Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents With HIV

Laboratory Testing

Drug-Resistance Testing

Genotypic and Phenotypic-Resistance Assays

Genotypic and phenotypic-resistance assays are used to assess viral strains and select treatment strategies. These assays provide information on resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). In some circumstances, INSTI-‍resistance tests may need to be ordered separately, and clinicians should check this with the testing laboratory. INSTI-resistance testing is particularly important in people who experience virologic failure while taking an INSTI-containing regimen or in those with prior use of injectable long-acting cabotegravir (CAB-LA) (either for treatment of HIV or as pre-exposure prophylaxis [PrEP]). Testing for fusion inhibitor resistance can be ordered separately when needed. There is currently no commercially available resistance test for the CD4 T lymphocyte post-‍attachment inhibitor ibalizumab, the gp120 attachment inhibitor fostemsavir, or the capsid inhibitor lenacapavir. For a description of co-receptor tropism testing, see Co-Receptor Tropism Assays.

Genotypic Assays

Genotypic assays detect drug-resistance mutations in relevant viral genes; in general, these assays require a plasma viral load of at least 500 to 1,000 copies/mL. Most genotypic assays involve conventional Sanger sequencing of the reverse transcriptase (RT), protease (PR), and integrase (IN) genes of circulating RNA in plasma to detect mutations that are known to confer drug resistance. A genotypic assay that assesses mutations in the gp41 (envelope) gene associated with resistance to the fusion inhibitor enfuvirtide is also commercially available. Genotypic assays can be performed rapidly, and results are available within 1 to 2 weeks of sample collection. Interpreting these test results requires knowledge of the mutations selected by different antiretroviral (ARV) drugs and of the potential for cross-resistance to other drugs conferred by certain mutations. The International AIDS Society–USA maintains an updated list of significant resistance-associated mutations in the RT, PR, IN, and envelope genes. The Stanford University HIV Drug Resistance Database also provides helpful guidance for interpreting genotypic resistance test results.¹ Various additional tools are available to assist providers in interpreting genotypic test results.^2-5 Clinical trials have demonstrated that consulting with specialists in HIV drug resistance improves virologic outcomes.⁶ Clinicians are thus encouraged to consult a specialist to interpret genotypic test results and design new, optimal ARV regimens.

A next-generation sequencing genotypic resistance assay that analyzes HIV-1 proviral DNA in host cells is now commercially available. This test aims to detect archived resistance mutations in people with HIV RNA below the limit of detection or with low-level viremia.

Phenotypic Assays

Phenotypic assays measure the ability of a virus to grow in different concentrations of ARV drugs. RT, PR, and, more recently, IN and envelope gene sequences derived from a person’s plasma HIV RNA are inserted into the backbone of a laboratory clone of HIV or used to generate pseudotyped viruses that express that person’s HIV genes of interest. Replication of these viruses at different drug concentrations is monitored by expression of a reporter gene and is compared with the replication of a reference HIV strain. The drug concentration that inhibits viral replication by 50% (i.e., the median inhibitory concentration [IC₅₀]) 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 that can produce results in 2 to 3 weeks are commercially available, but they cost more to perform than genotypic assays. In addition, interpreting phenotypic assay results can be complicated by incomplete information regarding the specific resistance level (i.e., fold increase in IC₅₀) associated with drug failure, although clinically significant fold increase cutoffs have been described for some drugs.^7-11 Again, consulting with a specialist to interpret test results can be helpful. 

Limitations of Genotypic and Phenotypic Assays

Limitations of both genotypic and phenotypic assays include lack of uniform quality assurance testing for all available assays, relatively high cost, and insensitivity to minor viral species. Drug‑resistant viruses that constitute <10% to 20% of the circulating virus population will probably not be detected by commercially available assays. This limitation is important to note because a wild‑type virus often re-emerges as the predominant population in the plasma after discontinuation of drugs that exert selective pressure on drug-resistant populations. As a consequence, the proportion of virus with resistance mutations can decrease to below the 10% to 20% threshold.^12-14 In the case of some oral ARV drugs, this reversion to predominantly wild-type virus can occur in the first 4 to 6 weeks after the drugs are discontinued. However, with injectable agents that have prolonged half‑lives (e.g., long-acting cabotegravir and rilpivirine [LA CAB/RPV]), drug pressure may persist for prolonged periods. Prospective studies have demonstrated that despite plasma reversion, reinitiating the same ARV agents (or those with similar resistance pathways) often leads to early treatment failure; the virus responsible for this failure is derived from a previously archived resistant virus.¹⁵ Therefore, for people taking a non–long-acting ARV regimen, drug-resistance testing in the setting of virologic failure should be performed while the person is still taking their ARV regimen or, if that is not possible, within 4 weeks after discontinuing their ARV regimen (AII). If more than 4 weeks have elapsed since the non–long-acting agents were discontinued, resistance testing may still provide useful information to guide therapy; however, it is important to recognize that previously selected resistance mutations can be missed due to lack of drug-selective pressure (CIII). Given the long half‑lives of the long-acting injectable ARV drugs, resistance testing (including testing for resistance to INSTIs) should be performed in all people who have experienced virologic failure on a regimen of LA CAB/RPV or acquired HIV after receiving CAB-LA as PrEP, regardless of the amount of time since drug discontinuation (AIII). However, the absence of detectable resistance in people not currently on antiretroviral therapy (ART) must be interpreted with caution when designing subsequent ARV regimens. Importantly, in addition to considering prior ART history, prior genotypic- or phenotypic-resistance test results should be obtained from old records when possible. Because the most current drug-resistance test may not be able to detect resistance mutations that were previously detected, these prior test results are clinically important and should be reviewed and considered when designing a new ARV regimen (AIII).

A next-generation sequencing genotypic assay that analyzes HIV-1 proviral DNA may provide additional information on drug resistance in people with low levels of plasma HIV RNA or in people whose levels are below the limit of detection (CIII). However, these assays might miss some or all previous drug-resistance mutations, and they should be interpreted with caution. The usefulness of these assays in the clinic is still under investigation and has yet to be fully determined.

Use of Resistance Assays in Clinical Practice

Note: See Table 5 below for recommendations for the use of drug resistance assays.

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 risk of acquiring drug-resistant virus is related to the prevalence of drug resistance in people with HIV who engage in activities that may result in HIV transmission within a given community. The prevalence of resistance and mutations by ARV drug class depends upon the population being studied (e.g., people with previous ARV exposure versus ARV-naive people), geography, and ARV class available in the region.²⁰ Pre-existing HIV drug resistance before initiation of ART is recognized as an issue for both high- and low-income countries. The prevalence of transmitted drug resistance (TDR) in high-income countries ranges from 9% to 14% and varies by country.^21-23 Pre-treatment drug resistance—which includes people exposed to ARVs prior to initiating first-line therapy (e.g., for PrEP or for the prevention of perinatal transmission), as defined by the World Health Organization—exceeds 10% in many countries.²⁰ In most TDR surveys, NNRTI resistance and NRTI resistance are the most common mutation class types detected, followed by PI- and INSTI-resistance mutations, respectively.^21-23

Resistance testing is recommended to guide therapy selection to optimize virologic response in all people starting ART (AII). A genotypic assay is preferred for this purpose (AIII). In early (acute and recent) HIV infection, in pregnant people with HIV, or in people willing and able to initiate ART on the day or soon after HIV diagnosis, treatment initiation should not be delayed pending resistance testing results. Once results are reported, the regimen can be modified if warranted (see Early [Acute and Recent] HIV Infection) (AIII). In the absence of ART, resistant viruses may decline over time to less than the detection limit of standard resistance tests. However, when ART is eventually initiated, even low levels of resistant viruses may still increase the risk of treatment failure.^24-26 Therefore, if ART is deferred, resistance testing should still be performed at the time of entry into care to optimize the chance of capturing transmitted resistance (AIII). In this situation, the genotypic resistance test result should be used for regimen selection in the future when the person begins ART. If a person received CAB-LA as part of ART or PrEP, genotypic resistance testing should include the IN gene.

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. It is often possible to detect resistance-associated mutations in viruses that were transmitted several years earlier.^27-29 Though no prospective trial has directly addressed whether drug-resistance testing before initiation of therapy confers benefit in this population, data from several studies, including one prospective clinical trial, suggest that virologic responses in people with baseline resistance mutations are suboptimal.^16-19,30-34 In addition, an analysis of early RT and PR genotypic resistance testing in ARV-naive people suggests that baseline testing in this population is cost-effective and should be performed.³⁵ Therefore, resistance testing in people with chronic HIV is recommended at the time of entry into HIV care (AII).

Although no definitive prospective data exist to support the choice of one type of resistance testing over another, genotypic testing is generally preferred over phenotypic testing because of lower cost, faster turnaround time, greater sensitivity for detecting mixtures of wild-type and resistant virus, and easier interpretation of test results (AIII). If therapy is deferred, repeat testing shortly before initiating ART may be considered, because the person may have acquired drug-resistant virus (i.e., superinfection) (CIII).³⁶ Standard genotypic drug-resistance testing in ARV-naive people involves testing for mutations in the RT and PR genes. Although reports of transmission of INSTI‑resistant virus are rare, as use of INSTIs increases, the potential for transmission of INSTI-resistant virus also may increase. The prior use of CAB-LA for PrEP also may increase the risk of INSTI resistance at the time of HIV diagnosis. When INSTI resistance is possible, providers should supplement standard, baseline, genotypic resistance testing with genotypic testing of the IN gene, which may need to be ordered separately (AIII).

The next-generation sequencing genotypic resistance assay that analyzes proviral DNA in host cells can be considered in people with baseline HIV RNA <1,000 copies/mL or when conventional HIV RNA drug-resistance testing is unsuccessful (CIII). As outlined above, the results should be interpreted with caution, as this assay might miss some or all previously existing drug-resistance mutations.

Use of Resistance Assays in the Event of Virologic Failure

Resistance assays are important tools to inform treatment decisions for people who experience virologic failure while on ART. Several prospective studies have assessed the utility of resistance testing to guide ARV drug selection in people who experience virologic failure. These studies have involved genotypic assays, phenotypic assays, or both.^6,37-43 In general, these studies have found that changes in therapy based on resistance test results produce better early virologic response to salvage regimens than regimen changes guided only by clinical judgment.

Resistance assays are important tools to inform treatment decisions for people who experience virologic failure while on ART. Several prospective studies have assessed the utility of resistance testing to guide ARV drug selection in people who experience virologic failure. These studies have involved genotypic assays, phenotypic assays, or both.^6,37-43 In general, these studies have found that changes in therapy based on resistance test results produce better early virologic response to salvage regimens than regimen changes guided only by clinical judgment.

In addition, one observational cohort study found that the use of genotypic drug-resistance testing in ART-experienced people with detectable plasma HIV RNA was independently associated with improved survival.⁴⁴ Thus, resistance testing is recommended as a tool for selecting active drugs when changing ARV regimens because of virologic failure in people with HIV RNA >200 copies/mL (AI for >1,000 copies/mL, AIII for 501 to 1,000 copies/mL, CIII for confirmed HIV RNA 201 to 500 copies/mL) (see Virologic Failure). In people with HIV RNA >200 copies/mL but <500 copies/mL, testing may be difficult to obtain outside of a research setting but still should be considered. Conventional drug-resistance testing in people with plasma viral loads ≤200 copies/mL is not recommended because there are unclear benefits and drug-resistance assays cannot be consistently performed at very low HIV RNA levels (AIII).

Resistance testing can also help to guide treatment decisions for people with HIV who have suboptimal viral load reduction (AII). Virologic failure in the setting of ART is, for certain people with HIV, associated with resistance to only one component of the regimen.^45-47 In this situation, substituting individual drugs in a failing regimen may be an option, but this concept will require clinical validation (see Virologic Failure).

Genotyping is preferred for resistance testing in people with HIV who experience virologic failure or suboptimal viral load reduction while on a first or second ARV drug regimen and in people for whom resistance mutation patterns are known or not expected to be complex (i.e., mutations that are straightforward, usually limited in number, or those that have clear significance) (AII). Often in these situations, the mutation patterns detected can be interpreted by algorithms used to predict the impact of subsequent regimens on virologic response. For people with HIV who have extensive treatment history, complex mutational patterns may occur. In such situations, the interpretation of complex genotypes and the impact of the mutation pattern on subsequent treatment regimens can be challenging. For these individuals, phenotypic-resistance testing may provide additional helpful information (BIII). Rather than only predicting the impact of the detected mutations, these assays can measure in vitro the actual fold change in drug susceptibility, as well as the actual impact of mutation combinations and interactions on each drug under consideration.

When compared with phenotypic testing, genotypic testing costs less to perform and has a faster turnaround time and greater sensitivity for detecting mixtures of wild-type and resistant virus. In addition, observations show that genotypic and phenotypic assays are comparable predictors of virologic response to subsequent ARV regimens.⁴⁸ In people with HIV who experience virologic failure while on INSTI-based regimens or in those with prior INSTI exposure, including to CAB-LA for HIV treatment or prevention, testing for INSTI resistance should be performed to determine whether to include drugs from this class in subsequent regimens (AII). In this circumstance, clinicians should confirm that, when they order a resistance test, their laboratory is testing for INSTI resistance in addition to NNRTI, NRTI, and PI resistance. If INSTI-resistance testing needs to be ordered separately (as is the case in some laboratories), clinicians should request this assay in addition to standard drug-resistance testing. The addition of phenotypic to genotypic testing is generally indicated for people with known or suspected complex drug-resistance mutation patterns (BIII).

The next-generation sequencing genotypic resistance assay that analyzes proviral DNA can be considered for people with HIV who are experiencing treatment failure and for whom conventional HIV RNA genotypic drug-resistance testing is unsuccessful or unavailable due to low HIV RNA levels (CIII). As outlined above, results should be interpreted with caution, as these assays might miss some or all previously existing drug-resistance mutations.

When the use of a CCR5 antagonist is being considered, a co-receptor tropism assay should be performed (AI) (see Co-Receptor Tropism Assays).

Use of HIV Proviral DNA Resistance Assays for Optimizing Antiretroviral Regimen in People With Viral Suppression

In the past decade, simpler, more potent, and better-tolerated ARV drugs have become available, and new ARV drugs will likely continue to emerge. Switching individual or multiple ARV drugs in a regimen is sometimes considered for people with HIV with suppressed viral load to simplify a regimen, avoid drug interactions or toxicity, or for other reasons. If a person’s viral load is suppressed, standard drug-resistance testing will not be successful.

The next-generation sequencing genotypic resistance assay that analyzes proviral DNA can be considered for people with viral suppression, particularly if complex or semi-complex pre-existing resistance is suspected. In individuals who have experienced no prior virologic failures and who are on their first or second regimen, or who have genotypic testing results from when they had prior virologic failures, the use of the proviral DNA genotypic test is unlikely to provide additional useful information. However, in individuals who have experienced multiple prior failures, have a prolonged history of prior ARV regimens, or for whom prior genotypic resistance test results are not available, it may be appropriate to utilize proviral DNA genotypic testing (CIII). When such testing is obtained, results should be combined with all prior genotypic and phenotypic test results to construct a cumulative genotype, which incorporates all current and previously detected drug-resistance mutations. Results from proviral DNA genotypes should be interpreted with caution, as these assays might miss some or all previously existing drug-resistance mutations.^49,50 The usefulness of these assays in the clinic is still under investigation and has yet to be fully determined.

Use of Resistance Assays in Pregnancy

In pregnancy, the goal of ART is to rapidly and maximally reduce plasma HIV RNA in order to provide optimal therapy for the pregnant person and to prevent perinatal transmission of HIV. Genotypic resistance testing is recommended for all pregnant people with HIV before initiation of therapy (AIII) and for those entering pregnancy with detectable HIV RNA levels while on therapy (AI). Phenotypic testing in those found to have complex drug-resistance mutation patterns may provide additional information (BIII). Optimal prevention of perinatal transmission requires prompt initiation of ART pending resistance testing results. Once the results are available, the ARV regimen can be changed as needed.

References

1. Paredes R, Tzou PL, van Zyl G, et al. Collaborative update of a rule-based expert system for HIV-1 genotypic resistance test interpretation. PLoS One. 2017;12(7):e0181357. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28753637.
2. Flandre P, Costagliola D. On the comparison of artificial network and interpretation systems based on genotype resistance mutations in HIV-1-infected patients. 2006;20(16):2118-2120. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17053360.
3. Vercauteren J, Vandamme AM. Algorithms for the interpretation of HIV-1 genotypic drug resistance information. Antiviral Res. 2006;71(2-3):335-342. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16782210.
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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16619162.
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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15909273.
6. Tural C, Ruiz L, Holtzer C, et al. Clinical utility of HIV-1 genotyping and expert advice: the Havana trial. 2002;16(2):209-218. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11807305.
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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15040535.
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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14976601.
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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17205478.
10. Naeger LK, Struble KA. Food and Drug Administration analysis of tipranavir clinical resistance in HIV-1-infected treatment-experienced patients. 2007;21(2):179-185. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17197808.
11. Naeger LK, Struble KA. Effect of baseline protease genotype and phenotype on HIV response to atazanavir/ritonavir in treatment-experienced patients. 2006;20(6):847-853. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16549968.
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. 1999;13(18):2541-2546. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10630523.
13. Miller V, Sabin C, Hertogs K, et al. Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure. 2000;14(18):2857-2867. Available at: https://pubmed.ncbi.nlm.nih.gov/11153667.
14. Devereux HL, Youle M, Johnson MA, et al. Rapid decline in detectability of HIV-1 drug resistance mutations after stopping therapy. 1999;13(18):F123-127. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10630517.
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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17041858.
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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12167680.
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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17725415.
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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17057609.
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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18269317.
20. World Health Organization. WHO releases HIV drug resistance report 2021. Available at: https://www.who.int/news/item/24-11-2021-who-releases-hiv-drug-resistance-report-2021. Accessed: July 29, 2022.
21. Rhee SY, Kassaye SG, Barrow G, et al. HIV-1 transmitted drug resistance surveillance: shifting trends in study design and prevalence estimates. J Int AIDS Soc. 2020;23(9):e25611. Available at: https://pubmed.ncbi.nlm.nih.gov/32936523/.
22. Guo C, Wu Y, Zhang Y, et al. Transmitted drug resistance in antiretroviral therapy-naive persons with acute/early/primary HIV infection: a systematic review and meta-analysis. Front Pharmacol. 2021;12:718763. Available at: https://pubmed.ncbi.nlm.nih.gov/34899288/.
23. Baxter JD, Dunn D, Tostevin A, et al. Transmitted HIV-1 drug resistance in a large international cohort using next-generation sequencing: results from the Strategic Timing of Antiretroviral Treatment (START) study. HIV Med. 2021;22(5):360-371. Available at: https://pubmed.ncbi.nlm.nih.gov/33369017/.
24. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18666824.
25. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19210162.
26. 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. Available at: https://pubmed.ncbi.nlm.nih.gov/20102271.
27. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17597449.
28. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15668873.
29. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18353964.
30. 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. 2004;292(2):180-189. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15249567.
31. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15247339.
32. 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. 2006;20(1):21-28. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16327315.
33. Kantor R, Smeaton L, Vardhanabhuti S, et al. Pretreatment HIV drug resistance and HIV-1 subtype C are independently associated with virologic failure: results from the multinational PEARLS (ACTG A5175) clinical trial. Clin Infect Dis. 2015;60(10):1541-1549. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25681380.
34. Phanuphak P, Sirivichayakul S, Jiamsakul A, et al. Transmitted drug resistance and antiretroviral treatment outcomes in non-subtype B HIV-1-infected patients in South East Asia. J Acquir Immune Defic Syndr. 2014;66(1):74-79. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24413039.
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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16206108.
36. Smith DM, Wong JK, Hightower GK, et al. HIV drug resistance acquired through superinfection. 2005;19(12):1251-1256. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16052079.
37. 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). 2002;16(3):369-379. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11834948.
38. Durant J, Clevenbergh P, Halfon P, et al. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial. 1999;353(9171):2195-2199. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10392984.
39. 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. 2000;14(9):F83-93. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10894268.
40. Cohen CJ, Hunt S, Sension M, et al. A randomized trial assessing the impact of phenotypic resistance testing on antiretroviral therapy. 2002;16(4):579-588. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11873001.
41. Meynard JL, Vray M, Morand-Joubert L, et al. Phenotypic or genotypic resistance testing for choosing antiretroviral therapy after treatment failure: a randomized trial. 2002;16(5):727-736. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11964529.
42. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14640390.
43. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14986258.
44. 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. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19620160.
45. Havlir DV, Hellmann NS, Petropoulos CJ, et al. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. 2000;283(2):229-234. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10634339.
46. 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. Trilège (Agence Nationale de Recherches sur le SIDA 072) Study Team). 2000;283(2):205-211. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10634336.
47. 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. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16555280.
48. Anderson JA, Jiang H, Ding X, et al. Genotypic susceptibility scores and HIV type 1 RNA responses in treatment-experienced subjects with HIV type 1 infection. AIDS Res Hum Retroviruses. 2008;24(5):685-694. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18462083.
49. Cutrell AG, Schapiro JM, Perno CF, et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis. 2021;35(9):1333-1342. Available at: https://pubmed.ncbi.nlm.nih.gov/33730748.
50. Blick G, Cerreta E, Mancini G, et al. Prior M184V/I and multiple prior virological failures have no impact on the efficacy of switching HIV+ adults to DTG/3TC through 96wks in SOLAR-3D. Presented at: The 12th International AIDS Society Conference on HIV Science. 2023. Brisbane, Australia. Available at: https://programme.ias2023.org/Abstract/Abstract/?abstractid=496.