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A Guide to Primary Care of People with HIV/AIDS Chapter 5: Antiretroviral Therapy 5 Table 5-4. Definitions of Therapeutic Failure Type Virologic failure Immunologic failure Clinical failure Definition Initial therapy: failure to decrease viral load by 1 log 10 c/mL by 1-4 weeks, to 25-50/mm 3 / year (this is an arbitrary definition; the average increase with viral suppression by the above definition is an increase of 100- 150 c/mm 3 /year). HIV-related complication, usually an AIDS-defining condition after antiretroviral therapy for ≥3 months. WHAT TO CHANGE TO How do you address intolerance or serious side effects? Assuming virologic control has been achieved, the goal is to find a substitute for the offending agent. In most cases, this is simply a single drug substitution using an agent in the same class with comparable potency. For example, for zidovudine (AZT) intolerance, stavudine (d4T) is commonly substituted. For indinavir-associated nephrolithiasis, the usual tactic is to reduce the dose, increase fluid intake, or substitute another PI for indinavir (IDV). What is intensification? Intensification is the addition of a drug, usually a single drug, to enhance antiretroviral activity in a patient who has a good but suboptimal response to therapy. This needs to be done at a time when the viral load has not increased to too high a level; for example, most authorities consider a viral load of >5,000 c/mL to be an indication for a completely new regimen. Common ploys for intensification are the addition of tenofovir (TDF) or abacavir (ABC), or a boosting of a PI with ritonavir (RTV) if that was not done initially. How do you deal with virologic failure? The usual method is to measure HIV resistance. If the strain is sensitive, it is important to closely examine the adherence issue or look for drug interactions or some other reason that the antiretroviral agent does not reach the virus. If the virus is resistant, this information is used to select the next regimen as described below. RESISTANCE TESTING What are the tests? There are 2 types of resistance tests: genotypic and phenotypic. Genotypic resistance measures mutations to the genes that are the target of antiretroviral drugs. These mutational changes predict resistance. Phenotypic resistance measures the activity of various drugs against the patient’s virus compared with “wild type” virus (untreated HIV strains). These tests are quite different in method of performance, but there is no consensus regarding their relative merit. Many people use genotypic resistance testing most frequently because it is faster and cheaper. Under any circumstances, interpreting both tests requires substantial expertise. It should be emphasized that the testing is valid only for the drugs that are being given at the time the test is done; drugs discontinued >2-6 weeks earlier may not be reliably tested because the resistant strains often become “minority species” when drug pressure is removed. Thus, a history of prolonged ART and virologic failure in the past often indicates resistance even if this is not revealed with the current test. What are the indications and requirements for resistance testing? The major indication for resistance testing is virologic failure, but testing is also sometimes done prior to initiation of therapy (see Table 5-5). The requirement for testing after virologic failure is an adequate viral load (usually >1,000 c/mL) to do the test. For patients who have failed therapy it is standard practice to sample while the drugs of interest are being given. Resistance to drugs discontinued >2-6 weeks before testing may not be expressed in the resistance testing, although this probably differs by individual patient and specific agent and has not been extensively studied. 32 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau
A Guide to Primary Care of People with HIV/AIDS Chapter 5: Antiretroviral Therapy Table 5-5. Resistance Testing Patient status Recommendation Comment Primary HIV infection Consider testing There are no studies to show use in this setting alters outcome of therapy, but the viral population is presumed to be relatively homogeneous, giving theoretical reliability to testing. Chronic infection – treatment-naive Chronic infection – treatment failure on therapy • First failure • Multiple failures Consider testing Recommended if testing requirements are met Recommended if testing requirements are met The concern is that resistant HIV may be archived making the test less reliable. Testing at this stage is best for predicting which agent will not work. Need viral load of >1000 c/mL to do the test. Patient may need to be receiving the antivirals that failed at the time of the test for resistance to be expressed. Resistant strains from prior therapy may not be expressed in the majority of strains tested; it is important to select next a regimen based on the current resistance test results, prior resistance tests, and treatment history. How should you treat someone who has run out of options? Extensive use of ART over several years combined with virologic failure and resistance leads to limited options for many patients. However, it appears that antiretroviral drugs are still beneficial in these patients because of reduced “fitness” of the virus. The implication is that the antiretroviral drugs force development and persistence of resistant mutations, and these mutated strains have reduced replicative capacity in vitro and presumably in vivo as well. Several studies show that discontinuation of ART is often followed after 4-8 weeks by a significant increase in viral load and a very rapid decline in the CD4 cell count. Thus, the goal of therapy for heavily treated patients who have few therapeutic options is often to continue these drugs despite virologic failure with the hope of maintaining the CD4 cell count and preventing HIV-related complications. Virologic control would be nice, but may be impossible or unrealistic. What is therapeutic drug monitoring (TDM)? TDM is the measurement of serum concentrations of antiretroviral drugs to determine if there are adequate levels to assure antiviral activity or to account for toxicity. Relatively few laboratories offer the test, and interpretation is confounded by limited experience and great variability among laboratories testing the same samples. Nucleosides are not tested because this would require measuring intracellular concentrations. It is usually PIs, which may have marginal levels, and to a lesser extent NNRTIs that are tested. Although TDM is not common in clinical practice at present, many experts feel it may become a standard component of treatment in the future with better standardization and more information about how to use the tests. The anticipated use is in situations in which levels are difficult to predict, as in renal failure, hepatic failure, pregnancy, concurrent use of drugs with possible drug interactions, use of once-a-day PIs with concerns about trough levels, and the monitoring of adherence. When is structured treatment interruption (STI) indicated? Although there are 4 reasons to suspend treatment temporarily, pulse therapy appears to be the most promising. • Immunization One rationale for STI, when used with patients who have prolonged virologic control, is to stop therapy to let the virus come back and “immunize” the patient in a fashion analogous to a vaccine. The theory seemed good, but has not proven successful, and most have abandoned this tactic except with the rare patient who was treated very early in the course of the disease. • Treatment failure A rationale for discontinuing treatment when it has failed due to drug resistance is to allow growth of “wild type virus” that is sensitive to antiretroviral agents. The theory, that STI would permit a new round of therapy against sensitive virus, has not proven successful for possibly predictable reasons. In many or most patients, the resistant strains are minority species that quickly become the dominant strains under renewed antiviral pressure. 5 U.S. Department of Health and Human Services, Health Resources and Services Administration, HIV/AIDS Bureau 33
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