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.

Eighth International Congress on Drug Therapy in HIV Infection

Glasgow, UK / November 12-16, 2006

Management of highly treatment-experienced patients was once characterized as salvage therapy, a term implying a low expectation of long-term treatment success. With development of several new agents effective in treatment-resistant HIV, the new goal is complete HIV suppression, an outcome that was first proven to be possible with the entry inhibitor enfuvirtide. Its success once raised concerns that it might be necessary to introduce novel antiretroviral drug classes to restore undetectability, but subsequent studies have demonstrated that new drugs from existing classes can be at least as effective. This was reinforced at this meeting when new data with ritonavir-boosted tipranavir (TPV/r), a protease inhibitor (PI), confirmed that the high rates of undetectability can be sustained indefinitely even among patients who are multiclass-resistant.

Extension Data: 96-week Results

The new extension data with TPV were generated by 96-week results from the phase III investigation called RESIST which provided the basis for the PI’s regulatory approval. In this new 96-week extension analysis of 1483 patients, there was little attrition over time among patients who had achieved a viral load <50 copies/mL at 48 weeks. Specifically, while 23% of patients who took TPV/r achieved a viral load of <50 copies/mL after 48 weeks, compared with 10% of those given a boosted comparator PI (CPI/r) (P<0.0001), 20.4% of the TPV/r patients remained at this level of viral suppression after 96 weeks compared to 9.1% of CPI/r patients.

Not surprisingly, more effective therapy is not only associated with better control of HIV but also better quality of life. In a substudy that looked specifically at the impact of treatment on quality of life in 1015 RESIST patients evaluated at 48 weeks, there were significant improvements in overall quality of life (P<0.05) as well as in the subcategories of general health perceptions, health distress, energy, and mental health. The improvements are credited to the fact that TPV/r had comparable tolerability to CPI/r but provided better control of HIV-related complications.

TPV/r generally provides similar tolerability when compared to other boosted PIs, according to Dr. David Cooper, National Centre in HIV, Sydney, Australia. One exception is a higher risk of liver enzyme abnormalities, but these elevations appear to impose modest if any clinical consequences. In a study evaluating TPV/r in 50 patients with or without hepatitis, the liver enzyme ALT was found to be increased in both groups, but there was no difference in liver toxicity.

“A mild to moderate increase in ALT as well as in cholesterol and triglycerides is frequently seen in TPV therapy, but hepatitis B or hepatitis C co-infection does not seem to increase the risk of liver toxicity of TPV/r,” reported Dr. Pilar García-Gascó, Servicio de Enfermedades Infecciosas, Hospital Carlos III, Madrid, Spain. Moreover, citing almost a 30% increase in HDL (from a baseline mean of 0.94 to 1.25 mmol/L at 12 months), she speculated that a parallel increase of HDL and total cholesterol “could ameliorate the negative lipid profile of the drug.”

Compassionate Use Program

The long-term safety of TPV/r has been further reinforced in new data generated by the compassionate use program that was initiated before regulatory approval. In data presented by Dr. Bruno Hoen, Centre Hospitalier Universitaire, Besançon, France, on 3920 highly treatment-experienced patients who had received at least one dose of TPV/r in this program, the median reduction in viral load was 1.8 log10 copies/mL and the median increase in CD4+ cells was 98 mm2. Again, the drug was reasonably well tolerated.

“No unexpected safety issues were seen,” reported Dr. Hoen, indicating that these data provide insight about the performance of this drug in a real-world setting. “Virologic and immunologic findings were consistent with the RESIST data.”

In another analysis of RESIST data, led by Dr. Sharon Walmsley, Director, Immunodeficiency Clinic, University of Toronto, Ontario, investigators were able to determine the level of lopinavir resistance at which TPV showed a significant advantage. Specifically, in patients who had three or fewer mutations, the advantage of TPV/r over LPV/r was not significant. When mutations climbed to four or more, TPV/r was far more likely to achieve viral suppression. For example, viral loads <50 copies/mL were observed in 44% of TPV/r-treated patients vs. 27% of LPV/r-treated patients in the presence of four or five mutations. In those with six to seven mutations, 26% in the TPV/r arm and 13% in the LPV/r arm achieved <50 copies/mL.

Overall, the series of clinical trials conducted in highly treatment-experienced patients that began with enfuvirtide and have included TPV and, more recently, darunavir, another PI that has demonstrated efficacy in this population, has demonstrated that optimal results are achieved when at least two active agents are included in a regimen switch. Consequently, updated guidelines from the U.S. Department of Health and Human Services and the International AIDS Society-USA Panel recommend the use of two or more fully active agents selected on the basis of resistance testing.

Novel Strategies

Several new drug classes in clinical development may also have an important role in the management of treatment-experienced patients because of their activity in the presence of conventional resistance. For example, convincing data have been obtained with the integrase inhibitor MK-0518 in both treatment-naive and -experienced individuals. In a study of heavily pretreated patients with extremely limited options, 67% of those receiving a high dose of this agent achieved viral load suppression to <50 copies/mL, according to Dr. Schlomo Staszewski, HIV Research Unit, J.W. Goethe University Hospital, Frankfurt, Germany.

While the drug pipeline includes new monoclonal antibodies directed at infected T-cells and a new class of agent called a maturation inhibitor, one of the drug classes moving most rapidly toward clinical application appears to be the CCR5 antagonists, which prevent the virus from attaching to the target cell membrane. In treatment-experienced patients, the CCR5 inhibitor vicriviroc reduced viral load in HIV patients with R5-monotropic virus by 1.83 log10 copies/mL in 24 weeks. However, Dr. Staszewski noted, the activity of CCR5 antagonists is significantly reduced in late-stage disease, treatment-experienced patients with X4 and dual/mixed tropic viruses, and the role of these agents in treatment regimens has yet to be clarified.

NNRTI Switching

Due to the broad array of treatment options, the opportunities for maintaining patients on an effective and well tolerated regimen have increased substantially over the last decade for second- and third-line regimens as well as for those who are highly treatment-experienced. While many patients are initiated on a regimen that contains a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside reverse transcriptase inhibitors (NRTIs), it has been common to switch to a PI if the NNRTI is poorly tolerated. However, new data confirm that it is also possible to switch from one NNRTI to another. While the two available NNRTIs, efavirenz and nevirapine, were shown to provide equivalent efficacy and safety in the 2NN study, their safety profiles differ. In particular, efavirenz is more likely to produce central nervous system (CNS) side effects, including mood disturbances and disturbing dreams, while nevirapine is more closely associated with rash. In an open-label pilot study presented by Dr. Michael Youle, Royal Free Hospital, London, UK, patients with CNS side effects associated with efavirenz were switched to nevirapine. CNS side effects resolved without change in viral control.

“No differences were seen in viral suppression, CD4+ cell count, or adverse events through week 24,” reported Dr. Youle, who presented data on 24 patients in a pilot program that is being evaluated for possible expansion.

Summary

Antiretroviral potency is critical but it will not lead to sustained HIV control if it is not delivered in a regimen that also provides acceptable tolerability and sufficient simplicity to allow patients to remain adherent indefinitely. There has been substantial progress in defining how to combine these attributes into single regimens, both at the time of initial therapy and over subsequent treatment regimens. While it is important to individualize therapies, recognizing that not all patients tolerate the same regimens equally well, the goal for all patients, regardless of treatment experience, is undetectability.