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Quality and Quantity in HIV Treatment: A Discussion of the Quad Therapy
Symposium Presented at ICAAC
A Summary by Kimberly Smith MD, MPH
For NATAP
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Symposium was CME accredited by Rush Medical College of Rush University
Rush-Presbyterian-St. Luke's Medical Center through an independent educational grant from GlaxoSmithKline
The new HIV treatment paradigm of quadruple (quad) therapy was recently discussed at a CME symposium at ICAAC. Presenters included Martin Markowitz, Calvin Cohen and Michael Norton, and the program was moderated by Kimberly Smith. This program reviewed new treatment models involving quad therapy, retroviral resistance, and viral dynamics as they relate to antiretroviral treatment initiation and the long-term management of patients with HIV disease. The central issue of the talks was whether clinical outcomes could be improved in HIV patients by the addition of a fourth antiretroviral agent.
Therapeutic regimens consisting of 4 active drugs are commonly being used as second, third, fourth and even fifth line regimens, specifically in those patients who have had resistance or rebound after their first or second line therapies. Many clinicians have begun to use quad regimens as first line therapy yet this treatment strategy remains quite controversial. The reasons for even examining these issues are that three drug regimens, the current standard of care, often do not adequately and durably control viral replication and may result in virologic rebound, as well as emergence of viral resistance which limits further treatment options. The addition of a fourth drug may improve the potency of the regimen thus improving its efficacy and durability. On the other hand some newer three drug regimens are beginning to demonstrate improved efficacy over the often cumbersome PI based regimens of the early HAART era.
Martin Markowitz reviewed the in vivo dynamics of HIV-1 infection which form the scientific rationale for combination therapy. The emergence of drug-resistant viral variants poses a challenge to effective pharmacological intervention at any stage of infection. Viral diversity is a consequence of high levels of viral replication. Since the mutation rate can be predicted based on the viral dynamics and the genome size, a mathematical model suggests that mono- and dual therapy have a high likelihood of failure. Even triple therapy may be at risk of failure in situations of advance disease and/or in the presence of pre-existing resistant variants. However, the model suggests that quad therapy would be less likely to fail in drug-naive patients harboring wild-type virus and in those harboring resistance to single agents. The dynamic nature of HIV replication combined with issues of genetic variation erect a barrier to effective therapy, particularly in patients with advanced disease and high baseline pretreatment viral loads. These factors suggest that compact, potent, and well-tolerated quad regimens may improve response to treatment in these challenging patient populations.
Calvin Cohen reviewed a number of recent clinical trials which evaluated the safety and efficacy of quad therapy. To date, the comparative trials have evaluated protease inhibitor (PI)-containing quad regimens. Both the AIDS Clinical Trials Group (ACTG) 388 and the ACTG 384 trials have compared PI-containing quad regimens to that of triple therapy in mostly treatment-naive patients. In the ACTG 388 trial, patients with advanced HIV were treated with lamivudine/zidovudine/indinavir plus either nelfinavir or efavirenz. While the efavirenz arm was well tolerated and resulted in a statistically superior better virologic response, the addition of nelfinavir actually worsened the response rate. ACTG 384 compared 4 drug regimens including efavirenz and nelfinavir plus either zidovudine/lamivudine or stauvidine/didanosine to three drug regimens containing the same nucleoside backbones with either efavirenz or nelfinavir. In this study initiating therapy with a quad regimen significantly delayed the time to first virologic or regimen failure when compared to three-drug regimens, except when compared to zidovudine/lamivudine/efavirenz. The NZTA4002 study is another clinical trial in which triple therapy with lamivudine/zidovudine plus nelfinavir in treatment-naive patients faired better than quadruple therapy with lamivudine/zidovudine plus amprenavir and abacavir. The results in this case, however are indicative of the choice of drugs tested; the negative results reflect the poor tolerability of the individual agents comprising the quad regimens. Data from these trials suggests that quad therapies may have greater potency than some three drug regimens, however studies have yet to consistently demonstrate better clinical outcomes of quad regimens compared to effective three drug regimens. The possibility remains however that more compact quad regimens may benefit from increased potency and tolerability and yield improved clinical outcomes.
Several studies have shown significant potency with the use of quad regimens of varied drug combinations. In some cases there can be more rapid viral load decline, which may decrease the chance of development of resistance. Two pilot studies showed that PI-sparing quad regimens have yielded favorable results. Trials such as the CNAF3008 and the COL30336, although involving small numbers of patients, have demonstrated a favorable potency, durability and tolerability with a compact (3 pill) abacavir/lamivudine/zidovudine/efavirenz quad regimen.
To date, no study has definitely shown that quad therapy has been more effective in comparison to a triple drug regimen. A number of ongoing trials, including ACTG5095 (AZT/3TC/ABC vs AZT/3TC/EFZ vs AZT/3TC/ABC/EFZ) and COL40263 (single class quads: abacavir/lamivudine/zidovudine (qd) plus tenofovir), have recently been initiated to test whether quad regimens are as effective as triple therapy.
An additional issue raised by the use of quad therapy is that of induction/maintenance treatment strategies. Once viral suppression can be attained using quad therapy, treatment can be de-intensified by stopping one agent and continuing a three drug regimen? Michael Norton reviewed the SUBURBS study in which subjects switched from a four drug regimen of ZDV/3TC/ABC/EFZ to ZDV/3TC/ABC after 48 weeks. In this study viral suppression and immunologic improvements were maintained, in addition, significant decreases in cholesterol were noted following the switch. The success of this and other similar studies prompted the development of a randomized trial, ESS40013, to further test this strategy. In this study, subjects initiated treatment with ABC/3TC/ZDV/EFV for 48 weeks then were randomized to continue the quad vs discontinue EFV and continue the three drug regimen. This study has completed enrollment and results are expected in 2003. In general, these trials will optimize the quad regimen to yield greater efficacy while sparing PIs and the toxicity often associated with their use.
Interesting questions that have yet to be answered regarding the role of quad therapy in the treatment of HIV include: Will a single-class quad regimen preserve future therapeutic options more than a multiclass quad regimen? Would minimizing the number of classes incorporated in a regimen diminish toxicities and improve adherence? It can be hypothesized that failure of multiclass quad regimens potentially limits the future treatment options, especially if combinations of agents are used that may lead to cross class resistance. This could leave the patient vulnerable to limited future treatment options. Conversely, a more potent quad regimen may actually limit viral replication more effectively and diminish the chance of developing resistance, with one or two class quad regimens preserving future treatment options even better. The new availability of the once a day agents that do not add very much to the pill burden certainly offers the option of using a single class quad regimen. However, the possibility of severely weakening the nucleoside class with the first regimen remains a significant concern that will only be addressed through clinical trials. Compact quad therapies such as those being tested in the ACTG 5095 and other studies will help to determine if well tolerated quads offer greater potency and durability without compromising tolerability thus warranting the addition of the fourth drug.
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