Tuesday, December 26, 2006

HIV/AIDS Stigma in Rural America

One of the largest obstacles to proper care of patients early in the AIDS epidemic was and may still be stigma associated with the disease. A common question throughout any major crisis and especially the AIDS epidemic is how the reaction in urbanized America differs from the more rural parts of the United States. To gain some insight into these issues, I have asked my parents to share their first experiences with AIDS patients and their thoughts on these issues. My father, Dr. James Raver, is a respiratory and intensive care specialist in the private sector of health care and my mother, Dr. Sue Raver, is a pediatrician in public health. Both of them live and work in rural western Maryland. I'm Charles Raver. To listen to the interview, please listen to the podcast at: http://www.bio.davidson.edu/people/dawessner/361HIV/podcast/AIDS_Pandemic_23.m4a

Wednesday, December 13, 2006

Side effects of HAART

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.

A study recently published in the Journal of Infectious Diseases credited AIDS treatment for saving 3,000,000 years of life in the United States (Walensky et al 2006). While effective treatment of common AIDS-related opportunistic infections has indeed benefited AIDS patients, the study cites treatments that decrease the virulence of the HIV virus as having the greatest impact on mortality rates of AIDS patients (Walensky et al. 2006). In the United States and countries that can afford it, the standard treatment for HIV is highly active antiretroviral treatment, HAART for short. HAART is composed of a combination of three or four drugs that fit into as many as three categories: reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. Each of these categories of drugs attempts to interrupt the viral life cycle at a different point. Reverse transcriptase inhibitors block the activity of reverse transcriptase, an enzyme the virus uses to build new DNA from its RNA. Protease inhibitors inhibit the activity of viral enzymes used by HIV to cleave new proteins for final assembly into new HIV virons. Fusion inhibitors, the newest addition to the HAART treatment, block entry of HIV into the cell membrane, preventing infection of uninfected cells. The medications of HAART complement each other and are taken together to give an additive effect.

While the HAART treatment has had a profound impact on the AIDS epidemic in America, it should be understood that the HAART treatment is not a cure for HIV and carries its own drawbacks. Until recently, the only HAART treatments available were complicated regimens that required patients to take a series of pills at varying times of the day. Atripla, a new once a day HAART treatment, has greatly simplified the HIV treatment regimen but it is not for everyone. Aside from its expense, it is likely that the HIV virus in some people will eventually evolve to become resistant to one or more drugs in Atripla, and those patients will have to revert to more complicated treatment regimens.

While side effects of HAART treatment vary considerably between individuals and the particular medicines making up their therapy, the most common side effects include diarrhea, nausea, and vomiting ("Side effects"). Lipodystrophy is another common side effect of HAART treatment in which fat is redistributed to other parts of the body (Ammassari 2001). Often in this condition, face and limbs become thin while one's breasts, stomach and/or neck enlarge. Hyperglycemia and onset of diabetes have also occurred in a significant number of HAART patients. Liver toxicity including liver failure, pancreatitis and neuropathy are other unpleasant and potentially life threatening side effects experienced by some patients. These side effects can amount to such a physical and psychological burden that patients skip doses or stop taking their medications all together which increases the likelihood of drug resistance developing. In fact, about 25 % of patients stop therapy within the first year on HAART because of side effects (d'Arminio Monforte 2000). Reconstitution of the immune system, a major goal of HAART treatment, may even carry risks in some patients. A debilitating inflammatory syndrome has recently been linked to HAART treatment (Stoll and Reinhold 2004).

This podcast installation was not meant to scare anyone away from seeking HAART therapy; indeed as I stated earlier, it is very effective in combating infection and allows many HIV positive patients to live longer healthier lives. My goal was to simply alert people to the fact that there are frequently side effects and complications associated with HAART treatment. Prevention is still the best treatment for HIV that carries no side effects.

Until next time this is Justin Fried....

Ammassari, A., Murri, R., Pezzotti, P., Trotta, M., Ravasio, L., De Longis, P., Caputo, S. Narciso, P., Pauluzzi, S., Carosi, G., Nappa, S., Piano, P., Izzo, C., Lichtner, M., Rezza, G., Monforte, A., Ippolito, G., Moroni, M., Wu, A., and A. Antinori. 2001. Journal of Acquired Immune Deficiency Syndromes, 28(5): 445-449.

d'Arminio Monforte, A., Lepri, A., Rezza, G. 2000. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naïve patients. AIDS, 14:499-507.

"Side Effects of HIV or Medication." The Body: The Complete HIV/AIDS Resourse. Retrieved October 12, 2006 from http://www.thebody.com/treat/side_effects.html.

Stoll, Mathias, and Reinhold Schmidt. 2004. Adverse events of desirable gain in immunocompetence: the Immune Restoration Inflammatory Syndromes. Autoimmunity Reviews, 3: 243-249.

"Side Effects of HIV or Medication." The Body: The Complete HIV/AIDS Resourse. Retrieved October 12, 2006 from http://www.thebody.com/treat/side_effects.html.

Walensky, R., Paltiel, A., Losina, E., Mercincavage, L., Schackman, B., Sax, P., Weinstein, M., and K. Freedberg. 2006. The survival benefits of AIDS Treatment in the United States. Journal of Infectious Diseases, 194: 11-19.

Monday, December 11, 2006

Selective Pressures on CCR5-Δ32 in the European Population

I'm Pete Levandoski

Recent research into the HIV pandemic has focused on the presence of individuals who do not become infected by HIV when exposed to the virus. So-called co receptors, which are essential for viral docking and infection, are thought to play a role in this immunity. One such co receptor is the protein CCR5, a chemokine receptor on the surface of T4 cells (Galvani et al.). Individuals who lack functional CCR5 protein do not become infected when exposed to HIV-1. A gene mutation, CCR5-Δ32, which causes a deletion of the allele for making CCR5, is present in about 10% of the European population (Galvani et al.). Homozygous individuals are completely immune to HIV-1 and heterozygotes while still susceptible to viral transmission, show slower progression of infection (Galvani et al.). A study done by Doctors Alison P. Galvani and. Montgomery Slatkin published in the December 9th, 2003 Proceedings of the National Academy of The Sciences in the United States, suggests that the higher rate of CCR5-Δ32 in European populations is the direct result of selection pressure caused by Small Pox epidemics.
Previous studies have tried to correlate the augmented prevalence of CCR5-Δ32 in Europe with the intense selection pressure caused by Bubonic Plague. Galvani et al. propose that a correlation between CCR5-Δ32 and Small Pox is a more likely scenario (Galvani et al.). To back this up, a population genetics model was set up using derivations of Hardy-Weinberg equations. These models assume that the CCR5-Δ32 is at least 700 years old and measure selection pressure caused by both diseases on CCR5-Δ32 since 1300 (Galvani et al.). Derivations of the Hardy-Weinberg equation, which factor in the frequency of outbreaks, percentage of mortality and age of the victims, were used to calculate the selection pressure of each disease on CCR5-Δ32. These models were used to determine whether or not each disease exerted enough selection pressure to cause 10% prevalence of CCR5-Δ32 in the European population over a 700 year period (Galvani et al.). This model shows conclusively that the Bubonic Plague did not exert enough selection pressure over 700 years to cause 10% prevalence of CCR5-Δ32 in the population while Small Pox did (Galvani et al.)..
Small Pox exerted higher selection pressure than Plague for a variety of reasons. Small Pox appeared in the population as early as 1,300 years before the first outbreak of Plague. Small Pox outbreak cycles were more frequent than Plague, correlating to a greater mortality (Galvani et al.). Finally, children, who had the greatest reproductive potential, were most susceptible to death by Small Pox while Bubonic Plague tended to eliminate people indiscriminately (Galvani et al.). All of these factors were included in the mathematical model, which showed that Small Pox was enough of a selecting force in Europe to cause the prevalence of CCR5-Δ32 to increase from 0-10% over 700 years.
There were two other pieces of evidence used by the authors to support their claim. The first came from noting that CCR5-Δ32 was present in a higher percentage of the population (14%) in Scandinavia, where Small Pox epidemics were most severe (Galvani et al.). When examined at the molecular level, the mechanism for infection by Small Pox virus involves the use of chemokine receptors, like CCR5, while Y. pestis infection in Plague is independent of these receptors (Galvani et al.).
The implications of this study on the future the HIV-1 pandemic are alarming. At least 700 years of fairly high selective pressure on a population by Small Pox conferred only 10% immunity (Galvani et al.). Since jumping species, HIV has already evolved into two subtypes, three groups and nine clades. In addition, co-infection with different clades is producing recombinant viruses, which are resistant to drug treatments and have stronger binding affinities for immune cells (Avert). HIV is evolving faster than the human race, which from a Darwinian perspective, does not bode well for our species. An interesting application of this data would be to run the same sort of population models in Africa. The selection pressure there on CCR5-Δ32 and other genes, which confer immunity to HIV, theoretically will be high. A measurement of the evolution of HIV immunity would be a helpful tool in determining the prospects for this embattled continent.

Avert. “Introduction to HIV types, groups and subtypes”. . Avert International Aids Charity: 13 July 2006. (21 October 2006).
Galvani, A.P. et al.. “Evaluating plague and smallpox as historical selectivepressures for the CCR5-Δ32 HIV-resistance allele”. Proceedings of the National Academy of The Sciences in the United States. Vol. 100, no. 25. 9 December 2003. pp. 15276-15279.

Monday, December 04, 2006

Mother to Child Transmission of HIV

When the AIDS epidemic commenced in the early 1980s, the high risk groups were identified as the 4 H’s: homosexuals, hemophiliacs, Haitians, and heroine users. Today, the face of the AIDS epidemic has transformed and women have the highest rates of infection. As more women become infected, the potential for vertical transmission from mother to child increases. Of the nearly seven million children newly infected with HIV in 2003, it is estimated that over ninety percent acquired the disease from mother-to-child-transmission. Similarly, it is estimated that over 90% of the HIV-infected children in sub-Saharan Africa acquired the infection vertically. While a combination of intervention methods can reduce the risk of vertical transmission to less than 2%, mother-to-child HIV transmission still persists worldwide, especially in developing countries which account for 95% of the vertically transmitted HIV cases.

Vertical HIV transmission is the cause of most cases of HIV in children below age 15, so it is important to understand how HIV passes from mother to child. Without intervention or treatment, the possibility of HIV transmission from mother to child is 15-30% in developed countries and 30-45% in developing countries. While 50-80% of infants are vertically infected during delivery, HIV transmission can also occur during pregnancy and after birth. During pregnancy, the fetus can become infected by contacting maternal blood through a placental hemorrhage or by swallowing infected amniotic fluid. Maternal factors which increase the chance of mother-to-fetus transmission include: maternal seroconversion during pregnancy, high viral load, malnutrition, other sexually transmitted diseases, and lack of or poor compliance with antiretroviral drug therapy.

During birth, factors that increase the risk of mother-to-child HIV transmission include: vaginal delivery, rupture of vaginal tissue, contact with maternal blood and vaginal secretions, and chorioamnitis. Pregnant women with chorioamnitis have a potentially increased white blood cell count that acts as a target for the HIV virus. Higher maternal viral load is positively correlated with vertical HIV transmission. Posnatally, the most significant risk factor is breastfeeding. The HIV virus has been isolated from breast milk, demonstrating the risk of long-term breastfeeding in infants. Transmission of HIV through breastfeeding occurs in 16-29% of cases. Specific risk factors during breastfeeding include: cracked nipples, mastitis (breast inflammation), breastfeeding for extended time periods, postnatal maternal seroconversion, high viral load, and low CD4 cell count. Mixed feeding of breast milk and other food sources has been shown to increase the risk of HIV transmission. Scientists hypothesize that an infant’s immune response is triggered by the introduction of new foods, attracting white blood cells to the gastrointestinal tract and increasing targets for the HIV viruses to spread infection.

The most successful methods of intervention to prevent mother-to-child HIV transmission include: antiretroviral medication for mother and child, caesarian section, and refraining from breastfeeding. While the recommended type and regimen of antiretroviral drugs for mothers varies, mothers on antiretroviral drugs have less than a 2% chance of transmitting HIV to their babies. The Pediatric AIDS Group Protocol 076 (PACTG 076) was an important study that demonstrated the effectiveness of using zidovudine in reducing vertical HIV transmission. This study showed that zidovudine given during pregnancy and labor and given to the baby during the first six weeks of life decreased the risk of vertical transmission by 66%. Another drug called nevirapine, a nonnucleoside reverse transcriptase inhibitor, is also effective in reducing vertical HIV transmission when given during pregnancy and after birth to the child. Aside from drug therapy, pregnant HIV positive women are also advised to have a cesarean section at 38 weeks to further reduce the risk of vertical transmission. Cesarean delivery reduces exposure of the infant to maternal fluids and tissues which is high during vaginal delivery. Finally, HIV positive women are encouraged to refrain from breastfeeding to reduce the risk of spreading HIV to their babies postnatally.

While the methods of preventing vertical HIV transmission are fairly effective, implementing these interventions in sub-Saharan Africa and other developing areas of the world is difficult due to cultural and economic barriers. While encouraging HIV-positive mothers to refrain from breastfeeding is a logical preventive measure against vertical HIV transmission, most women in poverty-stricken areas cannot afford to pay for formula or do not have access to clean drinking water to prepare the formula. Also, women who stop breastfeeding to protect their children from HIV risk the stigma of being labeled as HIV positive. These obstacles, combined with the lower level of access to antiretroviral drugs in developing countries, create obvious barriers to decreasing vertical HIV transmission worldwide.

I'm Meredith Prasse. Thanks for listening.