HIV AIDS laboratory findings: Difference between revisions

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# HIV [[viral load#HIV viral load test|viral load]].
# HIV [[viral load#HIV viral load test|viral load]].


==Diagnostic Testing==
====Screening Tests====
====Screening Tests====
Most HIV tests used to screen for HIV infection detect the presence of antibodies against HIVs. Detectable antibodies usually develop within 2–8 weeks after infection, but may take longer. There are three different screening tests:
Most HIV tests used to screen for HIV infection detect the presence of antibodies against HIVs. Detectable antibodies usually develop within 2–8 weeks after infection, but may take longer. There are three different screening tests:

Revision as of 22:39, 4 November 2014

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editors-in-Chief: Ujjwal Rastogi, MBBS, Ammu Susheela, M.D. [3]

Overview

A number of laboratory tests are important for initial evaluation of HIV-infected paients. Two surrogate markers (CD4 T-cell count (CD4 count), plasma HIV RNA) are routinely used to asses immune function and level of viral viremia.

Laboratory Findings

Sequence of Appearance of Laboratory Markers for HIV-1 Infection
Note. Units for vertical axis are not noted because their magnitude differs for RNA, p24 antigen, and antibody. Modified from MP Busch, GA Satten (1997)[1] with updated data from Fiebig (2003),[2] Owen (2008),[3] and Masciotra (2011, 2013). [4][5]
Image obtained from CDC [1]

Types of HIV Tests

  • Laboratory tests for the diagnosis of HIV infection are of three types:
  1. Screening tests
  2. Supplemental tests
  3. Confirmatory tests
  • Severity of disease and rate of progression are estimated by measurement of:
  1. CD4 count.
  2. HIV viral load.

Diagnostic Testing

Screening Tests

Most HIV tests used to screen for HIV infection detect the presence of antibodies against HIVs. Detectable antibodies usually develop within 2–8 weeks after infection, but may take longer. There are three different screening tests:

  1. ELISA test (based on antigen-antibody and enzyme substrate reactions).
  2. Rapid Tests (Dot blot and Latex Agglutination Tests).
  3. Simple Tests (Particle agglutination tests).

Both simple and rapid tests are readily available and cheaper as compared to ELISA although they may not be as sensitive.

Supplemental Tests

These are used to validate results obtained by the screening tests and are of two types:

  1. Western blot tests
  2. Immunofluorescence tests

Confirmatory Tests

These test aim at the following:

  1. Demonstration of Viral Antigen (P24).
  2. Isolation of HIV.
  3. Detection of viral nucleic acid.

The confirmatory tests can diagnose HIV infection even during the window period (initial two to three weeks of infection), in which both the screening and the supplemental tests fail to diagnose the infection. However these are done in the reference centers thus time consuming and costly.

Important Considerations

  • The window period is the time between the initial infection and the development of detectable antibodies against the virus. This period varies between 1 to 6 months prior to which antibody testing is generally negative and a possible HIV infection can be missed. Detection of the virus using polymerase chain reaction (PCR) during the window period is preferable, and evidence suggests that an infection may often be detected earlier than when using a fourth generation enzyme immunoassay screening test. Positive results obtained by PCR are later confirmed by antibody tests.[6]
  • Routinely used HIV tests cannot be used in neonates born to HIV-positive mothers because of the presence of maternal antibodies to HIV in the child's blood. Prior to 18 months, HIV infection can only be diagnosed by PCR, testing for HIV pro-viral DNA.[7]

CD4 T-Cell Count

The CD4 count serves as the major laboratory indicator of immune function in patients who have HIV infection. It is one of the key factors in deciding whether to initiate ART and prophylaxis for opportunistic infections, and it is the strongest predictor of subsequent disease progression and survival according to clinical trials and cohort studies.[8][9]

A significant change (2 standard deviations) between two tests is approximately a 30% change in the absolute count or an increase or decrease in CD4 percentage by 3 percentage points.

  • Use of CD4 Count for Initial Assessment. The CD4 count is one of the most important factors in the decision to initiate ART and/or prophylaxis for opportunistic infections. All patients should have a baseline CD4 count at entry into care.
  • Use of CD4 Count for Monitoring Therapeutic Response. An adequate CD4 response for most patients on therapy is defined as an increase in CD4 count in the range of 50–150 cells/mm3 per year, generally with an accelerated response in the first 3 months. Subsequent increases in patients with good virologic control show an average increase of approximately 50–100 cells/mm3 per year for the subsequent years until a steady state level is reached.[10] Patients who initiate therapy with a low CD4 count or at an older age may have a blunted increase in their count despite virologic suppression.

Frequency of CD4 Count Monitoring. In general, CD4 counts should be monitored every 3–4 months to:

  1. Determine when to start ART in untreated patients.
  2. Assess immunologic response to ART.
  3. Assess the need for initiation or discontinuation of prophylaxis for opportunistic infections .

The CD4 cell count response to ART varies widely, but a poor CD4 response is rarely an indication for modifying a virologically suppressive ARV regimen. In patients with consistently suppressed viral loads who have already experienced ART-related immune reconstitution, the CD4 cell count provides limited information, and frequent testing may cause unnecessary anxiety in patients with clinically inconsequential fluctuations. Thus, for the patient on a suppressive regimen whose CD4 cell count has increased well above the threshold for opportunistic infection risk, the CD4 count can be measured less frequently than the viral load. In such patients, CD4 count may be monitored every 6 to 12 months, unless there are changes in the patient’s clinical status, such as new HIV-associated clinical symptoms or initiation of treatment with interferon, corticosteroids, or anti-neoplastic agents.

Factors that affect absolute CD4 count. The absolute CD4 count is a calculated value based on the total white blood cell (WBC) count and the percentages of total and CD4+ T lymphocytes. This absolute number may fluctuate among individuals or may be influenced by factors that may affect the total WBC and lymphocyte percentages, such as use of bone marrow–suppressive medications or the presence of acute infections. Splenectomy [11][12] or coinfection with human T-lymphotropic virus type I (HTLV-1) [13] may cause misleadingly elevated absolute CD4 counts. Alpha-interferon, on the other hand, may reduce the absolute CD4 number without changing the CD4 percentage.[14] In all these cases, CD4 percentage remains stable and may be a more appropriate parameter to assess the patient’s immune function.

Plasma HIV RNA Testing

  • Plasma HIV RNA (viral load) should be measured in all patients at baseline and on a regular basis thereafter, especially in patients who are on treatment, because viral load is the most important indicator of response to antiretroviral therapy (ART) (AI).
  • Analysis of 18 trials that included more than 5,000 participants with viral load monitoring showed a significant association between a decrease in plasma viremia and improved clinical outcome.[15]
  • The viral load testing serves as a surrogate marker [16] for treatment response and can be useful in predicting clinical progression.[17][18]
  • The minimal change in viral load considered to be statistically significant (2 standard deviations) is a threefold, or a 0.5 log 10 copies/mL change.
  • Optimal viral suppression is generally defined as a viral load persistently below the level of detection (<20–75 copies/mL, depending on the assay used).
  • However, isolated “blips” (viral loads transiently detectable at low levels, typically <400 copies/mL) are not uncommon in successfully treated patients and are not thought to represent viral replication or to predict virologic failure.[19]
  • In addition, low-level positive viral load results (typically <200 copies/mL) appear to be more common with some viral load assays than others, and there is no definitive evidence that patients with viral loads quantified as <200 copies/mL using these assays are at increased risk for virologic failure.[20][21][22]
  • For the purposes of clinical trials the AIDS Clinical Trials Group (ACTG) currently defines virologic failure as a confirmed viral load >200 copies/mL, which eliminates most cases of apparent viremia caused by blips or assay variability. This definition may also be useful in clinical practice.

HLA-B*5701 Screening

  • The hypersensitivity reaction to Abacavir (ABC HSR) is a multiorgan clinical syndrome typically seen within the initial 6 weeks of ABC treatment. This reaction has been reported in 5%–8% of patients participating in clinical trials when using clinical criteria for the diagnosis, and it is the major reason for early discontinuation of ABC. Discontinuing ABC usually promptly reverses HSR, whereas subsequent rechallenge can cause a rapid, severe, and even life threatening recurrence.[23]
  • Studies that evaluated demographic risk factors for ABC HSR have shown racial background as a risk factor, with white patients generally having a higher risk (5%–8%) than black patients (2%–3%). Several groups reported a highly significant association between ABC HSR and the presence of the major histocompatibility complex (MHC) class I allele HLA-B*5701. [24][25]
  • Because the clinical criteria used for ABC HSR are overly sensitive and may lead to false-positive ABC HSR diagnoses, an ABC skin patch test (SPT) was developed as a research tool to immunologically confirm ABC HSR.[26]
  • A positive ABC SPT is an ABC-specific delayed HSR that results in redness and swelling at the skin site of application. All ABC SPT–positive patients studied were also positive for the HLA-B*5701 allele. The ABC SPT could be falsely negative for some patients with ABC HSR and, at this point, is not recommended for use as a clinical tool. The PREDICT-1 study randomized patients before starting ABC either to be prospectively screened for HLA-B*5701 (with HLA-B*5701–positive patients not offered ABC) or to standard of care at the time of the study (i.e., no HLA screening, with all patients receiving ABC) [27]
  • The overall HLA-B*5701 prevalence in this predominately white population was 5.6%. In this cohort, screening for HLA-B*5701 eliminated immunologic ABC HSR (defined as ABC SPT positive) compared with standard of care (0% vs. 2.7%), yielding a 100% negative predictive value with respect to SPT and significantly decreasing the rate of clinically suspected ABC HSR (3.4% vs. 7.8%).
  • The SHAPE study corroborated the low rate of immunologically validated ABC HSR in black patients and confirmed the utility of HLA-B*5701 screening for the risk of ABC HSR (100%

sensitivity in black and white populations).[28]

  • On the basis of the results of these studies, the Panel recommends screening for HLA-B*5701 before starting patients on an ABC-containing regimen (AI).
  • HLA-B*5701–positive patients should not be prescribed ABC (AI), and the positive status should be recorded as an ABC allergy in the patient’s medical record (AII).
  • HLA-B*5701 testing is needed only once in a patient’s lifetime; thus, efforts to carefully record and maintain the test result and to educate the patient about its implications are important.
  • The specificity of the HLAB*5701 test in predicting ABC HSR is lower than the sensitivity (i.e., 33%–50% of HLA-B*5701–positive patients would likely not develop confirmed ABC HSR if exposed to ABC). HLA-B*5701 should not be used as a substitute for clinical judgment or pharmacovigilance, because a negative HLA-B*5701 result does not absolutely rule out the possibility of some form of ABC HSR. When HLA-B*5701 screening is not readily available, it remains reasonable to initiate ABC with appropriate clinical counseling and monitoring for any signs of ABC HSR (CIII).

NIH Recommendations for HLA-B*5701 Screening

Screening for HLA-B*5701 is recommended before starting patients on an abacavir (ABC)-containing regimen to reduce the risk of hypersensitivity reaction (HSR) (AI).

  • HLA-B*5701-positive patients should not be prescribed ABC (AI).
  • The positive status should be recorded as an ABC allergy in the patient’s medical record (AII).
  • When HLA-B*5701 screening is not readily available, it remains reasonable to initiate ABC with appropriate clinical counseling and monitoring for any signs of HSR (CIII).

Coreceptor Tropism Assays

  • HIV enters cells by a complex process that involves sequential attachment to the CD4 receptor followed by binding to either the CCR5 or CXCR4 molecules and fusion of the viral and cellular membranes.[29]
  • CCR5 inhibitors (i.e., maraviroc [MVC]), prevent HIV entry into target cells by binding to the CCR5 receptor.[30]
  • Phenotypic and, to a lesser degree, genotypic assays have been developed that can determine the coreceptor tropism (i.e., CCR5, CXCR4, or both) of the patient’s dominant virus population.
  • One assay (Trofile, Monogram Biosciences, Inc., South San Francisco, CA) was used to screen patients who were participating in studies that formed the basis of approval for MVC, the only CCR5 inhibitor currently available.
  • Other assays are under development and are currently used primarily for research purposes or in clinical situations in which the Trofile assay is not readily available.

Background

  • The vast majority of patients harbor a CCR5-utilizing virus (R5 virus) during acute/recent infection, which suggests that the R5 variant is preferentially transmitted compared with the CXCR4 (X4) variant.
  • Viruses in many untreated patients eventually exhibit a shift in coreceptor tropism from CCR5 to either CXCR4 or both CCR5 and CXCR4 (i.e., dual- or mixed-tropic; D/M-tropic).
  • This shift is temporally associated with a more rapid decline in CD4 T-cell counts, although whether this shift is a cause or a consequence of progressive immunodeficiency remains undetermined.[31][32]
  • Antiretroviral (ARV)-treated patients who have extensive drug resistance are more likely to harbor detectable X4- or D/M-tropic variants than untreated patients who have comparable CD4 T-cell counts.[33]
  • The prevalence of X4- or D/M-tropic variants increases to more than 50% in treated patients who have CD4 counts <100 cells/mm.

Phenotypic Assays

  • There are now at least two high-throughput phenotypic assays that can quantify the coreceptor characteristics of plasma-derived virus.
  • Both involve the generation of laboratory viruses that express patient-derived envelope proteins (i.e., gp120 and gp41).
  • These pseudoviruses are either replication competent (Phenoscript assay, VIRalliance, Paris, France) or replication defective (Trofile assay, Monogram Biosciences, Inc.).
  • These pseudoviruses then are used to infect target cell lines that express either CCR5 or CXCR4. In the Trofile assay, the coreceptor tropism of the patient-derived virus is confirmed by testing the susceptibility of the virus to specific CCR5 or CXCR4 inhibitors in vitro.
  • The Trofile assay takes about 2 weeks to perform and requires a plasma HIV RNA level ≥1,000 copies/mL.
  • The performance characteristics of these assays have evolved. Most of patients enrolled in premarketing clinical trials of MVC and other CCR5 inhibitors were screened with an earlier, less sensitive version of the Trofile assay.[34]
  • This earlier assay failed to routinely detect low levels of CXCR4-utilizing variants. As a consequence, some patients enrolled in these clinical trials harbored low, undetectable levels of CXCR4-utilizing viruses at baseline and exhibited rapid virologic failure after initiation of a CCR5 inhibitor.[35]
  • This assay has since been revised and is now able to detect lower levels of CXCR4-utlizing viruses. In vitro, the assay can detect CXCR4-utilizing clones with 100% sensitivity when those clones make up 0.3% of the population.
  • Although this more sensitive assay has had limited use in prospective clinical trials, it is now the only one that is commercially available. For unclear reasons, a minority of samples cannot be successfully phenotyped with either generation of the Trofile assay.
  • In patients with plasma HIV-1 RNA below the limit of detection, coreceptor usage can be determined from proviral DNA obtained from peripheral blood mononuclear cells; however, the clinical utility of this assay remains to be determined.

Genotypic Assays

  • Genotypic determination of HIV-1 coreceptor usage is based on sequencing the V3-coding region of HIV-1 env, the principal determinant of coreceptor usage.
  • A variety of algorithms and bioinformatics programs can be used to predict coreceptor usage from the V3 sequence. When compared to the phenotypic assay, genotypic methods show high specificity (~90%) but only modest sensitivity (~50%–70%) for the presence of a CXCR4-utilizing virus. *Given these performance characteristics, these assays may not be sufficiently robust to completely rule out the presence of an X4 or D/M variant.[36]
  • Recent studies in which V3 genotyping was performed on samples from patients screening for clinical trials of MVC suggest that genotyping performed as well as phenotyping in predicting the response to MVC.[37]
  • Consequently, the opportunity to assess treatment response to MVC in patients whose virus was considered R5 by genotype but D/M or X4 by phenotype was limited to a relatively small number of patients.
  • It is also important to note that the genotyping approaches used in these studies are not routinely available from clinical laboratories in the United States at this time.
  • Given the uncertainty regarding the genotypic assays and fewer logistical barriers to obtaining a phenotype in the United States than elsewhere, the Panel recommends that a phenotype be used as the preferred coreceptor tropism screening test in the United States.
  • Other potential clinical uses for the tropism assay are for prognostic purposes or for assessment of tropism prior to starting antiretroviral therapy (ART), in case a CCR5 inhibitor is required later (e.g., in a regimen change for toxicity). Currently, sufficient data do not exist to support these uses.

NIH Recommendations for Coreceptor Tropism Assays

  • Coreceptor tropism assay should be performed whenever the use of a CCR5 inhibitor is being considered (AI).
  • Coreceptor tropism testing might also be considered for patients who exhibit virologic failure on a CCR5 inhibitor (CIII).

References

  1. ↑ Busch MP, Satten GA (1997). "Time course of viremia and antibody seroconversion following human immunodeficiency virus exposure". Am J Med. 102 (5B): 117–24, discussion 125-6. PMID 9845513.
  2. ↑ Fiebig EW, Wright DJ, Rawal BD, Garrett PE, Schumacher RT, Peddada L; et al. (2003). "Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection". AIDS. 17 (13): 1871–9. doi:10.1097/01.aids.0000076308.76477.b8. PMID 12960819.
  3. ↑ Owen SM, Yang C, Spira T, Ou CY, Pau CP, Parekh BS; et al. (2008). "Alternative algorithms for human immunodeficiency virus infection diagnosis using tests that are licensed in the United States". J Clin Microbiol. 46 (5): 1588–95. doi:10.1128/JCM.02196-07. PMC 2395119. PMID 18322061.
  4. ↑ Masciotra S, McDougal JS, Feldman J, Sprinkle P, Wesolowski L, Owen SM (2011). "Evaluation of an alternative HIV diagnostic algorithm using specimens from seroconversion panels and persons with established HIV infections". J Clin Virol. 52 Suppl 1: S17–22. doi:10.1016/j.jcv.2011.09.011. PMID 21981983.
  5. ↑ Masciotra S, Luo W, Youngpairoj AS, Kennedy MS, Wells S, Ambrose K; et al. (2013). "Performance of the Alere Determine™ HIV-1/2 Ag/Ab Combo Rapid Test with specimens from HIV-1 seroconverters from the US and HIV-2 infected individuals from Ivory Coast". J Clin Virol. 58 Suppl 1: e54–8. doi:10.1016/j.jcv.2013.07.002. PMID 23911678.
  6. ↑ Weber B (2006). "Screening of HIV infection: role of molecular and immunological assays". Expert Rev. Mol. Diagn. 6 (3): 399–411. doi:10.1586/14737159.6.3.399. PMID 16706742.
  7. ↑ Tóth FD, Bácsi A, Beck Z, Szabó J (2001). "Vertical transmission of human immunodeficiency virus". Acta Microbiol Immunol Hung. 48 (3–4): 413–27. PMID 11791341.
  8. ↑ Mellors JW, Muñoz A, Giorgi JV, Margolick JB, Tassoni CJ, Gupta P et al. (1997) Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 126 (12):946-54. PMID: 9182471
  9. ↑ Egger M, May M, Chêne G, Phillips AN, Ledergerber B, Dabis F et al. (2002) Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 360 (9327):119-29. PMID: 12126821
  10. ↑ Kaufmann GR, Perrin L, Pantaleo G, Opravil M, Furrer H, Telenti A et al. (2003) CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: the Swiss HIV Cohort Study. Arch Intern Med 163 (18):2187-95. DOI:10.1001/archinte.163.18.2187 PMID: 14557216
  11. ↑ Zurlo JJ, Wood L, Gaglione MM, Polis MA (1995) Effect of splenectomy on T lymphocyte subsets in patients infected with the human immunodeficiency virus. Clin Infect Dis 20 (4):768-71. PMID: 7795071
  12. ↑ Bernard NF, Chernoff DN, Tsoukas CM (1998) Effect of splenectomy on T-cell subsets and plasma HIV viral titers in HIV-infected patients. J Hum Virol 1 (5):338-45. PMID: 10195261
  13. ↑ Casseb J, Posada-Vergara MP, Montanheiro P, Fukumori LM, Olah I, Smid J et al. (2007) T CD4+ cells count among patients co-infected with human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1): high prevalence of tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). Rev Inst Med Trop Sao Paulo 49 (4):231-3. PMID: 17823752
  14. ↑ Berglund O, Engman K, Ehrnst A, Andersson J, Lidman K, Akerlund B et al. (1991) Combined treatment of symptomatic human immunodeficiency virus type 1 infection with native interferon-alpha and zidovudine. J Infect Dis 163 (4):710-5. PMID: 1672701
  15. ↑ Murray JS, Elashoff MR, Iacono-Connors LC, Cvetkovich TA, Struble KA (1999) The use of plasma HIV RNA as a study endpoint in efficacy trials of antiretroviral drugs. AIDS 13 (7):797-804. PMID: 10357378
  16. ↑ Hughes MD, Johnson VA, Hirsch MS, Bremer JW, Elbeik T, Erice A et al. (1997) Monitoring plasma HIV-1 RNA levels in addition to CD4+ lymphocyte count improves assessment of antiretroviral therapeutic response. ACTG 241 Protocol Virology Substudy Team. Ann Intern Med 126 (12):929-38. PMID: 9182469
  17. ↑ Marschner IC, Collier AC, Coombs RW, D'Aquila RT, DeGruttola V, Fischl MA et al. (1998) Use of changes in plasma levels of human immunodeficiency virus type 1 RNA to assess the clinical benefit of antiretroviral therapy. J Infect Dis 177 (1):40-7. PMID: 9419168
  18. ↑ Thiébaut R, Morlat P, Jacqmin-Gadda H, Neau D, Mercié P, Dabis F et al. (2000) Clinical progression of HIV-1 infection according to the viral response during the first year of antiretroviral treatment. Groupe d'Epidémiologie du SIDA en Aquitaine (GECSA). AIDS 14 (8):971-8. PMID: 10853978
  19. ↑ Havlir DV, Bassett R, Levitan D, Gilbert P, Tebas P, Collier AC, Hirsch MS, Ignacio C, Condra J, Günthard HF, Richman DD, Wong JK (2001). "Prevalence and predictive value of intermittent viremia with combination hiv therapy". JAMA. 286 (2): 171–9. PMID 11448280. Retrieved 2012-05-08. Unknown parameter |month= ignored (help)
  20. ↑ Gatanaga H, Tsukada K, Honda H, Tanuma J, Yazaki H, Watanabe T, Honda M, Teruya K, Kikuchi Y, Oka S (2009). "Detection of HIV type 1 load by the Roche Cobas TaqMan assay in patients with viral loads previously undetectable by the Roche Cobas Amplicor Monitor". Clin. Infect. Dis. 48 (2): 260–2. doi:10.1086/595707. PMID 19113986. Retrieved 2012-05-08. Unknown parameter |month= ignored (help)
  21. ↑ Damond F, Roquebert B, Bénard A, Collin G, Miceli M, Yéni P, Brun-Vezinet F, Descamps D (2007). "Human immunodeficiency virus type 1 (HIV-1) plasma load discrepancies between the Roche COBAS AMPLICOR HIV-1 MONITOR Version 1.5 and the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 assays". J. Clin. Microbiol. 45 (10): 3436–8. doi:10.1128/JCM.00973-07. PMC 2045351. PMID 17715371. Retrieved 2012-05-08. Unknown parameter |month= ignored (help)
  22. ↑ Willig JH, Nevin CR, Raper JL, Saag MS, Mugavero MJ, Willig AL, Burkhardt JH, Schumacher JE, Johnson VA (2010). "Cost ramifications of increased reporting of detectable plasma HIV-1 RNA levels by the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 version 1.0 viral load test". J. Acquir. Immune Defic. Syndr. 54 (4): 442–4. doi:10.1097/QAI.0b013e3181d01d1d. PMC 2901889. PMID 20611035. Retrieved 2012-05-08. Unknown parameter |month= ignored (help)
  23. ↑ Hetherington S, McGuirk S, Powell G, Cutrell A, Naderer O, Spreen B; et al. (2001). "Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir". Clin Ther. 23 (10): 1603–14. PMID 11726000.
  24. ↑ Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C; et al. (2002). "Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir". Lancet. 359 (9308): 727–32. PMID 11888582.
  25. ↑ Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W; et al. (2002). "Genetic variations in HLA-B region and hypersensitivity reactions to abacavir". Lancet. 359 (9312): 1121–2. doi:10.1016/S0140-6736(02)08158-8. PMID 11943262.
  26. ↑ Phillips EJ, Sullivan JR, Knowles SR, Shear NH (2002). "Utility of patch testing in patients with hypersensitivity syndromes associated with abacavir". AIDS. 16 (16): 2223–5. PMID 12409746. Retrieved 2012-05-10. Unknown parameter |month= ignored (help)
  27. ↑ Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, Thorborn D, Benbow A (2008). "HLA-B*5701 screening for hypersensitivity to abacavir". N. Engl. J. Med. 358 (6): 568–79. doi:10.1056/NEJMoa0706135. PMID 18256392. Retrieved 2012-05-10. Unknown parameter |month= ignored (help)
  28. ↑ Saag M, Balu R, Phillips E, Brachman P, Martorell C, Burman W, Stancil B, Mosteller M, Brothers C, Wannamaker P, Hughes A, Sutherland-Phillips D, Mallal S, Shaefer M (2008). "High sensitivity of human leukocyte antigen-b*5701 as a marker for immunologically confirmed abacavir hypersensitivity in white and black patients". Clin. Infect. Dis. 46 (7): 1111–8. doi:10.1086/529382. PMID 18444831. Retrieved 2012-05-10. Unknown parameter |month= ignored (help)
  29. ↑ Moore JP, Kitchen SG, Pugach P, Zack JA (2004). "The CCR5 and CXCR4 coreceptors--central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection". AIDS Res Hum Retroviruses. 20 (1): 111–26. doi:10.1089/088922204322749567. PMID 15000703.
  30. ↑ Fätkenheuer G, Pozniak AL, Johnson MA, Plettenberg A, Staszewski S, Hoepelman AI, Saag MS, Goebel FD, Rockstroh JK, Dezube BJ, Jenkins TM, Medhurst C, Sullivan JF, Ridgway C, Abel S, James IT, Youle M, van der Ryst E (2005). "Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1". Nat. Med. 11 (11): 1170–2. doi:10.1038/nm1319. PMID 16205738. Retrieved 2012-05-10. Unknown parameter |month= ignored (help)
  31. ↑ Connor RI, Sheridan KE, Ceradini D, Choe S, Landau NR (1997). "Change in coreceptor use correlates with disease progression in HIV-1--infected individuals". J. Exp. Med. 185 (4): 621–8. PMC 2196142. PMID 9034141. Retrieved 2012-05-10. Unknown parameter |month= ignored (help)
  32. ↑ Koot M, Keet IP, Vos AH, de Goede RE, Roos MT, Coutinho RA, Miedema F, Schellekens PT, Tersmette M (1993). "Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS". Ann. Intern. Med. 118 (9): 681–8. PMID 8096374. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  33. ↑ Hunt PW, Harrigan PR, Huang W, Bates M, Williamson DW, McCune JM, Price RW, Spudich SS, Lampiris H, Hoh R, Leigler T, Martin JN, Deeks SG (2006). "Prevalence of CXCR4 tropism among antiretroviral-treated HIV-1-infected patients with detectable viremia". J. Infect. Dis. 194 (7): 926–30. doi:10.1086/507312. PMID 16960780. Retrieved 2012-05-10. Unknown parameter |month= ignored (help)
  34. ↑ Whitcomb JM, Huang W, Fransen S, Limoli K, Toma J, Wrin T, Chappey C, Kiss LD, Paxinos EE, Petropoulos CJ (2007). "Development and characterization of a novel single-cycle recombinant-virus assay to determine human immunodeficiency virus type 1 coreceptor tropism". Antimicrob. Agents Chemother. 51 (2): 566–75. doi:10.1128/AAC.00853-06. PMC 1797738. PMID 17116663. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  35. ↑ Westby M, Lewis M, Whitcomb J, Youle M, Pozniak AL, James IT, Jenkins TM, Perros M, van der Ryst E (2006). "Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir". J. Virol. 80 (10): 4909–20. doi:10.1128/JVI.80.10.4909-4920.2006. PMC 1472081. PMID 16641282. Retrieved 2012-05-10. Unknown parameter |month= ignored (help)
  36. ↑ Lin NH, Kuritzkes DR (2009). "Tropism testing in the clinical management of HIV-1 infection". Curr Opin HIV AIDS. 4 (6): 481–7. doi:10.1097/COH.0b013e328331b929. PMC 2874683. PMID 20048714. Retrieved 2012-05-10. Unknown parameter |month= ignored (help)
  37. ↑ McGovern RA, Thielen A, Mo T, Dong W, Woods CK, Chapman D, Lewis M, James I, Heera J, Valdez H, Harrigan PR (2010). "Population-based V3 genotypic tropism assay: a retrospective analysis using screening samples from the A4001029 and MOTIVATE studies". AIDS. 24 (16): 2517–25. doi:10.1097/QAD.0b013e32833e6cfb. PMID 20736814. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)

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