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16th Annual Canadian Conference on HIV/AIDS Research

Toronto, Ontario / April 26-29, 2007

Reported by:

Sharon L. Walmsley, MD, FRCPC

Division of Infectious Diseases UHN-Toronto General Hospital

Associate Professor of Medicine University of Toronto Toronto, Ontario

Christos M. Tsoukas, MD, FRCPC

Associate Director McGill AIDS Centre

Professor of Medicine McGill University Montreal, Quebec

MEASURABLE SUCCESS

HIV/AIDS researchers and clinicians have experienced tangible successes since AIDS emerged into the medical consciousness over a quarter-century ago. In tertiary care clinics such as those in which we both practice, approximately 70% of patients now maintain undetectable viral loads on potent antiretroviral (ART) regimens, while mean CD4+ cell counts in most of our patients are between 400 and 500 per mm3—clearly a tremendous advance in a real-life clinic setting where both naive and highly experienced patients are being managed. In HIV-infected women, the use of an effective ART in mothers with an undetectable viral load at the time of delivery has reduced the risk of maternal to fetal HIV transmission from approximately 25% in the past to less than 1% today.

We have also decreased mortality from HIV-related illnesses over the past few decades by over 90%. These gains are not just being made in naive patients but in patients with multi-drug experience as well. In the TORO (T-20 vs. Optimized Regimen Only) trial, for example, viral loads in 45% of heavily pre-treated patients dropped <400 copies/mL after 48 weeks of lopinavir/ritonavir plus the fusion inhibitor enfuvirtide (T-20) compared with only 18% of patients on the boosted protease inhibitor (PI) regimen alone.

Similar results were seen in the RESIST (Randomized Evaluation of Strategic Intervention in Multidrug-Resistant Patients with Tipranavir) 1 and 2, where all patients had resistance to all three available drug classes, including at least one PI. Again, 43% of patients receiving boosted tipranavir plus enfuvirtide achieved a viral load of <400 copies/mL at week 48 vs. 27% on the boosted PI arm alone. Highly experienced patients enrolled in the POWER (Performance of TMC114/ritonavir When Evaluated in Treatment-experienced Patients with PI Resistance) 1 and 2 trials did quite well on boosted darunavir therapy alone, among whom 44% achieved a viral load of <50 copies/mL at week 48. Still, more patients at 58% achieved the same reduction in viral load when enfuvirtide was added to boosted darunavir, suggesting that a new compound that interferes with a third target of the HIV replication cycle significantly enhances already potent boosted PI regimens.

Indeed, it was on the strength of study findings from TORO, RESIST and POWER that HIV treatment guidelines have redefined ART therapy goals for treatment-experienced patients; namely, to re-establish maximal virological suppression and drive down viral load levels to <50 copies/mL. Fortunately, the ARTs we now use have been modified to facilitate easier adherence and we can often achieve these new low viral load goals using once-daily tablets, co-formulations and higher-strength tablets, all of which help reduce pill burden. Food restrictions and the need for refrigeration have also been largely lifted, again simplifying adherence to ART regimens.

CONFRONTING THE STUMBLING BLOCKS

Yet with all of our triumphs, much progress remains to be made. Results from the HIV vaccine trials have proved disappointing to date. Nor were there very encouraging findings from an analysis of a clinically advanced microbicide: investigators found that HIV transmission rates actually increased in patients exposed to the microbicide and there were some unexpected toxicities as well. These trials have since been discontinued.

For many reasons, our prevention methods are simply not as effective as we would have hoped, and infection rates continue to rise here and elsewhere. Then there are toxicities associated with both short-term but in particular long-term use of ART therapies, notably lipodystrophy, dyslipidemia and an increased risk of cardiovascular disease (CVD) mortality. Based on a large international cohort of over 36,000 patient-years, the D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) investigators, for example, found the relative risk of myocardial infarction in the overall cohort was 1.15 for each year patients were on PI therapy (Friis-Moller et al. N Engl J Med 2003;349(21):1993-2003).

We must continue to rely on ritonavir to boost our PI regimens and for many patients, ritonavir is not well tolerated. It also requires refrigeration in the absence of a co-formulation, which raises confidentiality issues for patients whose medicines risk being exposed when others use the same refrigerator.

But the most worrisome of all factors that threaten to undermine effective use of current ARTs is the development of drug resistance and cross-resistance within drug classes. In Canada today, approximately 10% of untreated patients already have evidence of drug resistance before treatment is started and this phenomenon is compromising our ability to establish an effective first-line regimen for at least some of them.

In a study population representative of over 200,000 HIV-positive patients being treated in the US, almost 80% of the cohort with a viral load >500 copies/mL who had samples submitted for resistance testing were resistant to any agent; 70% were resistant to the nucleoside reverse transcriptase inhibitors (NRTIs); 42% were resistant to PIs; 31% were resistant to non-NRTIs; and approximately 45% were resistant to two or three ART drug classes. Resistance testing helps us make choices about second- and third-line regimens for our treatment-experienced patients but this is only a guide and resistance patterns are often difficult to interpret, complicating therapeutic decision-making.

Nearly one-third of our HIV-infected patients are also on their third-line regimen or beyond: as patients live longer, their treatment needs will inevitably evolve as resistance to older ARTs develops.

It is therefore imperative that we continue to develop increasingly sophisticated ART agents to meet the real need for salvage therapy without the prohibitively high toxicity associated with past attempts at mega-HAART (i.e. strategies consisting of six to eight compounds).

VIRAL-ENCODED ENZYMES: UPDATE ON INTEGRASE INHIBITION

For HIV to replicate, the virus needs three viral-encoded enzymes: reverse transcriptase, protease and integrase. We already have agents that interrupt viral replication at both the reverse transcriptase and the protease stage of the replication cycle but we are just now in the process of evaluating ARTs that stop viral replication at the integrase stage. Integrase catalyzes the insertion of HIV DNA into the genome of the host cell and integration in turn is required for stable maintenance of the viral genome as well as for viral gene expression and replication.

The HIV-1 integrase strand transfer inhibitor raltegravir has demonstrated activity against multi-drug-resistant HIV. It is also additive or synergistic in vitro with other currently available ARTs. In a 10-day monotherapy study, researchers found treatment with raltegravir resulted in a 2 log reduction in viral load (Markowitz et al. J Acquir Immune Defic Syndr 2006;43(5):509-15).

A phase II study in naive patients randomized to lamivudine and tenofovir plus either efavirenz or raltegravir also showed that viral suppression was more rapid and the rate of adverse events was lower with raltegravir than with efavirenz, some 60 to 80% of patients on raltegravir achieving a viral load of <50 copies/mL at week 4 compared with 25% of patients on efavirenz (XVI International AIDS Conference 2006, Abstract THLB0214). More recently, published results from a 24-week trial of patients with triple-class-resistant virus found that the integrase inhibitor had potent ART activity when added to optimized background therapy (Grinsztejn et al. Lancet 2007;369(9569):1261-9). At week 24, the mean change in viral load from baseline was approximately -1.8 log10 copies per mL in all raltegravir dosage groups (200, 400 and 600 mg) vs. -0.35 log10 copies/mL for placebo controls. More importantly, approximately 60% of all patients receiving raltegravir, regardless of the dose, achieved a viral load of <50 copies/mL compared with only 13% of placebo controls.

As was previously observed, the ART effects produced by raltegravir were documented as early as week 4 and effects were sustained through week 24 across all raltegravir groups as well. Again at all doses, raltegravir had a safety profile similar to that of placebo and there were no dose-related toxicities.

The integrase inhibitor has now been evaluated in two phase III studies, the BENCHMRK (Blocking Integrase in Treatment Experienced Patients with a Novel Compound Against HIV: Merck)-1 study, carried out in Europe, Asia, the Pacific and Peru, and BENCHMRK-2 in North and South America. In both studies, patients were resistant to three classes of ARTs (NRTI, non-NRTIs and PIs) and had been on therapy for approximately 11 years, at an average of about 12 different drugs each. Background therapy was again optimized and patients were then randomized to either raltegravir 400 mg b.i.d. or placebo. (Enfuvirtide was used for the first time as part of the optimized background in approximately 20% of each cohort.)

The primary end point was the percentage of patients who achieved a viral load of <400 copies/mL at week 16. If patients showed signs of virologic failure at week 16 or beyond, they were able to carry on in an open-label raltegravir arm. At baseline, mean CD4+ cell counts ranged from 146 to 163 cells/mm3, while plasma viral loads ranged from 4.5 to 4.7 log10 copies/mL. A total of 462 patients combined received raltegravir in the two studies.

At 24 weeks, viral load was reduced to <400 copies/mL in 77% of raltegravir-treated patients in both studies vs. 41% of patients on optimized background therapy alone. Viral loads dropped to <50 copies/mL in 62% of patients receiving the integrase inhibitor, again in both trials, compared with 33 to 36% of optimized background controls. The best responses were seen among raltegravir patients who received both enfuvirtide and darunavir as part of their optimized background therapy but even among those patients whose optimized background did not contain either of these agents, viral loads dropped to <400 copies/mL at week 16 in almost three-quarters of patients receiving raltegravir. The toxicity profile in both studies was similar between those who received raltegravir and those who did not and experience to date suggests that the compound does not affect lipids, at least not out to 24 weeks of use.

Another compound of the same class, elvitegravir in combination with ritonavir, has been compared with a boosted PI regimen in treatment-experienced patients. In this particular study, the optimized background therapy consisted of NRTIs coupled with an investigator-selected PI vs. an optimized NRTI regimen with elvitegravir (PI use in the elvitegravir arm was initially prohibited but the use of enfuvirtide was permitted in both groups at investigators’ discretion).

At week 24, viral load had been reduced by 1.4 and 1.7 log10 copies/mL in patients who received one of the higher doses of elvitegravir (either 50 or 125 mg q.d.) vs. a reduction of 1.2 log10 copies/mL in the boosted PI arm. At week 16, approximately 40% of patients had achieved a viral load of <50 copies/mL. Again, the integrase inhibitor was well tolerated, with a similar incidence of adverse events between the treatment arms.

OTHER STRATEGIES

Another novel agent, a cellular chemokine receptor-5 (CCR5) antagonist known as maraviroc, is currently being evaluated in treatment-experienced patients as well. CCR5 is a human chemokine receptor and represents a potential host target for small-molecule antagonists to inhibit HIV infection. After 24 weeks of therapy, data from a large phase II study showed that approximately 42 to 48% of patients receiving either once-daily or twice-daily maraviroc experienced a drop in their viral load to <50 copies/mL vs. approximately 25% of control patients.

SUMMARY

Despite our remarkable successes in the management of HIV disease over the past few decades, questions and challenges remain. To begin, we still have not determined the optimal time to initiate ART therapy, although we do know that once HAART is begun, it should not be stopped. Nor do we know if the new ART agents should be reserved for salvage therapy or incorporated in first-line regimens, although those studies are currently being carried out. When the new agents do become available, our most immediate challenge will be to learn how to integrate the new ARTs into current practice—how best to combine them in which patients and at what stage of the infection. Nevertheless, the emerging ARTs with their novel therapeutic targets provide us with another opportunity to achieve meaningful improvements in clinical outcome for our patients and represent a bright new hope for the management of HIV disease now and in the future.