Host, disease, and antiretroviral factors are associated with normalization of the CD4:CD8 ratio after initiating antiretroviral therapy
2015; Elsevier BV; Volume: 136; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2015.05.047
ISSN1097-6825
AutoresAlan Winston, Sophie José, Martin Fisher, John Walsh, Mark Nelson, Richard Gilson, Frank A. Post, Margaret Johnson, Clifford Leen, David Chadwick, Phillip Hay, Jillian Pritchard, Anjum Tariq, Caroline Sabin,
Tópico(s)HIV-related health complications and treatments
ResumoBy effectively suppressing plasma HIV-viremia, modern combination antiretroviral therapy (cART) prevents ongoing damage to the immune system from uncontrolled HIV replication and allows immune recovery. Although AIDS-defining conditions are now rare in effectively treated people living with HIV, non–AIDS-defining illnesses such as cardiovascular disease, renal disease, cognitive impairment, and cancer are reported to occur at higher rates and at a younger age than in matched HIV-uninfected control populations.1Schouten J. Wit F.W. Stolte I.G. Kootstra N.A. van der Valk M. Geerlings S.E. et al.Cross-sectional comparison of the prevalence of age-associated comorbidities and their risk factors between HIV-infected and uninfected individuals: the AGEhIV cohort study.Clin Infect Dis. 2014; 59: 1787-1797Crossref PubMed Scopus (485) Google Scholar It has been postulated that immunosenescence and persistent immune activation, even in the context of effective control of HIV-viral replication, may be the underlying pathogenic factors that drive such non–AIDS-defining comorbidities2Deeks S.G. Lewin S.R. Havlir D.V. The end of AIDS: HIV infection as a chronic disease.Lancet. 2013; 382: 1525-1533Abstract Full Text Full Text PDF PubMed Scopus (1125) Google Scholar and the monitoring of markers of immunosenescence may play a valuable role in the clinical management of people living with HIV. The CD4:CD8 ratio is one such readily available marker.Few reports have described factors associated with normalization of the CD4:CD8 ratio after the initiation of cART. We aimed to assess such factors within the UK Collaborative HIV Cohort (UK CHIC) study.Individuals initiating cART (defined as at least 3 antiretroviral agents) from 2000 onwards at the 11 UK CHIC centers that provided CD8+ count and laboratory marker data were eligible. Exclusion criteria included less than 6 months of follow-up after initiating cART, no baseline CD4:CD8 ratio, and pregnancy at any point during or immediately preceding the initiation of cART. Subjects were followed from the initiation of cART to the earliest of discontinuation of cART, death, last recorded date seen, or January 1, 2013.The CD4:CD8 ratio was calculated for any pair of CD4 and CD8 counts measured on the same day. Where there were repeated CD4 or CD8 counts on any given day, the average of all CD4 or CD8 counts on that day was used to calculate the ratio. Time to normalization of the CD4:CD8 ratio (defined as a ratio of ≥1.0 on a minimum of 2 occasions at least 30 days apart) was assessed using Kaplan-Meier and Cox Proportional Hazards models, allowing a maximum follow-up time of 5 years.In regression analyses, factors considered as potentially associated with normalization of the CD4:CD8 ratio were baseline CD4+ and CD8+ count, plasma HIV RNA, previous AIDS-defining illnesses, type of cART regimen (nucleoside reverse transcriptase inhibitor [NRTI] backbone and third antiretroviral agents), calendar year of starting cART, recent HIV seroconversion (patients known to belong to the UK Register of Seroconverters3The UK register of HIV seroconverters: methods and analytical issues. UK register of HIV seroconverters (UKRHS) Steering Committee.Epidemiol Infect. 1996; 117: 305-312Crossref PubMed Google Scholar who initiated cART within 1 year of HIV diagnosis), viral hepatitis coinfection (hepatitis B and C), age, sex, ethnicity, mode of HIV acquisition, and laboratory parameters (hepatic transaminases, albumin, alkaline phosphatase, creatinine, and hemoglobin).Sensitivity analyses were performed to assess the effects of including time-updated changes in CD4+ cell count from baseline and time-updated plasma HIV RNA as predictors in the primary analysis. Subgroup analyses were also performed in which only those achieving a CD4+ count response of more than 100 cells/μL increase within the first year of cART and those achieving and maintaining viral suppression on cART were included.Of 12,200 subjects initiating cART within the UK CHIC centers over the study period, 1,884, 706, and 353 subjects were excluded because of less than 6 months of follow-up, no CD4:CD8 ratio at baseline, and pregnancy, respectively, leaving a final cohort of 9,257 subjects. Baseline characteristics are presented in Table I. At baseline, median CD4:CD8 ratio was 0.24 (interquartile range [IQR], 0.15-0.35). After 1, 2, and 5 years, the median (IQR) CD4:CD8 ratio was 0.46 (0.31-0.67), 0.53 (0.36-0.76), and 0.65 (0.47-0.90), with 7.3%, 10.6%, and 18.3% having a ratio of 1 or more, respectively.Table IBaseline characteristics of 9257 individuals starting cARTParameterResultAge (y), mean ± SD38 ± 9.2Sex, n (%) Male7748 (83.7) Female1509 (16.3)Mode of HIV acquisition, n (%) Sex between men6011 (64.9) Injecting drug use199 (2.2) Heterosexual2585 (27.9) Other/unknown462 (5.0)Ethnicity, n (%) White5981 (64.6) Black African1728 (18.7) Black other473 (5.1) Other/unknown1075 (11.6)HBV coinfection, n (%) No6389 (69.0) Yes296 (3.2) No test2572 (27.8)HCV coinfection, n (%) No6803 (73.5) Yes445 (4.8) No test2009 (21.7)Duration of known HIV infection (y), median (IQR)2.0 (0.3-5.6)Calendar year of starting cART, n (%) 2000-20031835 (19.8) 2004-20073001 (32.4) 2008-20124421 (47.8)cART regimen class, n (%) NNRTI-based6322 (68.3) PI-based2484 (26.8) Other451 (4.9)AIDS event, n (%) No8146 (88.0) Yes1111 (12.0)Baseline viral load (log10copies/mL), median (IQR)4.8 (4.1-5.3)Baseline CD4 (cells/μL), median (IQR)230 (140-320)Baseline CD8 (cells/μL), median (IQR)895 (604-1290)Baseline CD4:CD8 ratio, median (IQR)0.24 (0.15-0.35)Raised ALT/AST (>100 IU/L), n (%) No7021 (95.3) Yes345 (4.7)Albumin (g/L), median (IQR)41 (38-44)Alkaline phosphatase (IU/L), median (IQR)73 (60-90)Creatinine (μmol/L), median (IQR)82 (73093)Hemoglobin (g/dL), median (IQR)13.6 (12.1014.6)ALT, Alanine transaminase; AST, aspartate transaminase; HBV, hepatitis B virus; HCV, hepatitis C virus; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Open table in a new tab A total of 1,636 (17.7%) individuals achieved a confirmed normalized CD4:CD8 ratio over 34,634 person-years of follow-up. Median (IQR) follow-up time was 3.0 (1.4-5.4) years. Factors associated with greater rates of normalization of the CD4:CD8 ratio after commencing cART are listed in Table II and included patient factors (female sex), HIV-disease factors (higher baseline CD4+ count, lower baseline CD8+ count, known acquisition of HIV infection in the past year), antiretroviral factors (commencing an NRTI backbone consisting of tenofovir/emtricitabine), and laboratory factors (lower alkaline phosphatase and higher hemoglobin).Table IIFactors associated with normalization of the CD4:CD8 ratio in the first 5 years of cART∗N = 6869 with available laboratory measures.FactorUnadjusted hazard ratio (95% CI)P valueAdjusted hazard ratio (95% CI)P valuePatient factors Calendar year of starting cART2000-20031.00—2004-20071.23 (1.08-1.40).0022008-20121.66 (1.44-1.92)<.001 Age (y)<301.00—1.00—30-400.76 (0.66-0.86)<.0010.95 (0.80-1.12).5240-500.67 (0.58-0.78)<.0010.81 (0.68-0.98).03≥500.79 (0.66-0.96).021.02 (0.81-1.28).89 SexMale1.00—1.00—Female1.29 (1.14-1.46)<.0011.78 (1.47-2.16)<.001 EthnicityWhite1.00—1.00—Black African0.83 (0.73-0.95).0070.81 (0.67-0.99).04Black other1.02 (0.77-1.27).860.85 (0.63-1.15).29Other/unknown0.95 (0.73-1.03).540.91 (0.75-1.10).33 Mode of acquisitionSex between men1.00—Heterosexual1.02 (0.92-1.14).72Other/unknown1.18 (0.96-1.46).11HIV-disease factors Seroconverter†In the UK Register of Seroconverters and started ART within 1 y of HIV diagnosis.No1.00—1.00—Yes2.44 (1.74-3.41)<.0011.96 (1.35-2.85)<.001 Hepatitis B coinfectionNo1.00—1.00—Yes0.72 (0.52-0.99).040.69 (0.45-1.04).08No test1.02 (0.92-1.13).701.24 (1.07-1.43).004 Hepatitis C coinfectionNo1.00—Yes1.15 (0.84-1.05).24No test0.94 (0.91-1.45).29 AIDS eventNo1.00—Yes0.70 (0.60-0.82)<.001 Baseline CD4+ (per 50 cells/μL)1.13 (1.12-1.14)<.0011.21 (1.20-1.22)<.001 Baseline CD8+ (per 50 cells/μL)0.96 (0.95-0.96)<.0010.93 (0.92-0.93)<.001 Baseline HIV RNA (copies/mL) 100,0000.86 (0.77-0.95).0051.12 (0.98-1.28).11Antiretroviral factors NRTI backboneTDF/FTC1.00—1.00—AZT/3TC0.63 (0.55-0.73)<.0010.59 (0.50-0.71)<.001ABC/3TC0.75 (0.64-0.89)<.0010.73 (0.59-0.91).005Other0.77 (0.67-0.89)<.0010.64 (0.53-0.78)<.001 Third antiretroviral agentEfavirenz1.00—1.00—Other NNRTI0.68 (0.56-0.82)<.0010.75 (0.60-0.93).009Lopinavir0.97 (0.84-1.13).731.05 (0.89-1.25).56Atazanavir1.14 (0.94-1.38).201.04 (0.81-1.33).76Darunavir1.33 (1.03-1.73).031.10 (0.81-1.49).54Other PI0.93 (0.70-1.23).590.77 (0.54-1.10).15Other antiretroviral(s)1.07 (0.87-1.32).540.76 (0.56-1.04).09Laboratory factors Raised ALT/AST (>100 U/L), yes (vs no)0.70 (0.51-0.95).02 Albumin (per g/L)1.17 (1.06-1.30).0031.17 (1.00-1.37).05 Alkaline phosphatase (per IU/L)0.98 (0.96-0.99).0020.98 (0.96-1.00).02 Creatinine (per μmol/L)1.01 (1.00-1.02).24 Hemoglobin (per g/dL)1.04 (1.01-1.07).0041.07 (1.03-1.12)<.001ABC/3TC, Abacavir/lamivudine; ALT, alanine transaminase; AST, aspartate transaminase; AZT/3TC, zidovudine/lamivudine; NNRTI, nonnucleoside reverse transcriptase inhibitors; PI, protease inhibitor; TDF/FTC; tenofovir/emtricitabine.∗ N = 6869 with available laboratory measures.† In the UK Register of Seroconverters and started ART within 1 y of HIV diagnosis. Open table in a new tab In sensitivity analyses, further adjusting the multivariable model for either the time-updated change in CD4+ count or the time-updated HIV RNA did not substantially change any of the associations observed between baseline factors and normalization of the ratio, including the antiretroviral therapy regimen (see Table E1 in this article's Online Repository at www.jacionline.org). In a subgroup analysis performed in 7551 individuals who achieved a CD4+ count gain of at least 100 cells/μL within the first year of commencing cART, 1468 (19.4%) achieved a confirmed ratio of 1 or more. In 5286 who achieved and maintained viral suppression, 907 (17.2%) achieved a normalized CD4:CD8 ratio. In this subgroup, baseline viral load and laboratory markers (albumin, alkaline phosphatase, hemoglobin) were no longer associated with the likelihood of achieving a normalized ratio. All NRTI backbones performed poorer than tenofovir/emtricitabine and being on an "other" nonnucleoside reverse transcriptase inhibitor (not efavirenz) was found to be marginally associated with a decreased likelihood of achieving a normalized ratio (adjusted hazard ratio [95% CI], 0.78 [0.60-1.02]).Within this large national cohort, we have found that normalization of the CD4:CD8 ratio occurred only in 18% of the PLWH treated with cART, suggesting that persistent immune dysfunction may be present in most of the cART-treated subjects.Our results are similar to those of other smaller cohorts reporting low rates of normalization of the CD4:CD8 ratio after commencing cART.4Leung V. Gillis J. Raboud J. Cooper C. Hogg R.S. Loutfy M.R. et al.Predictors of CD4:CD8 ratio normalization and its effect on health outcomes in the era of combination antiretroviral therapy.Plos One. 2013; 8: e77665Crossref PubMed Scopus (59) Google Scholar As expected, higher baseline CD4+ count, lower baseline CD8+ count, and recent HIV seroconversion were predictors of an improved hazard ratio of normalization of the CD4:CD8 ratio. In our cohort, baseline CD4+ count was 230 (IQR, 140-320) cells/μL. Our study included subjects who commenced cART since the year 2000. In more recent years, the CD4+ count threshold to commence cART has increased.5Williams I. Churchill D. Anderson J. Boffito M. Bower M. Cairns G. et al.Special Issue: British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012 (2013 update).HIV Med. 2014; 15: 1-85Crossref Scopus (7) Google Scholar A greater proportion of subjects may achieve a normalized CD4:CD8 ratio if cART is commenced at a higher CD4+ count or earlier during the duration of HIV infection. Indeed, in a recent cohort analysis assessing subjects commencing cART during primary HIV infection,6Thornhill J. Inshaw J. Oomeer S. Kaleebu P. Cooper D. Ramjee G. et al.Enhanced normalisation of CD4/CD8 ratio with early antiretroviral therapy in primary HIV infection.J Int AIDS Soc. 2014; 17: 19480Crossref PubMed Google Scholar 45% of the subjects commencing therapy within 6 months of HIV acquisition achieved normalization of the CD4:CD8 ratio.An interesting finding from our study is the association between the type of antiretroviral therapy, both the NRTI backbone and the third antiretroviral agent, and normalization of the CD4:CD8 ratio. Regarding the NRTI backbone, a tenofovir/emtricitabine-containing regimen is associated with a greater chance of CD4:CD8 ratio normalization compared with other NRTI backbones. Differences in CD4+ count gain between differing NRTI backbones and differences in virological outcome between differing NRTI backbones could drive such findings. Indeed, differences in CD4+ cell count gain and virological end points between differing NRTI backbones are apparent in clinical studies.7Gallant J.E. DeJesus E. Arribas J.R. Pozniak A.L. Gazzard B. Campo R.E. et al.Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV.N Engl J Med. 2006; 354: 251-260Crossref PubMed Scopus (814) Google Scholar, 8Sax P.E. Tierney C. Collier A.C. Fischl M.A. Mollan K. Peeples L. et al.Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy.N Engl J Med. 2009; 361: 2230-2240Crossref PubMed Scopus (271) Google Scholar In view of this, we undertook sensitivity analyses to assess what effects CD4+ count changes and a lack of virological suppression may have on our findings. When taking into account these factors, the associations we observed were not altered when adjusting for the effects of CD4+ count changes, suggesting that CD4+ count gain per se was not the underlying driver of associations observed between the type of antiretroviral therapy and the normalization of the CD4:CD8 ratio.In general, we observed higher rates of CD4:CD8 ratio normalization with the third agents most frequently used in clinical practice, namely, efavirenz in the nonnucleoside reverse transcriptase inhibitor class and lopinavir, atazanavir, and darunavir in the protease-inhibitor class. Currently in the United Kingdom, the use of these other third antiretroviral drugs or other combinations is reserved for individuals with confounding medical conditions or specific contraindications to guideline-driven antiretroviral therapies. It is possible that such confounding factors may explain our findings. The reason for selecting a specific antiretroviral regimen is not captured within the UK CHIC cohort.The definition of a "normal" CD4:CD8 ratio is controversial. We have used a cutoff of 1.0, which has been widely used,9Mendez-Lagares G. Garcia-Perganeda A. del Mar del Pozo-Balado M. Genebat M. Ruiz-Mateos E. Garcia Garcia M. et al.Differential alterations of the CD4 and CD8 T cell subsets in HIV-infected patients on highly active antiretroviral therapy with low CD4 T cell restoration.J Antimicrob Chemother. 2012; 67: 1228-1237Crossref PubMed Scopus (30) Google Scholar whereas other reports have used a cutoff ratio of 1.2.4Leung V. Gillis J. Raboud J. Cooper C. Hogg R.S. Loutfy M.R. et al.Predictors of CD4:CD8 ratio normalization and its effect on health outcomes in the era of combination antiretroviral therapy.Plos One. 2013; 8: e77665Crossref PubMed Scopus (59) Google Scholar A consideration for the definition of a "normalized ratio" is the clinical associations with this surrogate marker. Because the UK CHIC study has only limited information on noninfectious comorbidities, we were unable to assess the clinical implications of the CD4:CD8 ratio or the impact of normalization of this ratio on disease end points as other cohorts have reported.10Mussini C. Lorenzini P. Cozzi-Lepri A. Lapadula G. Marchetti G. Nicastri E. et al.CD4/CD8 ratio normalisation and non-AIDS-related events in individuals with HIV who achieve viral load suppression with antiretroviral therapy: an observational cohort study.Lancet HIV. 2015; 2: e98-e106Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar This was not the aim of this analysis, however. Rather, the aim of our study was to assess the factors associated with the normalization of the CD4:CD8 ratio within a large clinical cohort. Our novel observations describing several factors associated with the normalization of the CD4:CD8 ratio, including antiretroviral factors, may be of use in future studies assessing the clinical implication of this potentially very useful and readily available surrogate marker in treated HIV disease. By effectively suppressing plasma HIV-viremia, modern combination antiretroviral therapy (cART) prevents ongoing damage to the immune system from uncontrolled HIV replication and allows immune recovery. Although AIDS-defining conditions are now rare in effectively treated people living with HIV, non–AIDS-defining illnesses such as cardiovascular disease, renal disease, cognitive impairment, and cancer are reported to occur at higher rates and at a younger age than in matched HIV-uninfected control populations.1Schouten J. Wit F.W. Stolte I.G. Kootstra N.A. van der Valk M. Geerlings S.E. et al.Cross-sectional comparison of the prevalence of age-associated comorbidities and their risk factors between HIV-infected and uninfected individuals: the AGEhIV cohort study.Clin Infect Dis. 2014; 59: 1787-1797Crossref PubMed Scopus (485) Google Scholar It has been postulated that immunosenescence and persistent immune activation, even in the context of effective control of HIV-viral replication, may be the underlying pathogenic factors that drive such non–AIDS-defining comorbidities2Deeks S.G. Lewin S.R. Havlir D.V. The end of AIDS: HIV infection as a chronic disease.Lancet. 2013; 382: 1525-1533Abstract Full Text Full Text PDF PubMed Scopus (1125) Google Scholar and the monitoring of markers of immunosenescence may play a valuable role in the clinical management of people living with HIV. The CD4:CD8 ratio is one such readily available marker. Few reports have described factors associated with normalization of the CD4:CD8 ratio after the initiation of cART. We aimed to assess such factors within the UK Collaborative HIV Cohort (UK CHIC) study. Individuals initiating cART (defined as at least 3 antiretroviral agents) from 2000 onwards at the 11 UK CHIC centers that provided CD8+ count and laboratory marker data were eligible. Exclusion criteria included less than 6 months of follow-up after initiating cART, no baseline CD4:CD8 ratio, and pregnancy at any point during or immediately preceding the initiation of cART. Subjects were followed from the initiation of cART to the earliest of discontinuation of cART, death, last recorded date seen, or January 1, 2013. The CD4:CD8 ratio was calculated for any pair of CD4 and CD8 counts measured on the same day. Where there were repeated CD4 or CD8 counts on any given day, the average of all CD4 or CD8 counts on that day was used to calculate the ratio. Time to normalization of the CD4:CD8 ratio (defined as a ratio of ≥1.0 on a minimum of 2 occasions at least 30 days apart) was assessed using Kaplan-Meier and Cox Proportional Hazards models, allowing a maximum follow-up time of 5 years. In regression analyses, factors considered as potentially associated with normalization of the CD4:CD8 ratio were baseline CD4+ and CD8+ count, plasma HIV RNA, previous AIDS-defining illnesses, type of cART regimen (nucleoside reverse transcriptase inhibitor [NRTI] backbone and third antiretroviral agents), calendar year of starting cART, recent HIV seroconversion (patients known to belong to the UK Register of Seroconverters3The UK register of HIV seroconverters: methods and analytical issues. UK register of HIV seroconverters (UKRHS) Steering Committee.Epidemiol Infect. 1996; 117: 305-312Crossref PubMed Google Scholar who initiated cART within 1 year of HIV diagnosis), viral hepatitis coinfection (hepatitis B and C), age, sex, ethnicity, mode of HIV acquisition, and laboratory parameters (hepatic transaminases, albumin, alkaline phosphatase, creatinine, and hemoglobin). Sensitivity analyses were performed to assess the effects of including time-updated changes in CD4+ cell count from baseline and time-updated plasma HIV RNA as predictors in the primary analysis. Subgroup analyses were also performed in which only those achieving a CD4+ count response of more than 100 cells/μL increase within the first year of cART and those achieving and maintaining viral suppression on cART were included. Of 12,200 subjects initiating cART within the UK CHIC centers over the study period, 1,884, 706, and 353 subjects were excluded because of less than 6 months of follow-up, no CD4:CD8 ratio at baseline, and pregnancy, respectively, leaving a final cohort of 9,257 subjects. Baseline characteristics are presented in Table I. At baseline, median CD4:CD8 ratio was 0.24 (interquartile range [IQR], 0.15-0.35). After 1, 2, and 5 years, the median (IQR) CD4:CD8 ratio was 0.46 (0.31-0.67), 0.53 (0.36-0.76), and 0.65 (0.47-0.90), with 7.3%, 10.6%, and 18.3% having a ratio of 1 or more, respectively. ALT, Alanine transaminase; AST, aspartate transaminase; HBV, hepatitis B virus; HCV, hepatitis C virus; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor. A total of 1,636 (17.7%) individuals achieved a confirmed normalized CD4:CD8 ratio over 34,634 person-years of follow-up. Median (IQR) follow-up time was 3.0 (1.4-5.4) years. Factors associated with greater rates of normalization of the CD4:CD8 ratio after commencing cART are listed in Table II and included patient factors (female sex), HIV-disease factors (higher baseline CD4+ count, lower baseline CD8+ count, known acquisition of HIV infection in the past year), antiretroviral factors (commencing an NRTI backbone consisting of tenofovir/emtricitabine), and laboratory factors (lower alkaline phosphatase and higher hemoglobin). ABC/3TC, Abacavir/lamivudine; ALT, alanine transaminase; AST, aspartate transaminase; AZT/3TC, zidovudine/lamivudine; NNRTI, nonnucleoside reverse transcriptase inhibitors; PI, protease inhibitor; TDF/FTC; tenofovir/emtricitabine. In sensitivity analyses, further adjusting the multivariable model for either the time-updated change in CD4+ count or the time-updated HIV RNA did not substantially change any of the associations observed between baseline factors and normalization of the ratio, including the antiretroviral therapy regimen (see Table E1 in this article's Online Repository at www.jacionline.org). In a subgroup analysis performed in 7551 individuals who achieved a CD4+ count gain of at least 100 cells/μL within the first year of commencing cART, 1468 (19.4%) achieved a confirmed ratio of 1 or more. In 5286 who achieved and maintained viral suppression, 907 (17.2%) achieved a normalized CD4:CD8 ratio. In this subgroup, baseline viral load and laboratory markers (albumin, alkaline phosphatase, hemoglobin) were no longer associated with the likelihood of achieving a normalized ratio. All NRTI backbones performed poorer than tenofovir/emtricitabine and being on an "other" nonnucleoside reverse transcriptase inhibitor (not efavirenz) was found to be marginally associated with a decreased likelihood of achieving a normalized ratio (adjusted hazard ratio [95% CI], 0.78 [0.60-1.02]). Within this large national cohort, we have found that normalization of the CD4:CD8 ratio occurred only in 18% of the PLWH treated with cART, suggesting that persistent immune dysfunction may be present in most of the cART-treated subjects. Our results are similar to those of other smaller cohorts reporting low rates of normalization of the CD4:CD8 ratio after commencing cART.4Leung V. Gillis J. Raboud J. Cooper C. Hogg R.S. Loutfy M.R. et al.Predictors of CD4:CD8 ratio normalization and its effect on health outcomes in the era of combination antiretroviral therapy.Plos One. 2013; 8: e77665Crossref PubMed Scopus (59) Google Scholar As expected, higher baseline CD4+ count, lower baseline CD8+ count, and recent HIV seroconversion were predictors of an improved hazard ratio of normalization of the CD4:CD8 ratio. In our cohort, baseline CD4+ count was 230 (IQR, 140-320) cells/μL. Our study included subjects who commenced cART since the year 2000. In more recent years, the CD4+ count threshold to commence cART has increased.5Williams I. Churchill D. Anderson J. Boffito M. Bower M. Cairns G. et al.Special Issue: British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012 (2013 update).HIV Med. 2014; 15: 1-85Crossref Scopus (7) Google Scholar A greater proportion of subjects may achieve a normalized CD4:CD8 ratio if cART is commenced at a higher CD4+ count or earlier during the duration of HIV infection. Indeed, in a recent cohort analysis assessing subjects commencing cART during primary HIV infection,6Thornhill J. Inshaw J. Oomeer S. Kaleebu P. Cooper D. Ramjee G. et al.Enhanced normalisation of CD4/CD8 ratio with early antiretroviral therapy in primary HIV infection.J Int AIDS Soc. 2014; 17: 19480Crossref PubMed Google Scholar 45% of the subjects commencing therapy within 6 months of HIV acquisition achieved normalization of the CD4:CD8 ratio. An interesting finding from our study is the association between the type of antiretroviral therapy, both the NRTI backbone and the third antiretroviral agent, and normalization of the CD4:CD8 ratio. Regarding the NRTI backbone, a tenofovir/emtricitabine-containing regimen is associated with a greater chance of CD4:CD8 ratio normalization compared with other NRTI backbones. Differences in CD4+ count gain between differing NRTI backbones and differences in virological outcome between differing NRTI backbones could drive such findings. Indeed, differences in CD4+ cell count gain and virological end points between differing NRTI backbones are apparent in clinical studies.7Gallant J.E. DeJesus E. Arribas J.R. Pozniak A.L. Gazzard B. Campo R.E. et al.Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV.N Engl J Med. 2006; 354: 251-260Crossref PubMed Scopus (814) Google Scholar, 8Sax P.E. Tierney C. Collier A.C. Fischl M.A. Mollan K. Peeples L. et al.Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy.N Engl J Med. 2009; 361: 2230-2240Crossref PubMed Scopus (271) Google Scholar In view of this, we undertook sensitivity analyses to assess what effects CD4+ count changes and a lack of virological suppression may have on our findings. When taking into account these factors, the associations we observed were not altered when adjusting for the effects of CD4+ count changes, suggesting that CD4+ count gain per se was not the underlying driver of associations observed between the type of antiretroviral therapy and the normalization of the CD4:CD8 ratio. In general, we observed higher rates of CD4:CD8 ratio normalization with the third agents most frequently used in clinical practice, namely, efavirenz in the nonnucleoside reverse transcriptase inhibitor class and lopinavir, atazanavir, and darunavir in the protease-inhibitor class. Currently in the United Kingdom, the use of these other third antiretroviral drugs or other combinations is reserved for individuals with confounding medical conditions or specific contraindications to guideline-driven antiretroviral therapies. It is possible that such confounding factors may explain our findings. The reason for selecting a specific antiretroviral regimen is not captured within the UK CHIC cohort. The definition of a "normal" CD4:CD8 ratio is controversial. We have used a cutoff of 1.0, which has been widely used,9Mendez-Lagares G. Garcia-Perganeda A. del Mar del Pozo-Balado M. Genebat M. Ruiz-Mateos E. Garcia Garcia M. et al.Differential alterations of the CD4 and CD8 T cell subsets in HIV-infected patients on highly active antiretroviral therapy with low CD4 T cell restoration.J Antimicrob Chemother. 2012; 67: 1228-1237Crossref PubMed Scopus (30) Google Scholar whereas other reports have used a cutoff ratio of 1.2.4Leung V. Gillis J. Raboud J. Cooper C. Hogg R.S. Loutfy M.R. et al.Predictors of CD4:CD8 ratio normalization and its effect on health outcomes in the era of combination antiretroviral therapy.Plos One. 2013; 8: e77665Crossref PubMed Scopus (59) Google Scholar A consideration for the definition of a "normalized ratio" is the clinical associations with this surrogate marker. Because the UK CHIC study has only limited information on noninfectious comorbidities, we were unable to assess the clinical implications of the CD4:CD8 ratio or the impact of normalization of this ratio on disease end points as other cohorts have reported.10Mussini C. Lorenzini P. Cozzi-Lepri A. Lapadula G. Marchetti G. Nicastri E. et al.CD4/CD8 ratio normalisation and non-AIDS-related events in individuals with HIV who achieve viral load suppression with antiretroviral therapy: an observational cohort study.Lancet HIV. 2015; 2: e98-e106Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar This was not the aim of this analysis, however. Rather, the aim of our study was to assess the factors associated with the normalization of the CD4:CD8 ratio within a large clinical cohort. Our novel observations describing several factors associated with the normalization of the CD4:CD8 ratio, including antiretroviral factors, may be of use in future studies assessing the clinical implication of this potentially very useful and readily available surrogate marker in treated HIV disease. UK CHIC Steering Committee: Jonathan Ainsworth, Sris Allan, Jane Anderson, Abdel Babiker, David Chadwick, Valerie Delpech, David Dunn, Martin Fisher, Brian Gazzard, Richard Gilson, Mark Gompels, Phillip Hay, Teresa Hill, Margaret Johnson, Sophie Jose, Stephen Kegg, Clifford Leen, Fabiola Martin, Mark Nelson, Chloe Orkin, Adrian Palfreeman, Andrew Phillips, Deenan Pillay, Frank Post, Jillian Pritchard, Caroline Sabin, Memory Sachikonye, Achim Schwenk, Anjum Tariq, and John Walsh. Central Co-ordination: University College London (Teresa Hill, Susie Huntington, Sophie Jose, Andrew Phillips, Caroline Sabin, and Alicia Thornton); Medical Research Council Clinical Trials Unit at UCL (MRC CTU at UCL), London (David Dunn and Adam Glabay). Participating Centers: Brighton and Sussex University Hospitals NHS Trust (M. Fisher, N. Perry, S. Tilbury, E. Youssef, and D. Churchill); Chelsea and Westminster Hospital NHS Foundation Trust, London (B. Gazzard, M. Nelson, R. Everett, D. Asboe, and S. Mandalia); King's College Hospital NHS Foundation Trust, London (F. Post, H. Korat, C. Taylor, Z. Gleisner, F. Ibrahim, and L. Campbell); Mortimer Market Centre, University College London (R. Gilson, N. Brima, and I. Williams); Royal Free NHS Foundation Trust/University College London (M. Johnson, M. Youle, F. Lampe, C. Smith, R. Tsintas, C. Chaloner, S. Hutchinson, C. Sabin, A. Phillips, T. Hill, S. Jose, A. Thornton, and S. Huntington); Imperial College Healthcare NHS Trust, London (J. Walsh, N. Mackie, A. Winston, J. Weber, F. Ramzan, and M. Carder); Barts and The London NHS Trust, London (C. Orkin, J. Lynch, J. Hand, and C. de Souza); Homerton University Hospital NHS Trust, London (J. Anderson and S. Munshi); North Middlesex University Hospital NHS Trust, London (J. Ainsworth, A. Schwenk, S. Miller, and C. Wood); The Lothian University Hospitals NHS Trust, Edinburgh (C. Leen, A. Wilson, and S. Morris); North Bristol NHS Trust (M. Gompels and S. Allan); University Hospitals of Leicester NHS Trust, Leicester (A. Palfreeman, K. Memon, and A. Lewszuk); South Tees Hospitals NHS Foundation Trust, Middlesbrough (D. Chadwick, E. Cope, and J. Gibson); Lewisham and Greenwich NHS Trust, Woolwich (S. Kegg, P. Main, Dr Mitchell, and Dr Hunter), St George's Healthcare NHS Trust (P. Hay and M. Dhillon); York Teaching Hospital NHS Foundation Trust (F. Martin and S. Russell-Sharpe); University Hospitals Coventry and Warwickshire NHS Trust, Coventry (S. Allan, A. Harte, and S. Clay); The Royal Wolverhampton Hospitals NHS Trust, Wolverhampton (A. Tariq, H. Spencer, and R. Jones); Ashford and St Peter's Hospitals NHS Foundation Trust, Chertsey (J. Pritchard, S. Cumming, and C. Atkinson); Public Health England, London (V. Delpech); and UK Community Advisory Board (M. Sachikonye). AppendixTable E1Results of antiretroviral factor sensitivity analysesAntiretroviral factorResults from sensitivity analysis adjusting for time-updated change in CD4+ cell countResults from sensitivity analysis adjusting for time-updated HIV RNAAdjusted hazard ratio (95% CI)P valueAdjusted hazard ratio (95% CI)P valueNRTI backbone TDF/FTC1.00—1.00— AZT/3TC0.66 (0.55-0.79)<.0010.63 (0.53-0.75)<.001 ABC/3TC0.70 (0.57-0.87).0010.74 (0.60-0.91).005 Other0.67 (0.55-0.81)<.0010.70 (0.58-0.85)<.001Third antiretroviral agent Efavirenz1.00—1.00— Other NNRTI0.76 (0.61-0.95).010.78 (0.63-0.97).03 Lopinavir0.97 (0.82-1.15).721.15 (0.97-1.36).12 Atazanavir1.01 (0.79-1.29).971.10 (0.86-1.41).45 Darunavir1.09 (0.81-1.47).581.16 (0.86-1.57).32 Other PI0.73 (0.51-1.05).090.80 (0.56-1.15).23 Other antiretroviral(s)0.61 (0.44-0.86).0040.83 (0.62-1.12).23ABC/3TC, Abacavir/lamivudine; ALT, alanine transaminase; AZT/3TC, zidovudine/lamivudine; NNRTI, nonnucleoside reverse transcriptase inhibitors; PI, protease inhibitor; TDF/FTC; tenofovir/emtricitabine. Open table in a new tab ABC/3TC, Abacavir/lamivudine; ALT, alanine transaminase; AZT/3TC, zidovudine/lamivudine; NNRTI, nonnucleoside reverse transcriptase inhibitors; PI, protease inhibitor; TDF/FTC; tenofovir/emtricitabine.
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