., Michel Alary, and Lucy Platt. “Injection drug use, commercial sex work, and the HIV/STI epidemic in the Russian Federation.” Sexually Transmitted Diseases 30 (January 2003): 46-8.
Luo, Robert F. and Joseph Cofrancesco Jr. “Injection drug use and HIV transmission in Russia.” AIDS 20 (2006): 935-936.
Rhodes, Tim, Lucy Platt, et. al. “Prevalence of HIV, hepatitis C, and syphilis among injecting drug users in Russia: a multi-city study.” Addiction 101 (February 2006): 252-266.
Shaboltas, Alla V., Olga V. Toussova, et. al. “HIV prevalence, sociodemographic, and behavioral correlates and recruitment methods among injection drug users in St. Petersburg, Russia.” Journal of Acquired Immune Deficiency Syndrome 41 (15 April 2006): 657-662.
World Health Organization. “Summary Country Profile for HIV/AIDS Treatment Scale Up: Russian Federation.” Available at http://www.who.int/hiv/HIVCP_RUSSIA.pdf. Accessed on November 16, 2006. WHO 2005.

Male Circumcision and HIV/AIDS

“When is it appropriate for public health practice to be on the side of an intervention that causes bodily injury?” (Franco)

I'm Erika Larson.

That is the question McGill’s Professor of Epidemiology, Eduardo Franco, asked when addressing circumcision as a possible method of reducing HIV prevalence. Circumcision has historically caused a polarizing debate across sectors of society including the pious, and the hygienic. Health workers have generally abstained from taking a side. However, new evidence that circumcision reduces infectivity of HIV may alter this precedent.

A recent study in the Journal of Infectious Diseases, Baeten et al. explore “Female to Male Infectivity of HIV-1 among Circumcised and Uncircumcised” in a cohort of Kenyan men. Unlike previous studies which did not isolate behavioral practices, this analysis designates per-sex act probabilities of HIV-1 transmission between circumcised and uncircumcised men.

Between 1993 and 1997, 745 Kenyan men, employed by six trucking companies around the Mombasa area, were recruited. After pre-counseling and informed consent, these men were examined for circumcision status, STD infection, and HIV-1 seropositivity using the ELISA antibody test. Follow-up visits included detailed accounts of sexual encounters and condom use. Each man attended a median of 4 follow-up visits over the span of 400 days. Risk reduction counseling and provision of free condoms accompanied follow-up visits.

Of the 95 uncircumcised men (13%), 11 experienced sercoconversion. Of the 650 circumcised men (87%), 32 seroconverted. Though the majority engaged in sexual activity with their wives, many were involved in extramarital sexual contact. The median number of sex acts per month (4.0) did not vary between circumcised and uncircumcised men. By using surveillance data to estimate prevalence for potential partners (wives, casual partners, and prostitutes), the researchers found an overall probability of acquiring HIV-1 through a single sex act was .0063. Female to male infectivity was higher for uncircumcised men than circumcised men (.0128 vs. .0051). Uncircumcised men were found to have over a 2-fold increased risk of HIV-1 infectivity per sex act.

Because the study could not trace the infection status or disease status of partners, some variants could not be isolated. However, ethnicity, occupation, and sexual risk behavior were statistically isolated. All results still revealed that uncircumcised men were at a higher risk for contracting HIV. The biological factors that cause this discrepancy could be the result of the thick skin that develops after circumcision which prevents HIV from targeting Langerhans cells.

Another study by French and South African researchers found results so dramatic that the control group was given the option to undergo the procedure. New research has created a wave of optimism in the scientific community. Dr. Seth Berkley, president of the International AIDS Vaccine Initiative, stated circumcision would be “an intervention that works over a person’s lifetime and could reduce HIV in a community setting.” Questions of acceptance as a risk-reduction policy were appeased in a recent South African study. In a survey of uncircumcised men, 70% stated they would undergo the procedure if it “proved to protect against sexually transmitted diseases.”

However optimism of community acceptance is marred by a false sense of security that circumcision could create. Increased risk behavior on the part of circumcised men could counter-act the benefits. For example 30% of uncircumcised men and 18% of circumcised men believed that the procedure would allow them to safely engage in sex with multiple partners.

Though we have already seen considerable risk-taking in prevention policy with needle exchange programs and safe injection facilities, circumcision continues to push the envelope on ethical approaches. Can we promote circumcision as a global policy to help weaken the horrifying forces of HIV? Is it feasible to pursue a worldwide circumcision effort especially in countries that rely on traditional practices (whose circumcision procedures may increase HIV-risk)? How can we prevent the unintentional consequences of viewing circumcision as a cure and the abandonment of safe-sex practices? Though circumcision does not affect HIV prevalence in men who have sex with men or IV drug users, it has huge possibilities on the African continent where heterosexual contact is the primary mode of transmission.