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New 2006 Recommendations of the International AIDS Society-USA Panel
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JAMA. Aug 16 2006;296:827-843.
In Toronto at IAS, Scott Hammer and colleagues present updated guidelines from the International AIDS Society - USA panel for starting antiretroviral therapy, the regimen to use, monitoring of patient response, and circumstances that should prompt changes in therapy.
Scott M. Hammer, MD; Michael S. Saag, MD; Mauro Schechter, MD, PhD; Julio S. G. Montaner, MD; Robert T. Schooley, MD; Donna M. Jacobsen, BS; Melanie A. Thompson, MD; Charles C. J. Carpenter, MD; Margaret A. Fischl, MD; Brian G. Gazzard, MA, MD; Jose M. Gatell, MD, PhD; Martin S. Hirsch, MD; David A. Katzenstein, MD; Douglas D. Richman, MD; Stefano Vella, MD; Patrick G. Yeni, MD; Paul A. Volberding, MD
The International AIDS Society-USA panel has published its antiretroviral therapy guidelines 7 times since 1996, a period that coincides with the rapid evolution in practice brought on by the HAART era. The rationale for issuing revised guidelines in 2006 is based on several developments: (1) continued refinement of the recommended initial treatment regimen with a focus on the nucleoside (or nucleotide) reverse transcriptase inhibitor (nRTI) components of nonnucleoside reverse transcriptase inhibitor (NNRTI)- and protease inhibitor (PI)-based regimens; (2) the US Food and Drug Administration (FDA) approvals of tipranavir and darunavir, which provide new options for management of treatment-experienced patients; (3) the redefinition of the goal of regimens for highly treatment-experienced patients to achieve plasma human immunodeficiency virus 1 (HIV-1) RNA levels below assay detection limits; (4) the availability of a triple-drug combination formulated in 1 pill to be given once daily; and (5) new information on drug-sparing therapeutic strategies, such as supervised treatment interruptions and ritonavir-boosted PI monotherapy.
"...treatment interruption for successfully treated patients is not recommended outside of clinical trials- In the setting of treatment experience, resistance testing should be performed while the patient is taking the failing regimen. -- Trials with newer antiretroviral agents have shown that it is possible to achieve plasma HIV-1 RNA levels below 50 copies/mL even in highly treatment-experienced patients- If at least 2 drugs cannot be identified, strong consideration should be given to maintaining the current regimen until new drugs become available, assuming immunologic and clinical stability -... If several potent drugs other than enfuvirtide are available, it may be best to defer enfuvirtide use until it becomes 1 of 2 available and fully active drugs (AII). However, since the goal of therapy is to achieve plasma HIV-1 RNA levels of less than 50 copies/mL, enfuvirtide often is required to achieve this degree of success among heavily antiretroviral-experienced patients-... Resistance assays may also be of value in selecting the initial treatment regimen, because transmission of drug-resistant HIV strains leading to suboptimal virologic responses... For patients without symptoms, therapy should be initiated at some point after the CD4 cell count declines below 350/μL but before it reaches 200/μL...:
On the horizon are investigational antiretroviral drugs in existing classes such as the NNRTIs etravirine and TMC-278, as well as drugs in novel classes. The development of CCR5 inhibitors illustrates the complexity and unpredictability of antiretroviral agent development. For example, CCR5 coreceptor antagonists have encountered challenges. Aplaviroc's development was stopped because of hepatotoxicity. Vicriviroc's development in treatment-naive patients was discontinued because of unexpected virologic failures and the drug is being carefully scrutinized to determine if lymphoma development is potentiated by the drug in treatment-experienced persons. Maraviroc's development in both treatment-naive and treatment-experienced persons is ongoing. Encouragingly, integrase inhibitors (MK-0518 and GS-9137) are showing promise,132-133 and proof-of-principle for the maturation inhibitor, PA-457, has been demonstrated in humans.134 It is quite possible that paradigms of treatment will be altered by 1 or more of these agents-that is, when to start therapy and with what, may well change in the years ahead.
Either of 2 basic 3-drug regimens continues to be recommended for initial therapy: NNRTI-based or PI ritonavir-boosted-based combinations. Of the NNRTIs, efavirenz is recommended due to its consistent efficacy demonstrated in numerous randomized trials and its toxicity profile
Of the ritonavir-boosted PIs, recommended components are lopinavir (AIa), atazanavir (BIII), fosamprenavir (BIII), or saquinavir (BIII)... Either of 2 basic 3-drug regimens continues to be recommended for initial therapy: NNRTI-based or PI ritonavir-boosted-based combinations. Of the NNRTIs, efavirenz is recommended due to its consistent efficacy demonstrated in numerous randomized trials and its toxicity profile ...... Recommended nRTI components in the initial regimen are tenofovir and emtricitabine (AIa), zidovudine and lamivudine (AIa), or abacavir and lamivudine (AIa). Tenofovir is well tolerated but should be used with caution, or avoided, in patients with preexisting renal insufficiency (AIa).
When to Change and What to Change
Recent Data
Despite availability of regimens that are potent, well tolerated, convenient, and relatively easy to take, many patients still require a change in regimen, often related to treatment-related toxic effects, intolerance, inconvenience, or failure. Trials with newer antiretroviral agents have shown that it is possible to achieve plasma HIV-1 RNA levels below 50 copies/mL even in highly treatment-experienced patients.66-67 Similarly, several studies have demonstrated that many treatment-related toxic effects can be avoided, reversed, or at least partially controlled with judicious modifications of antiretroviral regimens.68-69
Changing for Treatment Failure
The benefits of plasma HIV-1 RNA suppression to less than 50 copies/mL on durability of response and prevention of emergence of resistance support using persistent elevations above this cutoff as a definition of virologic failure. Previous guidelines recommended establishing a plasma HIV-1 RNA target of at least 0.5 to 1 log10 HIV-1 RNA copies/mL below baseline for patients with more advanced treatment failure and a high level of multidrug resistance. However, several recent studies evaluating newer antiretroviral agents designed to have activity against multidrug-resistant virus have demonstrated that a high proportion of heavily treatment-experienced patients can achieve HIV-1 RNA levels of less than 50 copies/mL.66, 72-73 When this is not achievable, stability of CD4 cell count and clinical status usually can be maintained for relatively long periods with reductions of HIV-1 RNA to levels at least 0.5 to 1.0 log10 copies/mL below baseline, although cumulative acquisition of new resistance mutations is a consequence of this approach. Isolated episodes of intermittent viremia or transient episodes of plasma HIV-1 RNA levels higher than 50 copies/mL but lower than 500 to 1000 copies/mL do not necessarily predict subsequent virologic failure and should not prompt an immediate change in therapy.74
For selecting subsequent therapy, data from recent trials showed no benefit of double-boosted PIs (2 active PIs and low-dose ritonavir) over single-boosted PIs.66, 72 Moreover, pharmacokinetic interactions, tolerance, and long-term adverse effects complicate double-boosted PI therapy.
Drug-Sparing Strategies
Ritonavir-Boosted PI Monotherapy. The potency and high genetic barrier to resistance of ritonavir-boosted PIs might make them potentially useful as initial therapy or as part of a simplification strategy. In the OK study, 42 participants were randomly assigned to continue lopinavir and ritonavir plus 2 nRTIs or to begin lopinavir and ritonavir monotherapy following suppression to less than 50 copies/mL on lopinavir and ritonavir plus 2 nRTIs. At 48 weeks, 81% and 95% of the participants in the 2 groups, respectively, maintained HIV-1 RNA levels lower than 50 copies/mL. This was not statistically different because the numbers in the trial were small.75 In the single-group, pilot ACTG A5201 study76 of 36 participants, simplification of therapy to atazanavir and ritonavir alone following 6 weeks of induction with atazanavir and ritonavir plus 2 nRTIs resulted in a 91% rate of suppression of plasma HIV-1 RNA to less than 50 copies/mL at 24 weeks. In both of these studies, PI mutations were not detected in the patients in whom monotherapy failed virologically. These data are still preliminary but add to the growing experience with nRTI-sparing strategies and suggest that further studies are warranted.
Treatment Interruptions and Intermittent Therapy.
Recent studies have demonstrated no beneficial effect, and sometimes deteriorating clinical outcomes, by using structured (or supervised) treatment interruptions (STIs) as a treatment strategy. Two general approaches have been evaluated: therapy interruption done at predefined intervals of time or interruption based on targeted CD4 cell responses.
The Staccato,77 Window,78 Trivacan,79 and Istituto Superiore di Sanita Pulsed Anti-Retroviral Therapy (PART)80 studies each looked at variable or fixed intervals of treatment interruptions that lasted from weeks to months. A common theme that emerged is that short intervals of stopping and starting therapy can be associated with relatively high rates of emergence of drug resistance and are generally not advisable. Longer intervals of starting and stopping therapy may not result in significantly more failure, but there is no clear consensus on the safety and value of this approach.
Other studies used CD4 cell count triggers of treatment interruption. The Strategies for Management of Anti-Retroviral Therapy study81 evaluated routine interruption of therapy when CD4 cell counts reached a threshold of more than 350/μL and reintroduction of therapy when the CD4 cell count decreased to less than 250/μL vs continuous therapy. There was increased progression to a new AIDS-defining event or death, as well as more non-HIV-related serious adverse events among those in the STI group than those in the control group. Similarly, the group whose treatment was interrupted by CD4 cell count in the Trivacan study was discontinued early as a result of an increased incidence of severe morbidity.78
Available data from ongoing trials evaluating treatment interruptions at higher CD4 cell counts are difficult to interpret, given their lack of statistical power to compare clinical end points.77, 80, 82
Some studies that used STI as a means to improve immunologic host responses to HIV through autoimmunization have shown some improvement in the level of HIV-1 viremia in the STI group compared with the control group. In one such study, the effect of the STI was small and several participants developed mutations associated with resistance to the drugs in their discontinued regimens and had difficulty reestablishing control of replication when therapy was reintroduced.83
New Drugs
Since the previous guidelines, 2 new drugs have become available for use in treatment-experienced patients.
Tipranavir. A PI designed to have activity against multi-PI-resistant virus is the combination of 500 mg of tipranavir with 200 mg of ritonavir twice a day. The Randomized Evaluation of Strategic Intervention in Multi-drug Resistant Patients with Tipranavir (RESIST) trials I84 and II75, 85 evaluated tipranavir in patients in whom PI-, NNRTI-, and nRTI-containing regimens had failed. Patients who had 2 or more mutations associated with high-level tipranavir resistance were not eligible for enrollment. The 2 studies had similar inclusion criteria and were conducted in North America, Europe, Australia, and Latin America. The tipranavir-plus-ritonavir group demonstrated greater reductions in plasma HIV-1 RNA levels and increases in CD4 cell counts than did the comparator PI group when each was combined with optimized background regimens. Of note, in this heavily treatment-experienced population, | | | |
