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.

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.