• What's New in the Guidelines?
• Panel Roster
• Financial Disclosure
• Introduction
• Baseline Evaluation
• Laboratory Testing
  • Laboratory Testing for Initial Assessment and Monitoring While on Antiretroviral Therapy
  • CD4 T-Cell Count
  • Plasma HIV RNA Testing
  • Drug-Resistance Testing
  • HLA-B* 5701 Screening
  • Coreceptor Tropism Assays
• Treatment Goals
• Initiating Antiretroviral Therapy in Treatment-Naive Patients
• What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient
• What Not to Use
• Management of the Treatment-Experienced Patient
  • Virologic and Immunologic Failure
  • Regimen Simplification
  • Exposure-Response Relationship and Therapeutic Drug Monitoring (TDM) for Antiretroviral Agents
  • Discontinuation or Interruption of Antiretroviral Therapy
• Considerations for Antiretroviral Use in Special Patient Populations
  • Acute HIV Infection
  • HIV-Infected Adolescents and Young Adults
  • HIV and Illicit Drug Users
  • HIV-Infected Women
  • HIV-2 Infection
  • HIV and the Older Patient
• Considerations for Antiretroviral Use in Patients with Coinfections
  • HIV/Hepatitis B Virus (HBV) Coinfection
  • HIV/Hepatitis C Virus (HCV) Coinfection
  • Mycobacterium Tuberculosis Disease with HIV Coinfection
• Limitations to Treatment Safety and Efficacy
  • Adherence to Antiretroviral Therapy
  • Adverse Effects of Antiretroviral Agents
  • Drug Interactions
• Preventing Secondary Transmission of HIV
• Conclusion
• Appendix A: Key to Acronyms
• Appendix B: Drug Characteristics Tables
  • Table 1
  • Table 2
  • Table 3
  • Table 4
  • Table 5
  • Table 6
  • Table 7
• Appendix C: Monthly Average Wholesale Price of Antiretroviral Drugs

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents

Panel's Recommendations

It is unknown if treatment of acute HIV infection results in long-term virologic, immunologic, or clinical benefit; treatment should be considered optional at this time (CIII). Therapy should also be considered optional for patients with HIV seroconversion in the previous 6 months (CIII). All pregnant women with acute or recent HIV infection should start a combination antiretroviral (ARV) regimen as soon as possible to prevent mother-to-child transmission (MTCT) of HIV (AI). If the clinician and patient elect to treat acute HIV infection, treatment should be implemented with the goal of suppressing plasma HIV RNA to below detectable levels (AIII). For patients with acute HIV infection in whom therapy is initiated, testing for plasma HIV RNA levels and CD4 count and toxicity monitoring should be performed as described for patients with established, chronic HIV infection (AII).  If the decision is made to initiate therapy in a person with acute HIV infection, genotypic resistance testing at baseline will be helpful in guiding the selection of an ARV regimen that can provide the optimal virologic response; this strategy is therefore recommended (AIII). If therapy is deferred, genotypic resistance testing should still be performed because the result may be useful in optimizing the virologic response when therapy is ultimately initiated (AIII). Because clinically significant resistance to protease inhibitors (PIs) is less common than resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in antiretroviral therapy (ART)-naive persons who harbor drug-resistant virus, a ritonavir (RTV)-boosted PI-based regimen should be used if therapy is initiated before drug-resistance test results are available (AIII).

Rating of Recommendations:  A = Strong; B = Moderate; C = Optional Rating of Evidence:  I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion

An estimated 40%–90% of patients acutely infected with HIV will experience symptoms of acute retroviral syndrome characterized by fever, lymphadenopathy, pharyngitis, skin rash, myalgias/arthralgias, and other symptoms [1-6]. However, acute HIV infection is often not recognized by primary care clinicians because symptoms are similar to those for influenza, infectious mononucleosis, or other illnesses. Additionally, acute infection can occur asymptomatically. Table 10 provides practitioners with guidance on the recognition, diagnosis, and management of acute HIV infection.

Diagnosis of Acute HIV Infection

Health care providers should maintain a high level of suspicion of acute HIV infection in patients who have a compatible clinical syndrome and who report recent high-risk behavior [7]. However, in some settings, patients may not always disclose or admit to high-risk behaviors or might not perceive their behaviors as high risk. Thus, symptoms and signs consistent with acute retroviral syndrome should motivate consideration of this diagnosis even in the absence of reported high-risk behaviors.

When acute retroviral syndrome is suspected, a plasma HIV RNA test is typically used in conjunction with an HIV antibody test to diagnose acute infection (BII). Acute HIV infection is often defined by detectable HIV RNA in plasma in the setting of a negative or indeterminate HIV antibody test. A low-positive HIV RNA level (<10,000 copies/mL) may represent a false-positive test because values in acute infection are generally very high (>100,000 copies/mL) [5-6]. A qualitative HIV RNA test can also be used in this setting. Interest in routine screening for antibody-negative acute infection has led to select centers performing virologic testing on all antibody-negative specimens, including the use of pooled HIV RNA testing on all seronegative serum samples [8]. In addition, a combination HIV antigen/antibody test (ARCHITECT), recently licensed by the Food and Drug Administration (FDA), could be used for this purpose. Patients diagnosed with acute HIV infection by a virologic test while still antibody negative or indeterminate should have confirmatory serologic testing performed over the next 3 months (AI). (See Table 10.)

Performance of Resistance Testing

Data from the United States and Europe demonstrate that transmitted virus may be resistant to at least one ARV drug in 6%–16% of patients [9-11]. If the decision is made to initiate therapy in a person with acute HIV infection, genotypic resistance testing at baseline to guide the selection of an ARV regimen will likely optimize virologic response; this strategy is therefore recommended (AIII). (See Drug-Resistance Testing.) If therapy is deferred, resistance testing should still be performed because the result may be useful in optimizing the virologic response when therapy is ultimately initiated (AIII).

Treatment for Acute HIV Infection

Clinical trials information regarding treatment of acute HIV infection is limited. Ongoing trials are addressing the question of the long-term benefit of potent treatment regimens initiated during acute infection. Potential benefits and risks of treating acute infection are as follows:

• Potential Benefits of Treating Acute Infection. Preliminary data indicate that treatment of acute HIV infection with combination ART has a beneficial effect on laboratory markers of disease progression [12-16]. Theoretically, early intervention could decrease the severity of acute disease; alter the initial viral setpoint, which can affect disease progression rates; reduce the rate of viral mutation as a result of suppression of viral replication; preserve immune function; and reduce the risk of viral transmission during this highly infectious stage of disease. Additionally, although data are limited and the clinical relevance is unclear, the profound loss of gastrointestinal lymphoid tissue that occurs during the first weeks of infection may be mitigated by the early initiation of ART [17-18].
  
  
• Potential Risks of Treating Acute HIV Infection. The potential disadvantages of initiating therapy include exposure to ART without a known clinical benefit, which could result in drug toxicities, development of drug resistance, continuous need for therapy with strict adherence, and adverse effect on quality of life.

Some of the potential benefits associated with treatment during acute infection remain uncertain and of unknown clinical relevance, while the risks are largely consistent with those for initiating therapy in chronically infected asymptomatic patients with high CD4 counts. The health care provider and the patient should be fully aware that the rationale for therapy for acute HIV infection is based on theoretical considerations, and the potential benefits should be weighed against the potential risks. For these reasons, treatment of acute HIV infection should be considered optional at this time (CIII). Because acute or recent HIV infection is associated with a high risk of MTCT of HIV, all HIV-infected pregnant women should start a combination ARV regimen as soon as possible to prevent perinatal transmission of HIV (AI) [19]. Following delivery, considerations regarding continuation of the ARV regimen as therapy for the mother are the same as for treatment of other nonpregnant individuals. Providers should consider enrolling patients with acute HIV infection in a clinical trial to evaluate the natural history of acute HIV and to determine the role of ART in this setting. Information regarding such trials can be obtained at www.clinicaltrials.gov or from local HIV treatment experts.

Treatment for Recent but Nonacute HIV Infection or Infection of Undetermined Duration

In addition to patients with acute HIV infection, some HIV clinicians also recommend consideration of therapy for patients in whom seroconversion has occurred within the previous 6 months (CIII). Although the initial burst of viremia among infected adults usually resolves in 2 months, rationale for treatment during the 2- to 6-month period after infection is based on the probability that virus replication in lymphoid tissue is still not maximally contained by the immune system during this time [20]. In the case of pregnancy, use of a combination ARV regimen to prevent MTCT of HIV is recommended (AI). For nonpregnant patients the current guidelines have provided a rationale for recommending initiation of ART in ART-naive patients with CD4 count between 350 and 500 cells/mm³ as well as a recommendation to consider therapy for those with CD4 count >500 cells/mm³. (See Initiating Antiretroviral Therapy.) Although these recommendations are primarily based upon data from patients with chronic infection, the potential benefit of early treatment on immune recovery and on attenuation of the pathologic effects of viremia-associated inflammation and coagulation could apply to those with early HIV infection as well. Based upon all of these considerations it is reasonable that clinicians share with patients the potential rationale for initiating ART during early HIV infection and offer treatment to those who are willing and able to commit to lifelong treatment.

Treatment Regimen for Acute or Recent HIV Infection

If the clinician and patient have made the decision to initiate ART for acute or recent HIV infection, the goal of therapy is to suppress plasma HIV RNA levels to below detectable levels (AIII). Data are insufficient to draw firm conclusions regarding specific drug combinations to use in acute HIV infection. Potential combinations of agents should be those used in chronic infection. (See What to Start.) However, because clinically significant resistance to PIs is less common than resistance to NNRTIs in ART-naive persons, an RTV-boosted PI-based regimen should be used if therapy is initiated before drug-resistance test results are available (AIII). If resistance test results or resistance pattern of the source virus are known, this information should be used to guide the selection of the ARV regimen.

Patient Follow-up

Testing for plasma HIV RNA levels and CD4 count and toxicity monitoring should be performed as described in Laboratory Testing for Initial Assessment and Monitoring While on Antiretroviral Therapy (i.e., HIV RNA at initiation of therapy, after 2–8 weeks, then every 4–8 weeks until viral suppression, then every 3–4 months thereafter) (AII).

Duration of Therapy for Acute or Recent HIV Infection

The optimal duration of therapy for patients with acute or recent HIV infection is unknown, but ongoing clinical trials may provide relevant data regarding these concerns. Difficulties inherent in determining the optimal duration and therapy composition for acute or recent infection (and the potential need for lifelong treatment) should be considered when counseling patients prior to initiation of therapy. Patients need to know that there are limited data regarding the benefits of stopping treatment, whereas strong data from studies in patients with chronic HIV infection show that stopping ART may be harmful [21].

Table 10. Identifying, Diagnosing and Managing Acute HIV-1 Infection

Suspecting acute HIV infection: Signs or symptoms of acute HIV infection with recent (within 2–6 weeks) high risk of exposure to HIVa Signs/symptoms/laboratory findings may include but are not limited to one or more of the following: fever, lymphadenopathy, skin rash, myalgia/arthralgia, headache, diarrhea, oral ulcers, leucopenia, thrombocytopenia, transaminase elevation. High-risk exposures include sexual contact with a person infected with HIV or at risk of HIV, sharing of injection drug use paraphernalia, or contact of potentially infectious blood with mucous membranes or breaks in skin.a

Differential diagnosis: Epstein-Barr virus (EBV)- and non-EBV (e.g., cytomegalovirus [CMV])-related infectious mononucleosis syndromes, influenza, viral hepatitis, streptococcal infection, syphilis

Evaluation/diagnosis of acute/primary HIV infection HIV antibody enzyme immunoassay (EIA) (rapid test if available) Reactive EIA must be followed by Western blot. Negative EIA or reactive EIA with negative or indeterminate Western blot should be followed by a virologic test.b Positive virologic testb in this setting is consistent with acute HIV infection. When acute HIV infection is diagnosed by a positive virologic test (such as HIV RNA or p24 antigen) that was preceded by a negative HIV antibody test, a confirmatory HIV antibody test should be performed over the next 3 months to confirm seroconversion.

Considerations for antiretroviral therapy: All pregnant women with acute or recent HIV infection should start on a combination ARV regimen as soon as possible because of the high risk of MTCT of HIV (AI). Treatment of acute and early HIV infection in nonpregnant persons is considered optional (CIII). Potentially unique benefits associated with ART during acute and early infection exist, although they remain unproven. The risks of ART during acute and early infection are consistent with those for initiating ART in chronically infected asymptomatic patients with high CD4 counts. If therapy is initiated, the goal should be for maintenance of maximal viral suppression. Enrollment in a clinical trial should be considered.

a  In some settings, behaviors conducive to acquisition of HIV infection might not be ascertained or might not be perceived as “high risk” by the health care provider or the patient or both. Thus, symptoms and signs consistent with acute retroviral syndrome should motivate consideration of this diagnosis even in the absence of reported high-risk behaviors. b  p24 antigen or HIV RNA assay. The p24 antigen is less sensitive but more specific than HIV RNA tests; HIV RNA tests are generally preferred. HIV RNA tests include quantitative branched DNA (bDNA), reverse transcriptase-polymerase chain reaction (RT-PCR), or qualitative transcription-mediated amplification (APTIMA, GenProbe).

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