Important note: Information in this article was accurate in November 2002. The state of the art may have changed since the publication date.
Antiretroviral news was sparse at the 42nd ICAAC, presumably because it followed the International AIDS Conference in Barcelona by only 2 months. Now that we have a yearly international conference once again (the International AIDS Conference alternating with the International AIDS Society Conference), ICAAC may play a less important role as a forum for HIV-related data. Nevertheless, several important studies related to the treatment of naïve patients were presented in San Diego, including studies of both approved and investigational drugs.
The MaxCmin1 study is a 48-week, open-label, randomized trial comparing two boosted PI regimens: IDV/RTV (800/100 mg bid) and SQV/RTV (1000/100 mg bid) [Gerstoft J, et al. Abstract H-172]. The trial included 306 PI-naïve and experienced patients, of whom 248 completed 48 weeks of therapy. While virologic failure was similar in the two arms (20% and 18%, respectively), switches from randomized treatment were more common among IDV/
RTV recipients (42% vs 28%), and were usually due to adverse events, most of which were gastrointestinal. Thus, while the on-treatment analysis showed no significant difference between arms, SQV/RTV was superior in the intent-to-treat (ITT), missing or switch=failure analysis, in which 53% vs 68% achieved HIV RNA <400 c/mL (p=0.014). Lipid profiles were also more favorable in the SQV/RTV group.
The SQV/RTV combination was also compared against EFV in the FOCUS trial, which enrolled 161 treatment-naïve participants [Montaner JSG, et al. Abstract H-167]. In this trial, SQV/RTV was dosed once daily (1600/100 mg qd), and both regimens included two NRTIs. EFV was significantly better tolerated than SQV/RTV, which was associated with more moderate-to-severe nausea (22.2% vs 3.8%) and vomiting (6.2% vs 0%). As a result, EFV was more effective by ITT analysis, with 71% achieving a viral load of <50 c/mL at 48 weeks compared to 51% in the SQV/RTV arm.
The soft-gel formulation of SQV (Fortovase) was used in both the MaxCmin1 and the FOCUS trials. There is now growing enthusiasm for reviving the use of the older hard-gel formulation (Invirase), since it achieves equivalent blood levels when boosted with RTV but is associated with fewer gastrointestinal side effects.
Long-term durability data were presented from Abbott's M97-720 trial, in which 100 treatment-naïve patients with HIV RNA >5000 c/mL received LPV/r in combination with d4T and 3TC [Murphy R, et al. Abstract H-165].
At 204 weeks, with data from 71 patients remaining on assigned therapy, 70% had HIV RNA <50 c/mL by ITT, non-completer=failure (NC=F) analysis, and 97% had HIV RNA <50 c/mL by as-treated analysis. CD4 counts continued to rise, with an increase in CD4 count of over 400 cells/mm3 observed at 204 weeks.
Results of the Gilead 903 study were reported at this year's International AIDS Conference in Barcelona [HHR 2002;14(5):4]. In this large, placebo-controlled trial, 600 patients were randomized to receive either tenofovir disoproxil fumarate (TDF) or d4T, each in combination with efavirenz plus 3TC. The virologic results were presented again, along with an expanded analysis of toxicity data [Gallant JE, et al. Abstract LB-2]. Both regimens were highly effective, with no differences in efficacy between the two arms. By ITT, missing=failure analysis, 82% and 81% achieved an HIV RNA <50 c/mL at 48 weeks (86% and 89% by ITT, missing=excluded analysis). However, TDF was associated with less toxicity than d4T, most notably in terms of lipid elevations. Fasting triglycerides, total and LDL cholesterol were significantly higher in the d4T arm at 48 weeks. In addition, mitochondrial DNA (mtDNA) levels in PBMCs increased from baseline to 48 weeks in the TDF arm, while there was no significant increase above baseline in the d4T arm. mtDNA levels were low at baseline in both groups, as has been reported in other studies of untreated HIV-infected patients, and it has been suggested that while HAART may help to restore normal mtDNA levels, this effect may be offset by the mitochondrial toxicity of specific NRTIs. A higher proportion of patients in the d4T arm had elevated lactate levels, and investigator-defined peripheral neuropathy was reported less frequently in TDF recipients.
The use of mtDNA assays is controversial, especially when levels are measured in PBMCs. These assays have not been well correlated with clinical adverse events. The Gilead 903 study is designed to continue for 3 years, which may provide an opportunity to help correlate in vitro toxicity assays with clinical outcomes.
Allavena presented results of the BIKS trial, an open-label, non-randomized multicenter study of lopinavir/ritonavir (LPV/r) plus EFV without NRTIs [Abstract H-169]. LPV/r was given at a dose of 533/100 mg (4 capsules) bid to compensate for the drug interaction with EFV. The trial enrolled 54 treatment-naïve participants and 19 who had failed a single PI but were NNRTI-naïve. At 24 weeks, 89% had an HIV RNA <400 c/mL by on-treatment analysis. The plan is to continue the trial for 48 weeks. Enthusiasm for so-called "NRTI-sparing regimens" has been driven in part by fear of NRTI-associated mitochondrial toxicity. With the availability of NRTIs/NtRTIs such as abacavir and tenofovir DF, which appear to be less toxic to mitochondria, it remains to be seen whether that enthusiasm will be maintained.
Maggiolo presented data from an open-label trial comparing a once daily regimen (ddI + 3TC + EFV) with two twice daily regimens, the "low pill burden regimen" of AZT/3TC + EFV and the "high pill burden regimen" of AZT/3TC + NFV [Abstract H-163]. Each arm included 34 participants. At 12 months, there was no difference between the two EFV-containing arms, but both were superior to the NFV-containing arms in terms of virologic suppression to <50 c/mL by ITT analysis. While one might be tempted to conclude that once or twice daily regimens with low pill burdens are superior to twice daily regimens with high pill burdens, the more obvious explanation is simply that EFV is more effective than NFV, which has been demonstrated in other trials.
Atazanavir (ATV) is an investigational protease inhibitor that does not appear to cause hyperlipidemia and has the advantage of being dosed once daily. A previous trial suggested that it was as potent as nelfinavir, but data on comparisons with "gold standard agents" such as efavirenz and LPV/r have been eagerly awaited to help determine the true potency of this agent. Kathleen Squires presented 48-week data from the BMS-034 trial, a large multi-center, randomized trial of ATV vs efavirenz (EFV) plus AZT/3TC in 805 treatment-naïve patients [Abstract H-1076]. The trial demonstrated equal potency of the two regimens, with 70% of ATV recipients achieving HIV RNA <400 c/mL vs 64% of EFV recipients by ITT, NC=F analysis (95% CI 1.2-11.7% for the difference between arms). Lipid profiles were more favorable in the ATV arm, with changes of +1% vs +18% in LDL cholesterol and -9% and +23% in triglycerides in the ATV and EFV arms, respectively. Five percent of ATV recipients developed jaundice or scleral icterus, a recognized side effect of ATV.
Unfortunately, results using the <50 c/mL HIV RNA assay were less impressive in both arms, and were much lower than what has been reported in other trials of EFV, such as DMP 006, GS 903, and others. Only 32% of ATV recipients and 37% of EFV recipients achieved an HIV RNA <50 c/mL at 48 weeks. A number of explanations have been proposed to explain these discrepant results. This was a multinational study, and there may have been differences in adherence that could have affected virologic response. Virologic response appeared to be lower in areas that enrolled larger numbers of injection drug users. Also, two different viral load assays were used in this study: The Roche Amplicor version 1.0 was used in some countries, while the version 1.5 assay was used in parts of the world where non-B sub-clades are more common. The version 1.5 assay is more likely to detect virus in patients who have undetectable viral loads (<50 c/mL) than using the version 1.0 assay. The results of this study have not yet been stratified by viral load assay, an analysis that should allow us to determine the contribution of assay differences toward the virologic response. Finally, the definition of virologic failure was more stringent than has been used in many other clinical trials. Patients with two consecutive HIV RNA measurements above 50 c/mL were counted as failures. This strict definition of failure has been adopted by the FDA but has been rejected by the AIDS Clinical Trials Group (ACTG) because of variability of viral load assays at low levels of HIV RNA. In addition, patients who discontinued the assigned study drug for any reason were also said to have failed therapy, including those who switched from AZT to another NRTI because of AZT side effects.
These results are somewhat difficult to interpret because of the relatively poor performance of both ATV and EFV using the <50 c/mL assay. Further analyses of the data should help to determine the degree to which the results can be explained by the various protocol-related factors. In the meantime, it is encouraging that ATV was generally well tolerated, did not cause hyperlipidemia, and appeared to be as effective as EFV in treatment-naïve patients.
Atazanavir levels (AUC and Cmin) are decreased by approximately 70% when the drug is combined with EFV, and a similar interaction is presumably seen with nevirapine, as well.
As with other PIs, ATV levels can be boosted by co-administration with RTV. Agarwala reported on a pharmacokinetics study in which 30 subjects were given ATV 300 mg qd for 10 days, after which they added RTV 100 mg qd [Abstract H-1716]. ATV Cmin was increased approximately 10-fold above that seen with ATV alone (at the reduced dose of 300 mg qd). These findings may have implications for co-administration of ATV with NNRTIs. Needless to say, boosting of ATV levels with RTV would undermine one of the most significant advantages of ATV-its lack of effect on lipid levels. It is possible that RTV boosting might also increase the risk of indirect hyper-bilirubinemia and jaundice, since Cmin appears to be the most important factor predicting bilirubin elevation [O'Mara E, et al. Abstract A-1253]. ATV can also be used to boost SQV levels, since it results in a 4- to 7-fold increase in the SQV AUC. Recommendations are that ATV be given at standard dose (400 mg qd) along with 1200 mg of SQV with a high-fat meal.
While amprenavir (APV) has a number of attractive features, the current formulation is difficult to take because of the large capsule size, high pill burden, and gastrointestinal side effects. Fos-amprenavir (GW433908, fos-APV) is a pro-drug of APV that is better absorbed and can be given at a dose of 2 pills twice daily, or 2 pills once daily with low-dose ritonavir. It is better tolerated than APV with fewer gastrointestinal side effects.
In the NEAT study, 251 treatment-naïve patients were randomized in a 2:1 open-label fashion to receive fos-APV (1400 mg bid) or nelfinavir (NFV) in combination with abacavir (ABC) and 3TC [Rodriguez-French A, et al. Abstract H-166]. In a preliminary 24-week analysis, 73% of the fos-APV recipients achieved an HIV RNA of <400 c/mL compared with 54% of those taking NFV (ITT analysis, 95% CI 6%, 31% for the difference between arms). Using the <50 c/mL assay, results were 54% vs 40%. In an as-treated analysis, 87% and 79% achieved an HIV RNA <400 c/mL, respectively. Virologic response was similar between arms among patients with baseline viral loads <100,000 c/mL. However, responses diverged in those with higher viral loads, with 71% vs 35% attaining HIV RNA <400 c/mL (42% vs 11% < 50 c/mL) in the fos-APV and NFV arms, respectively. It should be noted that while the difference between the performance of fos-APV and NFV was striking among patients with high viral loads, there was also a less pronounced difference in virologic response among the fos-APV recipients themselves: 62% with baseline viral loads <100,000 c/mL achieved an HIV RNA <50 c/mL compared to 42% with baseline viral loads >100,000 c/mL. Grade 2-4 diarrhea was observed in 17% of patients randomized to receive NFV and in 5% of those taking fos-APV.
This trial suggests that fos-APV will be an attractive improvement over the current formulation of APV, with excellent tolerability, convenient dosing, and superior performance compared to NFV, especially in patients with high baseline viral loads.
Emtricitabine (FTC) is a once daily nucleoside analog reverse transcriptase inhibitor (NRTI) with a toxicity and resistance profile similar to that of 3TC. Saag presented preliminary results from a large trial comparing d4T with FTC, each in combination with ddI EC and efavirenz in 571 treatment-naïve patients [Abstract LB-1]. At 24 weeks, FTC was superior to d4T, with 87% vs 79% of patients achieving HIV RNA <400 c/mL (p=0.02), and 81% and 70% achieving HIV RNA <50 c/mL (p=0.02). CD4 cell count increase was 156 cells/mm3 among FTC recipients vs 119 among d4T recipients (p<0.05). Virologic failure occurred in 4% of those on FTC vs 10% of those randomized to d4T (p=0.01), and time to virologic failure was longer in the FTC arm, as well (p=0.0006). Adverse events were more common in the d4T arm, with more nausea, paresthesias, and hyperlactatemia.
This trial confirms the efficacy and safety of FTC as an NRTI component of HAART regimens. However, the differences in efficacy and tolerability seen in this trial may say more about problems with the combination of ddI and d4T than about FTC itself, and it is possible that the results would have been similar had the study been carried out using 3TC instead of FTC. Nevertheless, FTC will be an attractive new drug, especially if it can be co-formulated with other once daily agents to improve convenience and adherence.
Other Investigational Agents
NRTIs: 3'-fluoro-2'3'-dideoxyguanosine (FLG) is active against both HIV and HBV, including NRTI-resistant HIV with multiple TAMs or multi-nucleoside resistant virus with the Q151M complex or the T69 insertion mutations [Zhang H, et al. Abstract H-182]. Related compounds have been associated with significant hepato-toxicity, so safety will be a major concern as this drug is developed.
Integrase inhibitors: Merck has two candidate compounds, L-870812 and L-870810 [Hazuda DJ, et al. Abstract H-1783]. The latter is now in phase I testing. S-1360 is in phase II testing, being developed by Shionogi and GlaxoSmithKline [Kobayashi Y, et al. Abstract H-184].
NNRTIs: TMC 125, from Tibotec-Virco, is a highly potent second generation NNRTI with activity against K103N and double mutants associated with resistance to currently available NNRTIs [Pauwels R, et al. Abstract H-1781]. We were hoping to have heard more by now from this exciting agent, but it is still in development, as is capravirine, another promising second generation NNRTI from Agouron.
PIs: TMC 114 is an investigational PI being developed by Tibotec-Virco that has activity against PI-resistance isolates [Pauwels R, et al. Abstract H-1781]. Tipranavir, from Boehringer-Ingelheim is in more advanced stages of development, and is also active against PI-resistant virus.
Entry Inhibitors: T-20 (enfuvirtide, Fuzeon) is a fusion inhibitor now being administered to patients in phase III trials and an expanded access program [see Bartlett, Treatment of Experienced Patients, p. 5]. As with any new agent, clinicians using T-20 should be careful not to defer the addition of this drug until after the patient has exhausted all other options. Not surprisingly, in the TORO-1 trial, T-20 had a better and more durable response when it was combined with drugs to which the patient's virus was susceptible [Lalezari JP, et al. Abstract H-1074]. A related compound, T-1249, is being investigated in phase I/II clinical trials [Gulick R, et al. Abstract H-1075]. Unlike T-20, it can be dosed once a day and is active against T-20-resistant isolates. The most common adverse reactions with both agents are injection site reactions. Other entry inhibitors include co-receptor antagonists, such as SCH-C, which interferes with viral binding to the CCR5 co-receptor [Doms RW, Abstract H-1782]. BMS-806 inhibits viral entry by blocking the interaction between gp120 and the CD4 receptor [Lin P, et al. Abstract H-181].
Perhaps the most important data pertaining to the treatment of antiretroviral-naïve patients were the NEAT study, comparing fos-amprenavir with nelfinavir, and, despite its somewhat confusing findings, the BMS-034 trial, comparing atazanavir with efavirenz. The NEAT trial also provided promising data on fos-amprenavir. In addition, studies such as GS 903 continue to suggest that there are real differences between agents with respect to their potential for causing long-term toxicity. Emerging data and development of new antiretroviral agents offer clinicians and patients a greater variety of options to choose from, and allow for easier dosing, better tolerability, and possibly less long-term toxicity. Indeed, optimists might argue that long-term toxicity may not be an inevitable outcome of antiretroviral therapy, though longer-term data will be needed to support their optimism.
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