Antiretroviral News for the 10th EACS, Dublin

Hopkins HIV Report 2006 Jan; 18(1):5-7

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

The 10th European AIDS Conference (EACS) was held in Dublin from November 17-20, immediately following the Lipodystrophy Conference, reported on in this issue by Joseph Confrancesco and Todd Brown. Dublin has become a sophisticated, cosmopolitan, international (and expensive!) city without losing its charm. (And it’s true what they say…the Guinness really does taste better in Ireland!)

Treatment-Naïve Patients
The Nuke-Sparing Strategy Takes Another Hit

The Hippocampe study (ANRS 121) compared NRTI-sparing vs. NRTI-containing regimens in treatment naïve patients with CD4 counts <350 cells/mm³ or viral loads >100,000 c/mL [Duvivier C, et al. Abstract PS1/3]. The protocol allowed use of any NRTI except d4T and ddC; NNRTIs allowed were nevirapine (NVP) and efavirenz (EFV); PIs were ritonavir-boosted indinavir (IDV/r) and lopinavir (LPV/r). The original aim of the study had been to compare metabolic and morphologic toxicity between the arms, but the study was terminated early after an analysis of 36-week data by the DSMB showed a significant difference favoring the NRTI-based regimens by both intent-to-treat and on-treatment analyses. NRTIsparing regimens had lower rates of virologic success and slower rates of viral load decline. In addition, the only resistance mutations observed were in those patients failing NRTI-sparing regimens.

These results are consistent with those of ACTG 5116, in which the combination of EFV + 2 NRTIs was superior to an NRTI-sparing regimen of EFV + LPV/r, in part because of a greater discontinuation due to drug toxicity in the NRTI-sparing arm [Fischl M, et al. Conf Retrovir Opportunistic Infect 2005 Feb 22-25;12:abstract no. 162]. Enthusiasm for NRTI-sparing regimens has waned in recent years, in part because of the disappointing results of these trials, and in part because of the improved tolerability, toxicity, and convenience of the newer NRTI backbones. Nevertheless, it should be noted that the problems with the NRTI-sparing regimens that have been tested to date are at least partly due to toxicity and tolerability issues that may not apply to all such regimens. For example, the combination of EFV + LPV/r has so far required use of the soft-gel capsule formulation of LPV/r, with an increased dose of LPV/r (4 caps bid) because of the interaction with EFV. Combinations of EFV with atazanavir/ritonavir (ATV/r), fosamprenavir/ritonavir (FPV/r), or the new tablet formulation of LPV/r might be better tolerated.

Options for Patients with Advanced Disease: Busting the PI Mythology

Some clinicians still cling to the dogma that patients with high viral loads or low CD4 cell counts at baseline need a PI-based regimen, though this dogma has never been supported by data. Jose Miro from Barcelona presented results from a 2-year, randomized, multicenter, open-label trial comparing NNRTI- vs. PI-based regimens as initial therapy in 60 patients with CD4 counts <100 cells/mm³ (mean baseline CD4 count 40 cells/mm³) [Abstract PS1/4]. At 2 years, there was no difference in virologic suppression by intent-to-treat or on-treatment analysis, and there was no difference in rate of disease progression or death. Immune response was at least as robust in the NNRTI arm as in the PI arm: CD4 increase was 271 vs 222 cells/mm³, respectively (P=NS), and the percentage of patients with CD4 counts >200 cells/mm³ was 94% vs 80% (P=NS). Increases in naïve and memory CD4 cells were also the same. CD8+CD38+, a marker of immune activation, decreased in both arms, but the decrease was greater in the NNRTI arm. NNRTI-based regimens were better tolerated: only 12% discontinued due to adverse events, vs. 32% in the PI arm.

This study is limited by its small sample size and by the choice of PIs. Those in the NNRTI arm took EFV, with NVP as a back-up for those who could not take EFV. However, the PI of choice was IDV/r (800/200 mg bid), with LPV/r as a back-up. Boosted IDV is infrequently used today because of its toxicity, which may have been further increased by use of a 200 mg boosting dose of RTV. Nevertheless, the results of this trial are consistent with those of a number of other studies that suggest that NNRTI-based regimens, especially EFV-based regimens, can be appropriate choices for patients with advanced disease. We are eagerly awaiting the results of what may be the definitive study: an ongoing ACTG trial comparing LPV/r + 2 NRTIs, EFV + 2 NRTIs, and LPV/r + EFV in treatment-naïve patients.

Treatment-Experienced Patients
Tipranavir: 48-week RESIST Results

Pedro Cahn presented the 48-week pooled analysis of two tipranavir (TPV) trials, RESIST-1 and RESIST-2 [Abstract LBPS3/8]. Earlier results from these trials have been previously reported and discussed [Lucas G, HHR 2005;17(2):1 and Lucas G HHR 2005;17(5):4] A total of 1,509 patients with extensive triple-class treatment experience were randomized to take TPV/r vs. a comparator boosted PI (CPI/r). Patients had to have PI mutations, but could not have more than 2 of the mutations that were thought at that time to be most predictive of TPV resistance: protease mutations at codons 33, 82, 84, and 90. Virologic response was superior in the TPV/r arm, and that superiority was maintained over the 48-week study period. A viral load reduction of over 1 log₁₀ c/mL was observed in 34% of those on TPV/r vs. 15% of those in the CPI/r group. Viral load decline was 1.14 and 0.54 log₁₀ c/mL, respectively. Suppression to <50 c/mL was observed in 23% and 10%, respectively. The best response was seen in TPV/r-treated patients who were previously enfuvirtide (ENF)-naïve and who used ENF in their background regimen: 35% achieved viral suppression to <50 c/mL vs. 14% in ENF-treated patients on the CPI arm. As has been reported in earlier presentations of these trials, TPV/r-treated patients were more likely to have grade 3 or 4 elevations in ALT, AST, cholesterol, or triglycerides than patients in the control arm.

Lopinavir/ritonavir Monotherapy Studies

The possibility of treating patients using monotherapy with a boosted PI has been best studied using LPV/r, and we heard more data in Dublin from ongoing monotherapy trials. Pulido presented week 72 data from the OK (“Only Kaletra”) study, in which 42 patients with no prior history of PI failure who were doing well (viral load <50 c/mL for >6 months) on a combination of LPV/r + 2 NRTIs were randomized to continue their current regimen or to switch to LPV/r monotherapy [Abstract #PS7.5/5]. At 72 weeks, virologic suppression to <50 c/mL by ITT, missing = failure analysis was achieved in 90.5% of those on LPV/r + 2 NRTIs and 81% of those on LPV/r monotherapy. Two patients in the former group discontinued due to hyperlipidemia, whereas in the monotherapy arm there was one loss to follow-up and 3 virologic rebounds. Among those who experienced rebound, there was no evidence of new resistance, and all patients resuppressed with addition of NRTIs. The best predictor of virologic rebound was suboptimal adherence as determined by medication refill records.

In the KalMo study, 60 patients who maintained virologic suppression for over 6 months on HAART were randomized to continue their current regimen or to switch to LPV/r monotherapy [Nunez EP, et al. Abstract PE 7.5.1]. Data were available on 51 patients who had completed 24 weeks of therapy. No patient experienced overt virologic failure (viral load >1000 c/mL), although there were two low-level rebounds (viral load 410 and 470 c/mL) on the LPV/r arm. One patient in the monotherapy arm and two in the standard HAART arm discontinued therapy due to adverse events.

The accumulating data on LPV/r monotherapy are promising, and suggest that this is a strategy worthy of further study. However, in each trial, there have been patients who have experienced virologic rebound, often for unclear reasons. Fortunately, no participant has developed PI resistance to date, and resuppression is achieved with addition of NRTIs. These observations raise the question of whether there are anatomical or pharmarcologic compartment issues that prevent this approach from working in 100% of patients.

Antiretroviral Strategies
SWAN: Switching to Atazanavir

José Gatell from Barcelona presented final, 48-week results from the SWAN study, an open-label, randomized trial in which 490 patients who were virologically suppressed on a PI-based regimen without a prior history of PI failure were randomized in a 2:1 fashion to switch to an ATV-based regimen or to continue their current PI [Abstract PS1/1]. ATV was unboosted except in the case of patients on tenofovir DF (TDF)-containing regimens, who represented approximately 10% of the participants. By intent-to-treat analysis, virologic rebound to >50 c/mL was more common among those who remained on their original PI-based regimen (16%) compared to those who switched to ATV (7%, p<0.01). Treatment failure for any reason occurred in 21% of those randomized to switch to ATV vs. 34% of those who remained on the original regimen (p<0.01). Although more participants in the original PI arm dropped out of the study following randomization, the differences between arms persisted when the analysis was restricted to the patients who were treated with the assigned regimen. Rates of discontinuation due to adverse events were the same in the two arms. Not surprisingly, jaundice or scleral icterus occurred only in the ATV arm (11%), while diarrhea and hyperlipidemia were more common in the original PI arm. There were no differences in transaminase elevations, including in patients with chronic hepatitis C.

It is worth noting that only 54% of the participants were on a ritonavir-boosted PI at baseline. When the data were analyzed based on boosting of the original PI regimen, the differences between the arms were significant only among those taking an unboosted PI-based regimen, most of whom were on nelfinavir or indinavir. In this subset analysis, virologic failure occurred in 5% of the ATV arm vs. 22% of the comparison arm (p>0.001). Overall, these results suggest that ATV is well tolerated with respect to gastrointestinal side effects and is less likely to cause hyperlipidemia than other PIs. It is associated with better efficacy than other unboosted PIs, but not necessarily compared to boosted PIs.

Blips: Still Common, Still Benign

Gaia Nebbia presented data on blips among patients on stable HAART for at least six months with virologic suppression to <50 c/mL [Abstract PS3/5]. Of 486 patients, 119 (24.%) experienced blips, of whom 70% had a single blip. There was no difference in the rate of virologic failure between “blippers” and “non-blippers,” and those who blipped did not experience the emergence of new resistance mutations.

These results are consistent with those of other studies, including Richard Nettles’ study from Hopkins, which found that blips were common and not associated with emergence of new resistance mutations [JAMA. 2005 Feb 16;293(7):817-29]. However, while the findings are reassuring, blips continue to pose a challenge to clinician managing patients in “real time.” A patient with a newly detectable viral load may be simply “blipping,” but he may also be experiencing early virologic failure. Unfortunately, there is no way to be sure without repeating the viral load.

New Agents

TMC125

Julio Montaner presented a 24-week analysis from TMC125-C203, a phase II double-blind, placebo-controlled, dose-escalation trial in which 240 triple-class experienced patients with viral loads >1,000 c/mL received an optimized background regimen plus either placebo or one of two doses (400 or 800 mg bid) of TMC125, the investigational NNRTI from Tibotec [Abstract LBPS3/7B]. After a DSMB review of 24-week data, doses were increased to 800 and 1,200 mg bid. The study required use of at least two active drugs in the optimized background regimen, which may explain why efficacy differences were not observed. The focus of Montaner’s presentation was on toxicity. In comparison to the placebo arm, there did not appear to be significant differences between TMC125 recipients and those on placebo with respect to diarrhea, headache, nausea, abdominal pain, fatigue, or any grade 3 or 4 adverse events or serious adverse events. There were no clear dose-related side effects. Mild-to-moderate rash was seen in 17% of those in the combined TMC125 arms vs. 11% in those on placebo. There was no relationship between rash and TMC125 dose, CD4 count, or gender. Median time to onset of rash was 13 days. There were also no consistent or frequent neuropsychiatric side effects.

Jeffrey Nadler presented 24-week efficacy and tolerability data from TMC125-C223, in which patients failing therapy with NNRTI resistance and at least 3 primary PI mutations were randomized in a 2:2:1 fashion to receive 400 mg bid (N=80) or 800 mg bid (N=79) of TMC125 or control (N=40) [Abstract LBPS3/7A]. Over 90% of participants had virus that was resistant to all licensed PIs, and the majority had at least 2 NNRTI mutations. At 24 weeks overall viral load change by ITT, noncompleter= failure analysis was -1.04 and - 1.18 log₁₀ c/mL in the 400 and 800 mg arms, respectively, vs. -0.19 in the control arm. When the analysis was confined to those whose background regimen included at least 2 drugs to which the patient’s virus was susceptible, viral load decline was considerably higher: -1.66, -1.49, and -0.49 log₁₀ c/mL, respectively. CD4 cell count increase was also higher and time to discontinuation of therapy longer in the TMC125-treated patients. The 800 mg bid dose was chosen for further development. However, a new formulation has now been developed that allows a dose of 200 mg bid (4 pills/day) which provides comparable exposure to 800 mg bid of the original formulation.

Unfortunately, another TMC125 study (C227) was recently discontinued based on review of preliminary results by the DSMB. This was an open-label, phase II study in PI-naïve patients failing a first-line NNRTI-containing regimen, who were randomized to receive TMC125 vs. a PI plus 2 NRTIs. After evaluation of the first 54 patients reaching 12 weeks, it was clear that the proportion of patients achieving or maintaining a viral load <50 c/mL was lower in the TMC125 arm than in the PI arm. The sponsors noted that this study was being conducted with the old formulation of TMC125, which is more dependent on food for bioavailability. It is also worth pointing out that the background regimen could include only 2 NRTIs, despite the fact that all patients had previously failed an NRTI-containing regimen, and had presumably developed some degree of NRTI resistance (at least M184V). The other trials involving TMC125, which use the newer formulation, are ongoing.

MK-0518: Merck’s Integrase Inhibitor

Results of a 10-day, dose-ranging, monotherapy trial of MK-0518, Merck’s investigational integrase inhibitor, were presented by Morales-Ramirez [Abstract LBPS1/6]. The trial was conducted in 35 HIV-infected, treatment naïve patients, who were assigned to take MK-0518 at doses of 100, 200, 400, or 600 mg twice daily vs. placebo. Viral load response in the MK-0518-treated patients was 1.7-2.2 log₁₀ c/mL at ten days, with no obvious differences among doses. There were no grade 3 or 4 laboratory abnormalities, no serious adverse events, and no discontinuations due to adverse events. A larger study comparing MK-0518 with efavirenz is in progress.

Development of aplaviroc, the GlaxoSmithKline candidate, has been abandoned because of significant liver toxicity. Five cases of liver toxicity have now been reported in patients treated with aplaviroc in clinical trials, affecting both treatment-naïve and experienced patients [Nichols WG, et al. Abstract #LBPS5]. The pattern of toxicity included increases in both hepatic transaminases and total bilirubin, an uncommon pattern of drug toxicity that has been associated with a high risk of liver failure or death.

Meanwhile, a study involving vicriviroc, the Schering-Plough agent, has been stopped [Fatkenheuer G, et al. Abstract PL6]. The trial compared vicriviroc with efavirenz in treatment-naïve patients, always a tough battle. Patients in the vicriviroc arm had lower rates of virologic suppression than those on efavirenz. It has been suggested that the differences may have been due to excessively low doses of vicriviroc, as there appeared to be a dose-response relationship in this trial involving 3 doses of vicriviroc.

The Pfizer compound, maraviroc, is still being studied in both naïve and experienced patients. A case of serious liver toxicity requiring transplantation was reported via press release and discussed in Dublin, but the relationship of the hepatotoxicity and maraviroc is unclear, since the patient had many other reasons for developing liver problems, including use of other hepatotoxic agents such as isoniazid, trimethoprim/sulfamethoxazole, LPV/r, and intravenous acetaminophen, the latter having been given after the development of hepatitis. The DSMB felt that the patient probably had hepatotoxicity due to other agents, but could not rule out the possibility that it was related to maraviroc. They recommended that ongoing phase 2b/3 trials be continued.

2006-01-10
HHR-2006-01-02

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