Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

XVI International AIDS Conference

Toronto, Ontario / August 13-18, 2006

The primary goal in HIV management is to achieve maximal and durable suppression of viral load (VL). Otherwise, keeping patients on suboptimal or failing regimens until they progress clinically—as they are forced to do in developing nations—will inevitably lead to the development of resistant mutations, stated Dr. Joep Lange, Professor of Medicine, University of Amsterdam, The Netherlands. There are many effective antiretroviral (ARV) combinations but as he suggested, “There are no better data than those from lopinavir/ritonavir [LPV/r]-containing regimens.”

Dr. Lange reviewed on-treatment analysis from the pivotal 720 trial in which ARV-naive patients were treated with LPV/r plus stavudine (d4T) and lamivudine (3TC). At seven years, findings showed that the virus remained undetectable in virtually all patients. The mean absolute increase in the CD4+ cell count in the same study was 776 cells/mm3. This increase occurred across all strata of CD4+ cell counts, “so patients who started out with a very low CD4+ cell count (<50 cells/mm3) also had this increase,” he observed, “and the vast majority had an increase of more than 500 cells/mm3 so these patients are immunologically almost normal or normal.” Indeed, data from four LPV/r studies in naive patients indicate that until patients have a VL in excess of 300,000 copies/mL, “there is no real difference in the virologic success rate, so we are dealing with a very robust regimen,” Dr. Lange confirmed.

Reassessing Protease Inhibition

The other breakthrough associated with boosted protease inhibitor (PI) regimens revealed that there is little evidence that resistance develops, even if patients do experience a rebound in their plasma VL. As explained by Dr. Charles Boucher, Associate Professor of Medical Microbiology, Utrecht University, The Netherlands, ritonavir-boosted PIs are usually more potent and have higher genetic barriers to resistance than unboosted PIs. “Furthermore, it may require multiple protease mutations for clinically significant drug resistance to occur,” he noted.

For example, in the 720 trial, no patient developed resistance to either LPV/r or d4T during the seven-year trial, indicating the boosted PI strategy may protect against the development of nucleoside analogue resistance as well. This is in contrast to the non-nucleoside reverse transcriptase inhibitors (NNRTIs), where a single mutation can confer resistance to the entire NNRTI class. Indeed, the emergence of NNRTI resistance in newly diagnosed patients in developed nations is a “worrying trend,” Dr. Boucher observed, precisely for this reason. “If you choose regimens with a high genetic barrier and which patients are able to take and not suffer from side effects, we can have long-term treatment success,” he stated.

Long-term Viability

If ARV potency is a key element to long-term treatment success, so, too, are tolerability of the regimen and ease of use. As Dr. Joseph Gathe, Clinical Instructor of Internal Medicine and Clinical Assistant Professor of Medicine, Baylor College of Medicine, Houston, Texas, reminded delegates, short-term side-effect toxicity from ARV regimens, especially gastrointestinal (GI) toxicity, is responsible for the majority of discontinuations within the first year of ARV therapy. Thus, minimizing toxicity is a prevailing principle in HIV management as well, he stressed.

A new tablet formulation of LPV/r available in the US since 2005 and with which Dr. Gathe has had considerable experience may resolve many of the limitations of the soft gel capsules.

The soft gel capsules are susceptible to high ambient temperatures—“a distinct issue in my clinic,” Dr. Gathe noted. They must also be taken with food in order to maximize the amount of drug available to the system. Perhaps most importantly, they contain a number of excipients, including castor oil, oleic acid and sorbitol, all of which are independently associated with GI side effects.

The new tablet formulation contains none of these excipients and should therefore be associated with lower rates of GI distress. Nor does it require refrigeration, and can be taken with or without food, thus providing consistent exposure to LPV/r regardless of meal conditions, Dr. Gathe noted. Moreover, fewer tablets than gel capsules—four rather than six daily—reduce the pill burden for ARV-naive patients. He reminded listeners, “We want to simplify the regimen and allow that regimen to be forgiving.”

Simplifying Regimens Through Monotherapeutic Strategies

One such strategy that will allow physicians to dramatically simplify treatment regimens is to use LPV/r monotherapy as maintenance or initial therapy. In a series of studies presented here, investigators demonstrated that this regimen achieves excellent, sustained virological control in the majority of patients with only low levels of virological rebound. In one such trial, Dr. William Cameron, University of Ottawa, Ontario, and multicentre colleagues randomized 104 naive patients to LPV/r plus zidovudine (ZDV) and 3TC for at least 24 weeks, followed by maintenance LPV/r monotherapy once patients had consistently achieved VLs of <50 copies/mL. Another 51 patients were randomized to efavirenz (EFV)/ZDV/3TC for the full 96-week study. Approximately 70% of patients in each treatment arm completed the trial. “The primary analysis was the intent-to-treat (ITT) proportion of patients who maintained a VL of <50 copies/mL through 96 weeks,” he reported.

At 96 weeks, “there was no significant difference in this outcome,” Dr. Cameron added, with 50% of patients in the LVP/r monotherapy arm remaining undetectable at study end point vs. 61% on the triple regimen. There were also “no discernable differences” in rates of virological rebound at higher VLs. More patients in the monotherapy arm did experience virological breakthrough when defined as VLs >50 copies/mL. However, as he noted, “Most virological breakthrough was at a low level and it was transient.” Patients experiencing low levels of virological breakthrough also spontaneously suppressed below 50 copies/mL, he added, while those with higher levels of virological breakthrough were re-suppressed with the reintroduction of ZDV/3TC.

Another multicentre study presented by Dr. Jose Arribas, Hospital La Paz, Madrid, Spain, demonstrated that at 48 weeks, LPV/r monotherapy given in a maintenance setting was non-inferior to continuation on LPV/r plus two NRTIs. In this study, patients were eligible if they had no history of virological failure while on a PI and two NRTIs, and if they had a VL <50 copies/mL for more than six months. The primary end point was per cent of patients without therapeutic failure, defined as VL >500 copies/mL.

At 48 weeks, 94% of patients in the LPV/r arm vs. 90% in the triple-therapy arm had VLs <500 copies/mL, with very similar numbers maintaining levels <50 copies/mL. Four patients with confirmed rebound after LPV/r monotherapy were reinduced with NRTIs and VLs remained low for the remainder of the study. “We estimate that approximately 85% of patients do not need to remain on two NRTIs to maintain HIV <50 copies,” Dr. Arribas noted, adding, however, that if patients are more than 10% non-adherent, viral suppression will be lost.

Summary

Current guidelines recommend triple-drug therapy be used on initiating an ARV regimen. However, issues such as toxicity, cost and complexity associated with triple-drug regimens is driving a search for simpler options. At this meeting, recent findings have shown that a monotherapy strategy, either as first-line or after successful VL suppression in ARV-naive patients, can simplify therapeutic management. Moreover, improved formulations of existing treatments have also made strides towards simplified and efficient regimens.

Note: At the time of printing, lopinavir/r is not approved as monotherapy in Canada.