ADVANCES IN THE TREATMENT OF HIV

ADVANCES IN THE TREATMENT OF HIV…

HIV OVERVIEW:

The outlook for people living with HIV has significantly improved over the past two decades. Many people who are HIV-positive can now live much longer, healthier lives when regularly taking antiretroviral treatment.

Life expectancy for people living with HIV and receiving treatment increased significantly from 1996 on. There is ongoing development of antiretroviral drugs. This has resulted in a highly effective HIV treatment regimen.

The survival rate for HIV-positive people has also dramatically improved since the first days of the HIV epidemic.

A CURE FOR HIV – HOW WOULD WE KNOW?

HIV hides in reservoir cells in the body and can remain silent as long as a patient takes antiretroviral therapy. As soon as a patient stops taking ARTs, the reservoir virus wakes up. The virus starts replicating all around the body again.

Currently there is the need for lifelong treatment of HIV with antiretroviral therapy (ART). The associated costs, adverse events, and stigma encourage a global scientific effort to find a cure. There are many interventions currently being assessed. The assesment is both in animal models and clinical trials.

HOW CAN SCIENTISTS REALLY KNOW THAT SOMEONE IS CURED?

In The Lancet HIV, Ravindra Kumar Gupta and colleagues describe follow-up with extensive tissue and blood sampling of an individual (referred to as the London patient). This case was originally reported 12 months ago.

The London patient is a man living with HIV. He was diagnosed with Hodgkin disease. He received a stem-cell transplant. The transplant came from a donor who carried a mutation in the CCR5 gene (CCR5∆32/∆32). CCR5 is a key receptor for most strains of HIV. Therefore, T cells or macrophages that do not express CCR5 are protected from infection. The protection is from strains of HIV that use this receptor.

After transplantation and cessation of ART, Gupta and colleagues report that the London patient’s plasma HIV RNA has remained undetectable for 30 months.

This period is indeed a very long time to remain aviraemic off ART. Particularly, considering the median time to viral rebound after cessation of ART, is 2–3 weeks. The investigators also assessed semen and cerebrospinal fluid, and samples of gut, lymph node, and rectal tissue. Low levels of HIV DNA were found in lymph node tissue and in blood CD4+ T cells. Furthermore all other samples were negative for HIV DNA.

THE SIGNIFICANCE OF THIS

Importantly, the low levels of HIV DNA found, were not intact. This is consistent with archived viral fragments that cannot replicate. Finally, Gupta and colleagues developed a mathematical model to predict the chance of viral rebound after stopping ART. The model is based on the number of infected cells (the size of the reservoir) and the number of susceptible target cells.

The London patient had greater than 90% Chimerism in circulating T cells. The researchers concluded that the chance of future viral rebound while off ART is negligible. In other words this is one of the major advances in the treatment of HIV. Is the London patient really cured? We will only know after prolonged follow-up and tissue sampling.

NO INTACT VIRUS v NO DETECTABLE VIRUS

There is one difficulty in quantifying a persistent virus in an individual on ART. It is that the ability to detect an infected cell depends on the total number of cells tested. This has an upper limit, particularly when sampling tissue sites. A second individual (Timothy Brown, sometimes referred to as the Berlin patient) received a stem-cell transplant. The transplant was from a CCR5∆32/∆32 donor. Timothy Brown has been off ART for more than 13 years with undetectable plasma HIV RNA. This patient also had extensive blood and tissue sampling to find infected cells. Almost all samples were virus free. However, some blood samples contained traces of HIV. In addition one sample from rectal tissue had traces of HIV. At the time of testing, this finding was thought to represent low-level contamination of the assay.

We now know that most viruses that persist on ART’s are defective and unable to replicate. In addition we are able to better quantify intact and defective virus with either near full-length sequencing or PCR-based assays.

Therefore, no intact virus might be a better definition of a cure for HIV, than no detectable virus.

WHAT DOES THIS MEAN IN THE EFFORTS TO DEFINE A CURE?

Could this be a helpful strategy to fine tune a cure? Previous work has suggested that less HIV antigen means less stimulation of antibody production. A lower frequency of infected cells on ART is associated with lower concentration and avidity of anti-HIV antibodies.

In both the London patient and Timothy Brown, detection of antibodies to HIV proteins diminished after transplantation. In addition they gradually declined over time, but the antibodies still persisted.

A key question now for the area of HIV cure is how soon can one know if someone has been cured of HIV? To answer this requires prolonged clinical observation and follow-up. In addition the answer requires regular testing of plasma HIV RNA. The next question is – is a reduction and eventual cessation in testing possible?  This is true if, over time, the chance of viral rebound becomes less likely? Reduced frequency of monitoring for disease relapse over time is a common practise in follow-up of many malignant diseases.

However, the duration and frequency of follow-up in such as setting is based on very large cohorts with a deep understanding of the natural history of the specific malignant disease. We will need more than a handful of patients cured of HIV to really understand the duration of follow-up needed and the likelihood of an unexpected late rebound in virus replication.

CONCLUSION

The finding of no intact virus in both blood and tissue can be reassuring for a patient. Such a patient may face great anxiety and uncertainty about whether and when viral rebound off ART might occur. This, in other settings has been completely unpredictable. Hence this qualifies as one of the most significant advances in the treatment of HIV.

Is the London patient truly cured? This, in light of the many cells sampled, and the absence of any intact virus. The additional data provided in this follow-up case report is certainly exciting. In addition it is encouraging but, in the end, only time will tell.

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