HIV Drug Resistance Profiles and Clinical Outcomes in Patients with Viremia Maintained at Very Low Levels

Michael R. Jordan, Julie Winsett, Aileen Tiro, Vuth Bau, Rony S. Berbara, Christopher Rowley, Nobel Bellosillo, Christine Wanke, Eoin P. Coakley

Beth Israel Deaconess Medical Center, Boston, USA.
Largo Medical Center, Clearwater, USA.
Monogram Biosciences, South San Francisco, USA.
Newton Wellesley Hospital, Newton, USA.
Tufts University School of Medicine, Boston, USA.
University of Massachusetts School of Medicine, Worcester, USA.

DOI: 10.4236/wja.2013.32010                

Abstract

We describe an observational study of clinical, virologic and drug resistance profiles in HIV-positive antiretroviral adherent subjects with stable low level viremia (LLV) 50 - 1000 copies/mL for more than 12 months. Subjects were followed from time of first detectable viral load (VL). In total, 102 episodes of LLV were detected among 80 individuals. The median (mean, range) HIV copy number at genotyping was 250 (486, <50 - 3900) copies/mL after 14 (17.9, 0 - 58) months of LLV. Few patients maintained LLV for the entire 9 years period of observation, with half (52%) experiencing viremic progression following a stable period of LLV either spontaneously or after treatment interruption or failed regimen intensification. In the setting of prolonged periods of sustained LLV, mean duration 22 (range 8 - 106) months, drug resistance (DR) was almost universal. Resistance to ≥1 on-treatment drugs was defined in 97% of specimens and DR to all drugs in the treatment regimen in over half of all patients. Evolution of DR mutations during the period of LLV was observed in 20/28 (71%) subjects with specimens available for follow-up testing. This evolution was associated with viremic progression to levels >1000 copies/mL (p = 0.03). Our data suggest that DR present in patients with LLV is likely to impact long term clinical outcomes, highlighting the importance of optimizing techniques to detect the presence of drug resistant HIV in the setting of LLV and the need for larger prospective studies to assess the emergence of DR in the setting of sustained LLV and the impact of this DR on treatment outcomes.

Keywords

HIV; Low Level Viremia; Treatment Experienced Patients; HIV Drug Resistance

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	G. Panos, G. Samonis, V. G. Alexiou, G. A. Kavarnou, G. Charatsis and M. E. Falagas, “Mortality and Morbidity of HIV Infected Patients Receiving HAART: A Cohort Study,” Current HIV Research, Vol. 6, No. 3, 2008, pp. 257-260. doi:10.2174/157016208784324976
[2]	R. P. Walensky, K. A. Freedberg, M. C. Weinstein and A. D. Paltiel, “Cost-Effectiveness of HIV Testing and Treatment in the United States,” Clinical Infectious Diseases, Vol. 45, Suppl. 4, 2007, pp. S248-S254. doi:10.1086/522546
[3]	World Health Organization, UNAIDS, UNICEF, “Towards Universal Access: Scaling up Priority HIV/AIDS Interventions in the Health Sector,” 2010. http://www.who.int/hiv/ pub/2010progressreport/en/ index.html
[4]	J. A. Aberg, J. E. Gallant, J. Anderson, et al., “Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: Recommendations of the HIV Medicine Association of the Infectious Diseases Society of America,” Clinical Infectious Diseases, Vol. 39, No. 5, 2004, pp. 609-629. doi:10.1086/423390
[5]	S. M. Hammer, J. J. Eron Jr., P. Reiss, et al., “Antiretroviral Treatment of Adult HIV Infection: 2008 Recommendations of the International AIDS Society-USA Panel,” JAMA, Vol. 300, No. 5, 2008, pp. 555-570. doi:10.1001/jama.300.5.555
[6]	Panel on Antiretroviral Guidelines for Adults and Adolescents, Department of Health and Human Services, “Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents,” 2011. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
[7]	A. M. Geretti, C. Smith, A. Haberl, et al., “Determinants of Virological Failure after Successful Viral Load Suppression in First-Line Highly Active Antiretroviral Therapy,” Antiviral Therapy, Vol. 13, No. 7, 2008, pp. 927-936.
[8]	C. H. Olsen, J. Gatell, B. Ledergerber, et al., “Risk of AIDS and Death at Given HIV-RNA and CD4 Cell Count, in Relation to Specific Antiretroviral Drugs in the Regimen,” AIDS, Vol. 19, No. 3, 2005, pp. 319-330.
[9]	C. Cohen, “Low-Level Viremia in HIV-1 Infection: Consequences and Implications for Switching to a New Regimen,” HIV Clinical Trials, Vol. 10, No. 2, 2009, pp. 116-124. doi:10.1310/hct1002-116
[10]	R. E. Nettles, T. L. Kieffer, R. P. Simmons, et al., “Genotypic Resistance in HIV-1-Infected Patients with Persistently Detectable Low-Level Viremia While Receiving Highly Active Antiretroviral Therapy,” Clinical Infectious Diseases, Vol. 39, No. 7, 2004, pp. 1030-1037. doi:10.1086/423388
[11]	N. H. Tobin, G. H. Learn, S. E. Holte, et al., “Evidence That Low-Level Viremias during Effective Highly Active Antiretroviral Therapy Result from Two Processes: Expression of Archival Virus and Replication of Virus,” Journal of Virology, Vol. 79, No. 15, 2005, pp. 9625-9634. doi:10.1128/JVI.79.15.9625-9634.2005
[12]	S. A. Van, S. Zhang, P. Reiss, et al., “Immunologic, Virologic, and Clinical Consequences of Episodes of Transient Viremia during Suppressive Combination Antiretroviral Therapy,” Journal of Acquired Immune Deficiency Syndromes, Vol. 48, No. 1, 2008, pp. 104-108. doi:10.1097/QAI.0b013 e31816a1d4f
[13]	Y. Mitsuya, M. A. Winters, W. J. Fessel, et al., “HIV-1 Drug Resistance Genotype Results in Patients with Plasma Samples with HIV-1 RNA Levels Less than 75 Copies/mL,” Journal of Acquired Immune Deficiency Syndromes, Vol. 43, No. 1, 2006, pp. 56-59. doi:10.1097/01.qai.0000232609.99705.a2
[14]	T. Doyle and A. M. Geretti, “Low-Level Viraemia on HAART: Significance and Management,” Current Opinion in Infectious Diseases, Vol. 25, No. 1, 2012, pp. 17-25. doi:10.1097/QCO.0b013e32834ef5d9
[15]	A. C. Karlsson, S. R. Younger, J. N. Martin, et al., “Immunologic and Virologic Evolution during Periods of Intermittent and Persistent Low-Level Viremia,” AIDS, Vol. 18, No. 7, 2004, pp. 981-989. doi:10.1097/00002030-200404300-00005
[16]	B. Taiwo, S. Gallien, E. Aga, H. Ribaudo, R. Haubrich, D. R. Kuritzkes and J. J. Eron Jr., “Antiretroviral Drug Resistance in HIV-1-Infected Patients Experiencing Persistent Low-Level Viremia during First-Line Therapy,” Journal of Infectious Diseases, Vol. 204, No. 4, 2011, pp. 515-520. doi:10.1093/infdis/jir353
[17]	M. Hermankova, S. C. Ray, C. Ruff, et al., “HIV-1 Drug Resistance Profiles in Children and Adults with Viral Load of <50 copies/ml Receiving Combination Therapy,” JAMA, Vol. 286, No. 2, 2001, pp. 196-207. doi:10.1001/jama.286.2.196
[18]	M. S. Hirsch, H. F. Gunthard, J. M. Schapiro, et al., “Antiretroviral Drug Resistance Testing in Adult HIV-1 Infection: 2008 Recommendations of an International AIDS Society-USA Panel,” Clinical Infectious Diseases, Vol. 47, No. 2, 2008, pp. 266-285. doi:10.1086/589297
[19]	R. E. Nettles, T. L. Kieffer, P. Kwon, et al., “Intermittent HIV-1 Viremia (Blips) and Drug Resistance in Patients Receiving HAART,” JAMA, Vol. 293, No. 7, 2005, pp. 817-829. doi:10.1001/jama.293.7.817
[20]	J. L. Sirvent, M. M. Socas, C. H. Calzadilla, A. M. Lirola and M. R. Valls, “Utility of Interrupting Antiretroviral Treatment before HIV Drug Resistance Testing in Patients with Persistently Detectable Low-Level Viremia,” Journal of Acquired Immune Deficiency Syndromes, Vol. 40, No. 1, 2005, pp. 111-113. doi:10.1097/01.qai.0000174650.33159.22
[21]	J. Ena, R. F. Ruiz de Apodaca, C. Amador, C. Benito and F. Pasquau, “Net Benefits of Resistance Testing Directed Therapy Compared with Standard of Care in HIV-Infected Patients with Virological Failure: A Meta-Analysis,” Enfermedades Infecciosas y Microbiología Clínica, Vol. 24, No. 4, 2006, pp. 232-237. doi:10.1016/S0213-005X(06)73768-5
[22]	J. V. Baker, G. Peng, J. Rapkin, et al., “CD4+ Count and Risk of Non-AIDS Diseases Following Initial Treatment for HIV Infection,” AIDS, Vol. 22, No. 7, 2008, pp. 841-848. doi:10.1097/QAD.0b013e3282f7cb76
[23]	J. Lawrence, D. L. Mayers, K. H. Hullsiek, et al., “Structured Treatment Interruption in Patients with MultidrugResistant Human Immunodeficiency Virus,” New England Journal of Medicine, Vol. 349, No. 9, 2003, pp. 837-846. doi:10.1056/NEJMoa035103
[24]	P. K. Lee, T. L. Kieffer, R. F. Siliciano and R. E. Nettles, “HIV-1 Viral Load Blips Are of Limited Clinical Significance,” Journal of Antimicrobial Chemotherapy, Vol. 57, No. 5, 2006, pp. 803-805. doi:10.1093/jac/dkl092
[25]	D. V. Havlir, R. Bassett, D. Levitan, et al., “Prevalence and Predictive Value of Intermittent Viremia with Combination HIV Therapy,” JAMA, Vol. 286, No. 2, 2001, pp. 171-179. doi:10.1001/jama.286.2.171
[26]	R. Mohey, L. B. Jorgensen, B. K. Moller, F. T. Black, J. Kjems and N. Obel, “Detection and Quantification of Proviral HIV-1 184 M/V in Circulating CD4(+) T Cells of Patients on HAART with a Viremia Less than 1,000 copies/ml,” Journal of Clinical Virology, Vol. 34, No. 4, 2005, pp. 257-267. doi:10.1016/j.jcv.2005.02.015
[27]	A. C. Karlsson, S. R. Younger, J. N. Martin, et al., “Immunologic and Virologic Evolution during Periods of Intermittent and Persistent Low-Level Viremia,” AIDS, Vol. 18, No. 7, 2004, pp. 981-989. doi:10.1097/00002030-200404300-00005
[28]	S. S. Kaplan, G. Ferrari, T. Wrin, et al., “Longitudinal Assessment of Immune Response and Viral Characteristics in HIV-Infected Patients with Prolonged CD4(+)/ Viral Load Discordance,” AIDS Research and Human Retroviruses, Vol. 21, No. 1, 2005, pp. 13-16. doi:10.1089/aid.2005.21.13
[29]	S. G. Deeks, J. N. Martin, E. Sinclair, et al., “Strong Cell-Mediated Immune Responses Are Associated with the Maintenance of Low-Level Viremia in AntiretroviralTreated Individuals with Drug-Resistant Human Immunodeficiency Virus Type 1,” Journal of Infectious Diseases, Vol. 189, No. 2, 2004, pp. 312-321. doi:10.1086/380098
[30]	S. G. Deeks, “Durable HIV Treatment Benefit Despite Low-Level Viremia: Reassessing Definitions of Success or Failure,” JAMA, Vol. 286, No. 2, 2001, pp. 224-226. doi:10.1001/jama.286.2.224
[31]	A. C. Karlsson, S. R. Younger, J. N. Martin, et al., “Immunologic and Virologic Evolution during Periods of Intermittent and Persistent Low-Level Viremia,” AIDS, Vol. 18, No. 7, 2004, pp. 981-989. doi:10.1097/00002030-200404300-00005
[32]	C. M. Vaamonde, D. R. Hoover, K. Anastos, et al., “Factors Associated with Poor Immunologic Response to Virologic Suppression by Highly Active Antiretroviral Therapy in HIV-Infected Women,” AIDS Research and Human Retroviruses, Vol. 22, No. 3, 2006, pp. 222-231. doi:10.1089/aid.2006.22.222
[33]	L. Q. Zhang, P. Simmonds, C. A. Ludlam and A. J. Brown, “Detection, Quantification and Sequencing of HIV-1 from the Plasma of Seropositive Individuals and from Factor VIII Concentrates,” AIDS, Vol. 5, No. 6, 1991, pp. 675-681. doi:10.1097/00002030-199106000-00006
[34]	E. P. Coakley, et al., “HIV Drug Resistance Profiles and Clinical and Virologic Outcomes among HIV-infected Subjects with Stable Detectable Plasma Viral Loads < 1000 copies/mL for at Least 12 Months,” CROI, 2002.
[35]	M. R. Jordan, M. Kearney, S. Palmer, W. Shao, F. Maldarelli, E. P. Coakley, C. Chappey, C. Wanke and J. M. Coffin, “Comparison of Standard PCR/Cloning to Single Genome Sequencing for Analysis of HIV-1 Populations,” Journal of Virological Methods, Vol. 168, No. 1-2, 2010, pp. 114-120. doi:10.1016/j.jviromet.2010.04.030
[36]	R. Chenna, H. Sugawara, T. Koike, et al., “Multiple Sequence Alignment with the Clustal Series of Programs,” Nucleic Acids Research, Vol. 31, No. 13, 2003, pp. 3497-3500. doi:10.1093/nar/gkg500
[37]	BioEdit, 2012. http://www.mbio.ncsu.edu/bioedit/bioedit.html
[38]	Mega 3.0, 2012. http://www.megasoftware.net
[39]	T. F. Liu and R. W. Shafer, “Web Resources for HIV Type 1 Genotypic-Resistance Test Interpretation,” Clinical Infectious Diseases, Vol. 42, No. 11, 2006, pp. 1608-1618. doi:10.1086/503914
[40]	I. Kousignian, S. Abgrall, S. Grabar, et al., “Maintaining Antiretroviral Therapy Reduces the Risk of AIDS-Defining Events in Patients with Uncontrolled Viral Replication and Profound Immunodeficiency,” Clinical Infectious Diseases, Vol. 46, No. 2, 2008, pp. 296-304. doi:10.1086/524753
[41]	S. Palmer, M. Kearney, F. Maldarelli, et al., “Multiple, Linked Human Immunodeficiency Virus Type 1 Drug Resistance Mutations in Treatment-Experienced Patients Are Missed by Standard Genotype Analysis,” Journal of Clinical Microbiology, Vol. 43, No. 1, 2005, pp. 406-413. doi:10.1128/JCM.43.1.406-413.2005
[42]	Y. Mitsuya, M. A. Winters, W. J. Fessel, et al., “HIV-1 Drug Resistance Genotype Results in Patients with Plasma Samples with HIV-1 RNA Levels Less than 75 copies/mL,” Journal of Acquired Immune Deficiency Syndromes, Vol. 43, No. 1, 2006, pp. 56-59. doi:10.1097/01.qai.0000232609.99705.a2