HealtyDayS

Sex Enhancer Libidus Warning

Health Canada is warning consumers not to use the natural health product Libidus because it contains an undeclared pharmaceutical ingredient, a modified form of vardenafil, which is similar to the active pharmaceutical ingredient found in the prescription drug Levitra. The use of Libidus could pose serious health risks, especially for patients with existing medical conditions such as heart problems, those taking heart medications, or those at risk for stroke.

Libidus is advertised as a natural sex enhancer for men and women and is not authorized for sale in Canada. The Canadian importer has been contacted and is recalling the product. Consumers who have purchased Libidus are warned not to use it and to consult with a health professional if they have used the product and have concerns about their health.

Products containing vardenafil should not be used by individuals who are taking any nitrate medication because combining these products could result in the development of potentially life-threatening low blood pressure.

The use of products containing vardenafil has also been associated with serious side-effects which include serious cardiac events such as heart attacks. In rare cases, the use of vardenafil may result in penile tissue damage and permanent loss of potency.

This product is manufactured in Malaysia by Bio-Gulf Sdn Bhd and imported into Canada for distribution by NorthRegentRX, of Winnipeg, Manitoba.

HIV Testing and CDC

CDC’s revised recommendations on HIV testing in the U.S. - that say HIV tests should become a routine part of medical care for residents ages 13 to 64 and that requirements for written consent and pretest counseling should be dropped - could harm the health and civil rights of people who receive the tests, the American Civil Liberties Union said in a release on Thursday, CQ HealthBeat reports (Reichard, CQ HealthBeat, 9/22).

The HIV screening recommendations, published in the Sept. 22 edition of CDC’s Morbidity and Mortality Weekly Report, say health care providers should continue routine HIV testing unless they establish that less than one of every 1,000 patients tested is HIV-positive, “at which point such screening is no longer warranted.” Providers do not have to require patients to sign written consent forms or undergo counseling before receiving an HIV test, but physicians must allow patients to opt out of the test, according to the guidelines.

The recommendations for HIV screening - which states can choose to adopt and modify - also say that all pregnant women should be tested for the virus unless they opt out and that women who inject illicit drugs, are commercial sex workers or who live in a higher prevalence region should be tested again in the third trimester of pregnancy (Kaiser Daily HIV/AIDS Report, 9/22). “CDC should be commended for trying to increase the number of people tested for HIV, but eliminating the only safeguards that guarantee that testing is voluntary and informed does little to ensure that people will receive the care they need,” Rose Saxe, a staff attorney with the ACLU AIDS Project, said, adding, “Without pre- and post-test counseling requirements, we risk losing a critical opportunity to educate people about HIV and how to prevent the spread of it” (ACLU release, 9/21). Saxe said privacy could be compromised under the guidelines because most states collect the names of HIV-positive people and “[m]any states also require doctors to report private information, such as drug use and sexual history about those who test positive.”

Kevin Fenton, director of CDC’s National Center for HIV, STD and TB Prevention, said the recommendations will make “routine HIV screening feasible in busy medical settings where it previously was impractical,” adding, “Making the HIV test a normal part of care for all Americans is also an important step toward removing the stigma still associated with testing” (CQ HealthBeat, 9/22).

Related Editorial
CDC “took the right step” in revising its HIV testing guidelines to recommend routine testing, which offers “the best hope to reduce the stubborn persistence of HIV infections in the American population,” a New York Times editorial says. “[T]imes have changed” since the “early days of the AIDS epidemic,” the editorial says, adding that new treatments have made early HIV diagnoses more “valuable,” that the stigma surrounding the disease seems to have lessened and that health officials have proven they can keep test results private.

In addition, written consent requirements “for HIV testing beyond the general consent forms signed by patients all too often scares patients away from a test that would help them,” the editorial says. Analogous policies to CDC’s revised recommendations for routinely testing pregnant women for HIV have “greatly reduced” HIV prevalence among infants, the editorial says, adding, “Surely it would be better for every [HIV-positive] individual to learn of his status as early as possible … [a]nd surely it would be better for community health if hidden chains of transmission could be detected and interrupted to slow the spread of infection”

HIV Treatment and Measurement

Preliminary research indicates that the initial HIV RNA level in untreated HIV-infected patients appears to have little value in predicting the rate of CD4 cell count decrease, potentially limiting its clinical value concerning the decision of when to begin antiretroviral therapy in an individual, according to a study in the September 27 issue of JAMA.

Depletion of CD4 cells is a characteristic of progressive human immunodeficiency virus (HIV) disease and a powerful predictor of the short-term risk of progression to AIDS, according to background information in the article. Blood levels of HIV are also thought to predict HIV disease progression risk. In addition to their role as predictors of the clinical outcomes of HIV infection, CD4 cell count and plasma HIV RNA level are commonly used as markers of the success of highly active antiretroviral therapy (HAART). Until this study was completed, however, the degree to which blood levels of HIV could predict the rate of CD4 cell loss in HIV-infected individuals with similar demographic characteristics to those seen in clinical practice was unclear.

To address this question, Benigno Rodríguez, M.D., of Case Western Reserve University, Cleveland, and colleagues conducted a study to estimate the extent to which presenting blood levels of HIV can account for or “explain” the rate at which CD4 cells are depleted among an untreated HIV-infected population of patients including women and ethnic minorities. The study included repeated analyses of 2 multicenter groups, with observations beginning in May 1984 and ending in August 2004. Analyses were conducted between August 2004 and March 2006. The participants included antiretroviral treatment–naïve, chronically HIV-infected persons (n = 1,289 and n = 1,512 for each of the 2 groups) who were untreated during the observation period (6 months or greater) and with at least 1 HIV RNA level and 2 CD4 cell counts available. Approximately 35 percent were nonwhite, and 35 percent had risk factors other than male-to-male sexual contact.

The researchers found that only a small proportion of the rate at which CD4 cells are lost (only 4 percent - 6 percent) in a given individual patient could be explained by presenting plasma HIV RNA level, suggesting that in chronic untreated HIV infection over 90 percent of the determinants of CD4 cell decline are not reflected in the amount of virus in blood at the time of initial medical evaluation.

“Our findings confirm previous observations that the magnitude of HIV viremia [the presence of a virus in the blood stream], as defined by broad categories of presenting HIV RNA level, is associated with the rate of CD4 cell loss and extend this observation to patient populations comprising both men and women. Despite this association, however, only a small proportion of the interindividual variability in the rate of CD4 cell decline can be explained by plasma HIV RNA level, even after accounting for the effect of measurement error,” the authors write.

“These findings represent a major departure from the notion that plasma HIV RNA level is a reliable predictor of rate of CD4 cell loss in HIV infection and challenge the concept that the magnitude of viral replication (at least as reflected by plasma levels) is the main determinant of the speed of CD4 cell loss at the individual level. The clinical implications are that in the majority of cases, an individual patient’s plasma HIV RNA level at the time of presentation for clinical care cannot predict, to a significant extent, the rate of CD4 cell decline that he or she will experience over the subsequent years and is therefore of limited clinical value in shaping the decision to initiate antiretroviral therapy,” the researchers write.

Teen Sexual Health

Laws that require minors to notify or get the consent of one or both parents before having an abortion reduce risky sexual behavior among teens, according to a Florida State University law professor in Tallahassee, Fla.

Jonathan Klick, the Jeffrey A. Stoops Professor of Law, and Thomas Stratmann, professor of economics at George Mason University, came to that conclusion after they looked at the rates of gonorrhea among teenage girls as a measure of risky sex in connection to the parental notification or consent laws that were in effect at the time.

The researchers found that teen gonorrhea rates dropped by an average of 20 percent for Hispanic girls and 12 percent for white girls in states where parental notification laws were in effect. The results were not statistically significant for black girls. The study will be published in an upcoming edition of The Journal of Law Economics and Organization.

“Incentives matter,” Klick said. “They matter even in activities as primal as sex, and they matter even among teenagers, who are conventionally thought to be short-sighted. If the expected costs of risky sex are raised, teens will substitute less risky activities such as protected sex or abstinence.”

In this case, the incentive for teens is to avoid having to tell their parents about a pregnancy by substituting less risky sex activities. In doing so, the researchers say, the rates of gonorrhea among girls under the age of 20 went down.

“This suggests that Hispanic and white teenage girls are forward looking in their sex decisions, and they systematically view informing their parents and obtaining parental consent as additional costs in obtaining an abortion, inducing them to engage in less risky sex when parental involvement laws are adopted,” Klick said. “Unfortunately, the data do not allow us to differentiate between the possibility that teens engage in less sex or they simply have the same amount of sex but are more fastidious in their condom use.”

The researchers ruled out the possibility that teens simply substitute risky sexual behaviors for which pregnancy is not a concern, such as oral or anal intercourse, because these activities still could transmit gonorrhea. The use of birth control pills also would not protect against the sexually transmitted disease.

The researchers used data from the Centers for Disease Control to determine the rates of gonorrhea for women by age and race for the years 1981 through 1998. Gonorrhea rates for teenage girls were compared to those of women 20 and older whose behavior would not be affected by the notification and consent laws. Using the rate of gonorrhea among older women as a control, the researchers were able to ensure that the decline in incidence among the teens was not simply reflective of an overall decline of the disease in the state.

Forty-four states, including Florida, have adopted laws requiring minors to obtain consent or notify one or both parents prior to an abortion, but the laws have been blocked by the courts or otherwise not yet enforced in nine of those states, according to the Center for Reproductive Rights.

 GRACE trial to explore gender-related differences in response to PREZISTA-based HIV therapy

Tibotec Therapeutics Clinical Affairs, a division of Ortho Biotech Clinical Affairs, LLC, announced today the initiation of the largest clinical study conducted to date in treatment-experienced adult women with HIV to evaluate gender differences in response to an HIV medication.

GRACE (Gender, Race And Clinical Experience), a multi-center, open-label Phase IIIb trial, will compare gender differences in the efficacy, safety and tolerability of PREZISTA (darunavir) tablets administered with other antiretroviral agents over a 48-week treatment period. The study also will explore racial differences in treatment outcomes.

PREZISTA, co-administered with 100 mg ritonavir (PREZISTA/rtv) and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor. PREZISTA received accelerated approval based on the 24-week analysis of HIV viral load and CD4+ cell counts from the pooled analysis of the TMC114-C213 (POWER 1) and TMC114-C202 (POWER 2) studies. Longer-term data will be required before the FDA can consider traditional approval for PREZISTA (see the full indication and important safety information below).

There is an urgent need to conduct clinical trials designed specifically for women with HIV. The ratio of women to men among Americans diagnosed with HIV has grown substantially since the HIV epidemic first emerged.

Today, women account for almost 30 percent of new HIV diagnoses in the U.S., and rates of HIV infection are particularly high among women of color. However, women have been underrepresented in HIV clinical trials despite research suggesting that women may have different tolerability issues to HIV medications than men.

“GRACE is a landmark study because HIV treatment trials - including those looking at treatment-experienced populations — have traditionally included very small numbers of women, especially in the earliest studies of new antiretroviral agents. We know that there are gender-specific complications associated with HIV disease. However, we do not know a great deal about how gender impacts the efficacy and side effects of HIV medications,” said Judith Currier, M.D., Associate Director of the University of California, Los Angeles, Center for Clinical AIDS Research and Education and a lead investigator in the GRACE study.

“The need for an increased focus on women living with HIV/AIDS was a key theme of the recent AIDS 2006 conference in Toronto, Canada. GRACE is an example of the steps that need to be taken to address the evolving HIV epidemic. The development of this trial included extensive collaboration with the HIV community,” said Dawn Averitt-Bridge, founder and Chair of the Board of The Well Project. “Women who participate in GRACE will play a very important role in advancing the understanding of HIV treatment in women.”

The GRACE study will include approximately 50 sites in the United States, Mexico and Canada, and will seek to enroll approximately 420 participants, 70 percent of whom will be women. Participants must be of 18 years or older, have a viral load of 1000 copies/mL or greater and have previous intolerance or failure to prior therapy consisting of a protease inhibitor and/or non-nucleoside reverse transcriptase inhibitor-based highly active antiretroviral treatment regimen of at least 12 weeks. All participants will receive PREZISTA/rtv (600/100mg twice a day) with an optimized background regimen chosen by the investigator and based on resistance testing and prior treatment history.

Indication
PREZISTA, co-administered with 100 mg ritonavir (PREZISTA/rtv) and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor.

This indication is based on Week 24 analyses of plasma HIV RNA levels and CD4+ cell counts from two controlled trials of PREZISTA/rtv in combination with other antiretroviral drugs. Both studies were conducted in clinically advanced, treatment-experienced (NRTIs, NNRTIs, and PIs) adult patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

The following points should be considered when initiating therapy with PREZISTA/rtv:

• Treatment history and, when available, genotypic or phenotypic testing should guide the use of PREZISTA/rtv.

• The use of other active agents with PREZISTA/rtv is associated with a greater likelihood of treatment response.

• The risks and benefits of PREZISTA/rtv have not been established in treatment-nave adult patients or pediatric patients.

Important Safety Information
PREZISTA does not cure HIV infection or AIDS, and does not prevent passing HIV to others. PREZISTA is contraindicated in patients with known hypersensitivity to any of its ingredients.

Coadministration of PREZISTA/rtv is contraindicated with drugs that are highly dependent on CYP3A for clearance and have a narrow therapeutic index (e.g., astemizole, terfenadine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, midazolam, or triazolam) and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Coadministration is not recommended with carbamazepine, phenobarbital, phenytoin, rifampin, lopinavir/ritonavir, saquinavir, lovastatin, pravastatin, simvastatin, or products containing St. John’s wort (Hypericum perforatum).

Caution should be used when prescribing agents such as sildenafil, vardenafil, tadalafil, or other substrates, inhibitors, or inducers of CYP3A in patients receiving PREZISTA/rtv. This list of potential drug interactions is not complete.

PREZISTA must be co-administered with 100 mg ritonavir and food to exert its therapeutic effect. Failure to correctly administer PREZISTA with ritonavir and food will result in reduced plasma concentration of darunavir that will be insufficient to achieve the desired antiviral effect. Please refer to ritonavir prescribing information for additional information on precautionary measures.

Severe skin rash, including erythema multiforme and Stevens-Johnson Syndrome, has been reported in subjects receiving PREZISTA during the clinical development program. In some cases, fever and elevations of transanimases have also been reported. In clinical trials (n=924), rash (all grades, regardless of causality) occurred in seven percent of subjects treated with PREZISTA; discontinuation due to rash was 0.3 percent. Rashes were generally mild-to-moderate, self-limiting and maculopapular. PREZISTA should be discontinued if severe rash develops.

PREZISTA should be used with caution in patients with known sulfonamide allergy.

New-onset or exacerbations of pre-existing diabetes mellitus and hyperglycemia, and increased bleeding in hemophiliacs have been reported in patients receiving protease inhibitors. A causal relationship between protease inhibitors and these events has not been established.

PREZISTA should be used with caution in patients with hepatic impairment. There are no data regarding the use of PREZISTA in patients with varying degrees of hepatic impairment; therefore, specific dosage recommendations cannot be made.

Redistribution and/or accumulation of body fat have been observed in patients receiving ARV therapy. The causal relationship, mechanism, and long-term consequences of these events have not been established.

Immune reconstitution syndrome has been reported in patients treated with ARV therapy.

The potential for HIV-cross-resistance among protease inhibitors has not been fully explored in PREZISTA/rtv treated patients.

PREZISTA should be used during pregnancy only if the potential benefit justifies the potential risk. There are no adequate and well-controlled studies in pregnant women. The effects of PREZISTA on pregnant women or their unborn babies are not known.

In the pooled analysis of POWER 1 and 2 studies, the most frequently reported drug-related adverse events of at least moderate to severe intensity in patients receiving PREZISTA/rtv-containing regimen were headache (3.8 percent), diarrhea (2.3 percent), abdominal pain (2.3 percent), constipation (2.3 percent), and vomiting (1.5 percent).

Please see full Prescribing Information for more details.

 Experts in this week’s BMJ express serious concerns about the public health impact of criminalising HIV transmission.

The Crown Prosecution Service for England and Wales has issued, for public consultation, new guidance on criminal prosecution for the “sexual transmission of infections which cause grievous bodily harm.” It is likely to be used mostly in relation to HIV.

“Although this attempt to introduce standardised criteria for prosecutions is welcome, we have serious concerns about the public health impact of using the law to criminalise disease transmission,” say Ruth Lowbury of the Medical Foundation for AIDS and Sexual Health and George Kinghorn of the Royal Hallamshire Hospital.

The government has made it a policy priority to increase uptake of HIV testing and is funding prevention programmes in England for the population groups most at risk. Services around the country offer voluntary testing, confidential partner notification, and education and support for affected individuals and their partners.

Crucially, these measures rely on a relationship of trust and confidence between patients and healthcare professionals, but the sustainability and success of this approach are hugely threatened by the policy of criminal prosecution, they argue.

Already there are indications that this use of the criminal law is having unintended negative consequences. Awareness is spreading among those infected with HIV that they face the threat of criminal prosecution, while media coverage has vilified those convicted as “AIDS assassins,” exacerbating the stigma already associated with infection.

No wonder those unlucky enough to become infected often choose to keep their status a secret, they write.

Individuals in this situation need help and support to plan how and to whom they will disclose their status, and to find strategies for protecting others from infection.

An estimated 20,000 people in the UK have HIV which is still undiagnosed, they add. There is a clear disincentive to testing when prosecution relies on defendants knowing they are infected. Meanwhile, those who do take the test may not agree to their partners being notified for fear of legal repercussions, thereby jeopardising essential public health control efforts.

Doctors need guidance on whether the potential for criminal prosecutions changes their legal and ethical duty of confidentiality, and how to advise their HIV positive patients, who may become “victims” or “defendants” if a prosecution occurs. There is also an urgent need for further research, to see whether criminalisation may be leading to reductions in uptake of HIV tests.

Putting aside the difficulties in attributing who infected whom, they conclude that, in the case of criminal prosecution for reckless transmission of HIV, the public interest is not best served by pursuing justice against the few at the expense of the health of the many.

HIV Research

The slow pace of AIDS research can be pinned, in no small part, on something akin to the square-peg-round-hole conundrum. The HIV-1 virus won’t replicate in monkey cells, so researchers use a monkey virus - known as SIVmac, or the macaque version of simian immunodeficiency virus - to test potential therapies and vaccines in animals. But therapies and vaccines that are effective on SIV don’t necessarily translate into human success. Now, using a combination of genetic engineering and forced adaptation, researchers at Rockefeller and the Aaron Diamond AIDS Research Center have created a version of the AIDS virus that replicates vigorously in both human and monkey cells - an advance that has the potential to revolutionize vaccine research.

In a paper published in today’s issue of Science, Paul Bieniasz, associate professor and head of the Laboratory of Retrovirology, describes how he and his colleagues maneuvered around the intrinsic immunity of primate cells by replacing just a few parts of the human virus - the ones responsible for blocking replication in monkey cells - with components from SIV. “Overall, the virus is a mixture of engineering and forced evolution,” Bieniasz says. “It sounds simple, in theory, but it took us two years to do.”

Bieniasz and Theodora Hatziioannou, a research scientist in the lab and the paper’s first author, had to overcome two major obstacles: the first was a protein called TRIM5 that, in monkeys, recognizes the outer shell or “capsid” of HIV-1 but not that of SIV. By swapping out the capsid region of the HIV-1 genome for that of the monkey virus, and then selectively growing the viruses that replicated most robustly, over several generations Hatziioannou created an HIV-1 mutant that could evade the monkey cells’ TRIM5 recognition.

Another bit of engineering was required to get around the second obstacle: APOBEC proteins produced by a host normally cause invading viruses to mutate so much that they can’t survive, but HIV-1 uses a protein called Vif to destroy APOBEC and prevent the attack. Monkey APOBEC proteins, however, aren’t susceptible to the human virus’s Vif. So Hatziioannou did another swap - the SIV Vif gene for the HIV one - and then another round of forced adaptation to create viruses that would multiply with vigor.

The researchers dubbed their end result simian tropic HIV (stHIV): a form of HIV-1 that only differs from the original by about 10 percent, but can effectively infect primate cells and be used to test potential therapies. “If we can make this virus work in animals the way it works in tissue culture, it will likely change the way that AIDS vaccine and therapeutics research is done,” Bieniasz says.

 New HIV diagnoses in Australia are the highest in a decade, according to a national report complied by UNSW researchers released this week.

The data show a significant drop in new diagnoses from 1996 to 2000, but a 41 percent increase between 2000 and 2005.

The findings are contained in the tenth HIV/AIDS, viral hepatitis and sexually transmissible infections in Australia Annual Surveillance Report, which has been prepared by researchers from UNSW’s National Centre in HIV Epidemiology and Clinical Research (NCHECR) for the Commonwealth Department of Health and Ageing.

The report, which is one of two from UNSW to be released at the Australasian Society for HIV Medicine’s annual conference in Melbourne, shows 930 people were diagnosed last year, while there were 890 in 1996.

Other findings include:

• Diagnosis of chlamydia has increased fourfold over the past ten years

• The diagnosis of gonorrhoea has doubled over the past ten years

• In NSW and Victoria, the diagnosis of syphilis doubled between 2001 and 2005

• Queensland has the highest increase in diagnosed newly acquired HIV infection over the past five years (48 percent), followed by Victoria (40 percent), South Australia (34 percent) and NSW (20 percent)

The second report, by UNSW researchers at the National Centre in HIV Social Research (NCHSR), finds that a quarter of HIV-positive gay men enrolled in one study have had unprotected intercourse with at least one casual partner whose status is unknown in the past six months.

Other findings in this report, that focuses on behavioural trends in sexually transmitted diseases, include:

• HIV-positive gay men were more likely to have had unprotected intercourse with casual partners than HIV-negative gay men

• Of the few HIV-positive people in relationships with HIV-negative partners, one in twenty sometimes have unprotected sex, according to one study

• More than 30 percent of heterosexual women and 28 percent of heterosexual men reported to have never used condoms with a casual partner in the previous six months

• HIV testing rates are lower for younger gay men (65 to 75 percent), compared with gay men more broadly (80 percent)
• The Federal Health Minister, Tony Abbott, has reportedly asked his advisory council to consider how to reduce the infection rate of HIV after the release of the report.

Prevent HIV Transmission

Scientists at Makerere University, in Kampala, Uganda, along with scientists from Johns Hopkins and other institutions worldwide, have begun the first clinical safety trial in Africa of a vaccine to prevent mother-to-child transmission of HIV through breastfeeding. Breast milk is a leading route of infection in the developing world, according to the United Nations World Health Organization, which estimates that each day 1,800 newborns are infected with the AIDS virus, 30 percent to 40 percent by virus carried in their mother’s milk.

Enrollment of the first newborn took place at Mulago Hospital in Kampala. The so-called phase I study is designed to test the safety of injecting newborns with the vaccine, formally known as ALVAC-HIV (vCP1521). If the vaccine is found to be safe in this study, and if it is later shown to be effective in reducing the chance of infants’ becoming infected during breastfeeding, researchers estimate that it could potentially stop up to 8,000 of Uganda’s 22,000 infections a year in children. Initial results are expected by mid-2007.

“A vaccine is the easiest way to help prevent mother-to-child transmission of the disease, as healthy alternatives to breastfeeding, such as infant formula, are not available or affordable to most new mothers in the developing world, many of whom do not know they are HIV positive,” says study protocol chair and pediatric infectious disease specialist Laura Guay, M.D., who will lead Hopkins’ efforts.

“Vaccines often involve several injections over a short period of time, whereas other drug therapies that might prevent transmission are less convenient and must be taken daily over a longer period of time and potentially have more side effects,” says Guay, an associate professor at The Johns Hopkins University School of Medicine.

Guay notes that discouraging breastfeeding altogether is not a practical option for many women because the lack of safe alternatives increases five- to sevenfold a newborn’s chances of dying of pneumonia or diarrhea, illnesses which breastfeeding can help prevent through nutrition and ingestion of the mother’s antibodies. Moreover, she says, it would be potentially harmful to deny this key means of nutrition to the 80,000 newborns in Uganda who do not contract HIV each year from their infected mothers, either from pregnancy, labor or delivery, or breast milk. Indeed, Guay points out that the Ugandan Ministry of Health has identified development of a vaccine as a key priority for reducing the country’s high HIV transmission rates.

The Ugandan-led study will involve 50 infants born to HIV-positive mothers in the local Kampala area, all of whom are otherwise in general good health, with key immune CD4 cell counts of 500 cells per cubic milliliter of blood or greater. Forty infants will be randomly assigned to receive the vaccine while 10 others will get placebo saline solution.

Eligible candidates will undergo initial examination at Mulago Hospital, in Kampala, and make later visits to Makerere-Hopkins’ Research Clinic, which specializes in AIDS research and care, allowing participants ready access to facilities for checkups and testing that will all be provided free of charge. Once enrolled, infants will be injected in four separate doses of 1 milliliter of vaccine each, over a period of three months. Participants will then be closely monitored through regular physical examinations and blood tests for the duration of the study, which is expected to last two and a half years. A group of local community members provided advice on how the study was to be carried out and participated in advance in educational seminars.

The goal of the Hopkins team is to eventually find a vaccine that will allow infants to develop immunity to HIV just as they would to polio, diphtheria and hepatitis B, after vaccination for those disorders. Many of these vaccines, researchers point out, are already combined into a single vaccination. The goal is to one day provide an AIDS vaccine as part of a child’s regular vaccination program.

Previous research using an ALVAC-HIV vaccine in adults in Uganda showed it to be safe, but it is not yet known if it is effective in preventing infection. In 2005, a phase I study done in newborns in the United States using a similar ALVAC-HIV vaccine found that the vaccine was very safe. Related clinical research from other institutions using the same vaccine is under way in Thailand, involving 16,000 participants, a much larger sample because researchers there are testing the vaccine’s broad effectiveness rather than its initial safety.

However, research in monkeys has shown that ALVAC-SIV vaccine was successful in preventing oral transmission through milk of simian immunodeficiency virus, or SIV, in 11 of 17 newborns given the vaccine.

The ALVAC-HIV vaccine is one of at least five HIV vaccines under study in Africa, all of which are being studied in adults. It is manufactured by extracting cell cultures that have been grown in embryonated chicken eggs. The cell cultures contain live and weakened canarypox virus, which does not infect humans, but has had genetic material from specific strains of HIV inserted into it. The theory, according to researchers, is that the human body could develop a cellular immunity to HIV by developing immunity to its genetic components in the non-harmful canarypox virus. More than 20 other test vaccines against the disease are in various stages of early development.

Studies are proceeding in multiple countries to assess other vaccines’ safety against all subtypes and various cross-mixes of the virus.

“A major advantage to this kind of research is that it opens up access to better AIDS care, including medications, regular checkups and home care, to the people of sub-Saharan Africa, where the need is great,” notes study co-investigator Brooks Jackson, M.D., M.B.A., professor and director of pathology at Hopkins. “We hope this study will lead to more effective research and treatment and more vaccine trials in infants in Africa.” Jackson, a pathologist and virologist, has studied HIV disease in Africa for the past 16 years.

According to the latest statistics from the United States Centers for Disease Control and Prevention, in 2004, more than 1 million Americans currently live with HIV, the virus that causes AIDS. However, the advent of antiretroviral therapy and better understanding of how to prevent transmission from mother to child have dropped the annual number of pediatric cases from nearly 2,000 in the early 1990s to under 200 in recent years, mostly to mothers who did not know they were HIV positive.

Herpes Vaccine

A study by a Montana State University researcher suggests a new avenue for developing a vaccine against genital herpes and other diseases caused by herpes simplex viruses.

In a study published earlier this year in the Virology Journal, MSU virologist William Halford showed that mice vaccinated with a live, genetically-modified herpes simplex virus type 1 (HSV-1) showed no signs of disease 30 days after being exposed to a particularly lethal “wild-type” strain of the virus.

In contrast, a second group of mice that received a more conventional vaccine died within six days of being exposed to the same “wild-type” strain.

“We have a clear roadmap for producing an effective live vaccine against genital herpes,” said Halford, who works in MSU’s Department of Veterinary Molecular Biology. “Although my studies were performed with HSV-1, the implications for HSV-2-induced genital herpes are clear. Overall the two viruses are about 99 percent genetically identical.”

An estimated 55 million Americans carry herpes simplex virus type 2 (HSV-2), which causes genital herpes. Infection is life-long. Approximately 5 percent of those with genital herpes - 2 million to 3 million Americans - suffer outbreaks one to four times annually. A vaccine offering life-long protection does not exist.

The key to Halford’s research was understanding how the herpes simplex virus overcame the body’s natural defenses.

A cell infected with the herpes simplex virus sends a warning to neighboring cells. This warning — an interferon response — causes neighboring cells to enter “an anti-viral state” akin to putting on a suit of armor, Halford said.

However, herpes produces a protein, ICP0, that tricks every infected cell into destroying its own armor. Once the cell’s armor is gone, the virus can propagate itself and spread to other cells, which are in turn tricked into lowering their defenses.

In his research, Halford created a vaccine where the genetic instructions that make ICP0 were disrupted. Without instructions on how to do its clever ICP0 trick, the virus can still establish an infection in animals, but the spread of the virus is stopped long before disease can occur.

“In short, we can disarm the virus such that it is absolutely unable to cause disease, but is still remarkably potent as a vaccine,” Halford said.

In a human vaccine, the genetic instructions for ICP0 would actually be removed, creating an “attenuated,” or weakened virus. The rest of the herpes simplex virus’ genetic code would remain intact. Measles, mumps, rubella, polio and yellow fever vaccines are all made from attenuated viruses.

Research in recent decades has focused on subunit vaccines, which are made from one piece of a virus (a protein subunit). Subunit vaccines are safer than attenuated virus vaccines because the subunit cannot replicate or cause disease. However, subunit vaccines have proven ineffective in protecting people against persistent infections like genital herpes and AIDS, Halford said.

“From a theoretical standpoint, subunit vaccines are poor mimics of a natural virus infection,” Halford said. “There’s not enough there for our immune systems to build a protective response against the actual virus.”

Halford, 38, is aware that his approach is controversial.

“This is where I’m young enough that I don’t know how long it can take to swing popular opinion among scientists and clinicians,” he said. “I would hope that in five to six years the scientific community would be willing to seriously consider these proposals.”

Halford hopes to find a commercial partner or secure government funding to advance his research toward a human vaccine.

“I’d like to take this concept from the chalkboard to the clinics,” he said.