The 11th CROI was marked by two "firsts": It was the first time CROI was blessed with glorious weather, and it was the first time that many of the more clinically focused participants felt they were walking away somewhat empty-handed. There were certainly important basic science data presented, as well as some compelling data on drug resistance, prevention of mother-to-child transmission, and treatment of HIV/HCV coinfection. But for the most part, the large randomized trials of antiretroviral therapy either were not submitted, were not accepted, or were relegated to poster sessions.

All-Nucleoside Regimens

We did hear more data from clinical trials involving several unorthodox "all-nuke" regimens. Jemseck presented the results of his pilot trial using didanosine (ddI), lamivudine (3TC), and tenofovir DF (TDF), each administered once-daily with food, with ddI dose adjustment to compensate for the TDF-ddI interaction [Abstract 51]. These results had been made public earlier in a letter to clinicians from Gilead Sciences. A total of 24 patients were enrolled in the trial, 38% of whom had baseline viral loads (VL) above 100,000 c/mL, and 58% of whom had CD4 counts <200 cells/mm³. The results were even more disastrous than those we've seen recently with the abacavir (ABC)/3TC/TDF combinations: 20 (91%) discontinued early due to a poor virologic response, and viral load response was only -0.75 log₁₀ c/mL at 4 weeks, -0.61 log₁₀ c/mL at 12 weeks, and -0.4 log₁₀ c/mL at 24 weeks or at the end of therapy. In fact, no patient achieved a viral load below 50 c/mL in this study. Genotypes were available in 20 patients, all of whom had the M184V or M184I mutations. Ten patients also had K65R, 7 of whom had K65R/K mixtures, suggesting emerging resistance.

The third (and hopefully last) trial to study the ABC/3TC/TDF combination was the TONUS study from France [Landman R, et al. Abstract 52]. Results were similar to those from the Charles Farthing's study [Abstract 43, 2nd IAS, Paris 2003] and the ESS 300009 trial [Gallant JE, Abstract 1722a, 43rd ICAAC, Chicago 2003]. The study enrolled 38 patients, with a median CD4 count of 222 cells/mm³ and a median viral load of 4.87 log₁₀ c/mL. The study was stopped prematurely because of poor results: 12 (33%) of 36 enrolled patients experienced virologic failure by week 24. Response was correlated with baseline viral load: 64% of those with baseline viral loads above 5 logs failed therapy, compared to 29% of those with viral loads between 4 and 5 logs, and none of the 8 patients with baseline viral loads below 4 logs. Among the 11 patients with available resistance data after virologic failure, 9 had both the M184V and K65R mutations and 2 had M184V alone. The authors also looked at drug levels, since there has been speculation about whether drug interactions could explain the poor results seen with such regimens. The 4-week plasma Cmin was adequate for all three drugs in 86% of patients, and there was no relationship between trough concentration and virologic response. They also presented preliminary data on intracellular concentrations, noting that metabolites of at least one drug were detected in all patients. Obviously, these early data don't rule out intracellular interactions, and we are looking forward to seeing more intracellular data from this and other studies in Bangkok later this year. The authors of the TONUS study noted that rescue therapy was always successful in this study, regardless of the resistance profile. This is consistent with both phenotypic and clinical data from other studies, including the GS 903 trial, in which patients failing therapy with various combinations of NNRTI resistance mutations, M184V, and K65R, were successfully treated with a variety of rescue regimens, some of which included TDF.

The uniformly negative findings from three ABC/3TC/TDF studies have raised questions about whether it is safe to use this combination with a fourth agent. There has been some interest in combining co-formulated AZT/3TC/ABC (Trizivir) with TDF, since this would be a simple and convenient NNRTI- and PI-sparing regimen, and since the addition of AZT would presumably alter resistance pathways and prevent the emergence of K65R. Richard Elion presented data from the multicenter COL40263 trial, in which 123 patients received AZT/3TC/ABC + TDF, all administered once daily [Abstract 53]. An interim analysis was performed on the 88 patients with at least 8 weeks of data because of the alarming findings from the ABC/3TC/TDF studies presented last year. They found that at week 24, 67% of subjects had VL <50 c/mL by observed analysis. Response was 79% for those with baseline VL <100,000 c/mL and 60% for those >100,000 c/mL. Of those who completed 24 weeks of therapy, virologic non-response was seen in 15%. It should be noted that an intention-to-treat analysis, while not presented, would have shown poorer results, since 22% of the 88 discontinued from the study prematurely, 8% because of virologic non-response. The resistance data from 8 patients who met criteria for virologic non-response were interesting and somewhat surprising: 3 had at least 1 thymidine analog mutation (TAM) with M184V, 2 had at least 1 TAM without M184V, 1 had K65R, and 2 had wild-type virus. No patient had an isolated M184V, which is the expected first mutation in patients failing AZT/3TC/ ABC or a number of other AZT/3TC-containing regimens.

What can we conclude about the all-nuke regimens presented to-date?

There are at least two that are completely unacceptable: ABC/3TC/TDF and ddI/3TC/TDF. The reasons are unclear, but the evidence seems to point to the low genetic barrier to resistance, with strong selective pressure on pre-existing mutants: K65R reduces susceptibility to all drugs in the regimen and M184V reduces susceptibility to all but TDF Two triple-NRTI regimens, ddI/d4T/ 3TC and ABC/ddI/d4T, have essentially been made obsolete because of the ddI/d4T component. In addition, they are less effective than standard HAART regimens. These unacceptable triple-nuke combinations should be distinguished from AZT/3TC/ ABC, which, while less effective than efavirenz (EFV)-based HAART regimens in ACTG 5095 [Gulick R, et al. Abstract 41, 2nd IAS, 2003], may still have a limited role in antiretroviral therapy. Efficacy of this regimen is still in the "ballpark" of what we consider acceptable, and in fact is comparable to historical data with a number of standard HAART combinations. Moreover, one could argue that the consequences of failure on AZT/3TC/ABC are minimal, provided failure is detected and acted on early. One would expect to see wild-type virus or an isolated M184V mutation with initial failure of this regimen, rather than the NNRTI resistance that is so often seen with failure of EFV- or NVP-based combinations. The argument could be made that in some patients, primarily those in whom adherence is questionable, the use of a less potent but more forgiving regimen might be a reasonable compromise.

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Where does that leave AZT/3TC/ABC + TDF?

All we can conclude from Elion's study is that it's not in the "completely unacceptable category." Whether this 4-nuke regimen is any better (or worse) than AZT/3TC/ABC alone can't be determined without a controlled trial, a trial that is unlikely to take place in light of ACTG 5095. One also wonders whether the once-daily dosing of this regimen, including once-daily dosing of AZT, might have contributed to the somewhat surprising resistance findings, with more TAMs and K65R than would have been expected. Perhaps once-daily dosing of AZT does not provide adequate protection against resistance, both to TDF and to AZT itself. Clearly, this regimen cannot be recommended based on the available data, but the results of Elion's study may be reassuring to patients who are already taking it with a good virologic response.

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Once-Daily Lopinavir/Ritonavir

Gathe presented 48-week data from an open-label comparison trial in which 190 patients were treated with lopinavir/ ritonavir (LPV/r, Kaletra) dosed at either 800/200 mg (6 capsules) qd or 400/100 mg (3 capsules) bid, each given with the NRTI backbone of TDF plus emtricitabine (FTC) [Abstract 570]. Results in the two arms were similar, with 70% and 64% of patients on the qd and bid arms achieving suppression to <50 c/mL by intent-to-treat analysis, respectively. Lipid levels were similar in the two arms, though moderate-to-severe diarrhea was significantly more common in patients on qd LPV/r (P=0.04). These data support once-daily dosing of LPV/r for naïve patients. However, patients with prior PI exposure and/or resistance should probably stick with bid dosing, since the higher and less variable trough concentrations are likely to lead to better suppression of PI-resistant virus. The higher rates of diarrhea may also be problematic, and suggest that once-daily dosing be reserved for those already tolerating twice-daily LPV/r. When the new formulation of LPV/r is developed, the lower pill burden and the change in the excipients may make once-daily dosing more feasible and tolerable.

It should be noted that these are the best data to-date on the NRTI backbone of TDF/FTC, which is being developed as a once-daily coformulation. TDF levels are significantly increased when coadministered with LPV/r, raising concerns about an increased potential for nephrotoxicity. It was reassuring that no nephrotoxicity was seen in this trial. It is also interesting that lipid elevations were somewhat less pronounced than they had been in the earlier Abbott 863 trial, in which LPV/r was combined with a d4T/3TC backbone.

This may reflect differences between d4T and TDF in their effects on cholesterol and triglycerides.

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New Agents in the Pipeline

Shortly before CROI, we learned that development of two promising agents, T-1249 and amdoxovir (DAPD), was being halted by the manufacturers. Nevertheless, there is still a pipeline for new antiretroviral agents, some of which are now in clinical phases of testing.

D-D4FC (Reverset, RVT) is a novel NRTI that has activity against wild-type and NRTI-resistant virus in vitro, though it is not active against the Q151M or T69 insertion mutations associated with multi-nucleoside resistance. Robert Murphy presented data from the RVT-202 trial, a dose-ranging, placebo-controlled trial involving 24 patients who received 10 days of monotherapy and 1 month of follow-up [Abstract 137]. Mean viral load reduction was approximately 1.7 logs, with no obvious dose response relationship at the three doses tests (50, 100, and 200 mg qd). The only reported adverse events were cold symptoms; there must have been something going around, because the placebo recipients reported the same symptoms at about the same frequency.

SCH-D, a CCR5 antagonist being developed by Schering, is a safer and more potent cousin of an earlier candidate drug, SCH-C. Laughlin presented a dose-escalation, placebo-controlled trial of 14 days of monotherapy, which demonstrated dose related virologic suppression, with 81% of patients on the highest dose (50 mg bid) achieving a reduction in viral load of >1 log₁₀ c/mL (45% >1.5 log₁₀ c/mL) [Schurmann D, et al. Abstract 140LB]. The drug was well tolerated; there were no serious adverse events that appeared to be drug related. One of the concerns about CCR5 antagonists is that they will either need to be restricted to those whose virus is exclusively R5 tropic or else coadministered with CXCR4 inhibitors, lest there be selection of potentially more virulent X4 virus. The one patient in this trial found to have a mixed R5/X4 population had only a 0.5 log drop in viral load. Another had transient detection of X4 virus after cessation of dosing, though he had more than a 1.5 log drop while on treatment.

GW873140 is another CCR5 antagonist that was studied in a double-blind, placebo-controlled trial involving 70 HIV negative volunteers [Demarest J, et al. Abstract 139]. The agent was well tolerated at doses ranging from 50 to 1200 mg and led to prolonged receptor binding.

BMS-488043 is an attachment inhibitor, a small molecule that binds to gp120, blocking the earliest step in the entry process: the attachment of gp120 to the CD4 receptor. Binding has been shown to be independent of coreceptor status. It is related to an earlier compound, BMS-378806, which had a shorter half-life and did not achieve target exposure levels. In a 7-day, placebo-controlled monotherapy study involving 28 patients, 24 of whom received doses of 800 or 1800 mg bid, maximum viral load reduction was 1.23 log₁₀ c/mL in the high-dose arm and 1.01 log₁₀ c/mL in the low-dose arm, with 58% of the low-dose group and 67% of the high-dose group experiencing 1 log drops in viral load, respectively (25% and 42% =1.5 log drop) [Hanna G, et al. Abstract 141]. There were no serious adverse events and no discontinuations due to toxicity.

SPD754 is a deoxycytidine analog (like 3TC, FTC, and ddC), that is active against 3TC- and AZT-resistant virus in preclinical studies, and that shows no in vitro evidence of mitochondrial toxicity. However, coadministration of SPD754 with 3TC results in decreased intracellular concen-trations of SPD754-triphosphate, which raises the IC50 of SPD754 against HIV with M184V [Bethell R, et al. Abstract 138

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Conclusions

The data presented at CROI won't be changing the way we treat naïve patients, but there were some useful studies. By now we should all be appropriately wary of untested regimens, especially triple-nucleoside combinations with low barriers to resistance. The role of the "4-nuke" combination of AZT/3TC/ABC + TDF remains uncertain. Once-daily dosing of LPV/r continues to show promise for PI-naïve patients, though gastrointestinal side effects and the high pill burden may prevent this approach from being widely accepted using the current formulation. Finally, there are some promising new drugs in the pipeline, especially among the entry inhibitor classes. Bangkok is not known for great July weather, so we'll hope for a lot of exciting presentations that will keep us in our seats.

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