News Author: Laurie Barclay, MD
CME Author: Hien T. Nghiem, MD
On December 1, the Department of Health and Human Services (DHHS) issued updated guidelines for the use of antiretroviral agents in teens and adults infected with human immunodeficiency virus type 1 (HIV-1).
"Antiretroviral therapy for treatment of Human Immunodeficiency Virus type 1 (HIV-1) infection has improved steadily since the advent of combination therapy in 1996," the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel) writes. "More recently, new drugs have been approved that offer new mechanisms of action, added potency, dosing convenience, and improved safety profiles, whereas some previously popular drugs are being used less often as their drawbacks become better defined. Resistance testing is used more commonly in clinical practice, and interactions among antiretroviral agents and other drugs have become more complex."
The Panel, a working group of the Office of AIDS Research Advisory Council, developed these guidelines to summarize current recommendations concerning how clinicians in the United States should use antiretroviral drugs to treat adults and adolescents with HIV infection, based on newly available evidence.
The revised guidelines highlight when to begin treatment, which drug combinations are preferred, which individual drugs or combination regimens should be avoided, and how continued clinical benefit can be assured even when antiretroviral drug resistance has developed.
Adherence to medications and some other treatment issues are still recognized as being important for management, but new evidence in these areas has not accrued rapidly enough to warrant revision of earlier recommendations in these areas. Additional topics, for example, HIV management during pregnancy, have been or will be the focus of greater in-depth attention by separate guidelines groups.
Key clinical questions most often encountered by clinicians making treatment decisions, and therefore addressed by the guidelines, are as follows:
* Key clinical and laboratory parameters to evaluate and monitor before and after starting treatment with antiretroviral agents;
* The impact of resistance testing in guiding treatment decisions;
* When to initiate treatment in patients with established HIV infection;
* Specific drugs that are preferred for initial therapy, as well as alternative treatment options, and identifying drugs or drug combinations that should not be used;
* Limitations to the safety and efficacy of antiretroviral treatment;
* Treatment goals and optimization of therapy in treatment-experienced patients who have virologic failure; and
* Special considerations regarding use of antiretroviral treatment in specific subgroups, such as acute HIV infection, adolescents infected with HIV, illicit drug users, pregnant women and other women infected with HIV, and patients who are coinfected with hepatitis B or C or tuberculosis.
Compared with the previous guidelines released October 10, 2006, the current guidelines recommend the following changes regarding laboratory evaluation:
* Genotypic drug resistance testing should be performed for all treatment-naive patients presenting for clinical care, regardless of whether antiretroviral therapy will be started right away (level of evidence, AIII). The rationale for this recommendation is that transmitted resistance mutation may be more easily identified sooner, rather than later, after infection. When treatment is actually to be started, repeat testing may be considered (level of evidence, CIII).
* Before starting treatment with a C-C chemokine receptor 5 (CCR5) antagonist, such as maraviroc, the Panel recommends tropism testing (level of evidence, AII). For patients with evidence of virologic failure during treatment with maraviroc or any CCR5 inhibitor, coreceptor tropism testing might also be considered (level of evidence, BIII).
* Testing of human leukocyte antigen (HLA)-B*5701 should be performed before starting abacavir therapy to lower the risk for hypersensitivity reaction (level of evidence, AI). Abacavir should not be prescribed for patients with positive HLA-B*5701 (level of evidence, AI), and the positive status should be recorded as an abacavir allergy in the patient's medical record (level of evidence, AII). When HLA-B*5701 screening is not readily available, abacavir may be started, but appropriate clinical counseling and monitoring is needed to detect any signs of abacavir-associated hypersensitivity reaction (level of evidence, CIII).
Compared with the previous guidelines, the current guidelines recommend the following changes regarding when to start antiretroviral treatment:
* Antiretroviral therapy should be started in patients with a history of an AIDS-defining illness or a cluster of differentiation 4 (CD4) T-cell count of less than 350 cells/mm3. The evidence underlying this recommendation is more conclusive for patients with a CD4 T-cell count of less than 200 cells/mm3 and with a history of AIDS (level of evidence, AI) vs those with CD4 T-cell counts between 200 and 350 cells/mm3 (level of evidence, AII).
* Regardless of CD4 T-cell count, the following groups should also receive antiretroviral therapy: pregnant women (level of evidence, AI); patients with HIV-associated nephropathy (level of evidence, AI); and patients coinfected with hepatitis B who should receive treatment for hepatitis B (level of evidence, BIII).
* Although the best time to begin treatment in asymptomatic patients with a CD4 T-cell count of more than 350 cells/mm3 is not clearly defined, the decision of whether to initiate therapy should consider the potential benefits and risks for treatment, comorbid conditions, and patient readiness and willingness to comply with long-term treatment.
The section on management of treatment-experienced patients was revised to include a review of the more recently available classes of antiretroviral agents (CCR5 antagonists and integrase inhibitors) and their roles in managing treatment-experienced patients with virologic failure. A discussion of immunologic failure is also included.
Based on new recommendations and new data regarding specific antiretroviral drugs, various tables have also been updated. Additional revisions to other sections of these guidelines are planned for release in 2008. The Panel further notes that HIV care is highly complex and is rapidly evolving, mandating that treatment for a specific patient should always be individualized based on sound judgment of the clinician and informed by the patient's own point of view and social context.
"The Panel expects new drugs from current and newer classes to become available soon," the guidelines statement concludes. "These may well affect choices in initial and secondary drug regimens. The Panel also anticipates continued progress in the simplicity of regimens and in reduced toxicity."
Department of Health and Human Services. Published December 1, 2007. http://www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf.
Clinical Context
Since 1996, antiretroviral therapy for treatment of HIV-1 infection has steadily improved. The Panel outlined current recommendations regarding when to initiate therapy, which drug combinations are preferred, which drugs or combinations should be avoided, and means to continue clinical benefit in the face of antiretroviral drug resistance. The Panel considered new evidence and adjusted recommendations accordingly. The following changes have been made to several sections of the October 10, 2006, version of the guidelines.
Study Highlights
* Patients entering care should have a complete medical history, physical examination, and laboratory evaluation.
* Laboratory assessment:
o The following laboratory tests should be performed for new patients during initial visits: HIV antibody testing; CD4 T-cell count; plasma HIV RNA level; complete blood count and metabolic panel; urinalysis; rapid plasma reagin or Veneral Disease Research Laboratory test; tuberculin skin test; Toxoplasma gondii immunoglobulin G test; hepatitis A, B, and C serologic tests; Papanicolaou test in women; and serum lipid profile.
o For patients with pretreatment HIV RNA levels of more than 1000 copies/mL, genotypic resistance testing is recommended when entering care.
o The Panel recommends performing genotypic drug resistance testing for all treatment-naive patients entering clinical care. This recommendation is based on the fact that transmitted resistance mutation may be detected at a time point closer to the time of infection than later. Repeat testing may be considered when therapy is to be initiated. In addition, HIV drug resistance testing should be performed in cases of virologic failure or suboptimal viral load reduction as well as in all pregnant women before initiation of therapy and for those entering pregnancy with detectable HIV RNA levels while receiving therapy.
o The Panel recommends tropism testing before initiation of a CCR5 antagonist, such as maraviroc. Coreceptor tropism testing might also be considered for patients exhibiting virologic failure while receiving maraviroc.
o The Panel recommends HLA-B*5701 testing before initiation of abacavir therapy to reduce the risk for hypersensitivity reaction. Patients with positive HLA-B*5701 should not be prescribed abacavir, and the positive status should be recorded as abacavir allergy in the patient's medical record. When HLA-B*5701 screening is not readily available, abacavir may be started, with appropriate clinical counseling and monitoring for any signs of abacavir-associated hypersensitivity reaction.
* When to start antiretroviral therapy:
o The Panel recommends that antiretroviral therapy be initiated in patients with history of an AIDS-defining illness or with CD4 T-cell count of less than 350 cells/mm3. The data supporting this recommendation are stronger for those with a CD4 T-cell count of less than 200 cells/mm3 and with history of AIDS vs those with CD4 T-cell counts between 200 and 350 cells/mm3.
o The Panel also recommends treatment of pregnant patients, patients with HIV-associated nephropathy, and patients coinfected with hepatitis B when treatment for hepatitis B virus is indicated, regardless of CD4 T-cell count.
o Optimal time to initiate therapy in asymptomatic patients with CD4 T-cell count of more than 350 cells/mm3 is not well defined. Whether to start therapy in these patients should take into account the potential benefits and risks associated with therapy, comorbidities, and patient readiness and willingness to adhere to long-term treatment.
* Management of treatment-experienced patients:
o Most patients receiving antiretroviral therapy maintain virologic suppression for 3 to 7 years.
o Antiretroviral treatment failure is not uncommon; therefore, it should be addressed aggressively.
o Newer classes of antiretroviral agents have demonstrated short-term efficacy and safety in the management of treatment-experienced patients with virologic failure.
o Immunologic failure is defined as a failure to achieve and maintain an adequate CD4 response despite virologic suppression.
o There is no consensus for when and how to treat immunologic failure.
Pearls for Practice
* The Panel recommends HIV drug resistance testing for persons with HIV infection when they enter care, tropism testing before initiation of a CCR5 antagonist, and HLA-B*5701 testing before initiation of abacavir therapy to reduce the risk for hypersensitivity reaction.
* The Panel recommends that antiretroviral therapy be initiated in patients with a history of an AIDS-defining illness or with a CD4 T-cell count of less than 350 cells/mm3; the data supporting this recommendation are stronger for those with a CD4 T-cell count of less than 200 cells/mm3 and with a history of AIDS.
* In addition, treatment is recommended for the following groups regardless of CD4 T-cell count: pregnant patients, patients with HIV-associated nephropathy, and patients coinfected with hepatitis B when treatment for hepatitis B virus is indicated.
