New Data on Treatment-Experienced Patients and Drug Resistance

Hopkins HIV Report 2007 Mar; 19(2):4-6

Gregory M. Lucas, M.D. Ph.D.
Johns Hopkins

Sunny Los Angeles afforded a nice respite from the dreary February doldrums of Baltimore, if you were fortunate enough to make it out of the airport before the storm. At this year’s CROI, data from new drugs continue be very encouraging for the treatment of experienced patients.

Raltegravir (MK-0518) in Treatment-Experienced Patients

Raltegravir (RAL) is an HIV integrase inhibitor in phase III clinical trials that is currently available through expanded access. Sixteen-week data from the BENCHMRK1 and -2 studies were presented in the late- breaker session by Cooper and Steigbigel in paired presentations [Abstracts 105aLB and 105bLB], the combined results of which are summarized below. In these trials, which have identical designs, 699 subjects with HIV RNA >1,000 c/mL and genotypic or phenotypic resistance to ≥1 drug from NRTI, NNRTI, and PI classes were randomized 2:1 to RAL plus optimized background (OBR) or placebo plus OBR. The average baseline CD4 count and viral load were 150 cells/mm³ and 40,000 copies/mL, respectively. Between 19% and 21% of subjects used enfuvirtide (ENF) for the first time as part of the OBR and 25%-50% used darunavir (DRV) for the first time. Thirty percent of participants had no active drugs in the OBR. At 16 weeks, HIV RNA <50 c/mL was achieved by 61% to 62% in the RAL arms compared to 33% to 36% in the placebo arms (p<0.001 for all comparisons with placebo). The average increases in CD4 cell counts were 83 to 86 cells/mm³ in the RAL arms compared to just 31 to 40 cells/mm³ in the placebo arms (P<0.001). RAL showed clear evidence of efficacy in all subgroups analyzed and adverse events were similar in the RAL and placebo arms. Genotypic changes were identified in the HIV integrase gene is 32 of 41 individuals with available samples who experienced virologic failure in the RAL arm.

CCR5 Inhibitor, Maraviroc, in Treatment-Experienced Patients

The efficacy of maraviroc (MVC) is being evaluated in treatment-experienced patients with R5-tropic virus in the MOTIVATE-1 and -2, phase III trials. It is noteworthy that only about 50% of highly treatment-experienced patients have R5 tropic virus, and MVC is not effective against X4-tropic or dual/mixed-tropic virus. Twenty-four-week results from the MOTIVATE trials were presented at the late-breaker session by Lalezari and Nelson in paired abstracts [Abstracts 104aLB and 104bLB], combined results from which are presented here. Triple-class-experienced/ resistant subjects (n=1,076) with viral load >5,000 c/mL and R5-tropic virus were randomized 1:2:2 to 1 of 3 arms, OBR plus placebo or OBR plus MVC (dosed once or twice daily). Patients receiving a PI (other than tipranavir) or delavirdine received 150 mg of MCV; all others received 300 mg of MVC (in each case MCV was dosed once or twice daily according to study arm allocation). The average CD4 cell counts and viral load levels were 170 cells/mm³ and 4.9 log₁₀ c/mL, respectively, and two-thirds on patients had fewer than 2 active drugs in their OBR. At 24 weeks the percent of participants with viral load <50 c/mL was 21% to 25% in the placebo arms, compared to 41% to 46% in the MCV arms (all comparisons with placebo statistically significant). Suppression rates were similar whether MCV was dosed once or twice daily. The average CD4 cell increases from baseline were 52-64 cells/mm³ in the placebo arms versus 102-111 cells/mm³ in the MCV arms.

10% of Treatment-Naïve Patients Have Drug-Resistant HIV, Maybe More if We Look Harder

Wheeler and colleagues presented data from the CDC Variant, Atypical, and Resistance HIV Surveillance System (VARHS) [Abstract 648]. Samples from 3,130 newly diagnosed HIV-infected subjects who were identified from 11 study sites in the US between 2003 and 2006 were tested for major drug resistance mutations. Overall, 10.4% of participants had drug resistance detected, with resistance to NNRTIs (6.9%) being more frequent than NRTI (3.6%) or PI (2.4%) resistance. Individuals with virus harboring resistance mutations to 2 or 3 drug classes were rare, 1.4% and 0.5%, respectively. This latest report is in line with prior data, which have estimated that between 5% and 15% of untreated individuals have drug resistance virus (http://www.aidsinfo.nih.gov).

A key limitation of standard resistance tests is that viral variants that represent <20% of the total population are not detected. However, a sensitive real-time polymerase chain reaction (PCR) can detect mutations at frequencies below 1%. The disadvantage of this technique is that specific mutations must be sought, rather than sequencing the entire region of interest for all mutations. Use of real-time PCR garnered attention two years ago when it was reported that at least 65% HIV-infected women who received single-dose nevirapine (sdNVP) to prevent mother to child transmission had evidence of NNRTI mutations using the sensitive method, compared to an estimated 30% to 40% using standard genotyping methods [Johnson JA, et al., J Infect Dis. 2005 Jul 1;192(1):16-23].

At this year’s CROI, Johnson and coworkers presented results from a study that used same rationale and methods to look for hidden resistance in treatment- naïve subjects [Abstract 639]. The researchers used real-time PCR on HIV RNA samples from 507 newly diagnosed, treatment-naïve individuals to search for the following mutations: reverse transcriptase – M41L, K70R, K103N, Y181C, M184V, T215F, T215Y; protease – L90M. Among 205 subjects who had wild-type virus by standard genotype, 30 subjects (15%) had at least one of the above mutations detected by the real-time PCR method – most frequently the K70R, M41L, or K103N. Moreover, among 302 subjects with at least one drug mutation identified by standard genotype, 7% had resistance detected to another drug class by the real-time PCR method. Similarly, Paredes and colleagues found that real-time PCR identified more HIV-infected, treatment-naïve pregnant women who harbored the M184V mutation in reverse transcriptase or the D30N mutation in protease than did standard genotyping [Abstract 658].

A burning question that arises from these data is whether mutations detected by ultrasensitive techniques are clinically relevant to the treatment of naïve patients. Johnson and colleagues [Abstract 639] took preliminary steps to address this issue by using real-time PCR to look for K103N, Y181C, and M184V in baseline samples from 316 treatment-naïve subjects who were starting treatment with efavirenz (EFV) plus lamivudine (3TC) plus abacavir (ABC) or zidovudine (AZT) in one of three clinical trials. Seven subjects had resistance mutations identified by standard bulk sequencing and 9 additional participants with resistance mutations were identified by real-time PCR. Seven of these 9 (78%) experienced virologic failure at 48 weeks, at rate that was significantly higher than the overall failure rate in the clinical trials of 30% (p=0.004).

Phenotypic Clinical Cutoffs Calculated for Darunavir (DRV)

Coakley and colleagues determined upper and lower fold-change cutoffs for phenotypic susceptibility to DVR using data from participants in the POWER studies [Abstract 610]. Subjects who used ENF were excluded from the analysis and the predicted activity of other drugs in OBR was adjusted for. Virologic changes from baseline to weeks 2, 4, and 8 were considered in formulating cutoffs. The lower clinical cutoff was defined as the fold-change in phenotypic susceptibility at which less than maximal virologic response to DRV was observed. The upper cutoff was defined as the fold-change in phenotypic susceptibility at which HIV RNA decreases from baseline were <0.3 log₁₀ c/mL (e.g., no meaningful response). The lower and upper clinical cutoffs for DRV were determined to be 10-fold and 90-fold changes in phenotypic susceptibility, respectively. At 6 weeks, the change in viral load from baseline in participants in the susceptible category (FC<10, n=96) was -2.3 log₁₀ c/mL, compared to -1.3 log₁₀ c/mL in the intermediate category (10<FC<90, n=71), and -0.4 log₁₀ c/mL in the resistant category (FC>90, n=5).

PI Sequencing: Darunavir Before Amprenavir, Need to Fear; Amprenavir before Darunavir, in the Clear

Concern has been raised that prior exposure to amprenavir (APV, now formulated as fosamprenavir) may compromise the subsequent activity of DRV more so than resistance to other PIs. APV and DRV are structurally related, and APV shares 6 of the 11 protease mutations that have been linked to reduced susceptibility to DRV (V32I, I47V, I50V, I54L/M, G73S, I84V). Data presented in Los Angles provided reassurance that prior use of APV is not an Achilles heel for DRV. Parkin and colleagues assessed samples from a clinical database for cross-resistance patterns between DRV and other PIs [Abstract 607]. Although the correlation coefficient for IC₅₀ fold-change was highest for APV and DRV, indicating an association, there was little to indicate that APV resistance translated into a high risk of DRV resistance. For example, only 12% of 1,340 samples that showed high-level resistance to APV demonstrated high-level resistant to DRV (fold-change >90), and 39% of these samples were fully susceptible to DRV (fold-change <10). This level of clinical cross-resistance was quite similar in comparisons between tipranavir (TPV) or lopinavir (LPV/r) and DRV. The converse, however, was not true. Among 855 isolates that demonstrated high or intermediate resistance to DRV (fold-change >10), 854 (99.9%) had high-level resistance to APV, compared to 734 (86%) to LPV/r and 416 (49%) to TPV.

Picchio and colleagues further explored the concern of APV/DRV cross-resistance in a retrospective analysis of data from the POWER studies, in which OBR plus DRV/r or placebo was compared in highly treatment-experienced patients [Abstract 609]. This group reported that prior APV use or resistance did not appear to have a large effect on the 48-week response to DRV. As shown in the table, 48-week outcomes with DRV/r were similar for participants with baseline exposure or resistance to APV and LPV.

Summary

The first integrase inhibitor likely to receive FDA-approval has demonstrated impressive efficacy at 16-weeks in the BENCHMRK studies. Phase II data presented by Markowitz at last year’s International AIDS Conference [Abstract THLB0214] intimate that this drug may even be able to give efavirenz a run for first-line therapy. Maraviroc also has demonstrated impressive early efficacy in experienced patients in the MOTIVATE trials. CCR5 inhibitors like maraviroc, however, have an inherent limitation in treatment experienced patients, in that up to 50% of such individuals cannot benefit from these agents because of the presence of X4-tropic or dual/mixed-tropic virus. In contrast, R5-tropic virus is nearly universal in acute HIV infection and is also found in a high percentage in chronically infected, treatment-naïve individuals. The most recent data from the CDC indicate that drug resistance in newly-diagnosed individuals remains stable at approximately 10%. However, more sensitive detection methods have suggested that we might just be seeing the tip of the iceberg with standard population genotypic assays. More data correlating real-time PCR results with clinical outcomes are needed. Finally, data presented at the conference provided reassurance that use of FPV is not likely to affect response rates to DRV.

2007-01-10
HHR-2007-03-02

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