Antiretroviral Update from the 46th ICAAC

Hopkins HIV Report 2007 Jan; 19(1):1-3, 12

Joel E. Gallant, M.D., M.P.H.
Johns Hopkins

New data on antiretroviral therapy were sparse at the 46th ICAAC, held in San Francisco in September. A few of the most important studies are discussed below.

More Data Supporting Earlier Initiation of Therapy

The Abbott 720 trial has been following patients treated with lopinavir/ritonavir (LPV/r) for up to 7 years. Prior presentations of the results from this study have demonstrated excellent virologic durability and impressive CD4 increases. Data presented at ICAAC further assessed the immunologic response to therapy with LPV/r, looking specifically at the effect of baseline CD4 count on CD4 response [King MA, et al. Abstract H-1401]. The authors found that those who started with CD4 counts <50 cells/mm³ experienced continued rises in CD4 count throughout the 7-year period, while those who started with higher CD4 counts reached a plateau at 6-7 years. However, those with lower CD4 counts never “caught up” with patients starting at higher counts. Over 7 years, the mean increase in CD4 count from baseline was 532, 476, and 495 cells/mm³ in those with CD4 counts <50, 50-199, and >200 cells/mm³, respectively.

These results are similar to those seen in the Dutch ATHENA cohort [Gras L, et al. Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: Abstract 530] and in the Hopkins cohort [Moore RD, Keruly JC, Clin Infect Dis. 2007 Feb 1;44(3):441-6].

The latter study, a larger observational cohort study, also demonstrated that differences in CD4 response were associated with differences in clinical outcome, despite virologic suppression. Data were also presented from a Canadian cohort of 299 patients, which found that patients who achieved virologic suppression, but failed to attain a CD4 count above 200 cells/mm³, remained at increased risk of clinical events within the first year of therapy (hazard ratio 3.08, p=0.055) and after the first year of therapy (HR=3.94, p=0.08) [Loutfy MR, et al. Abstract H-1403].

Data were also presented from the PISCIS cohort, an ongoing, multicenter study of HIV-infected adults treated at 10 Spanish hospitals [Jaen A, et al. Abstract H-1059]. Treatment-naïve patients who initiated treatment prior to the diagnosis of AIDS and who remained on HAART for at least 1 month were included in the analysis. The authors found that patients with lower CD4 counts (<200 or 200-350 cells/mm³ compared to >350 cells/mm³) at the time of initiation were more likely to progress to AIDS or death than those with higher CD4 counts after adjusting for lead time. Factors associated with progression after adjustment for sex, age, and time of initiation included lower CD4 count, higher viral load, and HCV coinfection. Later initiation of therapy (after 2001) was associated with a decreased risk of progression.

Current treatment guidelines recommend therapy for symptomatic patients or patients with AIDS, and recommend consideration of therapy in patients with CD4 counts <350 cells/mm³ or viral loads >100,000 c/mL, though CD4 threshold is generally given more weight than the viral load threshold. The studies discussed here provide further support for earlier initiation of therapy. There is less enthusiasm now for deferring therapy until the CD4 count approaches 200 cells/mm³, and accumulating data suggest that initiating HAART at CD4 counts above 350 cells/mm³ may be beneficial. The question of when to start therapy may become more pressing if the CDC recommendations on routine HIV testing [MMWR Recomm Rep. 2006 Sep 22, 55(RR14);1-17; and “Update from the IDSA 44th Annual Meeting in Toronto” on p4 of this issue] become widely implemented. Routine testing should result in earlier diagnosis, with a larger proportion of newly diagnosed patients having CD4 counts above current guidelines criteria for initiation.

Boosting Fosamprenavir with Less Ritonavir

Pharmacokinetic data have supported the use of fosamprenavir boosted by only 100 mg of ritonavir rather than the approved dose of 200 mg/d, but there have been no clinical data supporting this combination. Kimberly Smith presented preliminary 24-week results from the ALERT study, in which 106 treatment-naïve patients were randomized to receive either atazanavir/ritonavir (ATV/r 300/100 mg QD) or fosamprenavir/ritonavir (FPV/r 1400/100 mg QD) along with tenofovir/ emtricitabine (TDF/FTC) [Abstract H1670a]. Virologic results were virtually overlapping, with 83% of ATV/r-treated patients and 79% of FPV/r-treated patients achieving a viral load below 50 c/mL by intention-to-treat (ITT), missing=failure analysis. By observed data analysis, the results were 88% and 84%, respectively. FPV/r was associated with a greater rise in triglyceride levels; there was a similar, modest rise in total and LDL cholesterol in both arms. As expected, hyperbilirubinemia and jaundice were more common in the ATV/r arm. Treatment-emergent resistance was observed in only one patient, who had baseline amprenavir resistance and developed further PI resistance on FPV/r.

This study was not powered to demonstrate non-inferiority of the FPV/r regimen, but the extremely similar results are encouraging. Larger trials with this regimen are in progress.

MK-0518 in Treatment-Experienced Patients

Preliminary 16-week data were presented at CROI earlier this year demonstrating impressive efficacy of Merck’s integrase inhibitor, raltegravir (RAL, MK-0518), in treatment- experienced patients [Grinsztejn B, et al. Conf Retroviruses Opportunistic Infect 2006 Feb 5-8;13: Abstract 159LB]. The 24-week results presented at ICAAC continue to be equally promising [Grinsztejn B, et al. Abstract H-1670b]. A total of 178 highly treatment-experienced patients with 3-class resistance were randomized to receive one of three doses of RAL (200, 400, or 800 mg bid) or placebo in combination with an optimized background regimen (OBR). At baseline, 42-58% had a phenotypic susceptibility score (PSS) of 0, meaning that they had no fully active agents in the background regimen. The PSS for protease inhibitors was 0 in 87-98%. By ITT analysis, viral load was suppressed to <400 c/mL at 24 weeks in approximately 70% and to <50 c/mL in 57-67% of those in the RAL arms compared to 16% and 14% of those on placebo, respectively. Those on RAL achieved a 2 log reduction in viral load–in most cases by 2 weeks–whereas the overall reduction in viral load among placebo recipients was only 0.4 log₁₀ c/mL. Even those with a PPS of 0 had impressive responses, with 54-69% achieving viral suppression to <400 c/mL. Enfuvirtide was used for the first time by approximately one-quarter of the patients and increased efficacy by approximately 20% in both groups. The drug was well tolerated, demonstrating a safety profile that was similar to placebo.

Further trials of this agent, dosed at 400 mg bid, are in progress in both treatment-experienced and naïve patients, and the drug is now available through an expanded access program (see “Expanded Drug Access: Etravirine (Formerly TMC-125)”on p8 of this issue).

Dosing of Boosted Atazanavir with Efavirenz in an NRTI-Sparing Regimen

Gary Thal presented the results of BMS121, a 48-week, open-label study in which 65 treatment-naïve patients were treated with efavirenz (EFV) plus one of two doses of ritonavir-boosted atazanavir (ATV/r), 300/100 or 400/100 mg qd [Ward D, et al. Abstract H-1057]. Virologic response was similar, with 77% and 87% achieving a viral load <50 c/mL (observed data analysis). However, the small size of the study and the lack of pharmacokinetic data make this study hard to interpret. The primary endpoint of the study was triglyceride elevation: triglycerides levels increased by 48% and 63% in the 300/100 and 400/100 mg arms, respectively. Perhaps the most clinically useful observation was that grade 3-4 bilirubin elevation was observed in 49% of those on the 400/100 mg arm compared to only 13% of those on 300/100 mg, suggesting that when combined with EFV, the lower dose of ATV should be used.

Darunavir Data

More data were presented from the POWER studies, previously reported clinical trials comparing four doses of darunavir/ritonavir (DRV/r, TMC114/r) plus an OBR. A pooled analysis of 924 patients demonstrated no differences in safety and efficacy based on gender, age, and race [Collier A, et al. Abstract H-1396]. A 24-week analysis involving 458 patients found that rates of virologic suppression to <50 c/mL in patients previously treated with LPV/r, FPV/r, and tipranavir/ritonavir (TPV/r) were 40-44% at 24 weeks, similar to the overall trial population [Lefebvre E, et al. Abstract H-1387].

Among over 56,000 sequences submitted to Virco for resistance testing from 2004-2005, susceptibility was greater to DRV than to tipranavir (TPV) or lopinavir (LPV) among heavily PI-resistant isolates [Picchio G, et al. Abstract H-0999]. Ninety-eight percent of the isolates had no more than 2 DRV-specific mutations and were predicted to be susceptible to DRV. There was some evidence of cross-resistance between DRV and TPV: 3.8% had evidence of resistance to both drugs, 6.4% had evidence of resistance to TPV with susceptibility to DRV, and 1.4% had resistance to DRV with susceptibility to TPV.

Another Induction-Maintenance Failure

The COOL study was a randomized, open-label trial in which 143 patients with viral loads below 50 c/mL on HAART for at least 6 months were randomized to take either three-drug therapy (EFV + TDF + 3TC) vs. two-drug therapy (EFV + TDF) [Girard PM, et al. Abstract H-1383]. The two-drug maintenance arm was clearly inferior to the standard therapy arm: The success rate (viral load <50 c/mL without drug modification at week 48) was 82% vs. 97%, respectively, by ITT analysis and 90% and 100% by as-treated analysis. The rationale for “simplifying” a regimen by discontinuing the best tolerated and least toxic of its components is not obvious. In addition, now that the combination of EFV, TDF, and emtricitabine (FTC) are available as a single tablet, this simplification strategy would involve switching from one to two pills per day.

Coreceptor Tropism and Response to HAART

A study from the Chelsea & Westminster Hospital in London assessed the impact of coreceptor tropism on rate of CD4 decline before therapy and on response to therapy [Waters LJ, et al. Abstract H-1667]. Of the treatment-naïve patients who started therapy and were included in the analysis, 229 had R5-tropic virus, and 60 had dual or mixed (D/M)tropic virus at baseline. Pre-HAART CD4 decline during the first 12 months was significantly more rapid in patients with D/M-tropic virus than in those with R5-tropic virus (approximately 40 vs. 15 cells/mm³, p=0.026). However, the magnitude of CD4 increase, the proportion who achieved virologic suppression, and the time to virologic suppression on HAART was no different. These data suggest that while coreceptor tropism is associated with disease progression in untreated patients, tropism is irrelevant once therapy is initiated (provided the therapy doesn’t include a coreceptor antagonist).

New Agents

Lalezari presented data from a double-blind, placebo-controlled, dose-ranging trial of HGS004, a monoclonal antibody that blocks binding to the CCR5 coreceptor [Abstract H-1668]. The study included 5 dose cohorts with 10 subjects per arm, 8 of whom received a single intravenous infusion of active drug (0.4, 8, 20, and 40 mg/kg) and 2 who received placebo. Antiviral activity was demonstrated for all but the lowest dose, and there was evidence of a prolonged response, with some patients demonstrating continued partial suppression for as long as 56 days. Since this is an IgG molecule, it is thought that it could be administered infrequently. Patients in this study who demonstrated evidence of a tropism shift did not respond to HGS004. There were no severe grade 3-4 adverse events, but two patients experienced an infusion-associated urticarial rash. A second related compound is showing evidence of greater potency and is being studied further.

Elvucitabine is a novel nucleoside analog from Achillion Pharmaceuticals with a long half-life (approximately 100 hours) that selects for the M184V mutation. Colucci presented results of a 7-day, monotherapy study comparing elvucitabine (10 mg qd) vs placebo [Abstract H-1670d]. Because of its long-half life and the risk of resistance following discontinuation of therapy, subjects took LPV/r alone for 21 days following completion of the monotherapy phase of the study. Patients on the active study drug experienced a 0.85 log₁₀ c/mL viral load reduction at day 7, and a 1.72 log₁₀ c/mL reduction at day 21, and mean CD4 count increase was 62 cells/mm³ at 7 days. The drug was well tolerated.

2007-01-10
HHR-2007-01-01

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