In a coded riposte to last week’s announcement that US treatment guidelines will shift towards later treatment, David Ho told last week’s Eighth Annual Conference on Retroviruses that "it is unclear to me whether we can say that HIV persistence is guaranteed for life. While the winds of therapy are now blowing in the direction of treating later, it is doubly important to continue studies to assess the impact of appreciably more potent regimens".
Ho was speaking during a symposium on Viral Reservoirs which heard Anthony Fauci of the National Institutes of Health insist that eradication of HIV was now an impossible dream. Ho attempted to demonstrate otherwise, presenting evidence from a five drug study using the most potent agents currently available to treat HIV infection.
His aim, he told the conference, was to test whether using five agents each known to individually reduce HIV replication by 1.5 log could produce a quicker decay in HIV replication than seen hitherto in studies of HAART. Ho believes that two of the underlying reasons for the inability of HAART to significantly reduce the reservoirs of latent HIV thought to undermine attempts at eradication are the persistent low levels of replication seen with current regimens, characterised by viral blips and evolution of drug resistant mutants in individuals with viral load below 500 copies, and the relative slowness with which viral replication is brought under control after beginning treatment. In his presentation Ho argued that the reservoir of latently infected cells is not static, but is constantly replenished by new infection during `blips’ in replication, as well as replication which continues to occur below the level of detection of current viral load tests (20 – 50 copies per mL).
A poster presented by Ho’s Aaron Diamond Centre colleague Marty Markowitz appears to support this view. The more viral load `blips’ observed , the slower the decay of the HIV reservoir.
Using a combination of lopinavir/ritonavir, tenofovir, 3TC and efavirenz in 22 individuals, Ho found that the speed of viral decay was significantly increased in comparison to a control group drawn from a study of viral dynamics after initiation of treatment with ritonavir/saquinavir/AZT and 3TC in patients with similar baseline viral load and CD4 counts (400 cells/mm3 and 5 log RNA in each group, evenly balanced between acute seroconverters and chronically infected individuals). A 1.4 log drop was seen within 5 days in the 5 drug group, and the decay rate was calculated to be twice as high in these patients. In this 14 day study, in which patients were hospitalised in order to permit very frequent viral load measurements, tolerability of the regimen was not reported.
Assuming that the efficacy of the five drug combination was 100% (in itself questionable, Ho said), the four drug combination had an efficacy of 79% and previous viral dynamics studies suggested an efficacy of 67% for ritonavir monotherapy, based on the earliest analyses of viral dynamics published in 1996 and 1997.
"Perhaps the `Highly’ in Highly Active Antiretroviral Therapy should be changed", Ho argued,"given what is known about the persistence of HIV replication in the face of current regimens".
Louie M et al. Using viral dynamics to document the greater anitiviral potency of a regimen containing lopinavir/ritonavir, efavirenz, tenofovir and lamivudine relative to standard HAART. 8th Annual Retroviruses Conference, Chicago, abstract 383, 2001.