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15th Annual Canadian Conference on HIV/AIDS Research

Quebec City, Quebec / May 25-28, 2006

Speakers here agreed that choosing a regimen for the management of HIV infection requires considerable insight, foresight and prudence, especially for treatment-experienced patients, where the wrong choice can seriously compromise treatment response.

Past Strategies, Present Resistance

“Over the last 20 years, some of the issues we’ve had to deal with have become increasingly more complex,” confirmed Dr. Sharon Walmsley, Associate Professor of Medicine, University of Toronto, Ontario. For example, many previously attempted strategies are now known to lead to increased drug resistance, including the use of sequential monotherapy. “Our responsibility now is to make sure we don’t keep doing that and to use drugs in combination instead.”

When patients do develop multidrug-resistant (MDR) virus, there is a risk that they will transmit the virus to others and reseed reservoirs, so that “resistant strains end up in the brain, the spinal cord and lymph nodes, later to emerge when patients are put on non-suppressive therapies,” Dr. Walmsley explained.

“Mega-HAART”—a term that essentially meant treating patients with everything available—seemed like a reasonable strategy at the time, but in practice, it involved too many pills, problems with adherence and high costs. As well, sub-inhibitory drug concentrations also select for resistant viral strains.

Scheduled treatment interruptions (STIs) were also once advocated under the hypothesis that reintroducing the agent after a pause in treatment would create renewed susceptibility. Following the outcome of the CTN 164 STI study carried out by Dr. Walmsley and colleagues (originally presented at CROI 2005),this strategy is no longer considered an adequate approach to a patient with MDR virus. In the study, results showed that patients were not more likely to suppress viral load on a new salvage regimen if they had undergone a STI first, and there was a small risk that they might progress during the STI, as Dr. Walmsley noted.

A strategy for MDR patients with multiple PI mutations is to employ two protease inhibitors (PIs) in combination at relatively high drug levels by boosting both with ritonavir (r) (PI/r). Pharmacokinetic studies show that prudence must be exercised as some PI/r strategies do have an additive therapeutic effect but others do not. For example, if saquinavir is used in combination with lopinavir/r, atazanavir or fosamprenavir, the effects are additive. However, protease levels of saquinavir are reduced by approximately 80% if combined with tipranavir. Also, using lopinavir/r together with fosamprenavir produces lower concentrations of both drugs, “so if you are going to use a double PI/r combination, use your pharmacist to help you figure out what dose might be best,” Dr. Walmsley cautioned.

Changing Paradigm

Fortunately, “the paradigm has changed,” Dr. Walmsley noted, as there are new agents that can produce good responses even in treatment-experienced MDR patients. From an entirely new drug class called entry inhibitors, enfuvirtide was the first among these novel antiretroviral therapies, but agents effective against resistant virus are now emerging from existing antiretroviral drug classes

In the RESIST 1 and 2 (Randomized Evaluation of Strategic Intervention in Multi-drug Resistant Patients with Tipranavir) trials, the PI tipranavir boosted with ritonavir (TPV/r) essentially doubled the proportion of highly treatment-experienced patients who achieved a viral load below <50 copies/mL at the end of 48 weeks vs. comparator PI/r (CPI/r) treatment. In the most frequently used CPI/r regimen, lopinavir/r, 11.5% patients achieved a viral load of <50 copies/mL at 48 weeks. Other CPIs used in RESIST included saquinavir/r, amprenavir/r and indinavir/r.

Over 33% of patients receiving TPV/r also achieved the primary end point, defined as a 1 log10 copies reduction in viral load at 48 weeks, vs. about 15% in the CPI/r arms. Patients receiving TPV/r were also 37% less likely to experience treatment failure at 48 weeks.

Data evaluation at 24 weeks in the RESIST trials also showed that TPV/r increased the proportion of patients achieving a treatment response at every level of the genotypic sensitivity score (GSS), and that the magnitude of response increased as well across each GSS when enfuvirtide was combined with TPV/r.

Trials in MDR patients clearly show that the use of two or more new agents effective against drug-resistant virus can produce robust responses. The TORO (T-20 vs. Optimized Regimen Only) studies (Lalezari et al. N Engl J Med 2003;348 (22):2175-85) with the entry inhibitor enfuvirtide had a similar design to the one used in the RESIST trials. As in RESIST, patients were randomized to either an optimized regimen of three to five antiretroviral agents or the optimized regimen plus the novel agent. Results showed that patients who received enfuvirtide fared better than those who did not, but those who received enfuvirtide with another active agent to which they had not been exposed and to which their infection remained susceptible did best of all. In those who received enfuvirtide plus another active agent (usually lopinavir/r, which remained a relatively new agent at the time of the study), 37% achieved a virologic response of <50 copies/mL—“something we had never seen before in drug-experienced patients,” Dr. Walmsley commented.

Emerging Options

Findings from RESIST 1 and 2 in MDR patients reaffirmed a similar result to TORO. Patients who received TPV/r plus another agent to which they had not been exposed and was active against their virus (usually enfuvirtide in this trial) did best of all. In these, some 36% achieving a viral load suppression <50 copies/mL at week 48.

“In the past year or two, we now have options, and the possibility of having a maximally suppressive regimen is real. So we have to make sure that we initiate that suppressive regimen when the patient can benefit from it and not to wait too long,” Dr. Walmsley concluded.

Issues for Consideration

As reviewed by Dr. Cécile Tremblay, Director, AIDS Clinical Care and Research Unit, CHUM-Hôpital Hôtel-Dieu, Montreal, Quebec, current guidelines recommend physicians use resistance testing when a regimen is failing and most provinces now use the VircoTYPE HIV 1 resistance report. In addition, “it is important to understand how resistance emerged,” she stressed, “and we need to take into account a patient’s history of antiretroviral treatment because mutations might be there that confer resistance that we do not see on the report.”

However, it is not as simple as switching to anti-HIV drugs to which the patient remains sensitive. For example, the nucleoside reverse transcriptase inhibitor (NRTI) treatment regimen should be left in place even in the presence of complete resistance to it. In one study cited by Dr. Jean-Guy Baril, Clinique Médicale du Quartier Latin, and Head, Service-Consultation-Liaison VIH/SIDA, Centre hospitalier de l’Université de Montréal, patients with an M184V mutation were clinically better if they remained on 3TC, even though their regimen was failing, than if they stopped. Thus, this agent class should remain part of rescue therapy for patients who have experienced treatment failure, he noted.

According to Dr. Mona Loutfy, Division of Infectious Diseases, North York General Hospital, and Assistant Professor of Medicine, University of Toronto, Ontario, the non-nucleoside reverse transcriptase inhibitors (NNRTIs), especially in patients who are NNRTI-naive, should be considered when devising a new regimen. As also seen in RESIST study results, combining TPV/r with a NNRTI was the best option in the study. However, as Dr. Loutfy cautioned, “The story is not all golden when it comes to an NNRTI, because a single mutation for NNRTIs leads to high-level cross-class resistance.”

Summary

Many of the early efforts to regain control of HIV infection in patients with MDR were discouraging. The development of novel agents that retain antiviral effect against HIV that is resistant to all other current therapies has provided new hope for long-term outcome. The lessons from the large phase III TORO and RESIST studies have suggested optimal benefits from these drugs are achieved when the patient can be started on at least two drugs that have predicted efficacy. This suggests that novel therapies should not be withheld until all other treatment options have been exhausted, but rather employed when there is at least one other agent with predicted efficacy with which they can be combined.