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Agents in Expanded Access: Key Data from the XVI HIV Drug Resistance Workshop

The following investigational drugs are discussed in this issue: elvitegravir, raltegravir, etravirine, maraviroc and vicriviroc.

Antiretroviral agents available through expanded access mechanisms enable treatment-experienced patients with multidrug-resistant HIV-1 to take advantage of new treatment options before such drugs have jumped through all the many hoops of U.S. Food and Drug Administration (FDA) approval. Thus, for a patient who has exhausted all possible treatment avenues, new hope may be found. But despite promising results in early clinical studies, one must always consider possible unknown pitfalls and toxicities.

Clinical experience with new agents available in expanded access has been relatively brief thus far, and researchers still have much to learn about the evolution of resistance to these agents. This issue of ResistanceWATCH News^© highlights key data presented at the XVI HIV Drug Resistance Workshop held June 12-16, 2007, in Barbados on antiretroviral agents available through expanded access in three drug classes: integrase inhibitors, CCR5 inhibitors, and the new nonnucleoside reverse transcriptase inhibitors (NNRTIs).

RESISTANCE TO INTEGRASE INHIBITORS

An essential step in the HIV life cycle involves integration of viral DNA into the DNA of the host cell. The HIV integrase enzyme mediates this process by snipping the ends of viral DNA to prepare them for integration, known as 3’ processing, and then transferring these viral DNA strands into the host chromosome, known as strand transfer. The most advanced integrase inhibitors undergoing clinical development function by blocking the strand-transfer reaction, including elvitegravir and raltegravir.

Although these agents are very potent in treatment-experienced individuals, previous research has shown that use of an integrase inhibitor must be supported with other active drugs in the regimen to avoid the rapid emergence of resistance to this class of agents that can compromise long-term virologic suppression. This is illustrated by data from a Phase II study of elvitegravir in which patients with no active drugs in their optimized background regimen (OBR) demonstrated a rapid decrease in HIV-1 RNA levels at Week 2 followed by viral rebound, whereas patients with at least one active drug in their OBR demonstrated sustained virologic suppression (Figure 1) [1]. Similarly, in two Phase III studies of raltegravir, only 57% of patients with no active drugs in their OBR maintained a viral load below 400 copies/mL through Week 16 compared with 85% to 89% of patients with one or more active drugs in their OBR [2,3].

A wealth of new data now provides insight into the genetic pathways leading to resistance to integrase inhibitors. An analysis of viral isolates obtained from 38 heavily treatment-experienced patients who had virologic failure on raltegravir during a Phase II trial identified integrase mutations in the vast majority (92%) [4].The mutations uncovered appeared to fall into two genetic pathways: one involving the N155H mutation in the integrase gene, and one involving Q148H/R/K. These reduced HIV susceptibility to the drug by 10-fold and 25-fold, respectively. Accumulation of additional mutations found in concert with N155H (i.e., L74M, E92Q, G163R) and Q148H/R/K (i.e., E138K, G140S/A) enhanced the level of drug resistance. These findings suggest that only a couple of mutations are needed to produce resistance to raltegravir, consistent with a relatively low genetic barrier to resistance for the two leading integrase inhibitors. In addition, this study also found that viral variants containing the N155H or Q148H/R/K mutations were cross-resistant to several different integrase inhibitors. 

In accord with this latter finding, the key mutations associated with resistance to raltegravir have also been identified in association with resistance to elvitegravir. In an analysis of 28 treatment-experienced patients who had virologic failure while receiving elvitegravir, the N155H, Q148H/R/K, E92Q, and E138K mutations were each identified in 39% of patients at the time of treatment failure [5]. Other mutations more unique to elvitegravir included S147G (in 32%) and T66I/A/K (in 18%). Given the large overlap in resistance mutations between elvitegravir and raltegravir, it is not surprising that viral variants obtained from patients with virologic failure on elvitegravir demonstrated more than 150-fold (range: 1.02-301) resistance to elvitegravir as well as more than 28-fold (range: 0.78-256+) resistance to raltegravir. In general, reductions in susceptibility to elvitegravir appeared greater than for raltegravir.

Additional in vitro analysis has identified sets of mutations that confer cross-resistance to five different integrase inhibitors, including raltegravir and elvitegravir (Table 1) [6]. What accounts for the high degree of cross-resistance among this class of agents? An obvious answer is that integrase inhibitors share a common mechanism of action. Indeed, all of these compounds possess a pharmacophore—a common molecular framework that is recognized at a receptor site—that interacts with the catalytic site of the HIV integrase to inactivate the enzyme. At least three sets of mutations common to both raltegravir and elvitegravir—E92Q, G140S + Q148H, and N155H—reside near the catalytic site of the integrase. In-depth in vitro analysis of these mutations showed that each had a negative effect on integrase function in the absence of an integrase inhibitor [7]. N155H markedly impaired strand-transfer activity, E92Q moderately affected both strand-transfer activity and 3’ processing activity, and G140S + Q148H strongly impaired both activities. Despite these impairments, these mutations conferred 7- to 14-fold resistance to raltegravir. These findings suggest that although resistance to integrase inhibitors can readily be selected, it comes at the price of impaired viral activity. This is similar to what has been seen with many NRTI and PI mutations.

Current evidence suggests natural resistance to these integrase inhibitors will not be encountered often, if at all. Some degree of varying levels of natural susceptibility to integrase inhibitors may occur across different viral subtypes (i.e., subtypes A, B, C) within group M HIV [8,9], but the prevalence of these amino acid polymorphisms and their clinical significance, if any, is unknown.

RESISTANCE TO CCR5 INHIBITORS

For HIV to gain entry to a CD4+ cell, the virus must interact with two different receptors on the cell surface (Figure 2). First, the gp120 protein of HIV binds to a CD4 receptor, and then a conformational change takes place in the virus that allows the gp120 V3 loop to interact with the chemokine receptors, either CCR5 or CXCR4. This then causes another conformational shift in HIV that facilitates fusion between the virus and target cell.

Figure 3. HIV-1 Entry into CD4+ Cells

Maraviroc, the first of the inhibitors targeting the CCR5 coreceptor, has recently gained FDA approval. A second agent, vicriviroc, is in advanced clinical development. Because these agents are active only against CCR5-tropic virus, individuals seeking to use these agents should undergo tropism screening to ensure that they carry R5-tropic HIV and not X4-tropic HIV or dual/mixed-tropic HIV (a combination of R5- and X4-tropic virus). Based on the observation that some individuals experiencing virologic failure on CCR5 antagonists harbored X4-tropic virus at the time of failure, some researchers had speculated that a shift in tropism may enable escape from CCR5 blockade. As it turns out, this is likely not the case.

Extensive analysis of HIV clones obtained from patients participating in the phase III MOTIVATE trials of maraviroc who had R5-tropic HIV at baseline but who were later found to have X4-tropic virus during treatment revealed that most of the X4-tropic virus that emerged was already present at baseline, albeit in small amounts [10]. Ten of 20 patients tested harbored X4-tropic virus at baseline at a low frequency (1%-6%), whereas 4 patients harbored a higher proportion of X4-tropic virus at baseline (>10%). For the other 6 patients, the X4-tropic clones identified during treatment appeared to be phylogenetically distinct from the baseline clones and the R5-tropic clones obtained during treatment, indicating a suspected separate ancestral origin and not a shift in viral tropism. Consistent with this view, the X4-tropic clones contained between 7 and 17 amino acid changes in the 35-amino acid V3 loop, further suggesting that a shift in viral tropism did not occur through mutational evolution given the large number of changes observed. The patients on maraviroc demonstrated an almost complete loss of R5-tropic virus during treatment—a phenomenon that may have enabled X4-using virus present at baseline to over grow and emerge.

Thus, it appears that HIV may escape from CCR5 antagonists by undergoing population shifts in the proportion of pre-existing variants with X4-tropism, as opposed to shifting tropism from CCR5 to CXCR4. This work also suggests that just as low-frequency resistance mutations can be missed by conventional sequencing techniques, the current standard tropism assays may sometimes lack sensitivity for detecting low-level clonal variants using the CXCR4 coreceptor that are mixed in a larger population of R5-using virus. The level of minority X4-using variants that need to be detected to avoid clinical failure with CCR5 inhibitors remains an unanswered question.

Aside from this apparent route of clinical resistance, additional mechanisms for CCR5-antagonist escape also appear to be at play. In an analysis of markers of virologic failure, plateaus in maximal viral inhibition below 95% were associated with maraviroc resistance; whereas increases in the 50% inhibitory concentration (i.e., fold change) were not [11]. These plateaus showing reduced maximal viral inhibition support a new hypothesis of CCR5-antagonist resistance that is emerging: that is, resistance appears to be mediated by changes in HIV-1 gp120 that allow HIV to utilize CCR5 for cell entry despite the presence of bound inhibitor [12]. More specifically, changes in the V3 loop, which plays an important role in coreceptor recognition and binding, appear to play a crucial role in facilitating resistance to CCR5 antagonists [11, 13]. These V3 loop changes often differ from patient to patient with resistance to CCR5 antagonists, thereby reflecting the heterogeneity of the gp120 sequence. In addition, these mutations seem to decrease viral fitness in vivo, since wild-type, R5-using, vicriviroc-sensitive HIV reemerges in the absence of vicriviroc pressure [13].

RESISTANCE TO ETRAVIRINE (TMC125)

Etravirine is designed to have activity against NNRTI-resistant HIV and an increased genetic barrier to resistance. Yet that barrier may be overcome sooner rather than later in heavily treatment-experienced individuals already harboring a number of resistance mutations unless other active drugs are present. As such, a recent study assessed the effects of baseline resistance on the 24-week virologic response to etravirine among treatment-experienced patients participating in the randomized DUET-1 and DUET-2 trials [14]. For this conservative analysis, patients who received enfuvirtide as a new drug in their OBR were excluded. Thirteen RT mutations were associated with a decreased virologic response to etravirine: V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S. Many of these mutations occurred in conjunction with other NNRTI-associated mutations. Y181V, G190S, and V179F had the strongest effect on virologic response. The number of etravirine-associated mutations present at baseline was a very strong predictor of virologic response (P=.0008). The poorest virologic response to etravirine was observed in patients with more than 3 of these etravirine-associated mutations at baseline. Additional analysis is still needed to define the impact of the etravirine-associated mutations, both singly and in combination with other mutations, on etravirine activity and durability. Initial data suggests that etravirine may contribute substantially to salvage regimens when combined with other active drugs, despite considerable NNRTI resistance. Its optimal use in earlier lines of therapy remains to be determined.

SUMMARY OF KEY POINTS

• Patients failing integrase inhibitors will commonly select for resistance. This appears to require only a limited number of mutations (i.e., a relatively low genetic barrier to resistance).

• Because the integrase inhibitors currently in clinical development share a similar molecular framework, resistance to one drug in this class may be sufficient to confer cross-resistance to the other agents.

• Resistance to CCR5 antagonists may occur through one of two mechanisms:

  • Emergence of pre-existing X4-topic variants present at low frequencies at baseline and not a shift in viral tropism from R5 to X4, as previously hypothesized.

  • Development of amino acid changes in the gp120 V3 loop that enable HIV to still use CCR5 for cell entry despite the presence of bound inhibitor.

• Similar to what has been seen for many RT and PI inhibitors, resistance to the integrase inhibitors and CCR5 antagonists comes at the cost of decreased viral activity and fitness. The clinical relevance of this is unknown.

• Etravirine-associated mutations are often found in conjunction with NNRTI-associated mutations, and increasing numbers of both types of mutations decrease the magnitude of virologic response.

 REFERENCES

1. Zolopa A, Mullen M, Berger D, et al. The HIV integrase inhibitor GS-9137 demonstrates potent ARV activity in treatment-experienced patients. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstract 143LB.

2. Cooper D, Gatell J, Rockstroh J, et al. Results of BENCHMRK-1, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstracts 105aLB.

3. Steigbigel R, Kumar P, Eron J, et al. Results of BENCHMRK-2, a phase III study evaluating the efficacy and safety of MK-0518, a novel HIV-1 integrase inhibitor, in patients with triple-class resistant virus. Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, California. Abstracts 105bLB.

4. Hazuda DJ, Miller MD, Nguyen BY, Zhao J. Resistance to the HIV-integrase inhibitor raltegravir: analysis of protocol 005, a Phase II study in patients with triple-class resistant HIV-1 infection. Program and abstracts of the XVI HIV Drug Resistance Workshop; June 12-16, 2007; Barbados. Abstract 8.

5. McColl DJ, Fransen S, Gupta S, et al. Resistance and cross-resistance to first generation integrase inhibitors: insights from a Phase II study of elvitegravir (GS-9137). Program and abstracts of the XVI HIV Drug Resistance Workshop; June 12-16, 2007; Barbados. Abstract 9.

6. Ren C, May S, Miletti T, Bedard J. In vitro cross-resistance studies of five different classes of integrase inhibitors in recombinant HIV-1. Program and abstracts of the XVI HIV Drug Resistance Workshop; June 12-16, 2007; Barbados. Abstract 1.

7. Malet I, Delelis O, Valantin MA, et al. Biochemical characterizations of the effect of mutations selected in HIV-1 integrase gene associated with failure to raltegravir (MK-0518). Program and abstracts of the XVI HIV Drug Resistance Workshop; June 12-16, 2007; Barbados. Abstract 7.

8. Myers RE, Pillay D.HIV-1 integrase sequence variation and covariation. Program and abstracts of the XVI HIV Drug Resistance Workshop; June 12-16, 2007; Barbados. Abstract 3.

9. Lewis M, Simpson P, Fransen S, et al. CXCR4-using virus detected in patients receiving maraviroc in the Phase III studies MOTIVATE 1 and 2 originates from a pre-existing minority of CXCR4-using virus. Program and abstracts of the XVI HIV Drug Resistance Workshop; June 12-16, 2007; Barbados. Abstract 56.

10. Van Baelen K, Clynhens M, Rondelez E, et al. Low level of baseline resistance to integrase inhibitors L731, 988 and L870,810 in randomly selected subtype B and non-B HIV-1 strains. Program and abstracts of the XVI HIV Drug Resistance Workshop; June 12-16, 2007; Barbados. Abstract 5.

11. Mori J, Mosley M, Lewis M, et al. Characterization of maraviroc resistance in patients failing treatment with CCR5-tropic virus in MOTIVATE 1 and MOTIVATE 2. Program and abstracts of the XVI HIV Drug Resistance Workshop; June 12-16, 2007; Barbados. Abstract 10.

12. Westby M, Smith-Burchnell C, Mori J, et al. Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. J Virol. 2007;81(5):2359-2371.

13. Tsibris AMN, Gulick RM, Su Z, et al. In vivo emergence of HIV-1 resistance to the CCR5 antagonist vicriviroc: findings from ACTG A5211. Program and abstracts of the XVI HIV Drug Resistance Workshop; June 12-16, 2007; Barbados. Abstract 13.

14. Vingerhoets J, Buelens A, Peeters M, et al. Impact of baseline NNRTI mutations on the virologic response to TMC125 in the Phase III clinical trials DUET-1 and DUET-2. Program and abstracts of the XVI HIV Drug Resistance Workshop; June 12-16, 2007; Barbados. Abstract 32.