Test and Treat on Trial

A strategy to implement universal HIV testing and immediate treatment is receiving increased attention and scrutiny from prevention researchers

By Regina McEnery

Highly active antiretroviral therapy (HAART) is remarkably effective at controlling viral replication and reducing viral load to below the limits of detection by standard assays. And because viral load is considered to be the principal predictor of heterosexual HIV transmission, scientists have postulated that widespread distribution of antiretrovirals (ARVs) among HIV-infected individuals, in addition to decreasing morbidity and mortality, might also reduce HIV incidence (1,2).

Despite years of research, new biomedical HIV prevention strategies—apart from adult male circumcision—have not materialized. “With no vaccine or microbicide on the horizon, we need to look at other approaches,” said Sarah Fidler of Imperial College, in a talk at the 5th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention, held from July 19-22 in Cape Town, South Africa. One approach that is receiving increased attention and scrutiny from researchers is test and treat, which calls for universal testing and immediate treatment for anyone found to be HIV infected.

The move toward earlier treatment of HIV-infected individuals was a major theme at the recent IAS meeting, and test and treat also received considerable attention (see Everything from Cause to Cure). IAS President Julio Montaner says researchers have been confident for several years that ARVs, if appropriately employed, provide a dual benefit. “Number one, they decrease morbidity and mortality rates among HIV-infected [individuals],” he says. “In addition, adequately treated people become, at the very least, less likely to transmit HIV. So if you treat a larger number of people, the impact on the epidemic could be significant.”

But despite endorsements from some researchers and mathematical models showing that this strategy could possibly even eliminate HIV in 50 years, there is little evidence to suggest test and treat is feasible. Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases (NIAID), cautions that this approach “may not work.” Speaking at the IAS conference, Fauci said, “We need to address that before we can promote it.” NIAID and others are now studying test and treat, including how much of an effect ARVs will have on reducing HIV transmission and the feasibility of implementing universal HIV testing.

“We need to determine these things factually or we’ll be in trouble,” says Myron Cohen, director of the Institute for Global Health and Infectious Diseases at the University of North Carolina, who is also studying test and treat.

Even if shown to work, there are numerous logistical and financial obstacles to implementing this strategy. Achieving universal testing is a considerable challenge, not to mention the cost of providing treatment to all infected individuals despite their disease status. Current guidelines for initiating treatment vary by country and circumstance. The World Health Organization (WHO) recommends that treatment be initiated when a person develops AIDS (as defined by having fewer than 200 CD4+ T cells in a microliter of blood) or an AIDS-related illness. Many developing countries adopt WHO guidelines in determining when an HIV-infected individual should begin therapy, but the IAS as well as leading government health agencies in the US and Europe have adopted 350 CD4+ T cells as the threshold for treatment based on accumulating evidence that suggests that earlier treatment is beneficial. An analysis of 18 HIV cohort studies concluded that the benchmark of 350 CD4+ T cells should be the minimum threshold for initiating therapy because deferring treatment was associated with higher rates of AIDS and death (3). And a recent study from the US and Canada found mortality rates declined even further if HIV-infected individuals started therapy when their CD4+ T-cell counts were between 350 and 500 (4).

Based on the current treatment guidelines, only about a third of people who need therapy are receiving it. “Why are you even thinking of test and treat if you can’t get all infected people [who need treatment now] on antiretroviral therapy?” Fauci asked at the IAS conference. He then answered his own question by saying these are complementary issues that need to be addressed at the same time.

The model

The mathematical model that sparked much of the current discussion regarding the viability of test and treat was developed by a quintet of researchers from the WHO (5). The authors of this study used South Africa to model a generalized HIV epidemic and predicted that by testing all adolescents and adults at least 15 years of age annually and providing ARVs immediately to those who are found to be infected, HIV incidence would drop from slightly more than 1% a year to .05% a year, effectively ending the epidemic within 50 years. The authors suggested that the epidemic would end because no new infections would occur and those already HIV infected would eventually die. The WHO researchers also plugged actual figures from Malawi into the South Africa model because the data from Malawi’s ARV treatment program is considered to be the most reliable, according to Brian Williams, a member of the WHO team who developed this model.

The WHO model is based on the assumptions that all HIV transmission is heterosexual, that 95% of the population receiving ARVs is compliant to therapy, and that access to second-line HAART regimens would be available. The modelers also assumed that the period of acute or primary infection, when viral load is highest and the risk of HIV transmission considered greatest, lasts only about two months, and contributes to only 10% of HIV transmissions.

“Their assumptions about the effect of this strategy are highly optimistic,” wrote David Wilson, an AIDS researcher at the University of New South Wales in Sydney, in a commentary three months after the model was published (6). “They assume that ARV therapy reduces infectiousness by 99%,” Wilson wrote. “This level of reduction is unlikely.”

Williams, who is now with the South African Centre for Epidemiological Modeling and Analysis, says the volume of emails and press coverage that the Lancet study generated exceeded anything he had experienced before. Many researchers raised questions about the assumptions made in the model. The WHO researchers acknowledge that better data on test and treat is needed, and they hope studies are done to determine if the approach is feasible. “The real obstacles are political, not scientific,” says Williams. “If you don’t have the political will it won’t work.”

Number of People Receiving Antiretroviral Therapy in Low- and Middle-Income Countries. Substantial progress has been made in expanding the availability of antiretroviral (ARV) treatment in low- and middle-income countries. An estimated 3.8 million to 4.3 million people were receiving ARVs by the end of 2008, according to data presented at the 2009 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. Sub-Saharan Africa, which has the highest number of HIV-infected people, accounts for about 75% of those on treatment and represents the most dramatic increase in ARV access over the past six years, which has been largely funded by foreign aid such as the US-funded President's Emergency Plan for AIDS Relief and the Global Fund to Fight AIDS, Tuberculosis and Malaria. Source: Reuben Granich.

Other researchers who have modeled test and treat have reached less rosy predictions, yet their analyses still suggest the strategy could help reduce HIV incidence. Based on a model developed by Montaner and colleagues from the British Columbia Centre for Excellence in HIV/AIDS, expanding access to HAART in British Columbia—where only about 50% of those medically eligible are receiving HAART—would decrease the number of new HIV infections by up to 60% over the next 25 years (7).

Rochelle Walensky, an associate professor of medicine at Harvard Medical School, used mathematical modeling to measure the impact test and treat could have in Washington, D.C. The US capital has the highest HIV prevalence in the country—an estimated 3% of the half-million residents are HIV infected. In a poster presented at the IAS conference, Walensky concluded that a test and treat strategy could potentially decrease the number of new HIV infections there by as much as 30% over the next five years.

Walensky’s model, which used data from a hospital-based treatment center in Washington, D.C., assumed adherence to both testing and treatment would be lower than in the WHO model. “Not everyone will be offered a test, not everybody will accept it, not everybody will be linked to care, not everyone will start ARVs, and not everyone, once they are on ARVs, will remain adherent,” says Walensky.

Walensky says the WHO model was intended to shake things up and push researchers to “think outside the box” at a time when effective prevention strategies are not being developed as fast as the AIDS community would like. “What I worry about is people who read the results and think we are going to easily clear the epidemic, when the model is only theoretical,” she says. “It’s not that this strategy does not hold great promise, but we need to keep expectations realistic.”

Determining feasibility

Several researchers are now trying to determine the feasibility of a test and treat strategy. NIAID, along with the US Centers for Disease Control and Prevention (CDC), is developing and sponsoring pilot studies that address the feasibility of universal HIV testing and explore which voluntary counseling and testing strategies work best in specific high-risk populations. HIV transmission risk is highest during the acute stage of HIV infection, so testing strategies would need to target individuals at greatest risk.

But getting high-risk individuals to undergo routine testing has proven difficult, even in countries where treatment is accessible and routine testing is recommended. A recent CDC analysis of 34 US states found 38% of individuals progressed to AIDS within a year after their HIV diagnosis, underscoring the failure to identify HIV-infected individuals soon after they became infected. And the WHO estimates that nearly 80% of HIV-infected adults in sub-Saharan Africa do not know whether they are infected.

Researchers say the reasons people fail to get tested regularly, if at all, varies based on the risk group and geographical region. “One of the critical epidemics [in the US] is among gay men,” says Steven Deeks, who co-directs the population and clinical science core at the GIVI Center for AIDS Research at the University of California in San Francisco. “There is easy access to testing and effective therapies yet they are not getting tested. The typical patient we see, with newly diagnosed HIV, has very advanced disease.”

The transition from testing to treatment would also occur more smoothly if HIV-infected individuals could access ARVs at the same facility where they are tested. However, this is often not the case. Fauci noted in a recent commentary that individuals frequently are diagnosed in settings apart from those where they ultimately receive treatment, and significant barriers impede the efficient movement from diagnosis to care, including lack of health insurance and denial of HIV status (8).

Assessing Compliance 

Adherence to therapy is one factor essential for the test and treat strategy to work, and researchers will need to study whether starting antiretroviral therapy sooner has any impact on long-term compliance rates. David Bangsberg, a Harvard Medical School researcher, and his colleague Norma Ware helped develop a model for adherence to antiretrovirals (ARVs) in Nigeria, Tanzania, and Uganda that incorporated more than 400 one-on-one interviews and field observations to explain high adherence rates in areas of extreme poverty (9).

“The reason people adhere so well, we believe, is because they start their ARVs during late-stage disease when they are bed-bound,” says Bangsberg. “On ARVs, they become strong and healthy again and become an economic resource rather than an economic drain. Doctors call it the Lazarus effect.” It remains to be seen, says Bangsberg, whether adherence would remain high if treatment was initiated before an individual becomes ill.

Researchers will also need to look more closely at patterns of drug resistance and transmission of drug-resistant viruses among HIV-infected individuals who aren’t compliant to therapy. —RM


Complexities of transmission

Scientists assessing the feasibility of test and treat will first have to measure how effective ARVs are in actually preventing transmission. Research from the Rakai Health Science Program (formerly the Rakai Project) in Uganda established nearly a decade ago that viral load is the chief predictor of the risk of heterosexual transmission of HIV and that transmission is rare among persons with less than 1,500 copies of HIV RNA per milliliter of blood (10). However, viral load in blood may not always correlate with viral load in semen, and HIV transmission can still occur even if an individual is on suppressive therapy (see Canvassing CROI, IAVI Report, Jan.-Feb. 2009).

“I love mathematical modeling,” says Cohen, “but the [WHO] model in question is driven by assumptions that if we test everybody, treat everybody, and the therapy works well, it will prevent transmission. It’s a far cry from having absolute veracity.”

Cohen is leading a trial in Africa, Asia, and Latin America that is looking at whether earlier initiation of ARVs can actually reduce the risk of heterosexual HIV transmission. The study will compare HIV transmission rates among serodiscordant couples based on whether the HIV-infected partner starts ARV therapy early or only when their CD4+ T-cell count drops to between 200 and 250. Plans are to enroll 1,750 couples in the seven-year study.

More research will also be necessary to study the relationship between the stage of HIV infection and the likelihood of transmission, as this has implications for the effect ARVs will have on transmission rates. There is scant clinical data showing what percentage of HIV infections actually get transmitted during the acute stage of infection, though it is thought to be high. A study of 235 heterosexual serodiscordant couples conducted by the Rakai Health Science Program found that the rate of transmission per coital act was highest during early-stage infection. The researchers found that among 23 heterosexual couples where the index partner became infected following enrollment in the study, 43% or 10 of the 23 HIV-infected individuals transmitted the virus to their monogamous partners approximately 2.5 months after their seroconversion. The rate of transmission decreased to 15% for the period of six to 15 months following seroconversion of the index partner, and declined even further to 3% between 31 and 40 months later. Rates of transmission increased again during late-stage infection, with 37% or 19 of 51 transmitted infections occurring during the six to 35 months before death (11).

The financial burden

Even if the science holds up, test and treat would still be extremely expensive to implement. At the IAS conference, much attention was focused on the sustainability of global HIV treatment programs given the current economic crisis. The Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Bank reported in July that some international treatment programs are facing drug shortages, resulting in interruptions in treatment after the global recession prompted some public and private donors to reduce their funding. And, in many countries, availability of second-line drug regimens is limited and often prohibitively expensive. This has some researchers wondering where additional money for implementing test and treat would come from.

UNAIDS estimates that US$25 billion will be required to achieve universal access to HIV treatment, prevention, care, and support in low- and middle-income countries by 2010, including $7 billion for provision of treatment based on the current treatment guidelines.

AIDS Funding. A snapshot of the increase in AIDS funding from different sources over the past five years. Source: Stefano Bertozzi

While the WHO researchers who developed the test and treat model suggest that implementing the strategy would require substantially more money in the short term—about $3.5 billion a year in South Africa and $85 billion total—the financial burden would be alleviated as the number of new infections started to decline. “I think test and treat is absolutely doable,” says Williams. But others are not as confident. “The proponents of this [test and treat] strategy are not being realistic and could do a lot of harm to treatment programs if there is a competition for resources,” says Ron Gray, a professor of population and family planning at the Johns Hopkins Center for Global Health.

Kristen Jill Kresge contributed reporting to this article.

1. Lancet 370, 1923, 2007 
2. N. Engl. J. Med. 342, 921, 2000
3. Lancet 373, 1352, 2009
4.N. Engl. J. Med. 360, 1815, 2009
5. Lancet 373, 48, 2009
6. Lancet 373, 1077, 2009
7. J. Infect. Dis. 198, 59, 2008
8. JAMA 301, 2380, 2009
9. PLoS Med. 6, e1000011, 2009
10. N. Engl. J. Med. 342, 921, 2000
11. J. Infect. Dis. 191, 1403, 2005