• July 24, 2008, Ziagen (abacavir sulfate): The U.S. Food and Drug Administration (FDA) has notified the maker of abacavir and abacavir-containing medications of the need to add information to the current BOXED WARNING about the recommendation to test all patients for the HLA-B*5701 allele before starting or restarting therapy with abacavir or abacavir-containing medications.

For recommendations on initiating HAART in HIV-infected pregnant women, refer to Management of HIV-Infected Pregnant Women Including Prevention of Perinatal HIV Transmission (see the New York State Department of Health Web site).

The decision to begin ARV therapy should be individualized and should incorporate an assessment of four major factors:

• The patient's risk of progression to illness or death if left untreated (see Appendix D in the original guideline document) (I)
• The patient's willingness to adhere to the therapy prescribed (II)
• Potential barriers to adherence (III)
• The risk of long-term toxicity (III)

Clinicians should involve patients when planning their treatment regimens. In conjunction with their clinicians, patients should make the final decision of when to initiate ARV therapy. (III)

Except when initiation of treatment is clinically urgent, clinicians should use more than one visit for education and counseling before committing a patient to a specific therapy. (II) Counseling and education should include the following:

• Available treatment options and potential benefits and risks of therapy (see Table 3 in the original guideline document)
• The need for strict adherence and the risk of viral drug resistance when adherence is suboptimal (see Section IV: The Importance of Patient Adherence below).
• Use of safer-sex practices and avoidance of needle-sharing activity, regardless of viral load, to prevent HIV transmission or superinfection (II)
• Counseling regarding specific issues relevant to the patient's individual clinical situation

Clinicians should discuss the risks and benefits of initiating ARV therapy with asymptomatic patients with two successive measurements of viral load >100,000 copies/mL and CD4 count >350 cells/mm³. This discussion should include the increased risk of transmitting HIV in the setting of higher viral load (see Table 3 in the original guideline document).

Clinicians should follow up with patients by phone or visit within 2 weeks of initiating therapy to assess tolerance and adherence to the ARV regimen. Adherence should be reinforced at regular intervals during the course of therapy. (III)

Coexisting Conditions

Clinicians should strongly recommend that women presenting in the third trimester of pregnancy, and patients with acute or progressive renal insufficiency, severe thrombocytopenia, or HIV encephalopathy, initiate ARV therapy.

Clinicians should strongly recommend that patients recovering from acute opportunistic infections initiate ARV therapy as soon as it is safe based on patient tolerability and drug-drug interactions.

The Importance of Patient Adherence

A team approach to achieving adherence should be used. Nurses, pharmacists, peer counselors, caseworkers, and others who work in outreach, evaluation, and support of adherence should be involved. (III)

The clinician should assess treatment readiness prior to initiation of treatment, adherence readiness for subsequent regimens, and adherence at every clinical visit. (III)

Interventions should be intensified in times of decreased adherence.

Information about patients' beliefs and attitudes should be communicated with all members of the healthcare team so that each provider can consistently address treatment adherence issues within the context of the overall treatment plan. (II)

If the patient is not fully committed to adhering to therapy, treatment should be delayed, and the clinician should continue to work on abating the patient's concerns. Appropriate referrals should be provided for support groups, mental health, and drug treatment. (III)

Refer to the original guideline document for the list of potential barriers to adherence.

Selecting an Initial Antiretroviral Regimen

Clinicians should perform genotypic resistance testing before initiating treatment in ARV therapy-naive patients to determine whether or not they are infected with drug-resistant virus. (III)

The goal of initial HAART in the ARV therapy-naïve patient should be to devise a regimen that will achieve maximal durable viral suppression (<50 copies per milliliter [mL]) and be tolerated for an indefinite period of time. (I)

Clinicians should involve their patients when deciding which HAART regimen is most likely to result in adherence. (III)

For ARV therapy-naïve patients, the initial HAART regimen should include a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) plus either a protease inhibitor (PI), or a non-nucleoside reverse transcriptase inhibitor (NNRTI). (I) When using a PI-based initial regimen, clinicians should use a ritonavir-boosted PI, unless there are relative contraindications.

Clinicians should not use nevirapine as part of the initial regimen in women with CD4 counts >250 cells/mm³ or men with CD4 counts >400 cells/mm³ because of an increased incidence of hepatotoxicity. (I)

For women considering pregnancy or likely to become pregnant, efavirenz or combination pills containing efavirenz should be avoided. If there are no alternatives for efavirenz in women of childbearing age, the clinician should strongly advise the use of effective contraception and should obtain a pregnancy test before initiating treatment. (I)

Refer to "Table 6: Recommended Antiretroviral Regimens for Initial Treatment of HIV Infection" in the original guideline document.

See also Appendix A of the original guideline document for specific dosing recommendations, adverse events, drug-drug interactions, and Food and Drug Administration (FDA) pregnancy categories for each ARV drug.

Monitoring of Patients Receiving ARV Therapy

Monitoring Markers of HIV Infection

Viral Load

In ARV treatment-naïve patients or patients who are on a successful regimen, plasma viral load should be measured at baseline and every 3 to 4 months thereafter. Patients with CD4 counts >500 cells/mm³ may only require viral load monitoring every 6 months. (III)

Viral load should be measured immediately before initiation or change of ARV therapy and every 2 to 4 weeks after initiation or change until maximal suppression is documented. Once maximal suppression is attained, monitoring of viral load should occur every 3 to 4 months. (III)

If there is a significant increase (3-fold increase or more) in viral load without clear explanation, measurement should be repeated to confirm virologic failure. (III)

Virologic failure should prompt the clinician to assess the patient's adherence and to check for the presence of viral resistance. (I)

Lymphocyte Subsets

Clinicians should measure CD4 cell counts at the time of diagnosis of HIV infection and every 3 to 4 months thereafter. (III)

The absence of a significant CD4 cell count increase should not be interpreted as treatment failure if the viral load declines appropriately. (III)

HIV Resistance Assays (See Table below)

Clinicians should perform resistance testing under the following circumstances:

• At baseline in the setting of acute HIV infection, regardless of whether ARV therapy is being initiated (genotypic testing)
• In ARV therapy-naïve patients before initiation of ARV therapy (genotypic testing) (III)
• In patients experiencing treatment failure or incomplete viral suppression while receiving ARV therapy (genotypic and/or phenotypic testing) (I)

When resistance testing is indicated, it optimally should be performed while patients are either receiving therapy or have been off therapy for less than 1 year. (III)

Clinicians should consult with an expert to interpret the results of resistance assays because the results of resistance assays are often complex. (I)

Key Point:

Resistance testing more reliably indicates drugs that are not likely to be effective rather than identifying those drugs that may suppress viral replication.

Adapted from the Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents (2006)

Antiretroviral Serum Levels (Therapeutic Drug Monitoring)

Monitoring blood levels of ARV drugs is not currently recommended. (III)

Laboratory Monitoring of Antiretroviral Therapy Side Effects

Bone Marrow Suppression

Complete blood counts should be measured before initiation of ARV therapy and at least every 4 months thereafter. For patients at high risk for bone marrow toxicity (e.g., those with advanced HIV infection, those with pre-treatment cytopenias, or those who are receiving zidovudine), blood counts may have to be monitored more frequently because significant cytopenias may occur. (III)

Pancreatitis

When patients receiving ARV therapy present with signs or symptoms suggestive of pancreatitis, clinicians should obtain serum amylase and lipase levels. (III)

If signs or symptoms of pancreatitis occur in patients taking ARV medications, the clinician should temporarily suspend the entire ARV regimen. A new ARV regimen may be initiated when enzymes are normalized but should not include ARV medications that are most likely linked to pancreatitis, such as stavudine.

An elevated serum amylase level should be confirmed with a serum lipase level. (III)

Clinicians should not prescribe didanosine for patients who have a history of pancreatitis. (III)

Lactic Acidosis/Hepatic Steatosis

When patients develop symptoms consistent with lactic acidosis syndrome in conjunction with an elevated lactate level (>2 millimoles per liter [mmol/L]) and decreased serum bicarbonate (<20 mmol/L), the clinician should temporarily discontinue the entire ARV regimen while an evaluation is conducted. (II)

Routine monitoring of serum lactate levels is not indicated in asymptomatic patients. (I)

Patients who are asymptomatic and have an unexplained decrease in serum bicarbonate level (<20 mmol/L) should be promptly re-evaluated with a repeat test and a venous or arterial lactate. (II) If a venous lactate is mildly elevated (2.1 to 5.0 mmol/L), an arterial lactate should be obtained, and re-assessment for the presence of symptoms associated with lactic acidosis should be performed. (I) If the lactate is persistently elevated, the arterial pH is abnormal, or the patient has become symptomatic, ARV therapy should be discontinued. (III)

Hepatotoxicity

Clinicians should obtain serum liver enzyme levels at baseline and every 3 to 4 months thereafter in patients receiving HAART. (III)

Clinicians should screen for alcohol use in patients with abnormal serum liver enzyme levels. (III)

Use of Nevirapine

Clinicians should not use nevirapine as part of the initial regimen in women with CD4 counts >250 cells/mm³ or men with CD4 counts >400 cells/mm³ because of an increased incidence of hepatotoxicity. (I)

When initiating an ARV regimen that includes nevirapine, clinicians should obtain serum liver enzymes at baseline, at the time of dose escalation (14 days), and 2 weeks after dose escalation. (III)

Clinicians should counsel patients to seek medical evaluation when signs and symptoms of hepatitis, severe skin reactions, or hypersensitivity reactions related to nevirapine occur. Serum liver enzymes should be obtained whenever patients develop a rash during nevirapine therapy, particularly during the first 18 weeks of therapy. (II)

In the setting of hepatotoxicity related to nevirapine, patients should not be re-challenged with nevirapine. (I)

Renal Toxicity

For all HIV-related patients receiving ARV therapy:

Clinicians should obtain urinalysis at baseline and annually thereafter.

Clinicians should measure serum creatinine levels and calculate glomerular filtration rates at baseline and every 3 to 4 months thereafter in HIV-infected patients. (III)

For patients receiving tenofovir:

For patients initiating a tenofovir-containing regimen, clinicians should calculate glomerular filtration rates at baseline, 1 month, and then at least every 3 to 4 months thereafter.

Clinicians should discontinue tenofovir when patients present with symptoms suggestive of Fanconi syndrome.

For patients receiving indinavir:

Clinicians should counsel patients receiving indinavir to drink at least 48 ounces of fluid per day.

Myopathy/Myositis

Measurement of serum creatinine phosphokinase (CPK) is not routinely indicated. If the patient becomes symptomatic (e.g., muscle pain or weakness), CPK should be measured. (II)

Monitoring for Allergic Reactions Associated with ARV Therapy

When patients receive any new ARV drugs, clinicians should educate them about the possibility of HAART-associated allergic reactions, including a hypersensitivity reaction, and the range of possible symptoms (refer to Table 9 in the original guideline document to view ARV drugs associated with allergic reactions). (III)

Clinicians should discontinue offending drugs when there is a moderate to severe skin reaction, mucous membrane involvement, systemic toxicity, or fever. (I)

Clinicians should avoid re-challenging patients with a medication that has been associated with a hypersensitivity reaction, especially in the setting of abacavir reactions and severe non-nucleotide reverse transcriptase inhibitor (NNRTI) reactions. (I)

In patients who develop mild rash in response to nevirapine, clinicians should avoid escalating the nevirapine dose to twice daily until after the rash has resolved. For patients with moderate to severe cutaneous toxicity, nevirapine should be discontinued and should not be re-challenged. Use of an alternate NNRTI should be avoided. (III)

Changing a Successful Initial HAART Regimen

Clinicians should change a successful initial HAART regimen when the patient's adherence will be compromised by continuing the current regimen. (III)

When considering a change in the ARV regime due to drug toxicity, the clinician should confirm that the viral load is maximally suppressed. (III) If maximal viral suppression has been achieved, the clinician should substitute the offending drug. (I)

The clinician should review results from previous resistance testing before changing a successful regimen. (III)

Failure to Achieve Goals of Initial HAART

Clinicians should address adherence, obtain resistance assays, and consult with an HIV Specialist before changing HAART regimens that have failed.

Clinicians should not change an ARV regimen when there is incomplete but significant viral suppression (>0.5 log reduction, or 3-fold, from baseline viral load value) compared with baseline and a more effective HAART regimen cannot be constructed as a result of drug resistance or intolerance.

Second-Line Regimen and Salvage HAART

Clinicians should consult with an HIV Specialist when constructing a second-line regimen and salvage therapy regimens.

Clinicians should review individual ARV history and results from HIV drug resistance testing when constructing salvage therapy regimens. Clinicians should consult with an expert to interpret the results of resistance assays. (I)

Clinicians should use a drug from a class that was not used in the first regimen when constructing a second-line regimen. (I)

When treating patients with high levels of HIV drug resistance, clinicians should consider using agents in novel ARV classes or with unique resistance profiles, such as the entry inhibitors or drugs available through clinical trials or expanded access.

Acute HIV Infection

Diagnosis of Acute HIV Infection

Clinicians should maintain a high level of suspicion for acute HIV infection in all patients presenting with a compatible clinical syndrome (see Table 10 in the original guideline document). When acute retroviral syndrome is suspected, a plasma HIV ribonucleic acid (RNA) assay should be used in conjunction with an HIV-1 antibody test to diagnose acute HIV infection. (III)

Confirmatory HIV antibody testing should be performed 3 to 6 weeks after diagnosis by HIV RNA testing. (III)

Management of Acute HIV Infection

Clinicians should counsel patients about the increased risk of transmitting HIV during acute HIV infection.

Clinicians should obtain baseline genotypic testing in the setting of acute infection, regardless of whether ARV is being initiated.

Clinicians should consult with an HIV Specialist to weigh the benefits and risks of initiating therapy in patients with acute HIV infection and should refer for research opportunities as appropriate (see Appendix F in the original guideline document). (III)

The clinician should counsel the patient regarding potential limitations of HAART during acute infection, and individual decisions should be made only after weighing the risks of therapy against the theoretical benefit of treatment (see Table 11 in the original guideline document). (III)

If the clinician and patient have made a decision to use ARV therapy for primary HIV infection, treatment should be based on the results of genotypic testing and implemented with the goal of suppressing plasma HIV RNA levels to below detectable levels. (I)

Management of Treatment Interruption

Patients should be discouraged from stopping HAART without first consulting with their clinician. (III)

When HAART is interrupted, clinicians should inform patients of the potential increased risk of transmitting HIV. Risk-reduction counseling and prevention interventions should be intensified at this time.

Before interrupting HAART in patients receiving ARV medications with prolonged half-lives, such as NNRTIs, clinicians should consult with an HIV Specialist for guidance on how to avoid the emergence of resistance.

Clinicians should not interrupt lamivudine, emtricitabine, or tenofovir (or combination pills containing these drugs) in patients who are co-infected with chronic hepatitis B without implementing another hepatitis B virus (HBV) treatment option.

Strategic treatment interruption (STI) is not recommended  in the management of the HIV-infected patient. (I)

Referring Patients to Research Studies

Referral of patients to research protocols should be 1) to provide treatment or diagnostic options that may be otherwise unavailable and that may enhance treatment outcome, and 2) to attempt to answer a relevant research question. (III)

Patients should be fully informed of any financial benefit their referral to a research study might have for the referring clinician. (III)

Patients should be informed that research studies often require major commitments of time and effort in addition to potential unforeseeable risk. (III)

The clinician should provide assistance to patients who want to participate in research studies. (III)

Definitions:

Quality of Evidence for Recommendation

1. Evidence from one or more properly randomized, controlled trial
2. Evidence from one or more well-designed clinical trial without randomization; from cohort or case-controlled studies
3. Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees

Electronic copies: Available from the New York State Department of Health AIDS Institute Web site.

Print copies: Available from Office of the Medical Director, AIDS Institute, New York State Department of Health, 5 Penn Plaza, New York, NY 10001; Telephone: (212) 268-6108.

• HIV specialist policy. New York (NY): New York State Department of Health; 2004 Dec. Electronic copies: Available in Portable Document Format (PDF) from the New York State Department of Health AIDS Institute Web site.
• ARV management tools. New York (NY): New York State Department of Health; Dec. Electronic copies: Available in Portable Document Format (PDF) from the New York State Department of Health AIDS Institute Web site.

Print copies: Available from Office of the Medical Director, AIDS Institute, New York State Department of Health, 5 Penn Plaza, New York, NY 10001; Telephone: (212) 268-6108.

This NGC summary is based on the original guideline, which is copyrighted by the guideline developer. See the New York State Department of Health AIDS Institute Web site for terms of use.

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