- Category: Search for a Cure
- Published on Tuesday, 02 July 2013 00:00
- Written by Keith Alcorn
Another case of prolonged control of HIV replication after stopping treatment was reported on this week at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013), indicating that cases of post-treatment control of HIV are not confined to the French VISCONTI cohort.
This report is likely to be joined by others in months to come after the organizers 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.
The new 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 positive for several HIV protein bands on a Western blot test, an indication of very recent infection.
At that time 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 zidovudine (AZT), lamivudine (3TC), and efavirenz just under 3 months after exposure to HIV and within 1 month of confirmed seroconversion, after an acute viral illness.
The man's viral load was suppressed below the limit of detection very quickly, and he experienced only 2 small rebounds in viral load above 10 copies/mL, around 2 years after starting treatment and 140 weeks into his course of therapy. 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 but below 100 copies/mL) before regaining viral control within 3 months of stopping treatment.
His 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 test was similarly unable to detect any HIV DNA. Neither HIV RNA nor p24 antigen was detected in gut tissue.
The patient’s immunological and virological characteristics were examined in detail. These were compared to HIV negative patients and 9 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 Tuesday 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 -- a characteristic associated with slower HIV disease progression. The HLA-I subtype was A 01, 02 B:44, 52.
ELISPOT showed a strong poly-functional CD8 cell response against both HIV gag and nef epitopes, as well as poly-functional HIV-specific response and a normal distribution of effector memory and central memory T-cells. These were comparable to those seen in elite controllers. The frequency of peripheral T-reg and Th17 cells was similar to those observed in HIV negative individuals and elite controllers.
Nevertheless, HIV could be recovered in the laboratory using a humanized 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 antiretroviral treatment very soon after infection and subsequently stop therapy retain long-term control over viral replication without medication.
Earlier this year, French researchers estimated that as many as 1 in 7 people who start treatment during 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 the French researchers are seeking collaborators in other countries to build a larger international cohort of patients for long-term follow-up.
J van Lunzen J et al. Functional cure after long-term HAART initiated during early HIV infection: a comprehensive case study. 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2013). Kuala Lumpur, June 30-July 3, 2013. Abstract TUPE246.