• 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

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

Genotypic and Phenotypic Resistance Assays

Genotypic and phenotypic resistance assays are used to assess viral strains and inform selection of treatment strategies. Standard assays provide information on resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Testing for integrase and fusion inhibitor resistance can also be ordered separately from several commercial laboratories. No genotypic assays for assessing resistance to CCR5 antagonists are currently commercially available for clinical use in the United States. (See Coreceptor Tropism Assays.)

Genotypic Assays

Genotypic assays detect drug-resistance mutations present in relevant viral genes. Most genotypic assays involve sequencing of the RT and PR genes to detect mutations that are known to confer drug resistance. Genotypic assays that assess mutations in the integrase and gp41 (envelope) genes are also commercially available. Genotypic assays can be performed rapidly with results available within 1–2 weeks of sample collection. Interpretation of test results requires knowledge of the mutations that different ARV drugs select for and of the potential for cross resistance to other drugs conferred by certain mutations. The International AIDS Society-USA (IAS-USA) maintains a list of updated significant resistance-associated mutations in the RT, PR, integrase, and envelope genes [1] (see also http://www.iasusa.org/resistance_mutations). The Stanford University HIV Drug Resistance Database (http://hivdb.stanford.edu) also provides helpful guidance for interpreting genotypic resistance test results. Various tools are now available to assist the provider in interpreting genotypic test results [2-5]. Clinical trials have demonstrated the benefit of consultation with specialists in HIV drug resistance in improving virologic outcomes [6]. Clinicians are thus encouraged to consult a specialist to facilitate interpretation of genotypic test results and the design of an optimal new regimen.

Phenotypic Assays

Phenotypic assays measure the ability of a virus to grow in different concentrations of ARV drugs. RT and PR gene sequences and, more recently, integrase and envelope sequences derived from patient plasma HIV RNA are inserted into the backbone of a laboratory clone of HIV or used to generate pseudotyped viruses that express the patient-derived HIV genes of interest. Replication of these viruses at different drug concentrations is monitored by expression of a reporter gene and is compared with replication of a reference HIV strain. The drug concentration that inhibits viral replication by 50% (i.e., the median inhibitory concentration [IC]₅₀) is calculated, and the ratio of the IC₅₀ of test and reference viruses is reported as the fold increase in IC₅₀ (i.e., fold resistance).

Automated phenotypic assays are commercially available with results reported in 2–3 weeks. However, phenotypic assays cost more to perform than genotypic assays. In addition, interpretation of phenotypic assay results is complicated by incomplete information regarding the specific resistance level (i.e., fold increase in IC₅₀) that is associated with drug failure, although clinically significant fold increase cutoffs are now available for some drugs [7-11]. Again, consultation with a specialist can be helpful for interpreting test results.

Further limitations of both genotypic and phenotypic assays include lack of uniform quality assurance for all available assays, relatively high cost, and insensitivity for minor viral species. Despite being present, drug-resistant viruses constituting less than 10%–20% of the circulating virus population will probably not be detected by available assays. This limitation is important because after drugs exerting selective pressure on drug-resistant populations are discontinued, a wild-type virus often re-emerges as the predominant population in the plasma. As a consequence, the proportion of virus with resistance mutations decreases to below the 10%–20% threshold [12-14]. For some drugs, this reversion to predominantly wild-type virus can occur in the first 4–6 weeks after drugs are stopped. Prospective clinical studies have shown that, despite this plasma reversion, reinstitution of the same ARV agents (or those sharing similar resistance pathways) is usually associated with early drug failure, and the virus present at failure is derived from previously archived resistant virus [15]. Therefore, resistance testing is of greatest value when performed before or within 4 weeks after drugs are discontinued (AII). Because detectable resistant virus may persist in the plasma of some patients for longer periods of time, resistance testing beyond 4 to 6 weeks after discontinuation may still reveal mutations. However, the absence of detectable resistance in such patients must be interpreted with caution in designing subsequent ARV regimens.

Use of Resistance Assays in Clinical Practice (Table 4)

No definitive prospective data exist to support using one type of resistance assay over another (i.e., genotypic vs. phenotypic) in different clinical situations. In most situations genotypic testing is preferred because of the faster turnaround time, lower cost, and enhanced sensitivity for detecting mixtures of wild-type and resistant virus. However, for patients with a complex treatment history, results derived from both assays might provide critical and complementary information to guide regimen changes.

Use of Resistance Assays in Determining Initial Treatment

Transmission of drug-resistant HIV strains is well documented and associated with suboptimal virologic response to initial ART [16-19]. The likelihood that a patient will acquire drug-resistant virus is related to the prevalence of drug resistance in HIV-infected persons engaging in high-risk behaviors in the community. In the United States and Europe, recent studies suggest the risk that transmitted virus will be resistant to at least one ARV drug is in the range of 6%–16% [20-25], with 3%–5% of transmitted viruses exhibiting resistance to drugs from more than one class [16, 24].

If the decision is made to initiate therapy in a person with acute HIV infection, resistance testing at baseline will provide guidance in selecting a regimen to optimize virologic response. Therefore, resistance testing in this situation is recommended (AIII) and a genotypic assay is preferred (AIII). In this setting, treatment initiation should not be delayed by pending resistance testing results. Once results are obtained, the treatment regimen can be modified if warranted by the results. (See Acute HIV Infection.) In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests but may still increase the risk of treatment failure when therapy is eventually initiated [26-28]. Therefore, if therapy is deferred, resistance testing during acute HIV infection should still be performed (AIII). In this situation, the genotypic resistance test result might be kept on record for several years before it becomes clinically useful. Because it is possible for a patient to acquire drug-resistant virus (i.e., superinfection) between entry into care and initiation of ART, repeat resistance testing at the time treatment is started should be considered (CIII).

Performing drug-resistance testing before ART initiation in patients with chronic HIV infection is less straightforward. The rate at which transmitted resistance-associated mutations revert to wild-type virus has not been completely delineated, but mutations present at the time of HIV transmission are more stable than those selected under drug pressure, and it is often possible to detect resistance-associated mutations in viruses that were transmitted several years earlier [29-31]. No prospective trial has addressed whether drug-resistance testing prior to initiation of therapy confers benefit in this population. However, data from several, but not all, studies suggest suboptimal virologic responses in persons with baseline mutations [16-19, 32-34]. In addition, a cost-effectiveness analysis of early genotypic resistance testing suggests that baseline testing in this population should be performed [35]. Therefore, resistance testing in chronically infected persons at the time of entry into HIV care is recommended (AIII). Genotypic testing is preferred in this situation because of lower cost, more rapid turnaround time, ability to detect mixtures of wild-type and resistant virus, and the relative ease of interpretation (AIII). If therapy is deferred, repeat testing just prior to initiation of ART should be considered because the patient may have acquired drug-resistant virus (i.e., superinfection) (CIII).

Standard genotypic drug-resistance testing in ARV-naive persons involves testing for mutations in the RT and PR genes. Although transmission of INSTI-resistant virus has rarely been reported, as use of INSTIs increases, the potential for transmission of INSTI-resistant virus may also increase. Therefore, providers may wish to supplement standard baseline genotypic resistance testing with genotypic testing for resistance to INSTI (CIII).

Use of Resistance Assays in the Event of Virologic Failure

Resistance assays are useful in guiding decisions for patients experiencing virologic failure while on ART. Several prospective studies assessed the utility of resistance testing in guiding ARV drug selection in patients with virologic failure. These studies involved genotypic assays, phenotypic assays, or both [6, 36-42]. In general, these studies found that early virologic response to salvage regimens was improved when results of resistance testing were available to guide changes in therapy, compared with responses observed when changes in therapy were guided only by clinical judgment. Additionally, one observational study demonstrated improved survival in patients with detectable HIV plasma RNA when drug-resistance testing was performed [43]. Thus, resistance testing appears to be a useful tool in selecting active drugs when changing ARV regimens for virologic failure in persons with HIV RNA >1,000 copies/mL (AI). (See Virologic and Immunologic Failure.) In persons with >500 but <1,000 copies/mL, testing may be unsuccessful but should still be considered (BII). Drug-resistance testing is not usually recommended in persons with a plasma viral load <500 copies/mL because resistance assays cannot be consistently performed given low HIV RNA levels (AIII).

Resistance testing also can help guide treatment decisions for patients with suboptimal viral load reduction (AII). Virologic failure in the setting of combination ART is, for certain patients, associated with resistance to only one component of the regimen [44-46]. In that situation, substituting individual drugs in a failing regimen might be possible, although this concept will require clinical validation. (See Virologic and Immunologic Failure.)

Genotypic testing is generally preferred for virologic failure or suboptimal viral load reduction in persons failing their first or second ARV drug regimen because of lower cost, faster turnaround time, and greater sensitivity for detecting mixtures of wild-type and resistant virus (AIII). Addition of phenotypic to genotypic testing is generally preferred for persons with known or suspected complex drug-resistance mutation patterns, particularly to PIs (BIII).

In patients failing INSTI-based regimens, testing for INSTI resistance should be considered to determine whether to include drugs from this class in subsequent regimens; genotypic testing is preferred (BIII). Although it is not a drug-resistance assay, a coreceptor tropism assay should be performed whenever the use of a CCR5 antagonist is being considered (AI). Coreceptor tropism testing should also be considered for patients who exhibit virologic failure on a CCR5 antagonist (CIII). However, such testing may be of limited value because the absence of detectable CXCR4-using virus does not exclude the possibility that CCR5 antagonist resistance may have developed. Assays for detecting resistance to CCR5 antagonists are not yet commercially available [47]. (See Coreceptor Tropism Assays.)

Use of Resistance Assays in Pregnant Women

In pregnant women, the goal of ART is to maximally reduce plasma HIV RNA to provide appropriate maternal therapy and prevent mother-to-child transmission (MTCT) of HIV. Genotypic resistance testing is recommended for all pregnant women prior to initiation of therapy (AIII) and for those entering pregnancy with detectable HIV RNA levels while on therapy (AI). Phenotypic testing may provide additional information in those found to have complex drug-resistance mutation patterns, particularly to PIs (BIII). Optimal prevention of perinatal transmission may require initiation of ART while results of resistance testing are pending. Once the results are available, the ARV regimen can be changed as needed.

Table 4.  Recommendations for Using Drug-Resistance Assays

References

1. Hirsch MS, Gunthard HF, Schapiro JM, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel. Clin Infect Dis. 2008;47(2):266-285.
2. Flandre P, Costagliola D. On the comparison of artificial network and interpretation systems based on genotype resistance mutations in HIV-1-infected patients. AIDS. 2006;20(16):2118-2120.
3. Vercauteren J, Vandamme AM. Algorithms for the interpretation of HIV-1 genotypic drug resistance information. Antiviral Res. 2006;71(2-3):335-342.
4. Gianotti N, Mondino V, Rossi MC, et al. Comparison of a rule-based algorithm with a phenotype-based algorithm for the interpretation of HIV genotypes in guiding salvage regimens in HIV-infected patients by a randomized clinical trial: the mutations and salvage study. Clin Infect Dis. 2006;42(10):1470-1480.
5. Torti C, Quiros-Roldan E, Regazzi M, et al. A randomized controlled trial to evaluate antiretroviral salvage therapy guided by rules-based or phenotype-driven HIV-1 genotypic drug-resistance interpretation with or without concentration-controlled intervention: the Resistance and Dosage Adapted Regimens (RADAR) study. Clin Infect Dis. 2005;40(12):1828-1836.
6. Tural C, Ruiz L, Holtzer C, et al. Clinical utility of HIV-1 genotyping and expert advice: the Havana trial. AIDS. 2002;16(2):209-218.
7. Lanier ER, Ait-Khaled M, Scott J, et al. Antiviral efficacy of abacavir in antiretroviral therapy-experienced adults harbouring HIV-1 with specific patterns of resistance to nucleoside reverse transcriptase inhibitors. Antivir Ther. 2004;9(1):37-45.
8. Miller MD, Margot N, Lu B, et al. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J Infect Dis. 2004;189(5):837-846.
9. Flandre P, Chappey C, Marcelin AG, et al. Phenotypic susceptibility to didanosine is associated with antiviral activity in treatment-experienced patients with HIV-1 infection. J Infect Dis. 2007;195(3):392-398.
10. Naeger LK, Struble KA. Food and Drug Administration analysis of tipranavir clinical resistance in HIV-1-infected treatment-experienced patients. AIDS. 2007;21(2):179-185.
11. Naeger LK, Struble KA. Effect of baseline protease genotype and phenotype on HIV response to atazanavir/ritonavir in treatment-experienced patients. AIDS. 2006;20(6):847-853.
12. Verhofstede C, Wanzeele FV, Van Der Gucht B, et al. Interruption of reverse transcriptase inhibitors or a switch from reverse transcriptase to protease inhibitors resulted in a fast reappearance of virus strains with a reverse transcriptase inhibitor-sensitive genotype. AIDS. 1999;13(18):2541-2546.
13. Miller V, Sabin C, Hertogs K, et al. Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure. AIDS. 2000;14(18):2857-2867.
14. Devereux HL, Youle M, Johnson MA, et al. Rapid decline in detectability of HIV-1 drug resistance mutations after stopping therapy. AIDS. 1999;13(18):F123-127.
15. Benson CA, Vaida F, Havlir DV, et al. A randomized trial of treatment interruption before optimized antiretroviral therapy for persons with drug-resistant HIV: 48-week virologic results of ACTG A5086. J Infect Dis. 2006;194(9):1309-1318.
16. Little SJ, Holte S, Routy JP, et al. Antiretroviral-drug resistance among patients recently infected with HIV. N Engl J Med. 2002;347(6):385-394.
17. Borroto-Esoda K, Waters JM, Bae AS, et al. Baseline genotype as a predictor of virological failure to emtricitabine or stavudine in combination with didanosine and efavirenz. AIDS Res Hum Retroviruses. 2007;23(8):988-995.
18. Pozniak AL, Gallant JE, DeJesus E, et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes--a 96-week analysis. J Acquir Immune Defic Syndr. 2006;43(5):535-540.
19. Kuritzkes DR, Lalama CM, Ribaudo HJ, et al. Preexisting resistance to nonnucleoside reverse-transcriptase inhibitors predicts virologic failure of an efavirenz-based regimen in treatment-naive HIV-1-infected subjects. J Infect Dis. 2008;197(6):867-870.
20. Weinstock HS, Zaidi I, Heneine W, et al. The epidemiology of antiretroviral drug resistance among drug-naive HIV-1-infected persons in 10 US cities. J Infect Dis. 2004;189(12):2174-2180.
21. Wensing AM, van de Vijver DA, Angarano G, et al. Prevalence of drug-resistant HIV-1 variants in untreated individuals in Europe: implications for clinical management. J Infect Dis. 2005;192(6):958-966.
22. Cane P, Chrystie I, Dunn D, et al. Time trends in primary resistance to HIV drugs in the United Kingdom: multicentre observational study. BMJ. 2005;331(7529):1368.
23. Bennett D, McCormick L, Kline R, et al. US surveillance of HIV drug resistance at diagnosis using HIV diagnostic sera. Paper presented at: 12th Conference on Retroviruses and Opportunistic Infections;  Feb 22-25, 2005; Boston, MA. Abstract 674.
24. Wheeler WH, Ziebell RA, Zabina H, et al. Prevalence of transmitted drug resistance associated mutations and HIV-1 subtypes in new HIV-1 diagnoses, U.S.-2006. AIDS. 2010;24(8):1203-1212.
25. Ross L, Lim ML, Liao Q, et al. Prevalence of antiretroviral drug resistance and resistance-associated mutations in antiretroviral therapy-naive HIV-infected individuals from 40 United States cities. HIV Clin Trials. 2007;8(1):1-8.
26. Johnson JA, Li JF, Wei X, et al. Minority HIV-1 drug resistance mutations are present in antiretroviral treatment-naive populations and associate with reduced treatment efficacy. PLoS Med. 2008;5(7):e158.
27. Simen BB, Simons JF, Hullsiek KH, et al. Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes. J Infect Dis. 2009;199(5):693-701.
28. Paredes R, Lalama CM, Ribaudo HJ, et al. Pre-existing minority drug-resistant HIV-1 variants, adherence, and risk of antiretroviral treatment failure. J Infect Dis. 2010;201(5):662-671.
29. Smith DM, Wong JK, Shao H, et al. Long-term persistence of transmitted HIV drug resistance in male genital tract secretions: implications for secondary transmission. J Infect Dis. 2007;196(3):356-360.
30. Novak RM, Chen L, MacArthur RD, et al. Prevalence of antiretroviral drug resistance mutations in chronically HIV-infected, treatment-naive patients: implications for routine resistance screening before initiation of antiretroviral therapy. Clin Infect Dis. 2005;40(3):468-474.
31. Little SJ, Frost SD, Wong JK, et al. Persistence of transmitted drug resistance among subjects with primary human immunodeficiency virus infection. J Virol. 2008;82(11):5510-5518.
32. Saag MS, Cahn P, Raffi F, et al. Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naive patients: a randomized trial. JAMA. 2004;292(2):180-189.
33. Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med. 2004;351(3):229-240.
34. Pillay D, Bhaskaran K, Jurriaans S, et al. The impact of transmitted drug resistance on the natural history of HIV infection and response to first-line therapy. AIDS. 2006;20(1):21-28.
35. Sax PE, Islam R, Walensky RP, et al. Should resistance testing be performed for treatment-naive HIV-infected patients? A cost-effectiveness analysis. Clin Infect Dis. 2005;41(9):1316-1323.
36. Cingolani A, Antinori A, Rizzo MG, et al. Usefulness of monitoring HIV drug resistance and adherence in individuals failing highly active antiretroviral therapy: a randomized study (ARGENTA). AIDS. 2002;16(3):369-379.
37. Durant J, Clevenbergh P, Halfon P, et al. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial. Lancet. 1999;353(9171):2195-2199.
38. Baxter JD, Mayers DL, Wentworth DN, et al. A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. CPCRA 046 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS. AIDS. 2000;14(9):F83-93.
39. Cohen CJ, Hunt S, Sension M, et al. A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy. AIDS. 2002;16(4):579-588.
40. Meynard JL, Vray M, Morand-Joubert L, et al. Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure: a randomized trial. AIDS. 2002;16(5):727-736.
41. Vray M, Meynard JL, Dalban C, et al. Predictors of the virological response to a change in the antiretroviral treatment regimen in HIV-1-infected patients enrolled in a randomized trial comparing genotyping, phenotyping and standard of care (Narval trial, ANRS 088). Antivir Ther. 2003;8(5):427-434.
42. Wegner SA, Wallace MR, Aronson NE, et al. Long-term efficacy of routine access to antiretroviral-resistance testing in HIV type 1-infected patients: results of the clinical efficacy of resistance testing trial. Clin Infect Dis. 2004;38(5):723-730.
43. Palella FJ, Jr., Armon C, Buchacz K, et al. The association of HIV susceptibility testing with survival among HIV-infected patients receiving antiretroviral therapy: a cohort study. Ann Intern Med. 2009;151(2):73-84.
44. Havlir DV, Hellmann NS, Petropoulos CJ, et al. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. JAMA. 2000;283(2):229-234.
45. Descamps D, Flandre P, Calvez V, et al. Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Trilege (Agence Nationale de Recherches sur le SIDA 072) Study Team). JAMA. 2000;283(2):205-211.
46. Machouf N, Thomas R, Nguyen VK, et al. Effects of drug resistance on viral load in patients failing antiretroviral therapy. J Med Virol. 2006;78(5):608-613.
47. Lewis M MJ, Simpson P, et al. Changes in V3 loop sequence associated with failure of maraviroc treatment in patients enrolled in the MOTIVATE 1 and 2 trials. Paper presented at: 15th Conference on Retroviruses and Opportunistic Infections.;  February 3-6, 2008; Boston, Massachusetts. Abstract 871.