time travel

Treating women who are infected with both the HSV-2 and HIV viruses with anti-herpes treatment can reduce the amount of HIV in the blood and genital secretions, according to the results of a trial published today in the New England Journal of Medicine.

A collaborative group of scientists from the Centre Muraz (Burkina Faso), the University of Montpellier (France) and the London School of Hygiene & Tropical Medicine (UK) carried out the trial among women co-infected with the human immuno-deficiency virus (HIV) and the virus that causes genital herpes (HSV-2) in Burkina Faso. The results showed that having the herpes virus increased the replication of HIV, and also revealed that the quantity of HIV in the blood and in the vagina was reduced by continuous anti-herpes treatment over 3 months.

These findings open new avenues for the prevention of HIV transmission and for the management of patients co-infected by the two viruses.

In 2005, an estimated 4.1 million people were newly infected with HIV, mostly through heterosexual intercourse1. This alarming number of infections highlights the urgent need to intensify and expand proven prevention methods, and further, to identify and implement new methods of HIV prevention.

A number of observational studies have indicated that HSV-2 enhances the risk of HIV-1 acquisition by around three-fold2. HSV-2 infection may also increase HIV-1 infectiousness by disrupting the genital mucosa and increasing the levels of HIV in the genital tract3, allowing easier transmissibility of the virus. In addition, the HIV viral load in the blood of HIV-1 infected patients increases, at least temporarily, during episodes of HSV reactivation.

Lead author Dr. Nicolas Nagot, of the London School of Hygiene & Tropical Medicine (LSHTM), explains: ‘Behavioural interventions are not always successful, as knowledge does not necessarily translate into sexual behaviour change. Therefore, innovative methods that target the biological susceptibility of individuals to acquire or transmit HIV are also required. A number of options to prevent HIV transmission are currently being investigated, including the role of vaginal microbicides, pre-exposure HIV prophylaxis, male circumcision, and – in the future – an HIV vaccine.’

‘The results of the trial are striking’, he adds. ‘They show that valacyclovir significantly reduces the frequency and quantity of HIV detectable in genital secretions and, in addition, reduces the quantity of HIV in the plasma. As expected, there was also dramatic reduction in the detection of symptomatic and asymptomatic presence of HSV-2. The effects appeared to gradually increase over the 3 month follow-up period, with no sign of abating.’

These results indicate a new way to possibly reduce the sexual transmission of HIV from already infected individuals to their partners, since the frequency and quantity of HIV in the female genital tract are closely related to the transmission of the virus.

The findings will need to be confirmed by further research, and there is already a large ongoing trial that is measuring direct transmission of HIV between discordant couples in several sites worldwide.

Dr Philippe Mayaud, one of Dr Nagot’s colleagues at the LSHTM concludes: ‘Our results have important potential implications for public health and clinical practice, as HSV-2 control could become a new form of HIV prevention targeting HIV-infected individuals, as well as providing clinical benefits. Importantly, an HSV vaccine that would either prevent HSV infection or diminish the clinical and sub-clinical manifestations of HSV with a similar efficacy on HIV as HSV suppressive therapy, would represent a long-lasting form of HIV prevention. The development and evaluation of an HSV vaccine should rank high on the international research agenda.’

Gareth Thomas, UK Minister for International Development, whose department DFID has provided supplementary funding for the research, said: “These exciting initial findings demonstrate why research into reducing HIV/ AIDS transmission is such a vital element of the fight against the disease. The UK Government has pledged to spend £1.5 billion tackling HIV/AIDS in developing countries between 2005 and 2008. We will follow the next stages of this research with interest.”

For further information, or to contact any of the study authors, please contact:
Philippe Mayaud, Clinical Research Unit, Department of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E 7HT; tel 207 927 2291; email: philippe.mayaud@lshtm.ac.uk

Notes to Editors:
1. Herpes simplex virus type-2 (HSV-2), a sexually transmitted virus, is one of the most common pathogens worldwide4. HSV-2 is a lifelong infection and is found in nearly 80% of HIV-infected patients. Once acquired, the virus cycles between latency (hidden in nerves), asymptomatic genital excretion of the virus (’shedding’), and clinical reactivations that can produce painful ulcers in and around the genitalia. The herpes virus can be targeted by specific HSV-2 antiviral drugs such as acyclovir, valacyclovir or famciclovir, which are relatively affordable medications with few side effects, and to which the herpes virus rarely becomes resistant. These drugs are effective in preventing the recurrence of disease and in curbing the transmission of HSV-2 from infected to uninfected partners5.

2. In 2001, an international workshop organised by WHO, UNAIDS and LSHTM called for randomised controlled trials of HSV-2 therapy to definitely establish a causal relationship between HSV-2 and HIV-1 infectivity and acquisition6. We have now completed the first two randomised placebo-controlled trials of herpes suppressive treatment (with valacyclovir at a dose of 500 mg twice daily for 3 months) among HIV-infected individuals. The studies were conducted in Burkina Faso among women who were dually seropositive for HIV and HSV-2. In the first trial (ANRS1285a) published in today’s issue of the New England Journal of Medicine7, we report on the impact of HSV suppressive treatment on plasma and genital HIV-1 levels among women who did not require ART and who did not require a treatment for their HSV infection (they had less than 6 episodes per year). In the companion trial (ANRS1285b), which has been published recently in AIDS8, we reported the impact of herpes suppressive therapy on plasma and genital HIV-1 levels among women who were taking highly active antiretroviral therapy (HAART).

The ANRS 1285b trial was conducted among 60 women who had been taking HAART for at least 4 months. This trial showed that valacyclovir had an additional impact on the residual shedding of HIV-1 despite good systemic control of the virus. This supports an effect of HSV-2 on independent mucosal HIV-1 replication – an important contribution to the HSV/HIV co-activation hypothesis.

Note on funding and sponsorship
This research was sponsored by France’s Agence Nationale de Recherches sur le Sida et les Hepatites (ANRS), with supplementary financial support from the United Kingdom’s Department for International Development (DFID).

The ANRS, created in 1992 to specifically respond to the many scientific challenges posed by the extension of the HIV/AIDS pandemic, coordinates research activities that span several disciplines from fundamental research, to clinical research, public health and socio-anthropological research.

DFID has been funding research on HIV/AIDS through a series of research programmes formerly called ‘Knowledge Programmes’ and currently ‘Research Programme Consortia’. The purpose of the current LSHTM-based Consortium on Sexual and Reproductive Health and HIV is to strengthen the evidence base to enable policy makers to identify and prioritise interventions that will improve reproductive and sexual health and reduce HIV incidence among economically poor populations in Africa and Asia; and to ensure that the research results are made available to policy makers at national and international levels in an intelligible and relevant form.

Footnotes:

1 – UNAIDS. 2006 Report on the Global AIDS Epidemic. Geneva, 2006.

2 – We have published several accounts of worldwide epidemiology: e.g. Weiss HA. Herpes 2004; 11:24A-35A; Cowan FM, et al. Sex Transm Infect 2003; 79; 286-290.

3 – Corey L, et al. N Engl J Med. 2004; 350(1): 11-20.

4 – Meta-analysis performed by our group: Freeman EE, et al. AIDS 2006; 20: 73-83.

5 – Several accounts of this in our work: eg. Mbopi-Keou F-X, et al. J Infect Dis 2000; 182: 1090-6.

6 – World Health Organisation. Herpes simplex virus type 2: Programmatic and research priorities in developing countries. Report of a WHO/UNAIDS/LSHTM workshop (London, 14-16 February 2001). Document WHO/HIV AIDS/2001.05. Geneva: WHO, 2001.

7 – Nicolas Nagot, Abdoulaye Ouedraogo, Vincent Foulongne, Issouf Konate, Helen A. Weiss, Laurence Vergne, Marie-Christine Defer, Didier Djagbare, Anselme Sanon, Jean-Baptiste Andonaba, Pierre Becquart, Michel Segondy, Roselyne Vallo, Adrien Sawadogo, Philippe Van de Perre, and Philippe Mayaud for the ANRS 1285 Study Group. Reduction of HIV-1 RNA Levels with Therapy to Suppress Herpes Simplex Virus. New Engl J Med 2007;356 (8): 790-9.

8 – Abdoulaye Ouedraogo, Nicolas Nagot, Laurence Vergne, Issouf Konate, Helen A. Weiss, Marie-Christine Defer, Vincent Foulongne, Anselme Sanon, Jean-Baptiste Andonaba, Michel Segondy, Philippe Mayaud and Philippe Van de Perre. Impact of suppressive herpes therapy on genital HIV-1 RNA among women taking antiretroviral therapy: a randomized controlled trial. AIDS 2006; 20: 2305-13.

From London School of Hygiene & Tropical Medicine

Researchers at the University at Buffalo and the University of Utah are beginning a clinical trial to test whether aspirin can improve a woman’s chances of becoming pregnant and of maintaining a pregnancy to term.

UB’s portion of the study is funded by a $2.8 million grant from the National Institute of Child Health and Development.

The trial is aimed at women who have miscarried a pregnancy in the past year.

“In women who have had their first miscarriage, the reasons for losing that pregnancy are in many instances unknown,” said Jean Wactawski-Wende, Ph.D., UB associate professor of social and preventive medicine and principal investigator of the UB clinical center.

“These women generally are advised to try to get pregnant again, but health-care providers can offer limited assistance on any specific actions to take to improve their next pregnancy outcome,” she noted. “If aspirin can help some women become pregnant or maintain a health pregnancy, it will be a critically important finding.

“Aspirin is available, inexpensive and has very few side effects,” she added. “We’re hopeful that this trial could produce an important finding.”

Statistics show that in the United States, 10-15 percent of couples trying to become pregnant are not able to conceive, 15-31 percent of pregnancies that do occur end in miscarriage, and 8-15 percent of pregnancies that continue beyond 20 weeks end in premature birth, putting these infants at risk for increased health problems.

Aspirin has been shown to have beneficial effects in humans, said Wactawski-Wende. “It is an anticoagulant and an anti-inflammatory agent. It may aid in implantation of the egg in the uterine wall, and has potential for producing a positive effect on blood flow to the placenta. It may aid in reducing preeclampsia. This clinical trial provides an opportunity to determine the impact of low-dose aspirin on many pregnancy outcomes.”

The Effects of Aspirin in Gestation & Reproduction trial, or EAGeR, will begin this spring and will continue for five years. The UB center will enroll 535 women. Another 1,070 will be recruited by investigators at the University of Utah, for a total enrollment of 1,600 women.

Participants must be between the ages of 18 and 40, have had one miscarriage in the year prior to entering the study, wish to become pregnant and are not already pregnant when they start the study. All will take 400 micrograms of folic acid (a B vitamin shown to reduce the chance of certain birth defects if started early) plus either an 80 milligram aspirin pill or a placebo pill daily.

The women will come to the UB study clinic twice a month for two months and will be followed for an additional four months in the clinic or by telephone. If they become pregnant they will be followed throughout the pregnancy. Participants will take their study pills daily, maintain daily records and provide both urine and blood samples.

Recruitment will begin shortly. “We are thrilled to be able to conduct this trial in Western New York and offer women in our community the opportunity to take part in this important study,” said Wactawski-Wende.

UB consultants include Richard Brown, Ph.D., Maurizio Trevisan, M.D., Moeen Abu-Sitta, M.D., John Yeh, M.D., Dennis Weppner, M.D., Lawrence Gugino, M.D., Ken Crickard, M.D., and Michael Sullivan, M.D.

The University at Buffalo is a premier research-intensive public university, the largest and most comprehensive campus in the State University of New York. The School of Public Health and Health Professions is one of five schools that constitute UB’s Academic Health Center.

From University at Buffalo

Plant-based omega-3 polyunsaturated fatty acids (PUFA) may have a protective effect on bone health, according to a team of Penn State researchers who carried out the first controlled diet study of these fatty acids contained in such foods as flaxseed and walnuts.

Normally, most of the omega-3 fatty acids in the diet are plant-derived and come mainly from soybean and canola oil. Other sources are flaxseed, flaxseed oil, walnuts and walnut oil. Smaller amounts also come from marine sources, mainly fish, but also algae. Omega-3s are thought to have an anti-inflammatory effect and may play an important part in heart and bone health.

“The unique thing about this study is that we know exactly what the participants ate because we closely controlled their food,” says Dr. Rebecca Corwin, associate professor of nutrition. “These people are really dedicated to spend a total of 24 weeks in the study with 18 weeks eating only what was supplied to them.”

Previous studies of omega-3s on bone health used oil supplements rather than whole food sources. The researchers note in a recent issue of Nutrition Journal, that “supplement studies typically do not involve control of the background diet, and it is possible that differences across studies could be explained by failure to control for other nutrients that affect bones.”

The researchers developed three diets that they fed sequentially to the 23 participants. Twenty of the subjects were men and three were postmenopausal women not on hormone replacement therapy for six months. This study was part of a larger one investigating the effects of omega-3 fatty acids on cardiovascular health. For six weeks the subjects ate either the control diet, dubbed average American diet or two other diets high in PUFA. After six weeks the group had three weeks off to resume their typical eating pattern and then for the next six weeks they ate one of the other diets. This continued for 24 weeks until all participants consumed six weeks of all the diets.

Monday through Friday the participants ate either breakfast or dinner in the diet center and packed the remaining meals, including weekend meals and snacks home. The researchers designed the diets so that individual body weight remained unchanged; participants carried out their normal activities and exercise levels. Blood tests showed that all subjects ate their supplied food and did not cheat on their regimens.

The two high PUFA diets had different amounts of linoleic acid (LA), an omega-6 fatty acid and alpha linolenic acid (ALA), an omega-3 fatty acid. Walnuts, which are high in omega-6 and omega-3 fatty acids, supplied half the total fat in both diets. They appeared in walnut granola, honey walnut butter, walnut pesto and as snacks. The ALA diet also contained flaxseed oil to increase the ALA content of the diet. Other sources of ALA, such as canola oil, were not used in this study.

Blood tests screened for two biological markers of bone health, one that indicates bone formation and one that indicates bone resorption or breakdown. Throughout life, two different types of cells – osteoblasts and osteoclasts – constantly build and break down bone. In this process they produce chemicals that researchers can measure in the blood. This process allows broken bones to heal, and bones to remain strong, but if more bone is lost than is rebuilt, osteoporosis occurs.

The biomarker for bone resorption, N-telopeptides, decreased significantly during the ALA diet and marginally during the LA diet compared to the average American diet. Levels of bone-specific alkaline phosphatases, a measure of bone building, were unaffected by the diets.

“If less bone is being resorbed and the same amount of bone is being created, then there is a positive balance for bone health,” says Corwin.

Some scientists believe that the ratio of omega-6 and omega-3 fatty acids is the important factor. The ratio of these fatty acids in the average American diet was about 9.5, while in the LA and ALA diets it was 3.5 and 1.6 respectively.

The researchers caution that it is unknown if the observed effects are due to increased ALA or conversion of ALA to eicosapentaenoic acid, EPA. Fish oils in fish, are the main source of EPA in the American diet.

The researchers note that “recent epidemiologic data suggest that the effects of dietary fats on bone health may be particularly strong in men.” So, while middle-aged men are often overlooked in studies of bone health, incorporating plant sources of omega-3 PUFA into the diet may not only improve cardiovascular health, but also enhance bone health.

The team included Corwin; Amy E. Griel, recent doctoral recipient and dietetic intern, Penn State dietetic internship; Penny M. Kris-Etherton, distinguished professor of nutrition at Penn Stsate; Kirsten Hilper, previous doctoral recipient, registered dietitian, Sodoexho USA; Guixiang Zhao, previous doctoral recipient, senior service fellow, Centers for Disease Control; and Sheila G. West, associate professor of biobehavioral health at Penn State.

The California Walnut Commission supported this research and partial support was provided by Penn State’s General Clinical Research Center NIH grant.