Accurate HIV incidence estimates are critical to the success of prevention trials
The key to winning the classic American game show The Price is Right is to come as close as possible to guessing the actual retail cost of a revolving platform piled high with luxury goods, without overbidding. Contestants automatically lose if they overestimate the dollar value. HIV researchers, much like these game-show contestants, are now learning that when it comes to estimating HIV incidence rates—the number of people who are newly infected with the virus over a period of time—there can be serious consequences to guessing too high.
"If you underestimate, that's OK. You just don't want to overestimate," says Zeda Rosenberg, chief executive officer of the International Partnership for Microbicides (IPM), a non-profit microbicide research and advocacy group. Recently two HIV prevention trials of microbicides were stopped prematurely because the observed incidence rate during the trial was so much lower than anticipated that the data safety monitoring board (DSMB; see VAX June 2007 Primer onUnderstanding Data Safety Monitoring Boards) determined it would be impossible to conclusively show if the intervention was effective or not.
These events, along with trends showing that HIV incidence is declining in many countries, has made many trial sponsors and funding agencies sensitive to the accuracy of HIV incidence estimates. Accurate incidence data are necessary for HIV prevention trials (see Primer, this issue). "In order to undertake an AIDS vaccine trial, you need to know the incidence," says Omu Anzala of the Kenyan AIDS Vaccine Initiative (KAVI) in Nairobi.
But accurately determining HIV incidence can be difficult because of the substantial lag time, typically about 10 years, between when a person is first infected and when they develop symptoms of the disease. Consequently many people are unaware of their status until long after they become infected. There are also several logistical challenges to determining incidence rates—many of the quicker methods that have been developed do not work universally and cohort studies where researchers follow a group of uninfected individuals over time, periodically testing them for HIV infection, are expensive and time consuming. Still, most researchers agree that conducting cohort studies to estimate incidence is critical and also offer many peripheral benefits. "The feasibility studies to determine true HIV incidence are extremely important," says Gita Ramjee of the Medical Research Council in South Africa. "They allow you to build capacity so that your Phase III trials are successful."
A handful of countries around the world have aggressively monitored HIV incidence for many years as a way to track their own epidemic's progress. Most often incidence data is reported from antenatal clinics because almost all pregnant women in many countries are tested for HIV infection so that health officials can protect their infants. But this data fails to capture HIV incidence in other groups that are considered at higher risk of HIV infection, including injection drug users (IDUs), men who have sex with men (MSM), and commercial-sex workers.
Thailand, a country lauded for its early and progressive response to HIV/AIDS, began a national surveillance program in 1984 and has been determining annual incidence rates ever since. Early on in the epidemic there was also a national effort in Thailand to determine new cases of HIV infection among particularly high-risk groups. This allowed Thai officials to detect the first wave of the epidemic in these individuals, says Supachai Rerks-Ngarm, a principal investigator at the Thai Ministry of Public Health. "Knowing what the real situation was like was the most important thing we could do to solve the problem," he says. This led to the requirement that all of the country's sex workers use condoms to limit the spread of HIV.
In Uganda, another place where early HIV prevention efforts are credited with stunting an exploding HIV/AIDS epidemic, public health officials started collecting HIV incidence data in 1989. From 1990 until around 2000, the HIV incidence in the general population hovered around 1%, says Anatoli Kamali of the Medical Research Council in Entebbe, Uganda. "This is good, reliable data on incidence," he adds. This low incidence level, compared to other African countries, was attributed to the government's endorsement of the ABC approach (abstinence, be faithful, use condoms). But since 2000 there seems to be a slight increase in HIV incidence within the general population, according to Kamali.
In many other countries there is very little current data on HIV incidence. Throughout Asia, for example, reliable HIV incidence data are scarce. Recently India revised its estimates on the number of HIV-infected people in the country based on declines in HIV prevalence among commercial sex workers and within the general population in some of the southern regions of the country (see Global News, this issue). Although there is very limited incidence data in India, the Joint United Nations Programme on HIV/AIDS concludes that based on the revised prevalence data, there is probably also a decline in incidence rates.
Even in South Africa, home to the world's largest HIV/AIDS epidemic, incidence data is limited. In 2005 researchers from the Human Sciences Research Council determined incidence rates in 16,000 South Africans and projected that the total number of new infections during the year was 571,000. The highest incidence rate of 5.6% was observed in women between the ages of 20 and 29. But the method used to collect this national incidence data, known as the BED assay, tends to drastically overestimate HIV incidence in African populations (see Primer, this issue). Salim Karim, director of the Centre for the AIDS Programme of Research in South Africa, therefore warns that the results from this study should be "regarded as tentative."
Beware of falling incidence
Another complicating factor is that HIV incidence can change rapidly, often declining due to effective prevention campaigns, the recent proliferation of HIV/AIDS treatment programs, and more accurate methods of assessment.
Thailand once had one of the most rapidly expanding epidemics in the world, but now HIV incidence seems to have trailed off outside high-risk groups. When the first AIDS vaccine efficacy trial with the AIDSVAX candidate was conducted in Thailand, the HIV incidence during the trial was 3.4%. In preparation for that Phase III efficacy trial, cohort studies had shown incidence rates as high as 6%. Since the completion of the trial HIV incidence in Thailand has dropped even further.
When the US Centers for Disease Control and Prevention started a Phase III trial in Thailand to test the efficacy of antiretroviral pre-exposure prophylaxis (see VAX May 2006 Spotlight article, Treatment as prevention) for blocking HIV transmission, they enrolled only IDUs because of a higher incidence rate in these individuals. Still this trial is only based on an expected 2% annual incidence.
The ongoing Phase III AIDS vaccine trial, which is evaluating the efficacy of a combination of Sanofi Pasteur's canarypox candidate and AIDSVAX, is also being conducted in Thailand. Rerks-Ngarm reports that among the volunteers at his sites the incidence is low but still within the statistical limits of the study.
The right cohort
Even as the HIV incidence rates drop in many areas, there are still a staggeringly high number of new HIV infections occurring globally—last year alone 4.3 million people were newly infected. Researchers are now considering conducting AIDS vaccine trials in sub-groups of individuals where HIV transmission rates tend to still be very high. "You can go anywhere and if you find the right populations, you can have a high enough incidence," says Karim. But the problem with working exclusively in high-risk populations is first identifying them and then working to recruit and retain them in long-term studies. Many research groups are gaining experience in these areas by conducting prospective incidence studies in high-risk volunteers in preparation for AIDS vaccine efficacy trials.
Kamali and others in several African countries are now working with cohorts of HIV discordant couples, where one partner is HIV infected and the other is not. In Uganda, Kamali's group in cooperation with IAVI has established a cohort of about 500 discordant couples and has observed an incidence rate of around 4%, nearly four times that seen in the general population. Susan Allen, an HIV/AIDS researcher from Emory University in Atlanta, was one of the pioneers of working with discordant couples. At sites affiliated with her program, the Zambia Emory HIV Research Project, the transmission rates among discordant couples ranges between 6% and 9% even with access to counseling and the best-available behavioral interventions.
"We are not just watching people get infected," says Kamali. "We are giving them everything that is available for HIV prevention and even with that comprehensive package we still observe, unfortunately, a high HIV incidence."
Anzala, in collaboration with IAVI, is conducting an HIV incidence study in Kangemi, Kenya involving 701 individuals, including discordant couples and commercial sex workers. Both this cohort and Kamali's discordant couple cohort will be participating in the upcoming Phase IIb AIDS vaccine trial known as PAVE 100. This trial will evaluate the safety and preliminary efficacy of the combination of DNA and adenovirus serotype 5 (Ad5) vaccine candidates developed by the Vaccine Research Center at the National Institutes of Allergy and Infectious Diseases.
Other groups including the US Military HIV Research Program are conducting incidence studies in preparation for AIDS vaccine trials. According to Rosenberg, IPM also plans to conduct incidence studies before starting efficacy trials with microbicide candidates in women at high risk of HIV infection.
In South Africa, where the largest number of HIV-infected individuals live, the HIV prevalence and incidence are generally so high that it is often unnecessary to recruit only high-risk volunteers. "I'm not saying that all the work should be done in South Africa, but you put out the fire where the fire is raging," says Ramjee.
Another advantage of conducting large cohort studies to determine HIV incidence is that they replicate the conditions of a clinical trial, where individuals are receiving regular counseling, education on their risk behaviors and HIV prevention, and have access to condoms. Other methods that have been designed to estimate incidence fail to do this (see Primer, this issue). "They look at incidence in populations that are not exposed to behavioral interventions, which could, and likely will, lower HIV incidence," says Matt Price, clinical program manager at IAVI.
Often the HIV incidence will be even lower among volunteers in an HIV prevention study than in the general population. "Every time you start working in a community the incidence drops," says Anzala. "The traditional way [cohort studies] of looking at incidence lets you decide if it is really a suitable community for doing a vaccine trial," says Anzala.
Conducting incidence studies prior to a clinical trial also provides an opportunity for researchers to cultivate relationships with the community members and leaders, start educational programs that will aid enrollment in future trials, and help establish both the infrastructure and technical know-how among people working at the clinical trial site. The importance of these factors can not be underestimated, according to Ramjee. "There's no point undertaking a clinical trial in an area where you have no community support," she says.
There is also valuable social science research that can be conducted during incidence studies. Researchers can study sexual behaviors and what is putting individuals most at risk for HIV infection, as well as pregnancy rates among female volunteers that can help determine condom use. "Invariably you obtain a lot of scientific data," says Kamali.