Infectious Diseases News Brief - July 30, 2010

[Current Issue -Table of contents]

Prolonged Infectiousness of Tuberculosis Patients in a Directly Observed Therapy Short-Course Program with Standardized Therapy

Background

Effective tuberculosis control is compromised by a lack of clarity about the timeframe of viable Mycobacterium tuberculosis shedding after treatment initiation under programmatic conditions. This study quantifies time to conversion from smear and culture positivity to negativity in unselected tuberculosis patients receiving standardized therapy in a directly observed therapy short-course (DOTS) program.

Methods

Longitudinal cohort study following up 93 adults initiating tuberculosis therapy in Lima, Peru. Baseline culture and drug susceptibility tests (DSTs) were performed using the MBBacT, proportion, and microscopic observation drug susceptibility (MODS) methods. Smear microscopy and MODS liquid culture were performed at baseline and weekly for 4 weeks then every other week for 26 weeks.

Results

Median conversion time from culture positivity to culture negativity of 38.5 days was unaffected by baseline smear status. Patients with fully susceptible tuberculosis had a median time to culture conversion of 37 days; 10% remained culture positive at day 60. Delayed culture conversion was associated with multidrug resistance, regardless of DST method used; non–multidrug resistance as defined by the proportion method and MODS (but not MBBacT) was also associated with delay. Persistent day 60 smear positivity yielded positive and negative predictive values of 67% and 92%, respectively, for detecting multidrug resistance.

Conclusions

Smear and culture conversion in treated tuberculosis patients takes longer than is conventionally believed, even with fully susceptible disease, and must be accounted for in tuberculosis treatment and prevention programs. Persistent day 60 smear positivity is a poor predictor of multidrug resistance. The industrialized-world convention of universal baseline DST for tuberculosis patients should become the standard of care in multidrug resistance–affected resource-limited settings.

Clinical Infectious Diseases 2010;51:371–378
http://www.journals.uchicago.edu/doi/abs/10.1086/655127

Antiretroviral vaginal gel shows promise against HIV

The results of a phase 2b proof-of-concept study of 889 HIV-negative women in KwaZulu-Natal, South Africa, have shown that a gel for vaginal application containing 1% of the antiretroviral drug tenofovir is safe and effective for preventing HIV. Antiretroviral drugs have been shown to effectively treat people living with HIV, and to prevent mother-to-child transmission, but this is the first time an antiretroviral gel has been shown to prevent sexually transmitted HIV.

After 2-5 years of gel use, there were 38 new infections in the treatment group, compared with 60 in the control group. Over this period, 39% of women using the gel were protected, and 54% were protected when the gel was used as prescribed—within 12 h before sex and 12 h after sex—for more than 80% of their sexual intercourse. After a year there were 50% fewer new HIV infections in those using the gel than in women using a placebo gel. The results are good news for microbicides, which have previously shown disappointing results and faced increasing scepticism about their potential use. The results of 11 trials of six candidate microbicides over the past 15 years have been negative.

The investigators, who presented their findings at the 18th International AIDS Society conference in Vienna, Austria, on July 20, also noted that the tenofovir-based gel halved the rate of new herpes simplex (HSV)-2 infections. HSV-2 infects about 80% of HIV-infected men and women worldwide.

The Centre for the AIDS Programme of Research in South Africa (CAPRISA 004) trial was launched in 2007, and if the results are confirmed, 1 323 000 new infections and more than 800 000 deaths could be prevented with the gel in the next 20 years in South Africa alone. Co-principal investigators Salim and Quarraisha Abdool Karim were cautiously optimistic when The Lancet visited the rural Vulindlela Clinic, one of the two trial sites, last week. "This is a first step, but we need basic science, supportive behaviour, and marketing research to move from a concept to putting something into the hands of women…It would be sad if this sits on the table. We could have a product in 3 years if we act, get confirmation of results and regulation", says Salim. Xoliswa Mthethwa, 26, who was a participant in the trial at the Vulindlela Clinic, says without hesitation: "The gel is number one. I would buy it."

A woman-controlled prevention method is urgently needed in Africa, where most women are economically, socially, and politically disempowered. Prevention strategies need to be made relevant for women. "As long as we have high rates of HIV infection in women in the 15–19 age group, which is synonymous with their transition from childhood to sexual activity, we cannot win the battle against HIV. Women are carrying a disproportionate burden of disease", said Quarraisha.

A CAPRISA survey of pregnant women attending seven Vulindlela clinics between 2005 and 2008 found that by age 16 years, one in ten women were infected with HIV, by 18 years one in five were infected, and by 24 years, one in two had HIV. "Any intervention after 18 years is too late, showing the devastation wreaked in communities across sub-Saharan Africa and the magnitude of the problem felt in KwaZulu-Natal, the epicenter of the pandemic," says Quarraisha. Maintainance and verification of adherence to the treatment was the "Achilles’ heel of the trial", says Salim. Adherence is difficult to measure accurately because it relies on self reporting, but there was evidence that the longer the trial went on the more adherence dropped off. Vulindlela site director Janet Frohlich says that among other factors, seroconversion of some women during the trial was likely to have had a detrimental effect on adherence in other women.

There was no evidence of any emergence of HIV-resistant strains with early, short-term, and intermittent use of the gel, and the only reported side-effect was a small increase in mild diarrhoea. Frohlich says that if confirmed, the CAPRISA trial results show that an antiretroviral-based microbicide could in time be an effective prevention strategy that can be safely used by women to prevent HIV infection.

The Lancet: Published online July 20, 2010 DOI:10.1016/S0140-6736(10)61123-3 http://download.thelancet.com/flatcontentassets/pdfs/S0140673610611233.pdf

NIH-Led Scientists Find Antibodies that Prevent Most HIV Strains from Infecting Human Cells Discovery to Advance HIV Vaccine Design, Antibody Therapy for Other Diseases

Scientists have discovered two potent human antibodies that can stop more than 90 percent of known global HIV strains from infecting human cells in the laboratory, and have demonstrated how one of these disease-fighting proteins accomplishes this feat. According to the scientists, these antibodies could be used to design improved HIV vaccines, or could be further developed to prevent or treat HIV infection. Moreover, the method used to find these antibodies could be applied to isolate therapeutic antibodies for other infectious diseases as well.

The discovery of these exceptionally broadly neutralizing antibodies to HIV and the structural analysis that explains how they work are exciting advances that will accelerate our efforts to find a preventive HIV vaccine for global use," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. "In addition, the technique the teams used to find the new antibodies represents a novel strategy that could be applied to vaccine design for many other infectious diseases."

Led by a team from the NIAID Vaccine Research Center (VRC), the scientists found two naturally occurring, powerful antibodies called VRC01 and VRC02 in an HIV infected individual's blood using a novel molecular device they developed that hones in on the specific cells that make antibodies against HIV. The device is an HIV protein that the scientists modified so it would react only with antibodies specific to the site where the virus binds to cells it infects.

The scientists found that VRC01 and VRC02 neutralize more HIV strains with greater overall strength than previously known antibodies to the virus. The researchers also determined the atomic-level structure of VRC01 when it is attaching to HIV. This has enabled the team to define how the antibody works and to precisely locate where it attaches to the virus. With this knowledge, they have begun to design components of a candidate vaccine that could teach the human immune system to make antibodies similar to VRC01 that might prevent infection by the vast majority of HIV strains worldwide.

"We have used our knowledge of the structure of a virus—in this case, the outer surface of HIV—to refine molecular tools that pinpoint the vulnerable spot on the virus and guide us to antibodies that attach to this spot, blocking the virus from infecting cells," explains Dr. Nabel, the VRC director.

Finding individual antibodies that can neutralize HIV strains anywhere in the world has been difficult because the virus continuously changes its surface proteins to evade recognition by the immune system. As a consequence of these changes, an enormous number of HIV variants exist worldwide. Even so, scientists have identified a few areas on HIV’s surface that remain nearly constant across all variants. One such area, located on the surface spikes used by HIV to attach to immune system cells and infect them, is called the CD4 binding site. VRC01 and VRC02 block HIV infection by attaching to the CD4 binding site, preventing the virus from latching onto immune cells.

"The antibodies attach to a virtually unchanging part of the virus, and this explains why they can neutralize such an extraordinary range of HIV strains," says Dr. Mascola, the deputy director of the VRC. With these antibodies in hand, a team led by Dr. Kwong, chief of the structural biology section at the VRC, determined the atomic-level molecular structure of VRC01 when attached to the CD4 binding site. They then examined this structure in light of natural antibody development to ascertain the steps that would be needed to elicit a VRC01-like antibody through vaccination.

Antibody development begins with the mixing of genes into new combinations within the immune cells that make antibodies. Examination of the structure of VRC01 attached to HIV suggested that, from a genetic standpoint, the immune system likely could produce VRC01 precursors readily. The researchers also confirmed that VRC01 does not bind to human cells—a characteristic that might otherwise lead to its elimination during immune development, a natural mechanism the body employs to prevent autoimmune disease.

In the final stage of antibody development, antibody-producing B cells recognize specific parts of a pathogen and then mutate, or mature, so the antibody can bind to the pathogen more firmly. VRC01 precursors do not bind tightly to HIV, but rather mature extensively into more powerfully neutralizing forms. This extensive antibody maturation presents a challenge for vaccine design. In their paper, Dr. Kwong and colleagues explore how this challenge might be addressed by designing vaccine components that could guide the immune system through this stepwise maturation process and facilitate the generation of a VRC01-like antibody from its precursors. The scientists currently are performing research to identify these components.

"The discoveries we have made may overcome the limitations that have long stymied antibody-based HIV vaccine design," says Dr. Kwong.

The two research teams included NIAID scientists from the VRC, the Laboratory of Immunoregulation, and the Division of Clinical Research, all in Bethesda, Md.; as well as researchers from Beth Israel Deaconess Medical Center in Boston; Columbia University in New York; Harvard Medical School and Harvard School of Public Health in Boston; The Rockefeller University in New York City; and University of Washington in Seattle.

http://www.niaid.nih.gov/news/newsreleases/2010/Pages/HIVantibodies.aspx