Designing Clinical Trials for HIV Eradication
This report is part of a series of focused summaries from the “5th International Workshop on HIV Persistence, Reservoirs & Eradication Strategies” held in St Maarten, December 6-9, 2011. This presentation was given by Doctor Daniel R. Kuritzkes from the Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA.
Doctor Kuritzkes first mentioned that although a number of promising approaches have led to testable hypotheses for an HIV cure, for which small animal and primate models may provide preliminary information, ultimately proof of concept and validation studies in human subjects will be required.
He identified 4 main questions to be answered:
- Can intensification suppress residual production?
- Is there functionally important decay of the reservoir?
- Can strategies aimed at reactivating latently infected cells decrease viral burden?
- Can combination approaches lead to drug-free control of HIV (functional cure)?
… and 4 possible goals :
- Radical (sterilizing) cure?
- Functional cure?
- Reduction (elimination) of residual viremia?
- Reduction (elimination) of the viral reservoir in specific compartments?
One of the major aspects that Doctor Kuritzkes discussed was the nature of end-points to be used in clinical trials of HIV eradication:
- Is there evidence of biological activity on proposed target or based on proposed mechanism?
- Is there a quantitative effect on viral reservoir?
- Residual plasma viremia?
- Proviral DNA in PBMC?
- Proviral DNA in tissue compartments (which one[s])?
- Cell/tissue-associated viral RNA?
- Do we have to check for the absence of viremia during analytic treatment interruption (ATI)?
Concerning the analysis of tissue compartments, he listed:
- Genital tract
Regarding the need for ATI, he presented Pros and Cons:
- Rigorous test of functional cure
- Suitable for qualitative or quantitative analysis
- Rebound versus no rebound
- Time to 1st positive viral load?
- Time to set point?
- Set point at new steady state?
- Risk of primary infection syndrome
- Risk of OI, CV events, death (SMART)
- Risk of transmission
Doctor Kuritzkes then addressed the issue of what kind of patients do we have to include first in eradication trials:
- Patients on suppressive ART
- Initial versus subsequent regimens?
- Highly treatment-experienced?
- Patients with well-preserved immune function (high CD4 counts) or advanced disease?
- “Elite” controllers?
- Patients with acute HIV infection?
- Patients requiring bone marrow transplantation?
Finally, regarding ethical considerations, Doctor Kuritzkes said that this needs a balance risk of significant toxicity, morbidity and mortality of novel strategies against the possible benefit to individual patients and knowledge gained overall. However, it is challenging to define an acceptable level of risk in the context of generally safe and effective life-long therapy.
If functional cure could be achieved but required a period of treatment with somewhat toxic drugs, how much toxicity would be acceptable?
-No more toxic than current ART regimens
-Would accept a small risk of fatal complications (e.g., similar to pancreatitis with ddI or HSR with abacavir)
-Would accept a modest risk of mortality similar to coronary artery bypass grafting (1-2%)
-Would accept a significant risk of mortality similar to bone marrow transplantation (10-20%)
In Doctor Kuritzkes view, those who should adjudicate those risks are:
- Funding agencies
- Biosafety committees/RAC
Finally, Doctor Kuritzkes listed a series of questions that remained to be addressed:
- Will absence of transmission need to be proven as well?
- How to assess long-term toxicities?
- Risk of relapse?
- Distinguishing relapse from reinfection
Related presentation : have a look at the « IAS Towards a Cure » lecture given by Doctor Alain Lafeuillade during the European AIDS Clinical Society (EACS) meeting in Belgrade, Serbia, on October, 2011, on the topic : « What Should Clinical Trials Assessing Cure Look Like? ».
This site needs a (free) registration : http://www.multiwebcast.com/eacs/2011/13th
Key words: HIV cure trials design, HIV eradication trial design