This July, a small group of intrepid Hopkins faculty members courageously left the balmy Baltimore summer behind to brave the infamously harsh winter of Rio, with its 75º temperatures, blue skies, and shivering scantily clad beachgoers, to attend the 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment. Rio is spectacular, of course… undoubtedly one of the most stunning cities on earth. Unfortunately, the meeting itself was held at a dreary conference center far beyond the suburbs. The conference center was deceptively named “RioCentro,” which can be translated to mean “downtown Rio,” but it was located somewhere near the Uruguayan border…or at least that’s how it seemed after 60 to 90 minutes on the bus. Oh well…we wouldn’t want our colleagues who stayed behind to be too jealous.

There was appropriate emphasis in Rio on the global epidemic and our response to it. New, clinically relevant presentations were few and far between, but here are a few of the studies pertaining to initial therapy, switching therapy, and new antiretroviral strategies.

Initial Therapy

Perhaps the most important clinical trial of antiretroviral therapy in naïve patients presented in Rio was the GS 934 study, for which 48-week data were presented by Anton Pozniak [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract WeOa0202]. This was a large trial in which 511 treatmentnaïve patients were randomized to receive efavirenz (EFV) plus either coformulated zidovudine/lamivudine (AZT/3TC) or tenofovir DF (TDF)/emtricitabine (FTC). At 48 weeks, the primary endpoint, virologic suppression to <400 c/mL by the FDA-mandated TLOVR (Time to Loss of Virologic Failure) analysis was significantly greater in the TDF/FTC arm compared to the AZT/3TC arm. Results were similar for the standard ITT analyses using both the <400 and the <50 cut-off. Excluding patients who were found to have had baseline NNRTI resistance, the TLOVR responses were 80% for the TDF/FTC arm and 70% for the AZT/3TC arm. The differences were primarily driven by the larger number of discontinuations due to adverse events in the AZT/3TC arm (9%) compared to the TDF/FTC arm (4%). This difference was especially notable for anemia, though there was also a suggestion of less nausea, vomiting, fatigue, and leukopenia in the TDF/FTC arm, as well.

Not surprisingly, the presence of baseline NNRTI resistance was associated with a decreased response to therapy with either regimen, emphasizing the importance of baseline resistance testing in treatment-naïve patients. Interestingly, this was not the case with baseline NRTI mutations. The analysis of treatment-emergence resistance from this study was somewhat surprising [McColl DJ, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract TuPp0305]. The resistance analysis involved 12 patients in the TDF/FTC group and 23 in the AZT/3TC group whose viral loads exceeded 400 c/mL. As expected, NNRTI resistance mutations (K103N and others) were seen frequently, in 73% to 75% of those who failed therapy and underwent resistance testing. What was unexpected was that no patient in either arm developed K65R, which had been observed in 7 patients failing TDF/3TC/EFV at the end of the first year of the GS 903 study [JAMA. 2004 Jul 14;292(2):191-201]. Interestingly, no patient with baseline NNRTI resistance developed K65R. In addition, although not statistically significant, M184V/I was numerically less common in patients on TDF/FTC , which had not been the case in the GS 903 study comparing TDF/3TC and stavudine (d4T)/ 3TC. Whether this is a real trend, and if so, whether it has to do with the difference in potency or pharmacokinetics of FTC vs 3TC is unclear. Only 1 thymidine analog mutation (TAM) was detected, in the AZT arm.

As in the GS 903 study, there was a significant difference in fasting total cholesterol favoring the TDF/FTC arm; the differences in fasting triglycerides were not significant. DXA scans were performed at 48 weeks in a subset of patients, and although these one-time results indicate that those on TDF/FTC have more limb fat than those on AZT/3TC, we will need to see follow-up data at 96 and 144 weeks before we can conclude that there is progressive lipoatrophy with AZT/3TC but not with TDF/FTC.

This study has important implications for the efficacy and tolerability of initial treatment regimens. For patients who are currently on AZT/3TC and doing well, the implications of the 48-week results are less clear. However, if we see continued separation between study groups in lipids and limb fat at 96 and 144 weeks, as was seen in GS 903, then it will provide support for switching therapy despite virologic suppression.

Problems with the combination of TDF and didanosine (ddI) have been raised recently, especially at last year’s ICAAC. The TEDDI trial confirmed previous reports of unacceptable rates of virologic failure with the combination of TDF/ddI/EFV; in this study, 25% of patients on that regimen experienced virologic failure by 12 weeks [van Lunzen J, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract TuPp0306]. We also saw follow-up data from the Spanish EFADITE study, in which patients on stable suppressive antiretroviral regimens were randomized to continue their current therapy or to switch to the combination of ddI/TDF/EFV.

While most patients maintained virologic suppression after switch, a significant decline in CD4 cell count was observed in that arm (-25 cells/yr vs +46 in controls) [Barrios A, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract WePe12.3C16]. The decline in CD4 count was associated with the use of higher doses of ddI in this study. It seems clear now that TDF/ddI is an unacceptable dual-NRTI backbone for patients on initial therapy or who have no TAMs. For experienced patients in whom resistance testing suggest that these are the two most active NRTIs, the combination can be considered, provided the dose of ddI is reduced and the CD4 count is monitored.

Antiretroviral Strategies: Monotherapy and Switching

At the 14th International AIDS Conference in Bangkok, we heard preliminary 24-week data on an interesting strategy involving 3TC monotherapy [Castagna A, et al. Int Conf AIDS. 2004 Jul 11-16;15: Abstract WeOrB1286]. These data were updated in Rio, with 48 week results [Castagna A, et al. Abstract WeFo0214]. Eligible patients were those who intended to interrupt therapy and who already had evidence of 3TC resistance. They were randomized to either stop therapy altogether or to continue 3TC alone. Patients in the 3TC monotherapy arm experienced a slower decline in CD4 count and had a lower viral load. They experienced a lower rebound in replication capacity after interruption of HAART and were more likely to maintain pre-existing resistance mutations. However, they did not develop any additional resistance mutations as a result of remaining on 3TC. This approach may be a reasonable alternative to treatment interruption in patients who already have the M184V mutation and in whom interruption is being considered. However, it should be noted that these were not patients on salvage therapy, but were patients with fairly high CD4 counts at the time of interruption. This would presumably not be an acceptable strategy in patients with more advanced disease and more extensive resistance.

Monotherapy strategies are also being explored using boosted PIs. We heard an update from Jose Arribas on the “OK” trial, which stands for “Only Kaletra.” In that study, 24 of 28 patients who switched from lopinavir/ritonavir (LPV/r) + 2 NRTIs to LPV/r alone maintained virologic suppression at 48 weeks. As we heard in previous presentations of these data, those who failed LPV/r monotherapy did not develop primary PI resistance mutations and were able to achieve virologic suppression with the addition of NRTIs. The reason for virologic failure in these patients, as well as in patients taking LPV/r monotherapy in other studies, has not been explained. The possibility of incomplete penetration into anatomical or physiologic compartments has been raised, since a handful of patients appear to fail despite good adherence, adequate drug levels, and no evidence of resistance. In a substudy of the OK trial, viral load responses in the two arms were compared using a highly sensitive viral load assay with a lower limit of detection of 3 c/mL [McKinnon JE, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract WeOa0203]. The investigators found no significant differences in viremia at baseline, week 4, or week 8. They also found no statistically significant difference in levels of viremia between those who ultimately experienced virologic failure and those whose viral loads remained suppressed, though virologic failure was typically preceded over several weeks by a rise in viremia using this assay.

An open-label, uncontrolled pilot study of monotherapy with boosted ATV, the ATARITMO trial, is also in progress [Vernazza P, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract WeOa0204]. As of this presentation, 24 patients have reached week 24, 22 of whom have viral loads <50 c/mL. Semen and CSF samples are available in 12 of the 24 subjects at week 24. Two semen and two CSF samples have detectable viral loads, again raising the question of penetration of single drugs into specific anatomic compartments.

Given the concerns about unexplained virologic failure and possible incomplete penetration into compartments with PI monotherapy, this strategy should be reserved for patients in clinical trials, at least for now.

The SWAN study was a study in which patients on a stable, suppressive boosted or unboosted PI-based regimen were randomized in a 2:1 fashion to stay on their current regimen or to switch to a once-daily atazanavir (ATV)-based regimen. The baseline regimen was either given twice daily and/or involved at least 3 pills per day. Patients must have been on a first or second HAART regimen and could not have failed a prior PI-based regimen. Of the 278 patients, 25 were also taking TDF and used boosted ATV. Those who switched to ATV were significantly less likely to experience viral rebound to >50 c/mL at week 24 (3% vs 8%), although viral rebound was more common among those who remained on an unboosted PI than those were on a boosted PI. Patients who switched to ATV also had more favorable lipid profiles, both in terms of total cholesterol and triglyceride levels.

Immune Response to HAART

Data are conflicting on whether there are differences among fully suppressive regimens with respect to immune response to therapy. Several studies were presented in Rio on this subject, and it’s fair to say that the data are still conflicting. Six-year follow-up data from the venerable Abbott 720 study of LPV/r + d4T + 3TC demonstrate that the CD4 count has continued to rise over time, with a mean increase of 529 cells/mm³; 81% had an increase of over 500 cells by year 6 [Landay A, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract WePe16.7B04]. This large and continuous increase in CD4 count has not been observed in many other trials of antiretroviral therapy, where the CD4 count eventually reaches a plateau. Another study looked at switches to LPV/r in patients on suppressive HAART regimens who were felt to have an inadequate CD4 response to therapy at 6 months [Pitrak D, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract WePe16.7B08]. The five patients who switched to LPV/r had a greater increase in CD4 count than the 5 who remained on their original regimens. In contrast, a large observational study found that discordant immune responses, in which patients experienced virologic suppression without a corresponding immune response to HAART, were no more common among patients taking NNRTIs compared to PIs [Sullivan AK, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract WePe12.2C02].

Kimberly Smith reported results from ACTG 5174, in which 60 patients who were doing well on HAART for over 1 year were randomized to receive continued HAART vs HAART plus human growth hormone (hGH), given at a dose of 1.5 mg sq qd [IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract TuOa0203]. After 24 weeks, those on the HAART alone arm then added hGH at a dose of 3.0 mg sq qd. In this trial, hGH was associated with a dosedependent increase in both naïve and total CD4 cells. These results are similar to those of a smaller pilot trial with longer-term follow-up data, in which hGH was also found to increase thymic mass [Napolitano LA, et al. IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract MoPpLB0104]. The clinical implications are completely unclear, especially since hGH is extremely expensive and not without side effects. In short, we still don’t know what to do with the patient whose viral load is suppressed but who has a lackluster CD4 response, but there are at least some data to suggest that there may be interventions available, short of interleukin-2 injections, that will improve the CD4 response. The harder question is whether these interventions will make a meaningful difference in outcome. Two large clinical trials of interleukin-2 have had a hard time demonstrating a clinical benefit, presumably because people with undetectable viral loads tend to do well regardless of their CD4 counts.

Conclusion

The profusion of HIV conferences dilutes the quality of the data and keeps us from our day jobs. Next year’s XVI International AIDS Conference will be held in Toronto (which is only a little farther from Baltimore by plane than the Brazilian conference center was from Rio by bus!). In between, we’ll have ICAAC, IDSA, EACS, and CROI, not to mention smaller meetings devoted to lipodystrophy, resistance, and pharmacology, just to name a few. Still, it’s encouraging to look back over a year’s worth of data, as spread out as it is, and realize that steady progress is being made in the management of HIV infection.

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