Definitions for the quality of the evidence (I, II, III) and the strength of recommendations (A, B, C) are provided at the end of the "Major Recommendations."
Goals, Benefits, and Risks of Antiretroviral Therapy (ART)
Clinicians should prescribe an ART regimen that is best able to delay disease progression, prolong survival, and maintain quality of life through maximal viral suppression (see Table below). (I)
|Table: Goals of Antiretroviral Therapy
- Maximal and durable suppression of viral replication (measured by viral load assays)
- Restoration and/or preservation of immune function
- Reduced human immunodeficiency virus (HIV)-related morbidity and mortality
- Improved quality of life
- Limitation of the likelihood of viral resistance to preserve future treatment options
The clinician should involve the patient in the decision-making process when determining whether to implement ART. The clinician should review the benefits and risks of treatment for each individual patient. (III) (See Table 2 in the original guideline document.)
Deciding When to Initiate ART
The decision to initiate ART should be individualized for each patient and incorporate assessment of the following factors:
- Risk of progression to illness or death if untreated
- Readiness and willingness to adhere to therapy; potential barriers to adherence
- Comorbidities and coexisting conditions
- Risk of HIV transmission to others if untreated
- Risk of toxicities and drug-drug interactions
Clinicians should involve the patient when planning treatment, and the patient should make the final decision of whether and when to initiate ART.
|Recommendations for Initiating ART
- Initiation of ART is recommended for each of the following patient groups after modifiable barriers to adherence are minimizeda:
- Are symptomatic from HIV, regardless of CD4 count, including any of the following conditions:
- HIV-associated neurocognitive disorder (HAND)b
- Severe thrombocytopenia
- HIV-associated nephropathy
- HIV-related malignancies
- Have an AIDS-defining condition
- Are pregnantc
- Have chronic hepatitis B virus (see the NGC summary of the NYSDoH AIDS Institute Hepatitis B Virus guideline)
- Have two successive measurements of CD4 counts ≤500 cells/mm3
- Have rapid decline in CD4 count, defined as >100 cells/mm3 per year
- Have two successive measurements of HIV RNA >100,000 copies/mL
- The following coexisting conditions should prompt consideration and discussion with patients about initiation of ART at CD4 counts >500 cells/mm3.a Clinicians should consult with a provider who has extensive experience with management of ART:
- There is no upper CD4 limit for initiating ART in patients who wish to receive it.
a See Table 3 in the original guideline document for evidence and ratings.
b HAND is currently used to encompass a hierarchy of progressive patterns of central nervous system involvement ranging from asymptomatic neurocognitive impairment (ANI), to minor neurocognitive disorder (MND), to the more severe HIV-associated dementia (HAD).
c For recommendations on initiating ART in HIV-infected pregnant women, refer to Management of HIV-Infected Pregnant Women Including Prevention of Perinatal HIV Transmission.
See Appendix B in the original guideline document for a comparison of the recommendations on when to initiate ART from the New York State Department of Health AIDS Institute, the Department of Health and Human Services, and the International AIDS Society – USA Panel.
Potential Barriers to Adherence
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. Counseling and education should include the following:
- Available treatment options and potential benefits and risks of therapy (see Table 4 in the original guideline document)
- The need for strict adherence and the risk of viral drug resistance when adherence is suboptimal (see "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
Initiating ART Following Acute Opportunistic Infections
Clinicians should strongly recommend that patients recovering from acute opportunistic infections initiate ART as soon as patient tolerability has been established and the potential for drug-drug interactions has been minimized.
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 and strategies for promoting adherence.
Selecting an Initial Antiretroviral Regimen
Clinicians should obtain genotypic resistance testing at baseline and should consider repeating the test prior to initiating treatment in ART-naïve patients. (AIII)
Clinicians should involve their patients when deciding which antiretroviral regimen is most likely to result in adherence. (AIII)
For ART-naïve patients, the initial preferred antiretroviral regimen should include a combination of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) plus either a ritonavir-boosted protease inhibitor (PI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or an integrase inhibitor. (AI)
For women considering pregnancy or not using effective contraception, efavirenz or combination pills containing efavirenz should be avoided. If there are no alternatives for efavirenz in women of childbearing age, clinicians should strongly advise the use of effective contraception and should obtain a pregnancy test before initiating treatment. (AI)
Selection of antiretroviral agents should be individualized to address each patient's concurrent morbidities and medications, ability to adhere to complex regimens, and personal tolerance for adverse medication effects. (AIII)
Clinicians should follow up with patients by phone or visit within 2 weeks of initiating therapy to assess tolerance and adherence to the antiretroviral regimen. Adherence should be reinforced at regular intervals during the course of therapy. (AIII)
The goal of the initial antiretroviral regimen is to achieve durable and maximal viral suppression (i.e., undetectable plasma HIV ribonucleic acid [RNA]) with minimal adherence challenges and long-term tolerability.
Refer to Tables 6-A and 6-B in the original guideline document for preferred and alternative ART regimens, respectively, for initial treatment of HIV infections and to Table 6-C for contraindicated and not recommended ART regimens for initial treatment of HIV infections.
See also Appendix A of the original guideline document for specific dosing recommendations, including dose adjustments due to renal or hepatic impairment, adverse events, drug-drug interactions, and U.S. Food and Drug Administration (FDA) pregnancy categories for each antiretroviral agent.
Monitoring of Patients Receiving ART
Monitoring Markers of HIV Infection
In ART-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 ART 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)
Refer to Table 7 in the original guideline document for interpretation of viral load.
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 ART is being initiated (genotypic testing)
- In ART-naïve patients before initiation of ART (genotypic testing) (III)
- In patients experiencing treatment failure or incomplete viral suppression while receiving ART (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 (see the New York State Department of Health AIDS Institute Web site for Clinical Education Initiative sites available for phone consultation). (I)
Resistance testing more reliably indicates drugs that are not likely to be effective rather than identifying those drugs that may suppress viral replication.
|Table: Recommendations for the Use of Drug Resistance Assays*
|Prior to initiating treatment in ART-naïve patients, including in the setting of acute HIV infection
||Determine if drug-resistant virus was acquired so that an appropriate regimen may be chosen.
|Virologic failure during ART
||Determine the role of resistance in drug failure, and maximize the number of active drugs in the new regimen.
|Suboptimal suppression of viral load after initiation of ARTa
||Determine the role of resistance, and maximize the number of active drugs in the new regimen if indicated.
|Not Generally Recommended
|More than 1 year after discontinuation of drugs
||Drug-resistance mutations may become minority species in the absence of selective drug pressure and may not be detectable. Current assays may not detect minority drug-resistant species.
|Plasma viral load <500 to 1,000 HIV ribonucleic acid (RNA) copies/mLb
||Resistance assays cannot be reliably performed because of the low copy number of HIV RNA.
*Adapted from the Department of Health and Human Services (DHHS) Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents (2006)
a In pregnant women initiating therapy, the clinician may not have as much time to monitor for suboptimal suppression.
b The cutoff will vary according to the manufacturer of the kit.
Antiretroviral Serum Levels (Therapeutic Drug Monitoring)
Monitoring blood levels of antiretroviral 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 ART 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)
When patients receiving ART present with signs and symptoms suggestive of pancreatitis, clinicians should obtain serum amylase and lipase levels. (III)
If signs or symptoms of pancreatitis occur in patients taking antiretroviral medications, the clinician should temporarily suspend the entire ART regimen. A new ART regimen may be initiated when enzymes are normalized but should not include antiretroviral medications that are most likely linked to pancreatitis, such as didanosine or 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 mmol/L) and decreased serum bicarbonate (<20 mmol/L), the clinician should temporarily discontinue the entire ART 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 reassessment 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, ART should be discontinued. (III)
Clinicians should obtain serum liver enzyme levels at baseline and every 3 to 4 months thereafter in patients receiving ART. (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 ART 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 rechallenged with nevirapine. (I)
For all HIV-infected patients receiving ART:
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.
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 ART
When patients receive any new antiretroviral drugs, clinicians should educate them about the possibility of ART-associated allergic reactions, including a hypersensitivity reaction, and the range of possible symptoms (see Table 9 in the original guideline document to view antiretroviral 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 perform HLA-B*5701 testing before initiating abacavir-based therapy.
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-nucleoside 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)
Prompt discontinuation of abacavir when a hypersensitivity reaction is suspected is necessary because symptoms will worsen over time. Once abacavir has been discontinued because of a possible or definite hypersensitivity reaction, abacavir should never be administered again. Re-challenge may result in an anaphylactic reaction with associated hypotension or death.
Changing a Successful Initial ART Regimen
Clinicians should change a successful initial ART regimen when the patient's adherence will be compromised by continuing the current regimen. (III)
When considering a change in the ART 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 ART
Clinicians should address adherence, obtain resistance assays, and consult with a provider with extensive experience in HIV treatment before changing ART regimens that have failed.
Clinicians should not change an ART 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 ART regimen cannot be constructed as a result of drug resistance or intolerance.
Second-Line Regimens and Salvage ART
(Currently under revision)
Clinicians should consult with a provider with extensive experience in HIV treatment when constructing a second-line regimen and salvage therapy regimens.
Clinicians should review individual antiretroviral 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 antiretroviral classes or with unique resistance profiles, such as the entry inhibitors or drugs available through clinical trials or expanded access.
Management of Treatment Interruption
Patients should be discouraged from stopping ART without first consulting with their clinician. (III)
When ART 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 ART in patients receiving antiretroviral medications with prolonged half-lives, such as NNRTIs, clinicians should consult with a provider with extensive experience in HIV treatment 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)
Quality of Evidence for Recommendation
- One or more randomized trials with clinical outcomes and/or validated laboratory endpoints
- One or more well designed, non-randomized trials or observational cohort studies with long-term clinical outcomes
- Expert opinion
Strength of Recommendation
- Strong recommendation for the statement
- Moderate recommendation for the statement
- Optional recommendation