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13th Conference on Retroviruses and Opportunistic Infections

Denver, Colorado / February 5-8, 2006

The introduction of HAART in 1996 transformed HIV infection from a fatal condition to a chronic disorder, sending mortality into a steep and sustained decline in countries where HAART has been available. HAART fell far short of ending the crisis of HIV, but it has provided infected patients an opportunity to delay disease progression and, in some cases, achieve a normal life expectancy. While the introduction of HAART was the critical first step, some of the progress in long-term control can be attributed to subsequent advances, which include less burdensome regimens, fewer risks of adverse events, and better sequencing of drugs to preserve options when initial therapies fail.

As reported by Dr. John G. Bartlett, Professor of Medicine and Chief, Division of Infectious Diseases, Johns Hopkins School of Medicine, Baltimore, Maryland, “The disappointments in HIV have been the near total failure in prevention, the lack of a vaccine, and the lack of a cure, but the successes in producing increasingly effective and better tolerated therapies has meant millions of lives saved.” He also noted that there have been 10 new agents introduced in the decade that HAART was defined. Not all of these have played an important role in expanding therapeutic options. In some cases, advances for identifying optimal initial HAART are a result of learning how available antiretroviral agents are best combined. Most importantly, the field has moved from achieving control to sustaining control.

Lessons Learned: ACTG 384 and 5095

The advances identified by Dr. Bartlett as important to improving management of HIV, particularly in regard to first-line management, included the randomized trial demonstrating that the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz was as effective as a protease inhibitor (PI); the AIDS Clinical Trials Group (ACTG) 384 study that demonstrated not all nucleoside reverse transcriptase inhibitors (NRTIs) provide comparable long-term HIV suppression; and the ACTG 5095 study that demonstrated triple NRTIs, although well tolerated, were not as effective as an efavirenz-based HAART for sustained HIV control.

“The ACTG 5095 trial was a shot heard around the world,” observed Dr. Bartlett, who indicated that it provided several lessons. While previous studies had suggested that simple and well-tolerated regimens had advantages for compliance that may be critical for long-term HIV suppression, ACTG 5095, which compared the combination of efavirenz, lamivudine (3TC) and zidovudine (ZDV) to abacavir (ABC), 3TC and ZDV, demonstrated that simplicity had its limitations. The study was halted prematurely due to an unacceptable failure rate in the ABC/3TC/ZDV arm, a result largely attributed to a low barrier to resistance. After several years in which a variety of triple-drug combinations had provided sustained HIV suppression, ACTG 5095 reaffirmed that potency matters. New data from the ACTG 5095 trial reinforce that message from a new angle. At the time that this trial was halted, it was observed that NRTI resistance mutations, particularly K65R, were producing cross- resistance that rapidly defeated the triple NRTI combination, a phenomenon not observed when two NRTIs are combined with a third agent from a different class.

The Role of Viral Decay Measurements

However, new substudy data suggest that efavirenz plus 3TC/ZDV appeared more potent than the triple NRTI combination as measured by viral decay rates, irrespective of resistance. The substudy results were presented by Dr. Kathleen E. Squires, Chair and Director, Division of Infectious Diseases and Environmental Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.

“The median first-phase viral decay rate of 0.56/day in the group receiving the triple NRTI regimen was significantly slower than the 0.67/day rate observed in the group receiving efavirenz and two NRTIs [P=0.02],” Dr. Squires reported. “The faster decay rate in the efavirenz arm is consistent with the overall trial results demonstrating that the triple NRTI therapy was inferior for HIV control.”

In this preplanned substudy, 64 patients from the ACTG 5095 trial, of which 25 were women, were evaluated. These were relatively well distributed among the three arms of the trial, including 25 patients in the triple NRTI arm, 18 in the arm receiving efavirenz and two NRTIs, and 21 in the third arm in which patients received efavirenz plus the triple NRTIs. The mean viral load at entry was 4.8 log10 copies/mL; the mean CD4+ cell count was 292 cells/mm3. The goal of this substudy was to compare therapies for both first-phase decay rates, which is the reduction in productively infected cells, and second-phase decay rates, which is the reduction in latently infected cells. The substudy also had a prespecified goal of comparing decay rates in men and women.

Second-phase decay rates did not differ significantly between the three groups, although there was a trend for an advantage in the group receiving efavirenz plus two NRTIs when compared to the triple NRTIs (P=0.09). In the analysis of first-phase decay, the difference was significant in favour of efavirenz plus two NRTIs. In the arm receiving efavirenz plus all three NRTIs, the decay rate was lower than that observed in the triple NRTI regimen (0.59/day vs.0.67/day), but the difference was not significant. However, it was noted that both efavirenz-containing regimens had an even greater relative advantage over the triple NRTI regimen for first-phase viral decay when there was a high baseline viral load. There were no significant differences in viral decay rates by gender.

The difference in decay rates may have contributed to the greater efficacy of the efavirenz-based triple therapy over the triple NRTI therapy in ACTG 5095 due to the likelihood that a faster elimination of infected cells would reduce opportunities for virologic failure. Previous studies have suggested that patients are unlikely to achieve a viral load of <400 copies/mL by 24 weeks if this level of suppression has not been reached within 16 weeks of starting therapy. The importance of rapidly achieving and then maintaining virologic control was one of the points emphasized by Dr. Bartlett.

“We have no promising approaches to eradicating latently infected cells, so at least for the time being, we are stuck with HIV as a chronic infection. The data suggest that there is a risk of HIV progression if viral load climbs above 50 copies/mL, so the goal is to achieve and maintain this level of viral suppression,” Dr. Bartlett told delegates.

Ongoing Search for Optimal Method of Viral Load Suppression

The concept that viral load should be maintained as low as possible has been well documented, but the definition of the best path to this goal continues to evolve. In the early days of HAART, the demands of the treatment regimens, which included complicated timing and dietary restrictions, made compliance an important obstacle to sustained suppression. Significant adverse events, such as persistent diarrhea, posed additional obstacles. Newer therapies with fewer acute adverse events and simpler dosing have served as important advances after potent HAART regimens became available. However, many adverse events not initially recognized as obstacles to long-term control, such as dyslipidemias and lipodystrophies, have subsequently had a negative impact on compliance and patient satisfaction. For the future, trials that are able to refine relative advantages between options will be critical to the evolution of HIV treatment.

As mentioned by Dr. Bartlett, “One of the key trials going forward will be ACTG 5142, which is comparing an efavirenz-based HAART to a lopinavir/ritonavir-based regimen.” This comparison has the potential to be revealing because of the different characteristics of these two therapies. While efavirenz plus two NRTIs is the most widely used initial HAART regimen in many countries, lopinavir/ritonavir has been a mainstay of PI therapy. Several advantages are credited with making efavirenz one of the most commonly prescribed front-line therapies, such as once-daily dosing and a low relative risk of hypercholesterolemia when compared to such PIs as lopinavir/ritonavir. However, the two agents have not been compared in a randomized trial. Dr. Bartlett indicated that a direct comparison has the potential to provide insight about how the specific characteristics of these two therapies influence long-term HIV suppression.

Summary

In the 10 years that HAART has been available, the principle of HIV suppression has not changed. An effective first-line regimen requires multiple drugs from at least two classes that pose a high barrier to resistance. However, numerous studies conducted over the past 10 years have been influential in refining the concepts that contribute to efficacy, such as both short-term and long-term tolerability and regimen simplicity. Despite the disappointment in identifying cures for HIV, which appear to remain about as distant now as they were 10 years ago, the progress in defining what regimens maintain control is bringing clinical medicine closer to the goal of permitting infected patients to achieve a normal life expectancy.