Important note: Information in this article was accurate in January 2006. The state of the art may have changed since the publication date.
Antiretroviral News From the 45th ICAAC
Hopkins HIV Report 2006 Jan; 18(1):1-4
Joel E. Gallant, M.D., M.P.H.
Johns Hopkins
The Katrina tragedy-cum-debacle resulted in the postponing of the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), originally scheduled to be held in New Orleans this fall. The conference was moved to Washington, DC, and despite the fact that it took place the week before Christmas, attendance was fairly high. The postponement of ICAAC meant that it would now be occurring less than two months before the Conference on Retroviruses and Opportunistic Infections (CROI), generally the most important scientific HIV conference of the year, and only one month after the Dublin EACS conference, which is covered in this issue. Nevertheless, we generally manage to glean some new data at each of the conferences, despite their frequency.
ACTG 5095
At ICAAC, Roy Gulick from Cornell presented long-awaited data from ACTG 5095 [Abstract H-416a]. Some readers might be thinking, “Long-awaited? Isn’t 5095 old news?” It’s true that the results of 5095 were presented in 2003 at the [IAS Conf HIV Pathog Treat 2003 Jul 13-16;2nd: Abstract No. 41], and subsequently published in the [N Engl J Med. 2004 Apr 29;350(18):1850-61]. However, those results involved only the comparison of the triple-nucleoside reverse transcriptase inhibitor (NRTI) arm, zidovudine/lamivudine/abacavir (AZT/ 3TC/ABC, Trizivir), versus the two combined, unblinded efavirenz (EFV) arms. The old news is that the triple-NRTI arm was stopped early because of a significantly greater rate of virologic failure; however, the other two arms of the trial continued, comparing EFV plus either AZT/3TC (Combivir) or AZT/3TC/ABC. As a reminder, this trial enrolled treatment-naïve patients with viral loads above 400 c/mL and no CD4 cell count entry criteria. Mean baseline viral load was 4.86 log10 c/mL, and 43% had viral loads of at least 100,000 c/mL. Mean CD4 cell count at entry was 240 cells/mm3. A total of 765 patients were randomized to one of the two EFV arms, of whom 78% completed the study. Two percent died, and 20% discontinued therapy, with no difference in discontinuation between arms. Median follow-up was 144 weeks.
The bottom line is that there was absolutely no difference between the two arms in terms of:
Finally, and perhaps most importantly, there was no difference in these end-points when the analysis was restricted to patients with baseline viral loads above 100,000 c/mL. There was also no difference in grade 3-4 toxicity, though there was a difference in the frequency of presumed hypersensitivity reaction, which occurred in 10% of those on the 3-NRTI arm, but also in 7% of those on the 2-NRTI arm, highlighting the fact that the abacavir hypersensitivity reaction is often over-diagnosed.
One of the unexpected findings in this study came from the multivariate analysis looking at predictors of virologic failure. In that analysis, blacks were 1.67 times more likely to fail therapy than whites (P=0.003), and patients who had hepatitis C coinfection were 1.57 times more likely to fail than those who did not (P=0.04). The investigators found that there was an interaction between race and adherence: blacks who self-reported non-adherence at 12 weeks had a significantly shorter time to virologic failure compared to adherent whites, blacks, or Hispanics or compared to whites and Hispanics reporting nonadherence. The reason for this surprising finding is unclear, but clearly needs to be teased out further with additional analyses of the adherence data. Potential reasons include different patterns of non-adherence (e.g. missed doses vs. longer or selective drug interruptions) or genetic/racial difference in drug metabolism, potentially leading to higher EFV levels and greater toxicity among blacks compared to whites and Hispanics.
The results of ACTG 5095 finally put a critical question to rest: Is the standard, 3-drug regimen enough, especially in patients with high baseline viral loads or low CD4 counts? Apparently it is, at least if you’re using a potent “anchor drug” like EFV. With the exception of a few more cases of abacavir hypersensitivity, the addition of a fourth agent (in this case, a third NRTI) didn’t seem to do much harm, but it clearly didn’t do any good, either. Together, these results and the disappointing results with NRTI-sparing regimens (see my EACS summary in this issue) suggest that we’ll still be using two NRTIs plus a third agent for some time to come.
Enfuvirtide: Add it? Subtract it?
Speaking of more aggressive regimens, a study by Moltó and colleagues randomized 15 treatment-naïve patients with viral loads above 10,000 c/mL and no relevant resistance to receive either a combination of lopinavir/ritonavir (LPV/r), EFV, 3TC, and tenofovir DF (TDF) or the same combination plus enfuvirtide (ENF) [Abstract H-528]. They found a significant difference in the slope of viral load decline at day 2 favoring the ENF arm (-0.260 vs. -0.347 log10 c/mL). By day 7, viral loads had declined from 5.1 to 3.98 logs in the control arm and from 4.98 to 3.55 logs in the ENF arm (P=0.06). The authors concluded that the addition of ENF to a potent 4-drug regimen increased potency by one-third. The clinical relevance of these findings is unclear, however. Does short-term potency translate into greater efficacy or durability? The results of ACTG 5095 suggest not, though we have not yet seen the data from 5095 looking at early viral decay dynamics. If those data show a more rapid decline in viral load in the 4-drug arm compared to the 3-drug arm, it will suggest that early antiretroviral potency is not necessarily associated with a better clinical outcome.
On the other hand, patients taking ENF can usually think of a number of reasons to stop taking it, and so can those who have to pay for it. But is it safe to stop ENF after viral suppression has been achieved? A study presented at ICAAC randomized 18 patients with at least 9 months of virologic suppression on an ENF-based regimen to either discontinue ENF (N=8) or to continue it (N=10) [Bonjoch A, et al. Abstract H-527]. Patients in both arms continued the other drugs in their regimen. All 10 of the patients who continued ENF maintained virologic suppression, whereas 3 of the 8 patients who stopped ENF experienced virologic rebound. The authors concluded that stopping ENF is associated with an increased risk of early rebound. This study is obviously too small to determine statistical significance. However, the apparent difference between the two arms isn’t surprising, given that most patients on ENF are on it for a reason: they frequently have few other suppressive options, and stopping ENF may leave them on an inadequate number of active drugs or on drugs that have only partial activity.
Once-Daily Trizivir/Tenofovir
Cal Cohen presented 48-week data on the previously presented COL40263 study, an uncontrolled trial of a 4-drug, all NRTI regimen of AZT/3TC/ABC plus tenofovir, administered once-daily at standard doses [Abstract H-521]. The trial enrolled 123 patients, who had a median baseline viral load of 5.1 log10 c/mL and a median CD4 count of 222 cells/mm3. Fifty-two patients (42%) discontinued therapy prematurely due to adverse events (14), loss to follow-up (13), virologic failure (12), or other reasons (13). Overall, virologic failure occurred in 11% of patients. At 48 weeks, 41% and 75% of patients had viral loads below 50 c/mL by ITT, M=F analysis and ITT observed analysis, respectively. Resistance data from the 14 patients failing therapy were presented by Richard Elion [Abstract H-1068]. At the last study visit on therapy, 5 of 14 patients had wild-type virus, and 9 of 14 had mutations, including TAMs plus M184V in 3, TAMs alone in 3, M184V alone in 1, and K65R in 2. Approximately one-third had phenotypic resistance to study drugs at the last visit.
These results are not a ringing endorsement for this regimen. The high drop-out rate is concerning, as is the resistance profile. Patients failing therapy in the three ACTG 5095 arms, even in the less effective triple-NRTI arm, typically had wildtype virus, M184V, and/or, in the case of the EFV arms, NNRTI resistance. However, they did not tend to have TAMs or K65R. The presence of these mutations in a sizeable proportion of failing patients raises questions about whether the use of once-daily AZT, clearly a twice-daily drug, might have led to insufficient AZT exposure throughout the dosing cycle, allowing for emergence of AZT-selected TAMs and TDF-selected K65R. Data from trials using the combination of twice daily Trizivir plus TDF, while not definitive, have shown more promising results [Moyle G, et al. 44th ICAAC 2004, Washington, DC. Abstract 1131].
Does Viral Suppression Really Matter?
A number of studies have suggested that the short-term prognosis for patients without complete virologic suppression is no worse than for those who maintain viral loads below 50 c/mL. These results have been seized on by those who reject what they refer to as the “dogma of undetectability.” However, data from the Danish HIV Cohort Study suggest that viral suppression really does make a difference, including a difference in mortality [Lohse N, et al. Abstract H-515, and Clin Infect Dis. 2006 Jan 1;42(1):136-44]. This study looked at virologic control during the first 6-18 months of therapy as a predictor of long-term outcome. The investigators divided the cohort into 3 groups based on the proportion of their viral loads that were detectable (>400 c/mL) during the 6-18 month period after starting HAART: patients in Group 1 never had detectable viremia, those in Group 2 sometimes had detectable viremia (1-99% of the time), and those in Group 3 always had detectable viremia. This was a large study: the analysis included almost 10,000 person-years of follow-up beginning 18 months after initiation of HAART. They found that compared with Group 1, adjusted mortality rate ratios (MRRs) were significantly higher in the groups with detectable viremia: 2.6 in Group 2 and 4.5 in Group 3. Six-year survival was 92.7%, 85.6%, and 76.1%, respectively. In Group 2, treatment interruption was associated with increased mortality (MRR 3.48). In addition, there were significant differences in CD4 cell count increase among the groups, and in rates of virologic suppression after 6 years (96%, 83%, and 57%).
This is in contrast to the results of a similar, concurrent trial, POWER-1, in which 53% and 18% of darunavir and control patients achieved suppression to <50 c/mL, respectively. Patients in the POWER-1 trial had considerably less treatment experience and PI resistance than those in POWER-2, which also helps to explain why use of concomitant use of ENF added less to the overall benefit in POWER-1 than in POWER-2: In the latter trial, 64% of ENF-naïve patients on the 600/100 mg bid dose arm who used ENF in their background regimen achieved viral load reduction to <50 c/mL, compared to 7% of control subjects, and compared to 39% overall for darunavir recipients in the trial. There were no significant differences in adverse events between the darunavir and control arms, and no clear dose-related toxicities [Berger, et al. Abstract H-1094].
Brecanavir (BCV, HPR10006) is a second-generation protease inhibitor (PI) from GlaxoSmithKline and Vertex that is active against many viral strains exhibiting high-level resistance to currently available PIs. Douglas Ward presented data from an open-label, single-arm study in which 31 treatment-naïve or -experienced patients with CD4 counts over 200 cells/mm3 and viral loads above 1,000 c/mL received a combination of BCV 300 mg bid boosted with ritonavir (RTV) 100 mg bid and two NRTIs [Abstract H-412]. Six of the 31 patients had PI-resistant virus, with a median of two primary PI mutations and 5 secondary mutations. The median phenotypic fold-change to lopinavir (LPV) was 4, with a median fold-change of 1 to BCV. At 24-weeks, 81% and 77% of patients had viral loads below 400 c/mL and 50 c/mL, respectively, by ITT missing=failure analysis. Those with baseline PI resistance experienced a median viral load reduction of 2.2 log10 c/mL. The drug appeared to be well tolerated, with no unexpected adverse events. Larger-scale comparative trials in treatment-experienced patients are now in progress.
Etravirine, an NNRTI, is discussed in my review of the Dublin EACS meeting, also in this issue, but under its previous name, TMC125. Howard Grossman presented data from the TMC125-C223 trial [Abstract H-416c]. This study was also presented in Dublin, and the study design is described in the EACS review. In the ICAAC presentation, 21% and 18% of patients on the etravirine 400 and 800 mg bid arms achieved viral load suppression to <50 c/mL at week 24 by ITT analysis, compared to 7.5% of those in the control arm. CD4 increases were 47, 48, and 10 cells/mm3, respectively. When ENF-naïve patients who used ENF in the background regimen were analyzed, there was a significant difference favoring both etravirine arms. The time to discontinuation was significantly shorter in the control arm: three-quarters discontinued therapy due to virologic failure. Rash occurred in 20% of etravirine recipients compared to 8% of control patients, and rash was felt to be at least possibly drug-related in 15%. The median time to onset of rash was 13 days, and median duration was 5 days. There was no clear association with CD4 count. Five patients (3%) discontinued therapy due to rash.
PA-457, being developed by Panacos, is the first “maturation inhibitor”; it targets the gag gene to block cleavage of CA-SP1, a precursor of the HIV capsid protein. Results of a dose-ranging, 10-day monotherapy trial of PA-457 vs. placebo were presented at ICAAC [Beatty G, et al. Abstract H-416d]. Participants taking 50, 100, or 200 mg/day of PA-457 had significantly greater viral load reduction at 10 days compared to patients in the placebo arm (-0.17, -0.48, and -1.03 vs. +0.03 log10 c/mL, respectively). The drug was well tolerated at all doses.
TNX-355 is an anti-CD4 monoclonal antibody from Tanox that selectively blocks attachment of HIV gp120 to the CD4 receptor. It is given by an intravenous infusion every 1-2 weeks. Norris presented data from a clinical trial comparing TNX-355 plus OBR vs. OBR alone in treatment-experienced patients [Abstract 4020].
Patients who received the highest dose, 10 mg/kg/wk, had a viral load reduction of 1.16 log10 c/mL at 24 weeks, compared to 0.2 log for control patients (p<0.001). Twenty-two percent achieved a viral load <400 c/mL, compared to 0% in the control arm. The drug was well tolerated, and in a separate presentation by Elliot Godofsky, the drug showed activity against R5-, X4-, and dual/mixed tropic viruses, and demonstrated evidence of synergy with ENF [Abstract 3844].
2006-01-10
HHR-2006-01-01
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