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Photo: CDC/ Hsi Liu, Ph.D., MBA; James Gathany The US Department of Health and Human Services (HHS) announced last week a partnership with pharmaceutical company AstraZeneca for the research and development (R&D) of antibiotics. Through its Biomedical Advanced Research and Development Authority (BARDA), HHS will invest an initial US$50 million and up to $170 million into the project over five years. BARDA and AstraZeneca will meet annually to update their portfolio of drug candidates, determining which projects to initiate, continue, or terminate. The first project will be the advanced development and, ideally, regulatory approval of a treatment comprised of two existing antibiotics—Aztreonam and Avibactam—which is currently undergoing phase 2 clinical trials. The partners will also test new and existing antibiotics for use against diseases considered to be leading bioterrorism threats. Last Tuesday, US President Barack Obama nominated Dr. Robert Califf to lead the US Food and Drug Administration (FDA), where he has been serving as deputy commissioner for medical products and tobacco since January. Califf is a cardiologist and researcher, and previously served as the director of the Duke Translational Medicine Institute—which advances R&D by facilitating cross-sector partnerships—and as founding director of the Duke Clinical Research Institute. If confirmed by the Senate, Califf will succeed Dr. Stephen Ostroff who has served as acting commissioner since former Commissioner Dr. Margaret Hamburg announced her resignation in February. After joining the FDA in January, Califf announced that streamlining the clinical trial process would be a major focus during his tenure. A new analysis in the Guttmacher Policy Review calls for increased US investment in multipurpose prevention technologies (MPTs)—products that protect against multiple risks, including unintended pregnancy, HIV and AIDS, and other sexually transmitted infections (STIs). There is currently only one MPT in phase 3 clinical trials—a female condom that prevents pregnancy, HIV and AIDS, and four STIs—as well as nine in phase 1 trials, and thirteen in preclinical development. Among these MPTs are female condoms and vaginal rings, gels, films, nanofibers, and tablets. As MPTs are primarily intended for use in low-resource settings, private-sector interest has remained low. Additional, non-financial barriers to MPT R&D include scientific and regulatory hurdles: most MPTs have two or more active ingredients, and could thus be subject to review by as many as three divisions within the FDA. The report notes that the US government is already the biggest funder of MPT R&D, accounting for 89 percent of the $6.5 million invested in MPTs in 2013. New Delhi, India, is currently experiencing the worst outbreak of dengue fever it has seen since 2010, with nearly 1,900 confirmed cases this year. All four of the known strains of dengue virus are present in India, however, new evidence from the All India Institute of Medical Science (AIIMS) suggests that a fifth, previously undetected strain of the dengue virus, may be partially to blame for the severity of this year’s outbreak. Recovery from dengue fever provides lifetime immunity against the specific strain, however, the introduction of a new strain would leave the entire population vulnerable. AIIMS recorded the potential new strain after testing an initial fifty samples from recent dengue patients and is working with the Indian Ministry of Health and Family Welfare to collect and test more samples before coming to a conclusion.

Female condoms. Photo: PATH/Patrick McKernTake a stroll through any pharmacy and you’ll see shelves stacked with male condoms of many varieties, but look for a female condom and you aren't likely to find one for sale. Though first introduced more than 20 years ago, female condoms are remain an unknown or inaccessible option for many women. But thanks to the efforts of dedicated product developers, public health professionals, and female condom advocates, that’s changing, as a slew of new female condom products are emerging and expanding the market. Today, in celebration of Global Female Condom Day, we look back at the history of the female condom and look ahead at what’s next for this female-initiated prevention tool.A game changing product with a slow start When the first female condom—known as the FC1—was introduced on the US market in 1993 by Wisconsin Pharmaceuticals (now the Female Health Company), it was hailed as a game-changer in sexual health. It checked off all the requirements for what product developers had heard women wanted—it had comparable effectiveness to male condoms, it could be inserted prior to sex allowing for less disruptive love-making, it was less physically restrictive for male partners, and most importantly, it was female-initiated. FC2 female condom. Photo: Female Health Company In spite of these advantages, the female condom never really caught on among American consumers. Many women were hesitant to try it because of its unfamiliar size and shape—it is larger than a male condom and doesn’t come neatly rolled up in a small package. Among those women who did try a female condom, many found it was difficult to insert and uncomfortable or noisy during sex. The FC1 was also many times more expensive than a male condom, which deterred some women and couples from trying it out.While the product received a tepid reception in the United States, women’s health and rights groups in middle- and low-income countries—where rates of unplanned pregnancy and STIs/HIV are alarmingly high and women may have few options to negotiate protection—saw the female condom as an important new tool to save women’s lives. Pilot introduction programs took off in countries including Brazil, Ghana, South Africa, and Zimbabwe. In response, the Female Health Company optimized the product, changing the material from polyurethane to nitrile to reduce production costs, and introduced the world to FC1’s successor—you guessed it: the FC2. In 2007, the FC2 was prequalified by the World Health Organization (WHO) making it eligible for bulk procurement. Today, the FC2 is available in 144 nations. Expanding choice in the female condom market Cupid Female Condom. Photo: Female Condom Market IntelligenceSpurred by increased advocacy to expand options for female-initiated prevention, researchers and product developers went to work on new female condom designs. In recent years, consumers have begun to see the fruits of this labor, as several new female condoms, each with different design variations, have emerged on the market. In 2012, the Cupid female condom—which uses a foam sponge on one end rather than a ring to provide stability—joined the FC2 as the second female condom to receive WHO prequalification.The female condom market is on the cusp of further diversification, as additional female condoms are awaiting WHO prequalification decision or soon to be submitted for review. Phoenurse female condom. Photo: Female Condom Market Intelligence Each of these options offers a different approach to addressing the drawbacks of the FC1. For example, the Air female condom contains an air bubble to help keep the product stable during sex, while the Phoenurse comes packaged with an insertion stick for optional use when inserting the product. The Velvet condom is similar to the FC2 design but made of natural rubber latex, while the VA w.o.w, like the Cupid, contains a sponge for internal stability, but instead has a rounded triangular outer ring to keep it secure.Another second generation female condom in early introduction is the Woman’s Condom, developed by GHTC member PATH. As a nonprofit product developer focused on user-centered design, PATH set out in the late 1990s to create a female condom that would be easy to use and comfortable for both partners. The product development team began by examining acceptability studies of existing female condoms and hosting focus groups with men and woman in several countries to better understand what users wanted from a product. Their design objectives became clear: “create a product that would be easy to handle, easy to insert, stay stable in the vagina during sex…[and] provide good sensation for both the male and female partner,” explained Maggie Kilbourne-Brook, program officer at PATH, adding “and if possible, users wanted it be more aesthetically pleasing.” The Women's Condom. Photo: PATH/Glenn Austin  PATH developed and tested more than 50 prototypes before freezing design development. To increase the ease of insertion, the Women’s Condom’ main pouch is compressed into a narrow, rounded capsule which women insert like a tampon. Within 30-60 seconds, this capsule dissolves, allowing the condom to expand within the vagina. To provide stability, four small foam pieces are used which adhere gently to the interior of the vagina. And unlike other female condoms, the Woman’s Condom is not pre-lubricated; instead it is packaged with separate lubricant users can apply following insertion.New designs under development The Origami Condom. Photo: Female Condom Market IntelligenceAs these aforementioned female condoms are introduced and vie for market share, additional female condoms are advancing through the research and development (R&D) process. Next to market will likely be the Origami Condom, which is moving into phase 2 clinical trials. The Origami female condom is quite a dramatic reimagining of the female condom. It’s a conical shaped device that is folded during insertion and expands like an accordion during sex. It’s made of a durable, flexible silicon material designed for wash and reuse. The Bill & Melinda Gates Foundation is also giving a boost to female condom development. Last year as part of its initiative to develop “next generation condoms,” the Gates Foundation announced grant funding for three early-stage female condom development projects. Researchers from Indiana University received funding to advance their “female pleasure condom” which has ribbed siding to increase stimulation and enhance sexual experience, while another grantee is developing an “air-infused female condom” that is “inflated and positioned using air pressure” to enable easier and quicker insertion. The third grant recipient is approaching the insertion challenge in an entirely different way, designing a sliding, easy to use, re-usable applicator for female condoms that works like a tampon applicator.The many challenges of female condom development and access  A woman demonstrates use of a female condom at a community meeting in Kenya. Photo: PATH/Eric Becker Studies have shown that including female condoms in condom promotion programs leads to increased levels of protected sex, meaning certain men and women are using female condoms in circumstances where male condoms would have otherwise not been used. And qualitative studies have found that having female condoms available as an option can help some women negotiate condom use with their partners. “It can shift the conversation,” explains Kilbourne-Brook, “It’s not male condom or nothing—it’s male condom, female condom, or nothing.” Even though female condoms deliver improved health outcomes, they are still a challenging value proposition for global procurers who purchase over 90 percent of female condoms. While prices are expected to drop as new products come to market and production volumes increase, female condoms will always cost more because of their design. Today, at bulk procurement prices, a buyer can purchase roughly 17 male condoms for the price of one FC2 female condom. And the fact that demand is so driven by price-sensitive bulk procurers changes the nature of the market, discouraging developers and manufacturers from investing in R&D to enhance consumer-experience or spending on marketing to increase appeal. Instead, it encourages companies to focus on developing the lowest cost product possible that meets the health need.Developers hoping to bring a new female condom into the US market also face an additional hurdle. Because female condoms were a new product category at the time the FC1 underwent regulatory review, the US Food and Drug Administration (FDA) decided to regulate female condoms as Class III medical devices—a classification typically reserved for higher risk medical products (male condoms are classified as Class II devices). Because Class III devices require more data and evidence for approval, it creates a more costly and lengthy process for developers. Most other regulatory authorities classify female condoms as Class II devices, and female condom advocates are calling on the FDA to down classify female condoms to pave the way for expanded choice. The path forward  Many advocates argue that for female condoms to make the leap from niche product to a staple in the bedroom worldwide, concerted marketing, education, and awareness campaigns are needed to demystify and destigmatize female condoms and boost their consumer appeal. To build momentum, Global Female Condom Day was launched in 2012 as an international day of action focused on increasing knowledge, availability, and use of female condoms. And this year, advocates will Dance4Demand to urge policymakers, donors, and health providers to increase their support for female condoms. While the female condom may have been slow to catch on, its supporters believe it can make such a leap. After all, many people forget that male condoms were at one point stigmatized as products used only by people engaged in morally questionable activity. It took a concerted effort from public health professionals, governments, and the private sector to bring them into the mainstream and make them the ubiquitous, widely-used product they are today. If the hopes of female advocates are realized, pharmacies everywhere may soon have to make some extra room on their shelves. ReferencesHoke TH, Feldblum PJ, Van Damme K, et al. Temporal trends in sexually transmitted infection prevalence and condom use following introduction of the female condom to Madagascar sex workers. International Journal of STD and AIDS. 2007; 18(7):461–466. Latka M, Gollub E, French P, Stein Z. Male-condom and female-condom use among women after counseling in risk-reduction hierarchy for STD prevention. Sexually Transmitted Diseases. 2000;27(8):431–437. Barbosa RM, Berquo E, Kalckmann S. Acceptability of the Female Condom in Different Social Contexts: Final Research Report. Brasilia, Brazil: Ministry of Health, Secretariat for Health Policies, National STD/AIDS Coordinating Office; 2000. Artz L, Macaluso M, Brill I, et al. Effectiveness of an intervention promoting the female condom to patients at sexually transmitted disease clinics. American Journal of Public Health. 2000;90(2):237–244. Macaluso M, Demand M, Artz L, et al. Female condom use among women at high risk of sexually transmitted disease. Family Planning Perspectives. 2000;32(3):138–144. Musaba E, Morrison CS, Sunkutu MR, Wong EL. Long-term use of the female condom among couples at high risk of human immunodeficiency virus infection in Zambia. Sexually Transmitted Diseases. 1998;25(5):260–264. Gollub EL, French P, Latka M, Rogers C, Stein Z. Achieving safer sex with choice: studying a woman’s sexual risk reduction hierarchy in an STD clinic. Journal of Women’s Health & Gender-Based Medicine. 2001;10(8):771–783.

New tools are needed to prevent HIV and AIDS, particularly among at-risk women. Photo: PATH/Gabe Bienczycki Sitting halfway around the world from my office in Washington, DC, looking out my Durban hotel window at the Indian Ocean, I am reminded just how small and interconnected our world really is. While home is a 24-hour journey from here, international travel is easy now. Like people, infectious diseases also move easily around the globe. As advocates gathered from across geographies, we are here in Durban to discuss research and development for new tools in the fight against HIV and AIDS. The excitement in our discussions is palpable as we think about where we have come in the HIV and AIDS epidemic to date, but also guarded as we look ahead to the daunting task of ending the epidemic forever. I traveled to Durban to participate in a partners meeting with the International Partnership for Microbicides (IPM). IPM, a GHTC member, is leading an exciting Phase III clinical trial program to determine if a new monthly vaginal ring it developed can prevent women from becoming infected with HIV and is safe for long-term use. The ring contains the antiretroviral (ARV) drug dapivirine, which is a new drug but part of the same class of ARVs currently in use for HIV and AIDS treatment. Initial efficacy results are expected as early next year. Dapivirine ring. Photo: IPM Throughout the meeting one thing became clear to me: we need new tools to combat the HIV and AIDS epidemic in South Africa, in Washington, DC, and everywhere in between. ARV treatment has helped save millions of lives. For the most part, people on treatment can live healthy and productive lives. That is, of course, if they have access to the medications they need, if they can take these medications daily, if they can keep regularly scheduled appointments with a health care provider, and perhaps most importantly, if they know they are infected in the first place. That’s a lot of ifs. What if we could prevent more infections in the first place? The new post-2015 development agenda about to be solidified by the United Nations later this month sets out to end the HIV and AIDS epidemic by 2030. This is a lofty goal that has policymakers and funders excited, but it should be regarded with caution as we look to the work that needs to be done. Truvada. Photo: CDC In the United States, the US Food and Drug Administration has approved the use of the ARV drug Truvada as a pre-exposure prophylaxis (known as PrEP) to prevent HIV infection among individuals who are determined to be at high risk for contracting HIV. PrEP is not yet approved for use in South Africa despite Truvada being an approved—and commonly used—drug for HIV and AIDS treatment. Why PrEP hasn’t been approved for use yet in South Africa is a complicated story, but unfortunately one that seems to haunt us in the global health advocacy community. All too often, we know what needs to be done to treat or prevent an infection, to save a mother’s life during childbirth, to keep a child alive during the most vulnerable early years of life, but politics keeps us from making progress. The stigma associated with HIV and AIDS is still real for women and men around the world. In the United States, it doesn’t help when we hear politicians talk about cutting funding for HIV and AIDS research because it doesn’t affect enough Americans anymore. Yes, we know how to treat people living with the disease, and yes, we know how to prevent mother-to-child HIV transmission, and yes, we even know how to prevent HIV infection in adults, but the reality is that politics are getting in the way. If we know how to save lives, it should not matter how policymakers personally feel about the way a disease is transmitted or the lifestyle of the populations most at risk for contracting a disease. Logic says that science should win this debate, but unfortunately, that is not the reality. To combat both the disease itself and a challenging global political environment, we need to keep our options open as we think about the tools we have and the tools that are needed to fight HIV and AIDS. We need to have an arsenal of tools that can be used safely and sometimes discretely by the people most at risk. IPM's monthly dapivirine ring has the potential to help women take more control over their health and reduce their risk. Too many women cannot negotiate the use of condoms (male or female) with their partners and therefore cannot be in control of their own HIV prevention. Developing and providing new options—like the dapivirine ring—that women could use as personal protection is essential. Further, we don’t just need to develop tools for the sake of new tools—we need to ensure that women and men have access to the most effective, affordable, and appropriate tools to address their health needs. I was fortunate to be able to accompany IPM and other partners on a visit to Qhakaza Mbokodo in Lady Smith, South Africa—one of the research clinics conducting IPM's Ring Study, which is one of two Phase III trials evaluating the ring. While there, I met an engaged and dedicated staff who have integrated themselves into a local community and really gotten to know the women who are participating in the trial. Women joined the trial voluntarily, many of them expressing an interest in helping to end a disease that is devastating their community or has killed a family member. They understand the potential risks associated with testing a new tool, and they know it might not be effective. But like me, as an advocate dedicated to preventing HIV, ending infectious disease epidemics, and empowering women to take control of their own health, they are all hopeful that the ring can be an effective tool to help us in the fight. We cannot end the HIV and AIDS epidemic with the current tools we have, and no one tool used alone—not PrEP, not the dapivirine ring, not condoms, not male circumcision—will get us to this goal. We need to have a comprehensive approach to the fight that involves both prevention and treatment. IPM's dapivirine ring program, regardless of the results, will teach us a lot about what works and what doesn’t. This is the way we must combat global health threats: with scientific rigor, with international partnership, and with robust investment in new tools. Erin Will Morton is GHTC’s Director

A new study suggests that with basic training, individuals can learn to accurately and safely test themselves for HIV and AIDS. Nearly 17,000 adult and adolescent citizens of urban Malawi were provided with testing kits, and within a year, more than three-fourths had self-tested. Across sub-Saharan Africa, only one-fourth of adults have recently been tested for HIV and AIDS, and only half of people living with HIV and AIDS know their status. The research team conducted repeat HIV and AIDS tests on 1,649 participants, and in 99.4 percent of cases, the results of self-testing proved accurate. The results also suggest that HIV and AIDS self-testing is culturally acceptable in urban Malawi and that pre- and post-test counselling was adequate, as no testing-related partner violence or suicides were reported. As the stigma surrounding HIV and AIDS remains a significant barrier to both testing and treatment, HIV and AIDS self-testing could be a game changer in curbing the epidemic. Photo: CDC/ James Stewart Researchers at the University of Queensland in Australia and the University of California, Berkeley have identified a protein—nonstructural protein 1 (NS1)—that may be the key to the dengue virus’ virulence. The virus infects nearly 400 million people each year, resulting in 22,000 deaths, primarily from fluid loss and damage to the blood vessels. The discovery dates back to the early 2000s, when a study in Thailand revealed a correlation between NS1 levels and the severity of the disease in patients. Further research demonstrated that NS1 attaches itself to another molecule which enables it to bind to blood vessel walls; NS1 also prompts the immune system to produce cytokines—proteins that weaken the blood vessels. Essentially, NS1 causes the immune system to react as it does to bacterial infections. These findings could pave the way for both a vaccine and a treatment against dengue fever. The team at Berkeley has demonstrated that NS1 could be used in a dengue vaccine, as the immune system readily detects NS1, rather than the dengue virus itself. In mice, NS1 provided protection against all four strains of the dengue virus, at rates of 60 to 100 percent efficacy. Furthermore, Dr. Paul Young of the University of Queensland believes that a drug for sepsis that is currently in clinical trials could be an effective treatment for dengue. The Drugs for Neglected Diseases initiative (DNDi) has completed phase I human clinical trials for SCYX-7158 (AN5568), a drug candidate with the “potential of becoming the first ever, oral-only, single-dose treatment” for human African trypanosomiasis (sleeping sickness), according to DNDi’s Dr. Antoine Tarral. The compound was identified by Anacor Pharmaceuticals, Inc. as part of DNDi’s lead optimization program, through which partners screened compounds from Anacor’s chemical library to identify those that combat sleeping sickness in a laboratory setting. The candidate was tested for safety and tolerability, as well as its effect on and interaction with the body, in 128 healthy volunteers. Due to the trials’ successful results, DNDi and partners will initiate phase 2 and 3 studies in 2016 in the Democratic Republic of the Congo. The leading treatment for sleeping sickness—also developed by DNDi—requires injections, and consequently skilled personnel; prior to the 2009 introduction of this therapy, the best option was an arsenic-based drug with extreme side effects.