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09 Oct 2018

Stigma, seroconversion and the search for an HIV cure.

This article first appeared on the HIV Cure website. 
By Dr Miranda Smith.

Reducing the persistent stigma and discrimination related to HIV infection drives clinician scientist Jintanat Ananworanich. Her research interests range from HIV infection in children to dissecting the very early stages of HIV infection in adults. We caught up with Dr Ananworanich while she was in Melbourne to deliver a public lecture at the Doherty Institute.

Lessons in acute HIV and social science

Acute HIV infection is a dynamic time as the virus and host immune system set the scene for what follows. Working with colleagues from the US Military HIV Research Program and the South East Asia Research Collaboration in HIV in Thailand, Dr Ananworanich has established world-leading clinical research studies to understand how and when HIV reservoirs form in early infection, and the potential strategies that could lead to HIV remission.

We asked Dr Ananworanich about the disappointment of the first treatment interruptions in people treated very early in their HIV infection, resulting in rapid virus rebound. “We had nothing to go by, except the VISCONTI patients and some other case reports. In those reports, it was said that because people have low reservoirs, that’s why they rebound later, and we had much lower reservoirs than in the VISCONTI [group]. So obviously we had hoped that people could control longer.” While the researchers didn’t promise a delayed rebound or defined outcome, Dr Ananworanich reflects on the impact of the results. “Humans have hope, and we had hope, and the participants had hope, and we were very disappointed. In a way not surprised, but still.”

Working with social scientist Professor Gail Henderson from the University of North Carolina has enriched the clinical study findings. Social science is now embedded in the research program. Dr Ananworanich reflects “this is really quite an experimental type of research and we’re doing something that is very different to standard of care… so, I really wanted to engage social scientists to ask ‘how can we do this better?’ or ‘are we doing everything we can to do this as best as possible?’ because it’s not without risk.” For Dr Ananworanich, the social research “has helped us tremendously, because, particularly with HIV cure research, we will be facing a lot of disappointments. You could say, ‘well, should we do it anymore because nothing seems to work’, but from the social science research, the participants are so optimistic and feel they have benefitted and they want more to be done.” The social science studies have brought participants’ wishes and preferences into focus, and have confirmed that the participants understand the risks. This shows that HIV cure research is ethical, and will help guide future trials. Dr Ananworanich has developed strong opinions on what type of social research is useful. She thinks the common ‘end of trial’ survey provides poor insight into people’s feelings at the moment of viral rebound or restarting treatment. Better awareness would come from social research done at the same time as clinical studies.

Community engagement and study recruitment

A current leading study in acute HIV is the RV254 cohort, which screens thousands of Thai participants each year for HIV. People screened and diagnosed with HIV start therapy within days. This group are carefully followed and potentially involved in further interventions to induce HIV remission.

Community engagement for RV254 encourages people to test for HIV earlier and more regularly. Media campaigns, celebrity endorsements and word of mouth have all been used to encourage testing. This simplifies the recruitment for HIV remission studies, because participants are drawn from the existing cohort. About 20% of people in the RV254 cohort are interested in being involved in additional HIV remission studies. Dr Ananworanich says “some people are just interested…and others don’t want to do it at all”. One of the biggest reasons people don’t want to participate is time, “because we follow them so frequently and it’s a big burden”.

One big limitation of the current cohort is the number of women involved. Just 14 of over 500 current participants are female. This is not because few women in Thailand have HIV, but because women come in for testing too late. Encouraging and normalising testing for HIV testing among women is a priority. As we have written before HIV can have different effects in women and men. Dr Ananworanich agrees that more needs to be done to understand these differences, “I do think there’s gender differences in every way – immunology, latency, and we would definitely like to look at that more.”

Treatment interruption

We asked Dr Ananworanich how they manage treatment interruptions. She explains that “most of our treatment interruption trials have been relatively short”. This is because researchers designed the trials to measure how long it takes for the viral load to reach 1000 copies per mL of plasma after treatment stops. In the Thai trials so far, people had detectable virus for just 4-7 days.

Dr Ananworanich explains that seroconversion is one of the biggest issues for treatment interruptions in people treated very early in HIV infection. Seroconversion is the development of detectable anti-HIV antibodies in blood, which occurs in the first weeks of HIV infection. These antibodies are detected in standard HIV tests. Some of the Thai cohort get treatment so early after infection that seroconversion doesn’t happen. Dr Ananworanich says “we’re more careful about that [seroconversion] and we tell people that they will definitely seroconvert if they come into the trial.” In Thailand, seroconversion can be life changing as HIV tests are needed for many jobs and opportunities.

There are also concerns about transmissibility during treatment interruption. Data from Thailand shows that plasma viraemia often correlates with low but detectable viraemia in genital secretions. As the Thai trials start to involve longer treatment interruptions, Pre-Exposure Prophylaxis (PrEP) will be offered to participants. This is an important step to minimise transmission risks, but it won’t work for everyone. As Dr Ananworanich explains, “it’s not perfect because only about 30-40% [of the cohort] have a regular partner, and then out of those, maybe half have told their partner, so even if you’re going to provide PrEP you might reach 20%, maybe 15-20%”. The solution at this stage is to be clear about the transmission risks of treatment interruption during participant selection. Dr Ananworanich says the risk of transmission is a definite worry. Researchers have to state clearly “you will be risking your sexual partner…are you certain you can use condoms for the entire period? If you’re not, then you shouldn’t come in”.

What about the kids?

Dr Ananworanich sees children as a unique population providing a huge incentive to develop an HIV cure. Dr Ananworanich says “it’s harder to treat HIV in children, they have higher viral loads and the drug regimens are not as good”. A current study is tracking every baby born in Thailand to mothers with HIV, getting those babies on treatment as soon as possible. Despite the challenges of treating HIV in babies and children, she sees this population as providing a unique opportunity. Dr Ananworanich says “we have such an opportunity to intervene so fast, faster than in adults… because even in the Fiebig I acutes, who are treated so early, they are already 10-14 days after infection, but in children, we could have hours.” Ananworanich says “HIV treatment for children is so hard, but for HIV cure research we have such an ample opportunity to do something different compared to adults. Even if you don’t help a child go into remission, if you can change the immune response development, the reservoir, if you can change any of these parameters and help them have better outcomes… that would be great.”

Adding cure to the mix

HIV treatment is so good, with simple dosing and effective HIV control, that it raises the bar for any cure or remission intervention. HIV treatment and the game-changing U=U declaration are powerful, but they don’t solve everything. Dr Ananworanich points out that “even with long acting ART you will never reduce the reservoir, you will never reduce the immune activation that much, and your immune system is not going to be normal”. She notes that HIV cure research is in its infancy; “we’re in the discovery phase, HIV cure research [at this stage] is not for everyone, it’s for the motivated few”.

Ananworanich sees efforts to drive HIV into remission as a necessary addition to the anti-HIV toolbox. “To me, HIV cure research is not necessarily replacing ART, but it’s finding something in addition that could make ART better or could make the whole treatment and prevention field better” “I cannot say what it will look like in the future, but the discovery towards a cure will help everyone, it will help make therapy better, it could help prevention because a lot of people are not reached.”

To combat stigma, Dr Ananworanich sees even HIV remission as a huge advance. “HIV is still a very stigmatised disease. I think that even if we don’t get eradication, but we get a remission, the idea that this is now a disease that can now be controlled… I think this would help people have more hope and also for society to look at HIV in a different way”. While it’s difficult to know what an HIV cure or remission might look like, Dr Ananworanich is optimistic. She concludes “this field is full of surprises”. Let’s see where it takes us.

The RV254 trial in person

Here’s a short video of Jinanat Ananworanich talking about the Thai RV254 trial: