Key Reports from the 2006 HIV Drug Resistance Workshop
In the silent war against HIV, scientists are decoding the virus's escape routes to build better defenses.
The XV International HIV Drug Resistance Workshop, held in Sitges, Spain in 2006, brought together nearly 250 leading investigators to tackle one of the most pressing challenges in HIV management. This gathering revealed that while approximately 10% of new HIV infections in developed nations involved drug-resistant viruses, the scientific community was responding with increasingly sophisticated countermeasures—from powerful new medications to deeper insights into how resistance spreads and evolves 1 2 9 .
Research presented at the workshop revealed that the landscape of transmitted drug-resistant HIV was evolving through three distinct waves, each with different characteristics and implications for treatment.
Peaked with resistance rates around 15-20%, primarily featuring Nucleoside Reverse Transcriptase Inhibitor (NRTI) mutations such as thymidine analog mutations (TAMs) and M184V. This wave resulted from the widespread use of medications like zidovudine, stavudine, and lamivudine, often administered as sequential mono- or dual therapy 2 .
Marked by a significant increase in Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) resistance, which had become the most frequently transmitted drug-resistant variant in many locations by 2006. This trend was attributed to the widespread use of efavirenz and nevirapine, combined with the persistence of NNRTI resistance mutations once selected 2 .
Featured concerning reports of transmitted multidrug-resistant (MDR) HIV, including the first documented cases of transmitted enfuvirtide-resistant HIV identified in southern France 2 .
The prevalence and patterns of transmitted resistance varied significantly across different regions, reflecting local treatment histories and practices.
| Region | Any Resistance | NRTI Resistance | NNRTI Resistance | PI Resistance | Study Years |
|---|---|---|---|---|---|
| Europe (SPREAD) | 9.1% | 5.4% | 2.6% | 3.0% | 2002-2003 |
| United States | 10% | 4% | 6% | 3% | 2000-2004 |
| North America/Australia | 13% | 3% | 11% | 3% | 2000-2006 |
| Switzerland | 8% | 3-12% | 0-7% | 0-5% | 1996-2005 |
| Germany | 9-13% | 5% | 3% | 2% | 2001-2005 |
Susan Little's research presented at the workshop highlighted that the overall increase in resistance from 1996 to 2006 (9% to 13%) was driven primarily by rising NNRTI resistance, which jumped from 5% to 11% during this period. Interestingly, this trend was most pronounced in California, whereas other regions showed different patterns 9 .
Beyond transmission patterns, workshop presentations delved into the complex mechanisms through which HIV develops and maintains resistance.
Research revealed that the reverse transcriptase mutation L74V/I was preferentially selected in patients taking NRTIs (particularly didanosine and/or abacavir) who were also exposed to NNRTIs 2 . This mutation had significant clinical implications:
The presence of L74V was associated with a 20-fold increase in Y181C-associated resistance to nevirapine and nearly 3-fold increased resistance to efavirenz 2 .
Investigators from Gilead identified L74V/I as an independent predictor of reduced response to tenofovir, alongside K65R and multiple thymidine analog mutations 2 .
An analysis of 3,476 clinical isolates found that L74I accounted for one-third of amino acid changes at position 74, suggesting it should be considered alongside L74V in resistance algorithms 2 .
Valentina Svicher from the University of Rome presented intriguing findings on patients who maintained enfuvirtide (T-20) in their regimens despite virological failure. Surprisingly, these patients experienced significant CD4 count increases even as their viral loads rose 6 .
Patients with the V38A/E mutation experienced particularly dramatic gains—CD4 counts increased 4.5 to 6-fold at weeks 24 and 36 compared to minimal changes in those without these mutations. This suggested that enfuvirtide might reduce HIV's cytopathic effect or provide immunological benefits independent of its antiviral activity 6 .
The workshop also highlighted promising new agents designed to overcome existing resistance, particularly for highly treatment-experienced patients.
Brecanavir (BCV) represented an exciting development in protease inhibitors, featuring picomolar potency and superior binding affinity compared to existing PIs. Phase II data from the STRIVE study demonstrated its potential against highly resistant viruses 5 .
| Protease Inhibitor | Median IC₅₀ (nM) | Median Fold-Change |
|---|---|---|
| Brecanavir | 0.5 | 5.9 |
| Tipranavir | 250 | 3.4 |
| Atazanavir | 74 | 69 |
| Lopinavir | 270 | 82 |
| Amprenavir | 230 | 21 |
| Saquinavir | 117 | 29 |
| Nelfinavir | 340 | 59 |
| Ritonavir | 1700 | 162 |
Despite the study population having extensive prior PI exposure (mean of 3.2 major PI mutations per isolate), 68% of viruses remained susceptible to brecanavir at sub-nanomolar concentrations. The mutation I84V was associated with reduced brecanavir susceptibility, particularly when combined with I47V 5 .
Several sophisticated technologies enabled the groundbreaking research presented at the workshop:
The conventional method for detecting resistance mutations in the majority viral population, but limited in detecting variants comprising less than 20% of the virus population 9 .
Highly sensitive techniques capable of detecting minor resistant variants representing as little as 1-2% of the total viral population, revealing previously undetectable threats 9 .
Direct measurement of viral replication in the presence of antiretroviral drugs, providing concrete data on drug susceptibility beyond genotypic predictions 5 .
Advanced statistical method used to identify complex relationships between multiple mutations and their collective impact on drug resistance 5 .
Tracking of viral evolution and transmission pathways by comparing genetic sequences across different patients and timepoints 4 .
The 2006 HIV Drug Resistance Workshop marked a significant evolution in our understanding of drug resistance—from recognizing the limitations of standard resistance testing to documenting the changing patterns of transmitted resistance and developing more potent therapeutics.
Perhaps the most encouraging news came from Deenan Pillay's report showing that the burden of infectious drug-resistant HIV had fallen by 20% from 2000 to 2003 in a well-monitored Brighton cohort. This suggested that improved treatments were reducing both viral loads and the transmission of resistant strains .
As Luc Perrin from Geneva noted in an overview, transmitted drug resistance rates appeared to be stabilizing across Europe, though the emergence of multidrug-resistant strains remained a serious concern 4 . The workshop collectively highlighted that while drug-resistant HIV continued to pose significant challenges, the scientific community was developing increasingly sophisticated tools to detect, understand, and combat this evolving threat.
The research presented would fundamentally shape treatment guidelines, emphasizing the importance of comprehensive resistance testing before initiating therapy and paving the way for new generations of antiretrovirals capable of suppressing even highly resistant viruses.