German researchers report case of 'functional cure' after very early HIV treatment

Man with HIV has remained off treatment for 9 years without viral rebound

Keith Alcorn
Published: 02 July 2013
Prof. Dr. med. Jan van Lunzen of the University Medical Center Hamburg-Eppendorf

Another case of prolonged control of HIV replication after stopping treatment was reported on Tuesday at the 7th International AIDS Society conference (IAS 2013), indicating that cases of post-treatment control of HIV are not confined to the French VISCONTI cohort.

The report is likely to be joined by others in months to come after the organisers of the VISCONTI cohort appealed today for researchers worldwide to join them in identifying people with HIV who are able to control viral replication at undetectable levels after stopping treatment – so-called 'functional cures'. The cases are described as 'functional' cures because although HIV is not eliminated from the body, it is failing to replicate, a condition also described as 'remission' by many researchers.

...although HIV is not eliminated from the body, it is failing to replicate, a condition also described as 'remission'.

The case involves a 67-year-old German man who probably acquired HIV in the summer of 1999 through sexual transmission. At the time of diagnosis he tested positive for HIV antibodies on an ELISA test and tested positive for several HIV protein bands on a Western blot test, an indication of very recent infection.

At the time of diagnosis he had a viral load above 1 million copies/ml and a CD4 cell count just below 500 cells/mm3.

He initiated antiretroviral therapy with AZT, 3TC and efavirenz just under three months after exposure to HIV and within one month of confirmed seroconversion, after an acute viral illness.

His viral load was suppressed below the limit of detection very quickly and he experienced only two small rebounds in viral load above 10 copies/ml, around two years after starting treatment and 140 weeks into his course of treatment. Throughout this period his CD4 cell count remained stable in the range 900 to 1000 cells/mm3.

In 2004, the patient chose to undergo a treatment interruption, at which time he experienced a small viral rebound (above 10 copies/ml but below 100 copies/ml) before regaining viral control within three months of stopping treatment. HIV has remained undetectable ever since and he shows no evidence of HIV DNA in peripheral blood mononuclear cells (PBMCs), nor any evidence of HIV RNA (indicating viral replication) in cerebrospinal fluid.

Use of an ultra-sensitive assay capable of detecting viral load as low as 1 copy/ml failed to detect any HIV RNA. A viral co-culture DNA-PCR was similarly unable to detect any HIV DNA.

The patient’s immunological and virological characteristics were examined in detail. These were compared to HIV-negative patients and nine so-called “elite controllers” – people with HIV who maintain a normal CD4 cell count and low viral load without the need for antiretroviral therapy.

In contrast to some other reported cases of HIV control after stopping treatment – described as 'remission' by some researchers, and as a functional cure by others – the case study reported today shows evidence of strong and broad CD8 T-cell responses and strong proliferative CD4 T-cell responses.

Analysis of the CCR5 co-receptor showed that the homozygous CCR5 promoter A59029G was present but no delta 32 deletion was present – a characteristic associated with slower HIV disease progression. The HLA-I subtype was A 01, 02 B:44, 52.

Neither HIV RNA nor p-24 antigen was detected in gut tissue.

ELISPOT showed a strong polyfunctional CD8 cell response against both gag and nef epitopes as well as polyfunctional HIV-specific response and a normal distribution of effector memory T-cells and central memory T-cells. These were comparable to elite controllers.

The frequency of peripheral Treg and Th17 cells was similar to those observed in HIV-negative individuals and elite controllers.

Nevertheless, HIV was recovered in the laboratory using a humanised mouse model after transplantation of the patient’s purified CD4 T-cells and anti-CD3/CD28 stimulation. This indicated the presence of HIV capable of replication.

What is the value of case reports of functional cures?

It is likely that other cases of remission or functional cure exist in patient populations all over the world, but it is unclear what proportion of people who start treatment very soon after infection and subsequently stop treatment retain long-term control over viral replication without medication.

Earlier this year, French researchers estimated that as many as one-in-seven people who start treatment in primary infection might be able to retain control over HIV after stopping treatment. This estimate was based on the results of the French VISCONTI cohort study which reviewed the outcomes of patients who had begun treatment very soon after primary infection and then stopped at some point.

However, there are no other data from cohort studies to support this estimate and French researchers are seeking collaborators in other countries to build a larger international cohort of patients for long-term follow-up.

Reference

van Lunzen J et al. Functional cure after long-term HAART initiated during early HIV infection: a comprehensive case study. Seventh International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, abstract TUPE246, Kuala Lumpur, 2013.

View the abstract on the IAS conference website.

NAM’s IAS 2013 bulletins have been made possible thanks to support from Bristol-Myers Squibb. NAM's wider conference news reporting services have been supported by Boehringer Ingelheim and Janssen.