February 13, 2003
When, on almost any regimen, someone experiences a lack of complete viral suppression there is an expectation that resistance will eventually be seen in the genetic material of HIV. It is clear that some drugs have a "higher" or "lower" likelihood of having virus resistance occur at the time of rebound. For example, there is a higher barrier to genotypic resistance (or in other words, fewer if any genetic mutations) seen with protease inhibitors that are boosted by low-dose ritonavir (RTV, Norvir), while there is a lower barrier seen in commonly used antivirals including 3TC (lamivudine, Epivir) and the non-nucleosides such as efavirenz (EFV, Sustiva) and nevirapine (NVP, Viramune).
However, in addition to understanding how fast these mutations can develop, it is important to also evaluate the "price" that HIV pays to create these mutations. It is clear that some mutations, even some that are easy for HIV to create -- such as with 3TC (low genetic barrier) -- may then decrease the ability of HIV to replicate, resulting in a lower viral load despite drug resistance. This study was done to evaluate the "price" that HIV pays when rebounding on a regimen containing the newer antiviral tenofovir (TDF, Viread).
The main approach here is to use a measurement known as replication capacity (RC). In other studies done in the past, there was an association with reduced replication capacity and the maintenance of lower viral loads. This study was done of viral isolates that have developed various mutations in the nucleoside family, including those that are seen if rebound occurs on TDF, specifically with the K65R mutation. While there were many viruses available in a data bank that had mutations to protease inhibitors (PIs), there were 1,040 isolates studied that did not show PI mutations and these results are instructive.
Compared to a standard strain used for comparison, the mutation that confers resistance to 3TC (M184V) showed a decreased RC, with 57 percent replication capacity. This was nearly identical to what was seen with the K65R mutations showing a 56 percent RC. When these two mutations occurred together, there was a 29 percent RC seen (although there was only three such isolates).
When there were a few mutations that occur with resistance to AZT (zidovudine, Retrovir)/d4T (stavudine, Zerit) (called TAMS, or thymidine analog mutations), there was less change in the RC at 80 percent of the standard. Of note, when there were four of the TAMS alone, HIV had an 82 percent RC, but when four TAMS were present with 184V, the RC was 47 percent, showing again the impact of this 184V mutation. There were no isolates available with these TAMS and K65R to compare with.
The researchers concluded that the reduced RC seen with the TDF (K65R) mutation might help explain why the viral load remained about 0.9 logs lower than baseline pre-treatment values in those on this agent who had viral rebound, despite this resistance. While the authors caution that complete viral suppression is always the goal of treatment, it is important to understand what options there are should resistance occur. Plus there is interest in understanding how clinicians can exploit decreased RC as a way to maintain at least partial control of HIV replication when full suppression cannot be realized.