Important note: Information in this article was accurate in January 2005. The state of the art may have changed since the publication date.
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On October 29, 2004, the DHHS released the most recent version of the federal guidelines for use of antiretroviral agents in HIV-infected adults and adolescents. Guidelines for use of anti-retroviral agents in HIV-1-infected adults and adolescents [Panel on Clinical Practices for Treatment of HIV Infection, Department of Health and Human Services (DHHS)]: This is a draft version posted on the AIDSInfo web site, http://AIDSinfo.nih.gov, with a request for comments, which should be sent to aidsinfowebmaster@aidsinfo.nih.gov. This document has been entirely rewritten. The most important changes are summarized in the “Indications to Treat” table on this page.
Minor changes in this section include a more precise definition of symptomatic HIV infection as an indication for therapy regardless of CD4 cell count or viral load. Additionally, the threshold viral load for considering therapy in asymptomatic patients with a CD4 count above 350 cells/mm3 has been increased to 100,000 c/mL. The specific recommendations for initiating antiretroviral therapy are summarized in the following table:
This section has been entirely revised to reflect: 1) availability of emtricitabine (FTC),
2) concern about the long term toxicity of stavudine (d4T), and 3) endorsement of tenofovir (TDF) plus lamivudine (3TC) or FTC as a recommended NRTI backbone. The regimen recommendations are summarized below.
In previous versions of the guidelines, it was stated that resistance testing in the setting of virologic failure must be performed while the patient is on therapy. This has now been changed to allow testing during administration or up to four weeks after discontinuation of therapy. This change is based on the results of multiple studies indicating that replacement by wild-type HIV occurs at least four weeks or later after discontinuation. Baseline resistance testing in chronically infected, treatment-naïve patients was not felt to be indicated in previous guidelines, but is now considered “an option.” This change is based on studies showing that resistance mutations in transmitted strains may persist for prolonged periods, although this is quite variable.
Planned Treatment Interruption
This is a new section of the guidelines that states that all antiretroviral agents should be stopped simultaneously when discontinuing therapy. The possible exception is in nevirapine- or efavirenz-containing regimens. Since serum concentrations of these drugs may persist for 21 days or longer, simultaneous discontinuation may result in a prolonged period of monotherapy. No specific strategy has been adequately studied to allow for a specific recommendation, but some authorities recommend discontinuation of the NNRTI before discontinuation of the nucleoside analogs, while others substitute a PI for 2-4 weeks prior to interruption to deal with this potential complication.
A second concern with respect to discontinuation is the possibility of a flare of HBV with the discontinuation of emtricitabine, lamivudine or tenofovir. The current recommendation in such cases is to carefully monitor such patients or to give adefovir.
A review of published studies on planned treatment interruption was conducted to establish recommendations in various clinical settings. Available data indicate that planned interruption cannot be recommended in patients experiencing virologic failure with resistance to multiple drugs in order to allow re-emergence of wild-type HIV. Treatment interruption is also not indicated in patients with acute HIV infection who have achieved virologic suppression in an attempt establish a better virologic set-point. However, discontinuation “may be offered” to patients who have experienced immune reconstitution (the “CD4-guided” treatment interruption strategy), although participation in a controlled trial would be preferred.
There are now sections dealing with HIV infection and antiretroviral therapy in adolescents, injection drug users, patients coinfected with hepatitis B or C, and patients with TB co-infection.
The latest version of the guidelines includes 29 tables. New tables include a tabulation of published clinical trials with 48 week outcome results and a comprehensive table dealing with adverse reactions. In addition, all of the previous tables have been extensively revised and updated.
The guidelines now define virologic failure as failure to achieve a viral load <400 c/mL at 24 weeks, failure to achieve a viral load <50 c/mL at 48 weeks, or a confirmed virologic rebound after virologic suppression. Immunologic failure is defined as the failure of the CD4 count to increase by 25-50 cells/mm3 over baseline during the first year, and clinical progression is defined as occurrence of an HIV-related event after at least three months of HAART. For practical purposes, recommendations for changing antiretroviral therapy are based on exclusively on virologic failure.
The guidelines contain a rewritten section on virologic failure that is too complicated to summarize. However, the key principles are 1) to assess adherence, intolerance and pharmacokinetic issues that may account for failure; 2) to use results of all current and prior resistance tests as well as drug treatment history in selecting a new regimen; 3) to employ at least three active agents; and 4) to use new agents, including drugs from new classes such as HIV entry inhibitors, when necessary.
Expertise: The panel recommends that HIV care should be provided by a clinician who has a patient load of at least 25 active HIV-infected patients.
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