Everything from Cause to Cure

Research presented at the biannual International AIDS Society Conference ran the gamut from early HIV infection to the search for a cure

By Daisy Ouya and Kristen Jill Kresge

With the theme “From Cause to Cure,” the 5th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention, which was held from July 19-22 in Cape Town, South Africa, brought together more than 7,500 delegates to discuss a range of questions regarding everything from the earliest events of HIV infection to how best to eradicate HIV from an infected individual. Françoise Barré-Sinoussi, co-recipient of the Nobel Prize for the discovery of HIV, spoke at the opening ceremony and cited two main challenges plaguing researchers. “One challenge we have is to develop a vaccine, another is to have a cure for AIDS,” she said.

Researchers continue to focus on developing new biological interventions to prevent the spread of HIV, including a vaccine, as well as implementing those already available, such as adult male circumcision. There was also a chorus of support for sustaining and increasing the availability of antiretroviral therapy (ART) and initiating treatment earlier in the course of HIV infection, both to save lives and prevent new infections from occurring (see VAX July 2009 Spotlightarticle, Test and Treat on Trial).

These themes are not new, but in the midst of a global economic crisis that threatens the sustainability of HIV/AIDS funding, the need to continue battling HIV through both treatment and prevention seemed an even more pervasive message. “HIV is not in recession,” emphasized Barré-Sinoussi. Stephen Lewis, co-director of AIDS-Free World, noted that HIV/AIDS programs have objectively strengthened health care systems, and he warned that a reduction in funding could “derail the gains” in preventing and treating HIV in poor countries.

When to start

The approach to treating HIV has changed dramatically over the past 25 years. There are now more than 30 licensed antiretrovirals (ARVs), and combination regimens of these drugs, which work remarkably well at controlling the virus. Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases, said that now a newly HIV-infected 20-year-old who receives appropriate treatment has a life expectancy of at least 69 years. “The results are striking, historic, and to some degree unprecedented,” Fauci said.

Over time, the way ARVs are administered has also changed. Early on, researchers thought the best approach was to treat an HIV-infected individual as early as possible. However, clinicians eventually became concerned about the toxicity of ARVs, as well as their cost, and tended to delay initiation of therapy until a person’s health began to decline. Also, because the availability of ARVs was severely limited in developing countries, guidelines were devised so that therapy was not administered until a person developed AIDS.

Now, evidence is accumulating that suggests starting therapy much earlier in the course of HIV infection may be beneficial, leading many researchers to call into question current treatment guidelines. “Everything seems to point toward earlier therapy,” said Fauci. This was a recurrent theme at the conference but was tempered by warnings about potential drug shortages in some countries that could jeopardize access to therapy, even for individuals already on treatment.

Earlier initiation of therapy may be beneficial because HIV can wreak havoc even when the immune system is effectively keeping the virus in check. Following HIV infection, it typically takes 8-10 years before a person’s immune system becomes exhausted by the virus and weakened to the point that a person develops AIDS. It was long thought that during this period when the immune system is battling the virus, HAART was not necessary. But researchers are now finding that the decade following infection is not benign. HIV continues to reproduce or replicate during this time, and the body’s immune system is chronically activated. This induces “inflammatory changes that are associated with an increased risk of mortality,” according to Wafaa El-Sadr, a professor in the department of epidemiology at Columbia University. “HIV is much more toxic than any drug you can throw at it,” said Julio Montaner, president of IAS.

El-Sadr presented data from the SMART study, conducted at more than 300 clinical research centers in 33 countries, which compared the clinical outcomes of nearly 5,500 HIV-infected individuals who were randomized to start ART early in the course of their infections, or later, when their levels of critical infection-fighting CD4+ T cells fell below 250 in a microliter of blood. The clinical definition of AIDS is when an HIV-infected person’s CD4+ T-cell level reaches 200. The study aimed to maximize the benefits of ART, while minimizing its risks, which can include serious adverse effects such as renal failure, heart disease, and cancers. The results of the SMART study showed that later initiation of therapy increased an individual’s risk of serious AIDS- and non-AIDS-related events.

Another study presented at the conference provided additional evidence that starting therapy earlier can improve clinical outcomes. The study, known as CIPRA HT 001, involved 816 HIV-infected adults in Haiti with CD4+ T-cell levels between 200 and 350. Half of the participants were randomly selected to start treatment within two weeks of enrollment, while the remaining volunteers did not receive ART until their CD4+ T-cell counts dropped below 200, in accordance with the current treatment guidelines set by the World Health Organization. At an interim review, the study’s data safety monitoring board (DSMB) found that early treatment improved survival rates—nearly four times as many volunteers who started therapy later had died compared to those who started earlier. Twice as many people in the group that received delayed therapy also had developed tuberculosis during the study. Based on these findings, the DSMB recommended the trial be stopped and that all volunteers be offered ART.

Together these studies suggest that perhaps the current treatment guidelines need to be reconsidered. If the CD4+ T-cell threshold is raised, many more people would need ART, dramatically increasing global treatment costs. But others argue earlier therapy is still a cost-effective strategy. “It doesn’t actually cost more money,” said Fauci, “it’s twice as expensive to care for people who don’t start early.”

As researchers reconsider the optimal time to begin therapy, there is also an ongoing push to expand availability of ARVs to help stem the spread of the virus. Although there is little clinical evidence, many researchers suggest that expanding access to therapy and initiating it as early as possible can be an effective prevention strategy. HAART lowers the amount of virus circulating in an infected individual, making it less likely they could transmit HIV to others. “HAART is an essential tool to curb the growth of the pandemic,” said Montaner, who called HIV therapy a “cost-averting intervention even in a fiscally challenging environment.”

The status of HIV prevention

Ronald Gray, professor in population and family planning at Johns Hopkins University, gave a thought-provoking plenary talk on the state of biomedical prevention. He pointed out that out of 29 trials evaluating the efficacy of different biomedical interventions, only four had shown significant success (three evaluating adult male circumcision and the other evaluating treatment of sexually transmitted infections to reduce HIV risk). Five showed possible harm. As such, Gray challenged the prevention community to urgently improve the design of clinical trials and to do a better job of screening candidates and strategies so that fewer large-scale trials, which are difficult and expensive, are conducted.

He challenged the microbicide field to improve preclinical testing of candidates. Citing Thomas Huxley’s famous quote, “The greatest tragedy of science is the slaying of a beautiful hypothesis by an ugly fact,” Gray suggested that researchers reassess the hypothesis that treating sexually transmitted infections such as herpes simplex virus-2 could lower the risk of HIV infection after multiple clinical trials have shown otherwise.

Gray also spoke about vaccine research and questioned the validity of current lab assays that are used in clinical trials to measure people’s immune responses to vaccine candidates. As for future work, he suggested that a priority for vaccine researchers should be exploring candidates that would act quickly at the mucosal surfaces, the most common entry point for HIV.

Fauci pointed out that vaccine researchers have already started focusing more on understanding the basic immunology of HIV and are using this to design improved vaccine candidates. And although the field is moving more toward basic research, Fauci said, “It’s not going to slow things down, I think it’s [actually] going to speed things up.”

Implementing circumcision

Ever since adult male circumcision (AMC) was shown to reduce a man’s risk of HIV infection, public health officials and researchers have been working to devise the best way to quickly offer this surgical procedure in regions where HIV infection rates are high and circumcision rates are low. Kawango Agot, of the Universities of Nairobi, Illinois, and Manitoba Project, gave an overview of progress on this front in the Kisumu district of Kenya. Since the Kenya National Voluntary Male Circumcision Program was initiated in November 2008, around 30,000 males have been circumcised through the public system, largely with support from donor agencies. One obstacle to implementing circumcision programs was the lack of trained medical professionals. In June, Kenya revised its health regulations to allow nurses to conduct the surgical procedure, and Agot’s group has found that after training and supervision, adverse events following AMC did not differ if the procedure was performed by nurses.

Working with sero-discordant couples in Kampala, Uganda, in which the man is HIV uninfected, Kenneth Mugwanya and co-workers at Case Western Reserve University School of Medicine found a high level of knowledge among men about the ability of AMC to reduce HIV infection risk. But only 50% of the men were interested in having the procedure. In the Dominican Republic, where only about 5% of adult men are circumcised, Maximo Brito of the University of Illinois in Chicago and colleagues found that after attending information sessions, about two-thirds of a study group of 368 Dominican and Haitian men were willing to undergo the surgical procedure.

It is still unknown whether AMC reduces rates of HIV infection in men who have sex with men (MSM), but Tim Lane of the University of California in San Francisco presented data from a study in Soweto, South Africa, showing that uncircumcised MSM had 4.5 times higher HIV infection rates than their circumcised counterparts. Lane said that about 40% of men in the Soweto cohort also had sexual relations with women. Therefore, “reducing the risk of HIV among MSM could benefit entire communities,” he said. Lane called for further research to assess the acceptability of an AMC trial for HIV prevention among MSM.

Daisy Ouya, contributing writer, is Program Manager, Information, Education, and 
Communication at IAVI in Nairobi, Kenya.