The Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents has updated guidelines for the use of antiretroviral (ARV) agents for HIV-1-infection in this population. The guidelines were posted onlineJanuary 10.
The DHHS panel, a working group of the Office of AIDS Research Advisory Council, aimed to provide recommendations for clinicians based on current evidence regarding ARV drugs used to treat adults and adolescents with HIV infection in the United States. The new guidelines, which update those issued December 1, 2009, highlight baseline evaluation; treatment goals; indications to begin ARV therapy (ART); choice of initial therapy in ART-naive patients; drugs or combinations that should be avoided; management of adverse effects, drug interactions, and treatment failure; and specific ART-related considerations applicable to various patient subgroups.
"...ART for the treatment of ...HIV infection has improved steadily since the advent of potent combination therapy in 1996," write panel co-chairs John G. Bartlett, MD, from Johns Hopkins University in Baltimore, Maryland, and H. Clifford Lane, MD, from National Institutes of Health in Bethesda, Maryland, and colleagues. "New drugs have been approved that offer new mechanisms of action, improvements in potency and activity even against multidrug-resistant viruses, dosing convenience, and tolerability."
Specific Updated Changes
Specific changes in these updated guidelines from the December 1, 2009, version of the guidelines include the following:
- The DHHS panel highlighted the importance of clinical research to answer remaining questions concerning the optimal safety and efficacy of ART, and it therefore encourages both protocol development and patient enrollment in well-designed, Institutional Review Board–approved clinical trials.
- For a patient receiving a suppressive ART regimen with a CD4 T-cell count well above the threshold for risk for opportunistic infection, clinicians seldom use changes in CD4 T-cell count to make decisions regarding ART changes. Therefore, the panel now recommends that the CD4 T-cell count may be monitored less often in such patients, such as every 6 to 12 months vs every 3 to 6 months, provided there are no clinical status changes, including the patient having new HIV-associated clinical symptoms or beginning treatment with interferon, corticosteroids, or antineoplastic agents.
- For some viral load assays, low-level positive viral load results (usually < 200 copies/mL) have been commonly reported. To eliminate most cases of viremia caused by isolated blips or test variability, the panel now defines virologic failure as a confirmed viral load of more than 200 copies/mL for the purpose of patient monitoring.
Recommendations on Drug-Resistance Testing
New recommendations regarding drug-resistance testing include the following:
- More specific recommendations are given regarding when to use genotypic testing to identify resistance to integrase strand transfer inhibitors (INSTIs).
- If transmitted INSTI resistance is suspected, it may be helpful to include genotypic testing for INSTI resistance because standard genotypic drug-resistance testing involves testing only for mutations in the reverse transcriptase and protease genes.
- For patients in whom an INSTI-based regimen fails, genotypic testing for INSTI resistance should be considered to help decide whether a drug from this class should be included in subsequent regimens.
Combination Regimens
Changes to the "What to Start" recommendations regarding initial combination regimens for the ARV-naive patient include the following:
- Maraviroc plus zidovudine/lamivudine is now considered to be an "Acceptable Regimen" after US Food and Drug Adminstration approval of maraviroc for use in ART-naive patients, based on findings from a randomized controlled trial using maraviroc plus zidovudine/lamivudine.
- Maraviroc plus tenofovir/emtricitabine and maraviroc plus abacavir/lamivudine are now considered to be regimens that may be acceptable, although additional definitive data are needed.
- Ritonavir-boosted saquinavir–based regimens are now designated as "Regimens that are Acceptable but Should be Used with Caution" vs "Alternative PI[Protease Inhibitor]-based Regimens." This change reflects a recent change in the Invirase (Genentech) product label because significant PR and QT interval prolongations were found in a healthy volunteer study.
Coinfection With Hepatitis B Virus
More specific recommendations are offered for treatment of patients with HIV coinfected with hepatitis B virus, including recommendations for patients with lamivudine/emtricitabine–resistant hepatitis B virus infection and for those unable to tolerate tenofovir-based regimens.
Coinfection With Tuberculosis
Updates to management of Mycobacterium tuberculosis/HIV coinfection reflect survival and clinical benefits of starting ART earlier in treatment-naive patients with active tuberculosis (TB) disease, based on findings from recent randomized controlled trials. The following recommendations address initiating ART in patients being treated for active TB but not yet on ART:
- ART should be given to all HIV-infected patients with diagnosed active TB.
- Patients with a CD4 T-cell count of less than 200 cells/mm3 should start ART within 2 to 4 weeks of starting TB treatment.
- Patients with a CD4 T-cell count of 200 to 500 cells/mm3 should start ART within 2 to 4 weeks, or at least by 8 weeks after starting TB treatment.
- Most panel members also recommend that patients with a CD4 T-cell count of more than 500 cells/mm3 start ART within 8 weeks of TB therapy.
New Table Formats
The most common and/or severe known ARV-associated adverse events, listed by ARV drug class, are displayed in a new table format.
Several sections and pertinent tables have also been updated, including those on coreceptor tropism assays, treatment goals, starting ART in treatment-naive patients, what drugs and regimens not to use, virologic and immunologic failure, regimen simplification, exposure-response relationship and therapeutic drug monitoring for ARV agents, acute HIV infection, HIV and illicit drug users, HIV-2 infection, drug interactions, and drug characteristics.
"The provider can make recommendations most likely to lead to positive outcomes only if the patient's own point of view and social context are well known," the panel concludes. "...The Panel anticipates continued progress in the simplicity of regimens, improved potency and barrier to resistance, and reduced toxicity. The Panel hopes the guidelines are useful and is committed to their continued adjustment and improvement."
Financial disclosures for members of the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents are available on the DHHS' AIDS Info site.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011.
Clinical Context
Treatment of HIV with antiretroviral therapy has improved steadily since the development of potent combination therapy in 1996. Since then, new drugs have been approved, offering new mechanisms of action and improvements in potency, dosing convenience, and tolerability. The DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents provides recommendations for HIV care practitioners based on current knowledge of ARV drugs.
The aim of this review is to provide new evidence and updates on current recommendations of HIV monitoring and treatment in adults and adolescents.
STUDY HIGHLIGHTS
- Key changes to update the December 1, 2009, version of the guidelines are summarized in the following:
- Frequency of CD4 T-cell count:
- For the patient on a suppressive regimen whose CD4 cell count has increased well above the threshold for opportunistic infection risk, the panel recommends that the CD4 count be monitored less frequently (eg, every 6 - 12 months instead of every 3 - 6 months), unless there are changes in the patient's clinical status, such as new HIV-associated clinical symptoms or initiation of treatment with interferon, corticosteroids, or antineoplastic agents (CIII).
- Viral load testing:
- The panel recognizes that low-level positive viral load results (typically <200 copies/mL) have been commonly reported with some viral load assays. For the purpose of patient monitoring, the panel defines virologic failure as a confirmed viral load higher than 200 copies/mL, which eliminates most cases of viremia caused by isolated blips or assay variability.
- Drug-resistance testing:
- Because standard genotypic drug-resistance testing involves testing for mutations in the reverse transcriptase and protease genes, if transmitted INSTI resistance is a concern, providers may wish to supplement standard genotypic resistance testing with genotypic testing for resistance to this class of drugs (CIII).
- In persons failing INSTI-based regimens, genotypic testing for INSTI resistance should be considered to determine whether to include a drug from this class in subsequent regimens (BIII).
- Initial combination regimens for the antiretroviral-naive patient: Changes to the "What to Start" recommendations include the following:
- A regimen consisting of maraviroc + zidovudine/lamivudine is now listed as an acceptable regimen because US Food and Drug Administration approval of maraviroc for use in ART-naive patients was based on the results of a randomized controlled trial using this regimen (CI).
- For maraviroc use, tropism testing should be performed before initiation of therapy; only patients found to have only CCR5-tropic virus are candidates for maraviroc.
- "Maraviroc + tenofovir/emtricitabine" and "maraviroc + abacavir/lamivudine" have been added as "regimens that may be acceptable but more definitive data are needed" (CIII).
- In response to a recent change to the Invirase (Genentech) product label based on findings from a healthy volunteer study that reported significant PR and QT interval prolongations, ritonavir-boosted saquinavir-based regimens have been moved from the alternative PI-based regimen category to the category of regimens that are acceptable but should be used with caution.
- HBV/HIV coinfection:
- Before initiation of ART, all persons who test positive for HBsAg should be tested for HBV DNA using a quantitative assay to determine the level of HBV replication (AIII).
- Persons with chronic HBV infection already receiving ART active against HBV should undergo quantitative HBV DNA testing every 6 to 12 months to determine the effectiveness of therapy in suppressing HBV replication. The goal of HBV therapy with NRTIs is to prevent liver disease complications by sustained suppression of HBV replication to the lowest achievable level.
- If not yet receiving therapy and HBV or HIV treatment is needed:
- Preferred regimen: The combination of tenofovir/emtricitabine or tenofovir/ lamivudine should be used as the NRTI backbone of a fully suppressive ARV regimen and for the treatment of HBV infection (AII).
- Alternative regimens: If tenofovir cannot safely be used, entecavir should be used in addition to a fully suppressive ARV regimen (AII); importantly, entecavir should not be considered to be a part of the ARV regimen (BII). In persons with known or suspected lamivudine-resistant HBV infection, the entecavir dose should be increased from 0.5 mg/day to 1 mg/day. However, entecavir resistance may emerge rapidly in patients with lamivudine-resistant HBV infection. Therefore, entecavir should be used with caution in such patients with frequent monitoring (~every 3 months) of the HBV DNA level to detect viral breakthrough.
- Other HBV treatment regimens include peginterferon alfa monotherapy or adefovir in combination with lamivudine or emtricitabine or telbivudine in addition to a fully suppressive ARV regimen; however, data on these regimens in persons with HIV/HBV coinfection are limited (BII).
- Because of safety concerns, peginterferon alfa should not be used in HIV/HBV-coinfected persons with cirrhosis.
- Mycobacterium tuberculosis with HIV coinfection: The panel provides the following recommendations on when to start ART in patients who are receiving treatment for active TB but are not yet on ART:
- All HIV-infected patients with diagnosed active TB should be treated with ART (AI).
- For patients with a CD4 count lower than 200 cells/mm3, ART should be initiated within 2 to 4 weeks of starting TB treatment (AI).
- For patients with a CD4 count of 200 to 500 cells/mm3, the panel recommends initiating ART within 2 to 4 weeks, or at least by 8 weeks after commencement of TB therapy (AIII).
- For patients with a CD4 count higher than 500 cells/mm3, most panel members also recommend starting ART within 8 weeks of TB therapy (BIII).
Clinical Implications
- A regimen consisting of maraviroc + zidovudine/lamivudine is now an acceptable drug regimen for antiretroviral-naive patients.
- If not yet receiving therapy and HBV or HIV treatment is needed, the preferred regimen is the combination of tenofovir/emtricitabine or tenofovir/lamivudine.
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