Surrogate Markers

“The lack of congruence between clinical classification and immunological depletion emphasizes the importance of considering parameters separately…In areas without access to CD4 counts, some children with severe immunological depletion might be missed [since they have no disease, they might be mistaken for healthy!]. Alternatively, a high CD4 count or percentage does not preclude severe disease.”

“our results suggest that for a given CD4 cell count, HIV-RNA and time from start of the drug (plus the other factors that we adjusted for in our model) the risk of AIDS or death is the same, regardless of the specific antiretroviral drug being used. It is important to note that these results do not suggest that the regimens assessed have equal clinical efficacy. Several published randomized clinical trials have shown that different regimens have different capacities to decrease the HIV-RNA and raise the CD4 cell count and this will lead to a difference in clinical efficacy for different drug regimens. Complete reliance on the ability of surrogate endpoints to evaluate treatment effect has led to adverse clinical outcome in other disease areas; one example being antiarrhythmia drugs. Therefore it is imperative to revisit and validate historical assumptions on a regular basis, especially in the case of new drug regimens. To be an ideal surrogate, two basic conditions should be satisfied, namely that the surrogate marker is a correlate of the clinical outcome being the only causal pathway of the disease process, and that the intervention’s entire effect on the clinical outcome is mediated through its effect on the surrogate…the above-mentioned references suggest that also in the field of HIV, it is necessary to validate surrogate markers against effect markers regularly to evaluate the true treatment effect of drugs and the predictive ability of surrogate markers on clinical progression. The relevance of these type of analyses is evident, knowing that complete reliance have been made on the virologic and immunologic markers to measure treatment effect of drugs released after 1997, even though the relative proportion of non-AIDS-related death has increased during the period of combination and highly active antiretroviral therapy, and treatment effects and regimens have changed dramatically since the release of these newer drugs.”

“The median post-seroconversion CD4 cell count [first CD4 cell count after becoming HIV-positive]was 674 million cells/l[iter] in those seroconverting between 1985 and 1990, 588 million cells/l for 1991 to 1994, 559 million cells/l for 1995 to 1998 and 494 million cells/l for 1999 to 2002. The post-seroconversion CD4 cell count decreased by an average of 8.4 million cells/l per year, after adjustment for potential confounders… These data suggest a possible decreasing trend in CD4 cell count immediately following seroconversion in Italy which requires further investigation.”

“A significant decrease in CD4 and CD8 and in total lymphocyte counts was only seen in subjects receiving ddI standard dose + TDF[Tenofovir]-containing regimens, despite the maintenance of viral suppression. More than 50% of these patients showed a decline of more than 100 CD4 cells at 48 weeks. [but how can this be if low viral load and high CD4 counts are both related to the same thing?]”

“Infection with malaria parasites frequently induces total immune suppression, which makes it difficult for the host to maintain long-lasting immunity [but mice with virtually no CD4+CD25+ immune cells were resistant to the malaria parasite, but not normal mice!]”

“a minority of patients will present a so-called ‘paradoxical response’, defined as a discrepancy between the plasma viral load (pVL) and the CD4 count. The first situation occurs in 7–15% of the patients. The CD4 count rises despite a persistently detectable pVL…The second type of paradoxical response is where the CD4 count does not rise despite a fully suppressed viral growth…This phenomenon seems to occur in 5–15% of the patients treated with HAART”

“Rates of disease progression and death were independent of age, sex, prior AIDS diagnosis, protease inhibitor use and plasma HIV RNA levels [viral load].”

“Curiously, in a subset of patients, the immunologic benefit persists [higher CD4 cell counts] despite virologic failure [increased levels of the HIV DNA/RNA that is supposedly killing the CD4 cells]. The mechanism of this ‘discordant’ response is not clearly understood...”

“Immunological status [largely CD4 cell counts] generally poorly reflected clinical condition”

“until controlled trials are able to prove the utility of an undetectable viral load as a surrogate marker for clinically relevant outcomes in heavily pre-treated patients, we believe that clinicians should show caution before striving for complete viral suppression at any cost”

“Significant improvements in CD4 cell count and plasma HIV RNA in recipients of IL-2 [interleukin 2] relative to control patients were associated with a nonsignificant trend toward improved clinical outcome [normally statistically insignificant trends are ignored, but if you really, really want to believe that your therapy is working...]”

“CD4 and CD8 T cell counts, and HIV-1 plasma viremia were quantitated before, during, and after episodes of STI [Sexually Transmitted Infections]. Increases in…viremia [viral load] and a decline in CD4+ T cell counts occurred during gonococcal cervicitis and returned to baseline after treatment…Similar changes were seen in women with pelvic inflammatory disease. Acute bacterial STI resulted in increased HIV-1 viremia”

“CD4 counts increased and plasma viral load decreased at month 2 in the whole group. However, no significant correlation was found between plasma viral load changes and CD4 count changes at any time point [but, wait a minute, these are supposed to both be reflective of the amount of HIV that is active!]”

“Peripheral CD4 cell counts did not correlate with levels of HIV-1 in the CVL [cervico-vaginal lavage] by DNA or RNA PCR or by amount of genital tract inflammation”

“our study, in which HIV-1-specific CD4+ T-cell responses were quantified by flow cytometric detection of antigen-induced intracellular cytokine [which should be more accurate than traditional ‘proliferation’ assays], show that most HIV-1-positive subjects with active disease (63%) have considerable frequencies of circulating HIV-1-specific CD4+ memory T cells. Moreover, the HIV-1-specific responder frequencies in subjects with active disease did not strongly correlate with viral load.”

“The clinical state (if the person is without symptoms) is not a major detriment [to administering anti-HIV drugs]: it is the [viral load surrogate marker] numbers that appear to decide the therapeutic course. I take issue with that approach...These drugs can be toxic and can be directly detrimental to a natural immune response to HIV…. This effective antiviral immune response is characteristic of long-term survivors who…have not been on any therapy. …[T]he current antiviral therapies…do not bring about the results achieved by a natural host anti-HIV response. This immune response, observed in long-term survivors, maintains control of HIV replication without the need for antiviral treatment.”

“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”

“At present there is no convincing evidence that the current surrogate markers [including CD4, CD8 and viral load measurements] can be reliably used to predict the clinical efficacy of new treatments.”

“[Table 1 in this paper shows that 95% of CD4 cell counts in perfectly healthy people are between 40-1680 per microliter or 290-2070, depending on the mathematical model used. Note that the CDC 1993 definition of AIDS includes people with a count below 200, within the normal limits for one model, and not far off for the other]”

“A higher number of infected cells [based on viral load measurement and CD4 cell counts] in symptomatic patients was evident, with the mean values ranging from 2,143 CD4+ T lymphocytes per HIV-1 proviral DNA copy for patients in CDC classes II and III to 816 ...for patients in CDC class IV [full blown AIDS] [Note that even the sickest class of patients had only 1/816 immune cells infected, yet immune cells are regenerated continuously. Furthermore, the individual values varied widely within the CDC classes of HIV infections/AIDS. Class II and III varied from about 1/10 to 1/500 cells infected and Class IV from about 1/20 to 1/8,000 cells infected]”

“Beneficial responses [to d4t/Stavudine] were seen in the majority of patients. In one study, of 9 patients with measurable serum p24 antigen, p24 became undetectable in 8 patients within 2-5 weeks of therapy [p24 testing is now rarely used as a surrogate for clinical improvements]…Other surrogate markers for HIV diseases progression (sustained increases in CD4 cells and weight gain) were also improved. [but no experiments that showed actual improvements in health were mentioned]”