Setting a Scientific Agenda for a House on Fire
AIDS Prevention Research Moves Ahead in Russia
By Emily Bass
There’s nothing eye-catching about the 8 Plus Clinic. No shingle outside gives away the building’s identity; the sole identifier is a small, colorful sign tucked behind the bars that cover all the windows. A muddy yard separates the one-story building from Gazovaya street in St Petersburg, and an improvised stepping stone pathway offers minimal protection from the slippery surface, which is particularly treacherous in late April when the long winter begins to thaw.
But as modest as it looks on the outside, the clinic is a landmark in the Russian AIDS landscape. The clinic—a project of the Biomedical Center, a non-profit research institute led by molecular biologist Andrei Kozlov—is conducting Russia’s first prospective incidence study of HIV in intravenous drug users (IDUs). For over a year, the clinic, which is named for the number of required study visits, has tracked the spread of the virus which infects more than 30% of St Petersburg’s IDUs. It has also established itself as a trusted source of voluntary counseling and testing, harm reduction and basic medical care to IDUs, who
generally risk being reported to the authorities, or arrested, each time they seek treatment.
They also face stigma in the general population: St Petersburg residents were so unwilling to have a clinic serving IDUs in their backyards that “it took us a year just to find a building,” says project coordinator Alla Shaboltas.
Inside the small building, Kozlov, Shaboltas and her team are on the frontlines of an exploding epidemic. Since 1998, the number of reported HIV infections has doubled each year—a frightening, exponential growth curve. Similar crises are building in neighboring countries, including Ukraine (which has the highest prevalence of any European country), Belarus and, more recently, Kazakhstan. Today, there are 230,000 documented cases of HIV in Russia—and the actual number is estimated at 800,000-1.5 million. The face of the epidemic is young: 60% of all infections are in 21-40 year olds. Recent data show that increasing numbers of women are being infected, and that rates of heterosexual transmission are on the rise (see box). These trends are indices of an ominous trajectory: an epidemic spreading from high-risk groups to the general population. “Recently we attended parliamentary hearings where the Russian authorities all started their speeches by saying, “Attention, attention, we are on the edge of a terrible disaster. Our house is on fire,” says Eduard Karamov, an outspoken virologist at Moscow’s Ivanovski Institute for Virology. “I said, Calm down, sit back, the fire started many years ago.’’
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Russia's Health Crisis
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Russia is not without resources to combat this new plague. Despite the Perestroika-era brain-drain which emptied entire labs, the country has retained a cadre of highly-trained research and medical professionals. It also possesses a well-established regulatory system for approving trials and products, and internal capacity to manufacture pharmaceuticals and vaccines
(see sidebar). Marshalling these resources into projects like the 8 Plus clinic could benefit Russia—and the world. IDU cohorts are a rarity in most countries with injection-driven epidemics, as are models for IDU-friendly services.
Unfortunately, the clinic is the exception rather than the rule. By all accounts, Russia’s steps to combat the epidemic have been ineffective, hampered by underfunding and lack of political support for rapid, innovative interventions in high risk groups like IDUs and sex workers. President Vladimir Putin has yet to make a public statement calling for a rapid response to the epidemic. Complicating matters, AIDS must compete for attention with other diseases, including hepatitis, multi-drug resistant tuberculosis, alcoholism and heart disease, which have run rampant since the disintegration of Soviet-era medical services.
The lack of political will has financial and policy implications: the country’s annual AIDS budget of US$5.5 million is primarily used for mandatory HIV testing. Active IDUs are ineligible for treatment for HIV or common co-infections such as hepatitis or TB, and drug-replacement programs which swap methadone or buprinorphen for injected drugs are illegal. The HIV care that does exist is handled by centralized Federal AIDS Centers. In the major urban centers of Moscow and St Petersburg, these centers each provide antiretroviral therapy (ART) to fewer than 2,000 people; in the more remote areas, state-of-the-art therapy is simply unheard of.
Against this bleak backdrop there are scattered points of light, mostly in the form of research sites and NGO-initiated projects. International funding supports most, if not all, of the targeted efforts to respond to the Russian epidemic—from needle exchange clinics to prison-based prevention programs. The 8 Plus Clinic is no exception. The project is supported by the the Biomedical Center (which receives both international and domestic funding) and the HIV Prevention Trials Network (HPTN), partnering with the University of North Carolina. Too small to make a dent, too necessary to be abandoned, these projects beg the question of what internationally-funded AIDS research can accomplish in the absence of political will to create programs for the most affected groups—and what the cost will be if the world fails to find out.
Growing research activity
The question of whether or not research can play a catalytic role in an AIDS response is not unique to Russia. But unlike many other regions of the world where AIDS is spreading unchecked, Russia’s pre-existing infrastructure provides a solid foundation for initiating interventions. Several groups are already building on this foundation, including London’s Imperial College, Johns Hopkins University, Yale University and the University of North Carolina. Russia has also received roughly $12 million from the US Biotechnology Engagement Program (BTEP), which aims to convert bioweapons capacity into public health-related research. A small portion of this—less than $1 million—is earmarked for AIDS vaccine research and development, which is underway at a handful of sites, including the Biomedical Center.
Jonathan Weber (Imperial College, London) is a co-investigator on a Moscow-based study of the long-term impact of short-course ART treatment during acute infection; he hopes to launch a microbicide trial in the Urals. Weber says that his experience with protocol approval, site development and staffing have been uniformly positive. Based on this infrastructure, “Russia is an ideal place to do clinical trials,” he says.
Russia has also landed on the international radar screen as a potential site for efficacy trials of AIDS vaccines. One compelling reason: with the exception of Thailand, almost no countries with IDU epidemics have taken steps to develop cohorts or conduct research with these groups. With its mix of sexual and IDU transmission, Russia’s epidemic would also make it possible to evaluate whether and how candidate vaccines protect against intravenous compared to sexual exposure (see IAVI Report, May-Jun 2002, p.6). Another key point: for reasons that are still poorly understood, the clade A strain that has spread like wildfire in Russia shows astonishingly little genetic diversity, with an average of just 3% difference among viral isolates from far-flung regions of the country. It’s a situation that “eliminates one of the variables [viral diversity] from a vaccine trial,” says molecular epidemiologist Francine McCutchan (Henry M. Jackson Foundation, Rockville, Maryland).
In fact, Russian scientists were advocating for AIDS vaccine research before the country’s own epidemic exploded. Biomedical Center head Andrei Kozlov, virologist Eduard Karamov, and Igor Sidorovich from Moscow’s Institute of Immunology were among those scientists who began lobbying for state-funded AIDS vaccine research in the late 1980s, when the first handful of AIDS cases appeared in Russia. Their call for action drew on the country’s deep roots in vaccine production: in its heyday the Soviet Union was a colossus in the vaccine field, manufacturing 1/3 of the global supply of smallpox vaccine used in the eradication campaign, and producing a wide array of human and veterinary vaccines for its sprawling empire.
In spite of this history, Russian officials did not warm to the call. “The logic was like this. First: An AIDS vaccine is impossible. Second: It’s unnecessary, because there is no AIDS problem in Russia. Third: Who are you going to give it to? Do you want to defend the gays and prostitutes?” recalls Sidorovich, a key member of the team which developed the Russian AIDS ELISA diagnostic in the late 1980s. (The diagnostic had to be field-tested in Uganda, because of the low HIV incidence in Russia at the time.)
Ultimately, the scientists won a half-victory. Since 1997 a Ministry of Science and Technologies program to develop new vaccines and diagnostics has included a funding stream for AIDS vaccine development. Originally, the AIDS vaccine development effort were centrally coordinated by the Biomedical Center. Since 2001 it has consisted of three independent teams—each of which received roughly $200,000 in 2003. One, based at a former bioweapons facility in Novosibirsk, focuses on vector-based strategies, including salmonella constructs. The Biomedical Center is developing a DNA vaccine, and a group at Moscow’s Russian Institute of Immunology (led by Igor Sidorovich and including Eduard Karamov) is developing a recombinant vaccine using the team’s novel adjuvant, polyoxidonium (PO), which is widely used in a licensed Russian flu vaccine.
The decision to split the program into three separate efforts may make it harder for each groups to assemble all of the elements needed to bring a candidate to trial. Missing pieces at one or more of the sites include access to non-human primate facilities and GLP-compliant vivariums for small animal studies. Where improvements are being made, it is with foreign dollars--for example, BTEP funding is helping to renovate the current vivarium at the Biomedical Center. In spite of these obstacles, the teams project a symbolic readiness—a best effort under difficult circumstances, designed to show their government, and the world, that there is AIDS vaccine research capacity in Russia.
Stumbling blocks and successes for trials
The combination of passionate local scientists and foreign dollars is promising—but there are still major hurdles to building a comprehensive AIDS research agenda. On a scientific level, one of the biggest stumbling blocks is the lack of sound epidemiological data about the crisis. “There is no history of cohort research in Russia,’ says Shaboltas.
In keeping with Soviet-era approaches, Russia has favored massive, mandatory-testing campaigns over targeted HIV surveillance. Since 1987 Russia has conducted over 200 million HIV tests—an average of 24 million a year—in a relatively random selection of the population, including job applicants, pregnant women, and hospital admittances. Given the many disincentives for IDUs to seek testing, this sampling method may not grasp prevalence in this group, nor can it provide accurate incidence data.
The ongoing HPTN trial at the 8 Plus Clinic will nail down some of this information. After screening nearly 1,000 IDUs—30% of whom proved to be already infected—the clinic is following 520 HIV-negative IDUs for 12 months, with biannual HIV tests. After six months the trial has achieved a retention rate of over 80%. While this is too low for vaccine efficacy trials, which last two to three years, it is a strong start with a population often perceived as difficult to engage in trials. The study’s community advisory board even includes former IDUs—a radical step for the Russian research world.
So far, the study’s findings confirm the catastrophic state of the epidemic. Unofficial interim data analyses show an HIV incidence rate of about 3%. Rough figures also show that the median age is 24 years; over 60% have secondary education; 40% are employed full time; 62% live with their parents; 11% own a home.
Another cohort initiative is underway in Moscow, where epidemiologists Chris Beyrer, Julie Stachowiak (Johns Hopkins University) and the NGO AIDSInfoshare (which Stachowiak co-founded) are building a sex worker cohort. After a series of thwarted attempts to engage the Moscow health system, Beyrer and Stachowski decided to train sex workers and AIDSInfoshare staff (many of whom have medical training) as lay epidemiologists. They have completed a qualitative phase and plan to launch a 500-woman cohort in late 2003.
Once cohorts are formed there are other hurdles, such as laws that constrain provision of treatment (including ART and hepatitis medications) to active drug users and other marginalized groups. The 8 Plus Clinic has had to walk a fine line between complying with state regulations and addressing volunteers’ well-founded fears about the legal repercussions of seeking care. In the ongoing trial, for example, volunteers are known solely by their numerical identifiers. Doctors never learn their patients’ names—and so are unable to report individuals’ HIV status or drug-use to the authorities.
These regulations also curtail the treatment that can be provided by research sites. Russia maintains a centralized surveillance and treatment system for diseases such as hepatitis B and C, which are endemic among drug users. As with HIV treatment, active drug users are ineligible for subsidized care, which is often minimal. 8 Plus project physician Natalya Khaldeeva would like to treat her patients—nearly all of whom have hepatitis B or C—and the site’s funds might be able to pay for it, but this offering is not feasible under current laws. The laws constraining treatment of active IDUs would also complicate large-scale vaccine trials, given the growing international consensus that volunteers who become infected should have access to ART. But, Beyrer says, research could help leverage change. “These trials are a long way off. We should proceed with all due speed. If it turned out that the law was the primary obstacle, then Russia might look at ways to deal with it,” he says.
A lack of central coordination
Perhaps the greatest unknown is whether research findings will affect government policies. Without state implementation of key findings, research projects will only impact a fraction of the population. Until recently there was no government monitoring to learn about successful interventions or to identify the optimal use of international dollars flowing into research and programs. In June the government formed an AIDS Advisory Council to provide this guidance, but it remains to be seen whether this council will make policy recommendations which counter the existing government positions.
Observers are cautiously optimistic. The advisory council is “a very positive sign,” says Pedro Chequer, head of the UNAIDS program in Russia, adding that “It looks like the country is being divided between international donors, without government coordination.”
As small as it is, the domestic AIDS vaccine effort has already suffered from the historic lack of coordination. The program has no provision for media outreach or public education, or for site preparedness activities. For now scientists shoulder these roles—with mixed results. In 2002, when the Moscow team from the state-funded AIDS vaccine development program submitted a trial application (which is still pending) for its candidate, team scientist Irina Nikolaeva wrote a press release. Neverthe-less, the media carried erroneous reports that Russia had discovered an AIDS vaccine.
To address this, the WHO-UNAIDS HIV/AIDS Vaccine Initiative has proposed consensus-building activities to the major Russian stakeholders. A plan has yet to emerge—a delay which may reflect the fact that the different teams work, by all accounts, more or less independently of one another.
On the positive side, public statements by Vadim Pokrovksi, the head of Russia’s Federal AIDS Centers, led to a recent flurry of media attention; Russian scientists also report growing support from individual politicians. Regionally, there is a growing AIDS activist movement, which recently held a summit on treatment access in Minsk.
Whether these elements will coalesce into a comprehensive response remains to be seen. “If we look at the democracy which has emerged in Russia, it’s good for people and even better for viruses,” says Igor Sidorovich. “Perestroika led to the destruction of state systems, which are only now being rebuilt. Let’s hope Russia is open not only to infection but to valuable technology and ideas. This is why our team has remained here. We hope we survive.”