|CD4+ counts||Inconsistent surrogate marker||Correlation with health||Clinical outcome|
|Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection.|| ||Seligmann M, Warrell DA, Aboulker J-P, Carbon C, Darbyshire JH, Dormont J, Eschwege E, Girling DJ, James DR, Levy J-P, Peto PTA, Schwarz D, Stone AB, Weller IVD, Withnall R, Gelmon K, Lafon E, Swart AM, Aber VR, Babiker AG, Lhoro S, Nunn AJ, Vray M.
| ||"The results of Concorde ... also call into question the uncritical use of CD4 cell counts as a surrogate endpoint for assessment of benefit from long-term antiretroviral therapy." A major double-blind study of AZT use in over 2000 HIV positive people : AZT increased the number of CD4 T-cells, but in spite of this people who received AZT earlier died at a faster rate|
| ||Lancet 1994; 343: 871-881||1994|
|The Effect of Acute Severe Illness on CD4+ Lymphocyte Counts in Nonimmunocompromised Patients.|| ||Aldrich J et al.
| ||“The data should also serve as a strong reminder that using the CD4+ cell count as a surrogate for HIV testing has a risk of markedly overestimating the diagnosis of HIV. Therefore, CD4+ cell counts should not be relied on for a presumptive diagnosis of HIV in lieu of consent for serologic testing.”|
| ||Arch Intern Med. 2000 Mar 13;160(5):715-6||2000|
|Differential Survival of Patients With AIDS According to the 1987 and 1993 CDC Case Definitions.|| ||Vella S et al.
| ||“We found that among those with CD4 lymphocyte counts less than [200 per cubic millimeter], survival was highly dependent on clinical status [i.e. current health]. Those who were asymptomatic or were symptomatic but with no AIDS-defining clinical conditions had considerably better survival outcomes than those who had clinical AIDS, suggesting that while CD4 lymphocyte count is a reasonable predictor of duration of survival among homogenous clinical groups, the presence of a clinical AIDS-defining condition plays a major role [i.e. CD4 cell counts, by themselves, are not good predictors of survival in HIV-positive people]”|
| ||JAMA. 1994 Apr 20;271(15):1197-9.||1994|
|Pooled Analysis of 3 Randomized, Controlled Trials of Interleukin-2 Therapy in Adult Human Immunodeficiency Virus Type 1 Disease.|| ||Emery S et al.
| ||“Significant improvements in CD4 cell count and plasma HIV RNA in recipients of IL-2 relative to control patients were associated with a nonsignificant trend toward improved clinical outcome”|
| ||JID. 2000 Aug;182(2):428-434.||2000|
|Surrogate End Points in Clinical Trials: Are We Being Misled?.|| ||Fleming TR, DeMets DL.
| ||“Surrogate end points have been misleading about the actual effects that treatments have on the health of patients...Surrogate end points are rarely, if ever, adequate substitutes for the definitive clinical outcome in phase 3 trials”|
| ||Ann Int Med. 1996 Oct 1;125(7):605-13.||1996|
|Surrogate markers in HIV disease.|| ||Peto T.
| ||“At present there is no convincing evidence that the current surrogate markers [including CD4, CD8, viral load measurements] can be reliably used to predict the clinical efficacy of new treatments.”|
| ||Journal of Antimicrobial Chemotherapy. 1996 May;37 (Suppl. B):161-170.||1996|
|Surrogate End Points in Clinical Trials: Are We Being Misled?|| ||Fleming TR, DeMets DL.
| ||“The summary of results from a 1993 state-of-the-art conference shows that the effect of treatment on the most popular surrogate, the CD4 cell count, did not accurately predict the effect of treatment on the clinical outcomes, that is, progression to AIDS or time to death.”|
| ||Ann Int Med. 1996 Oct 1;125(7):605-13.||1996|
|The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter.|| ||Katzenstein, D.A., et al.
| ||"CD4 [T4] cell counts were not significantly associated with the risk of progression" to disease and "along with other recent analyses and experimental developments these conditions also suggest a need to re-evaluate current concepts about HIV pathogens including the concept that a systemic depletion of CD4 T-cells is the hallmark of the disease".|
| ||NEJM 335, 1091-8 (1996).||1996|
|1|| ||Goodwin, J.G.
| ||"The T- and B-cell measurers - having run through the sick, the elderly, the young, the pregnant, the bereaved - had finally run out of diseases...... And now it's starting all over again, this time with T-cell subsets...... Why not let us unimaginative immunologists publish to our heart's content?...... My strongest argument is this: Measurement of T and B cells and their subsets in disease has no clinical meaning......... But most non/immunologists do not realise this........ Nonimmunologists have naturally assumed that any subject occupying so much Journal space must be relevant in some way - a logical but incorrect assumption"|
| ||Journal of the American Medical Association 246, 947-948 (1981).||1981|
|The use of highly active antiretroviral therapy (HAART) in patients with advanced HIV infection: Impact on medical, palliative care, and quality of life outcomes|| ||Brechtl et al.
| ||“Improvements in CD4 counts but no corresponding improvements in quality of life”.|
| ||J Pain Symptom Manage. 2001;21:41-51.||2001|
|Human immunodeficiency virus type 1 RNA level and CD4 count as prognostic markers and surrogate end points: a meta-analysis.|| ||HIV Surrogate Marker Collaborative Group.
| ||"Short-term changes in these markers (CD4 count) are imperfect as surrogate end points for long-term clinical outcome because two randomized treatment comparisons may show similar differences between treatments in marker changes but not similar differences in progression to AIDS/death."|
| ||AIDS Res Hum Retroviruses 2000 Aug 10;16(12):1123-33||2000|
|Inflammatory Reactions in HIV-1-Infected Persons after Initiation of Highly Active Antiretroviral Therapy.|| ||DeSimone JA et al.
| ||“Inflammatory reactions involving opportunistic infections, AIDS-associated malignant conditions, and other noninfectious diseases have recently been described in patients infected with HIV-1. These conditions often appeared shortly after the introduction of HAART and were associated with pronounced ... increases in CD4(+) T-lymphocyte counts [normally considered signs of success of therapy]”|
| ||Ann Int Med. 2000 Sep 19;133(6):447-454.||2000|