Skip to main content

Advertisement

SpringerLink
Log in

HIV, Aging, and Viral Coinfections: Taking the Long View

  • Co-infections and Comorbidity (S Naggie, Section Editor)
  • Published:
Current HIV/AIDS Reports Aims and scope Submit manuscript

Abstract

Viral suppression of human immunodeficiency virus (HIV) with combination antiviral therapy (cART) has led to increasing longevity but has not enabled a complete return to health among aging HIV-infected individuals (HIV+). Viral coinfections are prevalent in the HIV+ host and are implicated in cancer, liver disease, and accelerated aging. We must move beyond a simplistic notion of HIV becoming a “chronic controllable illness” and develop an understanding of how viral suppression alters the natural history of HIV infection, especially at the intersection of HIV with other common viral coinfections in the context of an altered, aging immune system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Smith CJ, Ryom L, Weber R, Morlat P, Pradier C, Reiss P, et al. Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration. Lancet. 2014;384:241–8.

    Article  PubMed  Google Scholar 

  2. Prejean J, Song R, Hernandez A, Ziebell R, Green T, Walker F, et al. Estimated HIV incidence in the United States, 2006–2009. PLoS One. 2011;6:e17502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Weber R, Sabin CA, Friis-Moller N, Reiss P, El-Sadr WM, Kirk O, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006;166:1632–41.

    Article  PubMed  Google Scholar 

  4. Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, et al. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373:705–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Osinusi A, Townsend K, Kohli A, Nelson A, Seamon C, Meissner EG, et al. Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection. JAMA. 2015;313:1232–9.

    Article  CAS  PubMed  Google Scholar 

  6. Wyles DL, Ruane PJ, Sulkowski MS, Dieterich D, Luetkemeyer A, Morgan TR, et al. Daclatasvir plus Sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med. 2015;373:714–25.

    Article  CAS  PubMed  Google Scholar 

  7. Sulkowski MS, Eron JJ, Wyles D, Trinh R, Lalezari J, Wang C, et al. Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial. JAMA. 2015;313:1223–31. These four references [4••–7••] are the landmark clinical trials demonstrating that second generation direct acting antiviral therapies are highly effective in patients with HIV/HCV coinfection, curing > 94% of patients, similar to the results seen in monoinfected patients.

    Article  CAS  PubMed  Google Scholar 

  8. Childs K, Taylor C, Dieterich D, Agarwal K. Directly acting antivirals for hepatitis C virus arrive in HIV/hepatitis C virus co-infected patients: from’mind the gap’ to’where’s the gap?’. AIDS. 2016;30:975–89.

    Article  CAS  PubMed  Google Scholar 

  9. Korf BR, Rehm HL. New approaches to molecular diagnosis. JAMA. 2013;309:1511–21.

    Article  CAS  PubMed  Google Scholar 

  10. Ashley EA. The precision medicine initiative: a new national effort. JAMA. 2015;313:2119–20.

    Article  CAS  PubMed  Google Scholar 

  11. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372:793–5. These three references [9•–11•] describe the techniques involved [9•] and the focus [9•–10•] of genomic or “precision medicine”. President Obama’s Precision Medicine Initiative promises Federal funding to promote research to improve our understanding of and to drive change in the fields of oncology, pharmacology, and prevention.

    Article  CAS  PubMed  Google Scholar 

  12. Effros RB. The silent war of CMV in aging and HIV infection. Mech Ageing Dev 2015. This paper is a thorough and thoughtful synthesis of the science of CMV and senescence, providing important insights into the effect of CMV on cellular immunity and age-related morbidity.

  13. Park LS, Tate JP, Justice AC, Lo Re 3rd V, Lim JK, Brau N, et al. FIB-4 index is associated with hepatocellular carcinoma risk in HIV-infected patients. Cancer Epidemiol Biomarkers Prev. 2011;20:2512–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Patel P, Hanson DL, Sullivan PS, Novak RM, Moorman AC, Tong TC, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992–2003. Ann Intern Med. 2008;148:728–36.

    Article  PubMed  Google Scholar 

  15. Crum-Cianflone N, Hullsiek KH, Marconi V, Weintrob A, Ganesan A, Barthel RV, et al. Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study. AIDS. 2009;23:41–50.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Silverberg MJ, Chao C, Leyden WA, Xu L, Tang B, Horberg MA, et al. HIV infection and the risk of cancers with and without a known infectious cause. AIDS. 2009;23:2337–45.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Park LS, Hernandez-Ramirez RU, Silverberg MJ, Crothers K, Dubrow R. Prevalence of non-HIV cancer risk factors in persons living with HIV/AIDS: a meta-analysis. AIDS. 2016;30:273–91. This paper is an exhaustive meta-analysis assessing non-HIV cancer risk factors in HIV+ in 113 publications. This analysis quantifies the high prevalence of smoking, HPV, HCV, and HBV in this population.

    Article  CAS  PubMed  Google Scholar 

  18. Lo Re 3rd V, Kallan MJ, Tate JP, Localio AR, Lim JK, Goetz MB, et al. Hepatic decompensation in antiretroviral-treated patients co-infected with HIV and hepatitis C virus compared with hepatitis C virus-monoinfected patients: a cohort study. Ann Intern Med. 2014;160:369–79. This study in 4280 HIV+/HCV+ on cART compared to 6079 HCV monoinfected individuals showed higher rates of hepatic decompensation among HIV+. Coinfected patients with baseline advanced liver fibrosis, severe anemia, diabetes, and nonblack race experienced higher rates of decompensation.

    PubMed  Google Scholar 

  19. Thio CL, Seaberg EC, Skolasky Jr R, Phair J, Visscher B, Munoz A, et al. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet. 2002;360:1921–6.

    Article  PubMed  Google Scholar 

  20. Gilson RJ, Hawkins AE, Beecham MR, Ross E, Waite J, Briggs M, et al. Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection. AIDS. 1997;11:597–606.

    Article  CAS  PubMed  Google Scholar 

  21. Colin JF, Cazals-Hatem D, Loriot MA, Martinot-Peignoux M, Pham BN, Auperin A, et al. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. Hepatology. 1999;29:1306–10.

    Article  CAS  PubMed  Google Scholar 

  22. Chen JY, Feeney ER, Chung RT. HCV and HIV co-infection: mechanisms and management. Nat Rev Gastroenterol Hepatol. 2014;11:362–71. This comprehensive review explains the mechanisms involved in accelerated fibrosis in patients with HIV/HCV coinfection. There is a helpful discussion on the pathways leading to hepatic fibrosis. There are two instructive figures, one on the pathogenesis of liver disease in HIV+/HCV+ and the other on viral interactions in the hepatocyte.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lim JK, Tate JP, Fultz SL, Goulet JL, Conigliaro J, Bryant KJ, et al. Relationship between alcohol use categories and noninvasive markers of advanced hepatic fibrosis in HIV-infected, chronic hepatitis C virus-infected, and uninfected patients. Clin Infect Dis. 2014;58:1449–58. This paper shows the association between increasing rates of alcohol consumption and increasing severity of fibrosis. Advanced hepatic fibrosis was more common among HIV-infected than uninfected independent of level of alcohol use.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33:562–9.

    Article  CAS  PubMed  Google Scholar 

  25. Pineda JA, Romero-Gomez M, Diaz-Garcia F, Giron-Gonzalez JA, Montero JL, Torre-Cisneros J, et al. HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis. Hepatology. 2005;41:779–89.

    Article  PubMed  Google Scholar 

  26. Brau N, Fox RK, Xiao P, Marks K, Naqvi Z, Taylor LE, et al. Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.-Canadian multicenter study. J Hepatol. 2007;47:527–37.

    Article  PubMed  Google Scholar 

  27. Lin W, Weinberg EM, Chung RT. Pathogenesis of accelerated fibrosis in HIV/HCV co-infection. J Infect Dis. 2013;207 Suppl 1:S13–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Morishima C, Paschal DM, Wang CC, Yoshihara CS, Wood BL, Yeo AE, et al. Decreased NK cell frequency in chronic hepatitis C does not affect ex vivo cytolytic killing. Hepatology. 2006;43:573–80.

    Article  PubMed  Google Scholar 

  29. Lin W, Weinberg EM, Tai AW, Peng LF, Brockman MA, Kim KA, et al. HIV increases HCV replication in a TGF-beta1-dependent manner. Gastroenterology. 2008;134:803–11.

    Article  CAS  PubMed  Google Scholar 

  30. Ryom L, Lundgren JD, De Wit S, Kovari H, Reiss P, Law M, et al. Use of antiretroviral therapy and risk of end-stage liver disease and hepatocellular carcinoma in HIV-positive persons. AIDS 2016. In this cohort of 49,000 patients the authors observed an increased incidence of ESLD/HCC among those with cumulative exposure to d4T, ddI, tenofovir, and (fos)amprenavir. Longer exposure to emtricitabine and nevirapine were associated with lower ESLD/HCC rates. The ddI/d4T-associated increased ESLD/HCC rate only started to decline 6 years after cessation. Mechanisms of drug toxicity and the potential for long lasting effects must be further expored.

  31. Sahasrabuddhe VV, Shiels MS, McGlynn KA, Engels EA. The risk of hepatocellular carcinoma among individuals with acquired immunodeficiency syndrome in the United States. Cancer. 2012;118:6226–33.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Ioannou GN, Bryson CL, Weiss NS, Miller R, Scott JD, Boyko EJ. The prevalence of cirrhosis and hepatocellular carcinoma in patients with human immunodeficiency virus infection. Hepatology. 2013;57:249–57.

    Article  PubMed  Google Scholar 

  33. Merchante N, Merino E, Lopez-Aldeguer J, Jover F, Delgado-Fernandez M, Galindo MJ, et al. Increasing incidence of hepatocellular carcinoma in HIV-infected patients in Spain. Clin Infect Dis. 2013;56:143–50.

    Article  PubMed  Google Scholar 

  34. Montes Ramirez ML, Miro JM, Quereda C, Jou A, von Wichmann MA, Berenguer J, et al. Incidence of hepatocellular carcinoma in HIV-infected patients with cirrhosis: a prospective study. J Acquir Immune Defic Syndr. 2014;65:82–6.

    Article  PubMed  Google Scholar 

  35. Sherman M. Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin Liver Dis. 2010;30:3–16.

    Article  CAS  PubMed  Google Scholar 

  36. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365:1118–27.

    Article  CAS  PubMed  Google Scholar 

  37. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379:1245–55.

    Article  PubMed  Google Scholar 

  38. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–50.

    Article  CAS  PubMed  Google Scholar 

  39. El-Serag HB, Kanwal F. Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology. 2014;60:1767–75. This paper provides insights into the changing epidemiology of HCC in the US, including the ever increasing burden of obesity and its association with these trends. A figure depicting time-trends of HCC by age groups and birth cohorts in the United States shows both the heterogeneity and south to north gradient of HCC incidence rates.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis. 2002;34:831–7.

    Article  PubMed  Google Scholar 

  41. Raymond HF, Hughes A, O’Keefe K, Stall RD, McFarland W. Hepatitis C prevalence among HIV-positive MSM in San Francisco: 2004 and 2008. Sex Transm Dis. 2011;38:219–20.

    Article  PubMed  Google Scholar 

  42. Giordano TP, Kramer JR, Souchek J, Richardson P, El-Serag HB. Cirrhosis and hepatocellular carcinoma in HIV-infected veterans with and without the hepatitis C virus: a cohort study, 1992–2001. Arch Intern Med. 2004;164:2349–54.

    Article  PubMed  Google Scholar 

  43. Park LS, Tate JP, Rodriguez-Barradas MC, Rimland D, Goetz MB, Gibert C, et al. Cancer incidence in HIV-infected versus uninfected veterans: comparison of cancer registry and ICD-9 code diagnoses. J AIDS Clin Res. 2014;5:1000318.

    PubMed  PubMed Central  Google Scholar 

  44. Berretta M, Garlassi E, Cacopardo B, Cappellani A, Guaraldi G, Cocchi S, et al. Hepatocellular carcinoma in HIV-infected patients: check early, treat hard. Oncologist. 2011;16:1258–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bourcier V, Winnock M, Ait Ahmed M, Sogni P, Pambrun E, Poizot-Martin I, et al. Primary liver cancer is more aggressive in HIV-HCV coinfection than in HCV infection. A prospective study (ANRS CO13 Hepavih and CO12 Cirvir). Clin Res Hepatol Gastroenterol. 2012;36:214–21.

    Article  PubMed  Google Scholar 

  46. Gramenzi A, Tedeschi S, Cantarini MC, Erroi V, Tumietto F, Attard L, et al. Outcome of hepatocellular carcinoma in human immunodeficiency virus-infected patients. Dig Liver Dis. 2013;45:516–22.

    Article  PubMed  Google Scholar 

  47. Yopp AC, Subramanian M, Jain MK, Mansour JC, Schwarz RE, Balch GC, et al. Presentation, treatment, and clinical outcomes of patients with hepatocellular carcinoma, with and without human immunodeficiency virus infection. Clin Gastroenterol Hepatol. 2012;10:1284–90.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Althoff KN, McGinnis KA, Wyatt CM, Freiberg MS, Gilbert C, Oursler KK, et al. Comparison of risk and age at diagnosis of myocardial infarction, end-stage renal disease, and non-AIDS-defining cancer in HIV-infected versus uninfected adults. Clin Infect Dis. 2015;60:627–38. In this cohort of nearly 100,000 subjects (~30 HIV+, ~70% uninfected), the authors report a greater risk of MI, ESRD, and non-AIDS cancers in HIV+ compared with uninfected adults. These comorbidities occurred at similar ages in both groups.

    Article  PubMed  Google Scholar 

  49. Robbins HA, Pfeiffer RM, Shiels MS, Li J, Hall HI, Engels EA. Excess cancers among HIV-infected people in the United States. J Natl Cancer Inst. 2015; 107. Using data from the HIV/AIDS Cancer Match (HACM) Study and the Surveillance, Epidemiology, and End Results program, the authors show a decline in the proportion of excess cancers that were AIDS defining (ie, KS, NHL, cervical cancer) with age and time since AIDS diagnosis. They observe a high rate of anal cancers in men who have sex with men, and high rates of lung and liver cancer among injection drug users.

  50. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015;386:1546–55. This is a systematic review and pooled analysis of global data on HBV prevalance. The authors note the wide variation in prevalence and quality of data collection between countries and highlight the need for preventive measures and consistent data collection.

    Article  PubMed  Google Scholar 

  51. McGlynn KA, London WT. The global epidemiology of hepatocellular carcinoma: present and future. Clin Liver Dis. 2011;15:223–43. vii-x.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Kellerman SE, Hanson DL, McNaghten AD, Fleming PL. Prevalence of chronic hepatitis B and incidence of acute hepatitis B infection in human immunodeficiency virus-infected subjects. J Infect Dis. 2003;188:571–7.

    Article  PubMed  Google Scholar 

  53. Konopnicki D, Mocroft A, de Wit S, Antunes F, Ledergerber B, Katlama C, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS. 2005;19:593–601.

    Article  PubMed  Google Scholar 

  54. Lee HC, Ko NY, Lee NY, Chang CM, Ko WC. Seroprevalence of viral hepatitis and sexually transmitted disease among adults with recently diagnosed HIV infection in Southern Taiwan, 2000–2005: upsurge in hepatitis C virus infections among injection drug users. J Formos Med Assoc. 2008;107:404–11.

    Article  PubMed  Google Scholar 

  55. Diop-Ndiaye H, Toure-Kane C, Etard JF, Lo G, Diaw P, Ngom-Gueye NF, et al. Hepatitis B, C seroprevalence and delta viruses in HIV-1 Senegalese patients at HAART initiation (retrospective study). J Med Virol. 2008;80:1332–6.

    Article  CAS  PubMed  Google Scholar 

  56. Nyirenda M, Beadsworth MB, Stephany P, Hart CA, Hart IJ, Munthali C, et al. Prevalence of infection with hepatitis B and C virus and coinfection with HIV in medical inpatients in Malawi. J Infect. 2008;57:72–7.

    Article  CAS  PubMed  Google Scholar 

  57. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73.

    Article  CAS  PubMed  Google Scholar 

  58. Wu CY, Lin JT, Ho HJ, Su CW, Lee TY, Wang SY, et al. Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B: a nationwide cohort study. Gastroenterology. 2014;147:143–151 e145. This nationwide cohort study from Taiwan demonstates a reduced risk of HCC in patients with chronic HBV treated with nucleoside analogue therapy, providing further evidence of the feasibility of cancer prevention in this population in which HBV is highly prevalent.

    Article  CAS  PubMed  Google Scholar 

  59. Soriano V, Puoti M, Peters M, Benhamou Y, Sulkowski M, Zoulim F, et al. Care of HIV patients with chronic hepatitis B: updated recommendations from the HIV-Hepatitis B Virus International Panel. AIDS. 2008;22:1399–410.

    Article  PubMed  Google Scholar 

  60. Fernandez-Montero JV, Vispo E, Barreiro P, Sierra-Enguita R, de Mendoza C, Labarga P, et al. Hepatitis delta is a major determinant of liver decompensation events and death in HIV-infected patients. Clin Infect Dis. 2014;58:1549–53.

    Article  CAS  PubMed  Google Scholar 

  61. Romeo R, Foglieni B, Casazza G, Spreafico M, Colombo M, Prati D. High serum levels of HDV RNA are predictors of cirrhosis and liver cancer in patients with chronic hepatitis delta. PLoS One. 2014;9:e92062. These papers [60• and 61•] provide further evidence that chronic hepatitis delta is associated with higher rates of cirrhosis and poorer outcomes in both HIV+ and uninfected patients.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Bruix J, Sherman M, American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Bruix J, Reig M, Sherman M. Evidence-based diagnosis, staging, and treatment of patients with hepatocellular carcinoma. Gastroenterology. 2016;150:835–53. This paper is a comprehensive and insightful review of the state of the science of HCC, stage specific therapeutic guidelines, and treatments in development.

    Article  PubMed  Google Scholar 

  64. European Association For The Study Of The L, European Organisation For R, Treatment Of C. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.

    Article  Google Scholar 

  65. Raffetti E, Fattovich G, Donato F. Incidence of hepatocellular carcinoma in untreated subjects with chronic hepatitis B: a systematic review and meta-analysis. Liver Int. 2016. This paper is a systemic review and meta-analysis of 66 studies with over 340,000 patients showing a signficantly higher incidence of HCC according to HBV status (symptomatic carrier, chronic hepatitis and compensated cirrhosis compared to inactive carrier), but, interestingly, not for geographical area after adjusting for age. Alcohol intake ≥60 g/dl and HBV genotype C were also associated with higher incidence of HCC.

  66. Lo Re 3rd V, Schuster M. Evaluating hepatitis B virus reactivation during solid tumor chemotherapy: evidence to guide pretreatment hepatitis B screening and prophylaxis. Ann Intern Med. 2016;164:64–5.

    Article  PubMed  Google Scholar 

  67. Perrillo RP, Martin P, Lok AS. Preventing hepatitis B reactivation due to immunosuppressive drug treatments. JAMA. 2015;313:1617–8. These papers [66•• and 67••] underscore the importance of screening for HBV prior to initiating immunosuppressive therapy. Both papers highlight the low uptake of HBV screening by oncologists and review the data showing the benefit of antiviral prophylaxis in reducing the risk for HBV reactivation in patients with chronic HBV receiving immunosuppressive therapy for cancer.

    Article  PubMed  Google Scholar 

  68. Soriano V, Labarga P, de Mendoza C, Pena JM, Fernandez-Montero JV, Benitez L, et al. Emerging challenges in managing hepatitis B in HIV patients. Curr HIV/AIDS Rep. 2015;12:344–52. This paper is a synthesis of the literature and an insightful look at challenges of managing hepatitis B in HIV+. The authors focus on the challenges of failure to suppress HBV viral load, viral breakthrough and reactivations. They highlight the importance of screening for liver cancer and they explore the complexity of viral coinfection (HCV, HDV).

    Article  PubMed  Google Scholar 

  69. Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294–301.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Shiels MS, Pfeiffer RM, Gail MH, Hall HI, Li J, Chaturvedi AK, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. 2011;103:753–62.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Silverberg MJ, Lau B, Justice AC, Engels E, Gill MJ, Goedert JJ, et al. Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America. Clin Infect Dis. 2012;54:1026–34.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Dubrow R, Silverberg MJ, Park LS, Crothers K, Justice AC. HIV infection, aging, and immune function: implications for cancer risk and prevention. Curr Opin Oncol. 2012;24:506–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Beachler DC, D’Souza G, Sugar EA, Xiao W, Gillison ML. Natural history of anal vs oral HPV infection in HIV-infected men and women. J Infect Dis. 2013;208:330–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Beachler DC, Weber KM, Margolick JB, Strickler HD, Cranston RD, Burk RD, et al. Risk factors for oral HPV infection among a high prevalence population of HIV-positive and at-risk HIV-negative adults. Cancer Epidemiol Biomarkers Prev. 2012;21:122–33.

    Article  CAS  PubMed  Google Scholar 

  75. Robbins HA, Fennell CE, Gillison M, Xiao W, Guo Y, Wentz A, et al. Prevalence of and Risk Factors for Oral Human Papillomavirus Infection among HIV-Positive and HIV-Negative People Who Inject Drugs. PLoS One. 2015;10:e0143698. This cross-sectional study of 199 people who inject drugs, found no association between recent drug use and oral HPV prevalence. Risk factors for oral HPV infection included being HIV+ and recently performing oral sex on a woman.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Beachler DC, Sugar EA, Margolick JB, Weber KM, Strickler HD, Wiley DJ, et al. Risk factors for acquisition and clearance of oral human papillomavirus infection among HIV-infected and HIV-uninfected adults. Am J Epidemiol. 2015;181:40–53. This longitudinal cohort study demonstrates higher risk of incident oral HPV infection in those with HIV infection, reduced current CD4 cell count, and increased numbers of oral sex partners. Factors associated with persistent infection were male sex, older age, and current smoking.

    Article  PubMed  Google Scholar 

  77. Dayton AI, Sodroski JG, Rosen CA, Goh WC, Haseltine WA. The trans-activator gene of the human T cell lymphotropic virus type III is required for replication. Cell. 1986;44:941–7.

    Article  CAS  PubMed  Google Scholar 

  78. Ott M, Emiliani S, Van Lint C, Herbein G, Lovett J, Chirmule N, et al. Immune hyperactivation of HIV-1-infected T cells mediated by Tat and the CD28 pathway. Science. 1997;275:1481–5.

    Article  CAS  PubMed  Google Scholar 

  79. Westendorp MO, Shatrov VA, Schulze-Osthoff K, Frank R, Kraft M, Los M, et al. HIV-1 Tat potentiates TNF-induced NF-kappa B activation and cytotoxicity by altering the cellular redox state. EMBO J. 1995;14:546–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kim RH, Yochim JM, Kang MK, Shin KH, Christensen R, Park NH. HIV-1 Tat enhances replicative potential of human oral keratinocytes harboring HPV-16 genome. Int J Oncol. 2008;33:777–82.

    CAS  PubMed  Google Scholar 

  81. Tugizov SM, Herrera R, Chin-Hong P, Veluppillai P, Greenspan D, Michael Berry J, et al. HIV-associated disruption of mucosal epithelium facilitates paracellular penetration by human papillomavirus. Virology. 2013;446:378–88.

    Article  CAS  PubMed  Google Scholar 

  82. Shoham N, Cohen L, Yaniv A, Gazit A. The Tat protein of the human immunodeficiency virus type 1 (HIV-1) interacts with the EGF-like repeats of the Notch proteins and the EGF precursor. Virus Res. 2003;98:57–61.

    Article  CAS  PubMed  Google Scholar 

  83. Zhong R, Bao R, Faber PW, Bindokas VP, Bechill J, Lingen MW, et al. Notch1 Activation or Loss Promotes HPV-Induced Oral Tumorigenesis. Cancer Res. 2015;75:3958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lee SH, Do SI, Lee HJ, Kang HJ, Koo BS, Lim YC: Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma. Lab Invest 2016. Both papers [82• and 83•] demonstrate relationships between HPV and Notch1 signaling and explore the role of Notch1 in the pathogenesis of head and neck cancer.

  85. van Manen D, Wout AB, Schuitemaker H. Genome-wide association studies on HIV susceptibility, pathogenesis and pharmacogenomics. Retrovirology. 2012;9:70.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Joshi D, O’Grady J, Dieterich D, Gazzard B, Agarwal K. Increasing burden of liver disease in patients with HIV infection. Lancet. 2011;377:1198–209.

    Article  PubMed  Google Scholar 

  87. Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol. 2006;44:S6–9.

    Article  PubMed  Google Scholar 

  88. Lopez-Dieguez M, Montes ML, Pascual-Pareja JF, Quereda C, Von Wichmann MA, Berenguer J, et al. The natural history of liver cirrhosis in HIV-hepatitis C virus-coinfected patients. AIDS. 2011;25:899–904.

    Article  PubMed  Google Scholar 

  89. Marcellin F, Roux P, Loko MA, Lions C, Caumont-Prim A, Dabis F, et al. High levels of alcohol consumption increase the risk of advanced hepatic fibrosis in HIV/hepatitis C virus-coinfected patients: a sex-based analysis using transient elastography at enrollment in the HEPAVIH ANRS CO13 cohort. Clin Infect Dis. 2014;59:1190–2.

    Article  PubMed  Google Scholar 

  90. Bailony MR, Scherzer R, Huhn G, Plankey MW, Peters MG, Tien PC. Association of HIV infection, hepatitis C virus infection, and metabolic factors with liver stiffness measured by transient elastography. J Infect Dis. 2013;208:1776–83. These studies [89• and 90•] underscore the effect of alcohol [89•] and metabolic factors [90•] in accelerating liver fibrosis; both studies use noninvasive markers of fibrosis, specifically measuring liver stiffness with transient elastography.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Merchante N, Rivero A, de Los S-GI, Merino D, Marquez M, Lopez-Ruz MA, et al. Insulin resistance is associated with liver stiffness in HIV/HCV co-infected patients. Gut. 2009;58:1654–60.

    Article  CAS  PubMed  Google Scholar 

  92. Mandorfer M, Payer BA, Schwabl P, Steiner S, Ferlitsch A, Aichelburg MC, et al. Revisiting liver disease progression in HIV/HCV-coinfected patients: the influence of vitamin D, insulin resistance, immune status, IL28B and PNPLA3. Liver Int. 2015;35:876–85. This is a comprehensive and insightful review of the many factors at play in acclerating progression of fibrosis in HIV/HCV coinfected patients.

    Article  CAS  PubMed  Google Scholar 

  93. Reiberger T, Ferlitsch A, Sieghart W, Kreil A, Breitenecker F, Rieger A, et al. HIV-HCV co-infected patients with low CD4+ cell nadirs are at risk for faster fibrosis progression and portal hypertension. J Viral Hepat. 2010;17:400–9.

    Article  CAS  PubMed  Google Scholar 

  94. Anderson JP, Tchetgen Tchetgen EJ, Lo Re 3rd V, Tate JP, Williams PL, Seage 3rd GR, et al. Antiretroviral therapy reduces the rate of hepatic decompensation among HIV- and hepatitis C virus-coinfected veterans. Clin Infect Dis. 2014;58:719–27.

    Article  CAS  PubMed  Google Scholar 

  95. Sanmartin R, Tor J, Sanvisens A, Lopez JJ, Jou A, Muga R, et al. Progression of liver fibrosis in HIV/hepatitis C virus-coinfected individuals on antiretroviral therapy with early stages of liver fibrosis at baseline. HIV Med. 2014;15:203–12.

    Article  CAS  PubMed  Google Scholar 

  96. van der Helm J, Geskus R, Sabin C, Meyer L, Del Amo J, Chene G, et al. Effect of HCV infection on cause-specific mortality after HIV seroconversion, before and after 1997. Gastroenterology. 2013;144:751–60. e752.

    Article  PubMed  Google Scholar 

  97. AASLD/IDSA: HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C: http://www.hcvguidelines.org/full-report/unique-patient-populations-patients-hivhcv-coinfection. Accessed 3/6/16. These guidelines are jointly authored by the AASLD/IDSA and offer up-to-date treatment recommendations for HCV according to genotype with attention to important details such as prior treatment status, renal disease, and HIV coinfection. The site is continually updated and is an excellent reference for everyday clinical treatment decisionmaking.

  98. Merchante N, Giron-Gonzalez JA, Gonzalez-Serrano M, Torre-Cisneros J, Garcia-Garcia JA, Arizcorreta A, et al. Survival and prognostic factors of HIV-infected patients with HCV-related end-stage liver disease. AIDS. 2006;20:49–57.

    Article  PubMed  Google Scholar 

  99. Chen J, Florian J, Carter W, Fleischer RD, Hammerstrom TS, Jadhav PR, et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology. 2013;144:1450–5. e1452.

    Article  PubMed  Google Scholar 

  100. Sulkowski MS, Naggie S, Lalezari J, Fessel WJ, Mounzer K, Shuhart M, et al. Sofosbuvir and ribavirin for hepatitis C in patients with HIV coinfection. JAMA. 2014;312:353–61. This is the landmark study that assessed the efficacy of an all-oral, interferon-free regimen for HCV genotypes 1, 2, and 3 in patients coinfected with HIV. Although published in 2014, the treatment regimen is obsolete for genotype 1, and paper should be viewed through the “historical” lens of the importance of involving HIV+ early on in such trials.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Kwo PY, Agrawal S. HCV/HIV Coinfection: A New Treatment Paradigm. Gastroenterology. 2015;148:1470–1.

    Article  PubMed  Google Scholar 

  102. Morgan TR, Ghany MG, Kim HY, Snow KK, Shiffman ML, De Santo JL, et al. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology. 2010;52:833–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584–93.

    Article  PubMed  Google Scholar 

  104. Labarga P, Fernandez-Montero JV, de Mendoza C, Barreiro P, Soriano V. Long-term survival and liver-related events after pegylated interferon/ribavirin therapy in HIV-infected patients with chronic hepatitis C. Antivir Ther. 2015;20:65–72.

    Article  CAS  PubMed  Google Scholar 

  105. Aleman S, Rahbin N, Weiland O, Davidsdottir L, Hedenstierna M, Rose N, et al. A risk for hepatocellular carcinoma persists long-term after sustained virologic response in patients with hepatitis C-associated liver cirrhosis. Clin Infect Dis. 2013;57:230–6.

    Article  CAS  PubMed  Google Scholar 

  106. Zator ZA, Chung RT. After the cure: management of HCV after achievement of SVR. Curr HIV/AIDS Rep. 2013;10:428–35.

    Article  PubMed  Google Scholar 

  107. Lu M, Li J, Zhang T, Rupp LB, Trudeau S, Holmberg SD, Moorman AC, Spradling PR, Teshale EH, Xu F, et al.: Long-Term Reduction in Liver Fibrosis, Based on Serum Biomarkers, in Patients With Sustained Viral Responses to Hepatitis C Virus Treatment. Clin Gastroenterol Hepatol 2016.

  108. Cohort ACH: Regression of liver stiffness after sustained hepatitis C virus (HCV) virological responses among HIV/HCV-coinfected patients. AIDS 2015, 29:1821–1830. Both studies [106• and 107•] show the beneficial effect of SVR after HCV therapy on regression of fibrosis using noninvasive markers of fibrosis. The endpoint of regression of fibrosis is emerging in importance in study design for HCV trials.

  109. Collins JM, Raphael KL, Terry C, Cartwright EJ, Pillai A, Anania FA, et al. Hepatitis B virus reactivation during successful treatment of hepatitis C virus with Sofosbuvir and Simeprevir. Clin Infect Dis. 2015;61:1304–6. This paper highlights the phenomenon of HBV reactivation during DAA therapy for HCV, a phenomenon that was not seen in the interferon era due to interferon’s activity agains HBV. It is essential to be aware of HBV status prior to initiating HCV therapy in order to assess risk of reactivation and to consider prophylactic HBV suppression.

    Article  PubMed  Google Scholar 

  110. Parrinello CM, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, et al. Cytomegalovirus immunoglobulin G antibody is associated with subclinical carotid artery disease among HIV-infected women. J Infect Dis. 2012;205:1788–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Naeger DM, Martin JN, Sinclair E, Hunt PW, Bangsberg DR, Hecht F, et al. Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease. PLoS One. 2010;5, e8886.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Rector JL, Thomas GN, Burns VE, Dowd JB, Herr RM, Moss PA, et al. Elevated HbA(1c) levels and the accumulation of differentiated T cells in CMV(+) individuals. Diabetologia. 2015;58:2596–605. This study demonstrated the association between unfavourable glucose and lipid profiles with accumulation of dCTLs in CMV(+) individuals. No associations were observed in CMV(−) individuals. These findings suggest CMV infection may be a modifier of metabolic risk factors in development of disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Pathai S, Bajillan H, Landay AL. High KP: is HIV a model of accelerated or accentuated aging? J Gerontol A Biol Sci Med Sc. 2014;69:833–42. This is an insightful review of the evidence that HIV accelerates age-related clinical syndromes. The authors explore HIV as a model of premature aging, considering the complexity of the interactions between antiretroviral therapy, modifiable risk factors (eg, smoking, substance abuse, alcohol) and coinfection in HIV+.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Digestive Diseases, VA Connecticut-Healthcare System, West Haven, CT, USA

    Tamar H. Taddei

  2. Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar St., PO Box 208019, New Haven, CT, 06520-8019, USA

    Tamar H. Taddei

  3. Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Vincent Lo Re 3rd

  4. Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School, 836 Blockley Hall, 423 Guardian Drive, Philadelphia, PA, 19104-6021, USA

    Vincent Lo Re 3rd

  5. Veterans Aging Cohort Study Coordinating Center, VA Connecticut Healthcare System, West Haven, CT, USA

    Amy C. Justice

  6. Division of General Internal Medicine, Yale University School of Medicine, New Haven, CT, USA

    Amy C. Justice

  7. Center for Interdisciplinary Research on AIDS, Yale University School of Public Health, New Haven, CT, USA

    Amy C. Justice

  8. Yale School of Medicine, Building 35A, Room 2-212 (11-ACSLG), 950 Campbell Avenue, West Haven, CT, 06516, USA

    Amy C. Justice

Authors
  1. Tamar H. Taddei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vincent Lo Re 3rd
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amy C. Justice
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amy C. Justice.

Ethics declarations

Conflict of Interest

Tamar H. Taddei reports grants from Bayer Healthcare Pharmaceuticals and consulting fees from Onyx (Amgen) Pharmaceuticals.

Amy C. Justice reports grants from NIH-NIAAA.

Vincent Lo Re III declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Disclaimer

The views expressed in this article are those of the authors and do not necessarily represent the views of the US Department of Veterans Affairs of the US Government. The content is the responsibility of the authors alone and does not necessarily reflect the views of or imply endorsement by the US Government.

Additional information

This article is part of the Topical Collection on Co-infections and Comorbidity

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Taddei, T.H., Re, V.L. & Justice, A.C. HIV, Aging, and Viral Coinfections: Taking the Long View. Curr HIV/AIDS Rep 13, 269–278 (2016). https://doi.org/10.1007/s11904-016-0327-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11904-016-0327-7

Keywords

Search

Navigation