HIV-positive individuals who started HAART when they have very severe immune damage may have impaired immune reconstitution, even if their CD4 cell count recovers enough to protect them against AIDS-defining infections, according to a study published in the December 15th edition of The Journal of Infectious Diseases. However, the US investigators also found that this impaired immune function did not translate into a higher incidence of opportunistic infections.
A total of 199 HIV-positive individuals were recruited to the study between 1997 and 1999 at 29 sites across the US. All the patients had a lowest ever CD4 cell count below 50 cell/mm3, indicating that they were extremely vulnerable to a life-threatening AIDS-defining infection, before they started HAART.
Following the initiation of anti-HIV therapy, all the patients had a sustained increase in CD4 cell count to at least 100 cells/mm3 and were enrolled into a trial to investigate the safety and efficacy of azithromycin antibiotic prophylaxis for the prevention of the life-threatening AIDS-defining condition Mycobacterium avium complex (MAC). Investigators examined how functional the individuals’ immune reconstitution was by examining their response to certain antigen tests and vaccinations.
Antibodies to tetanus and hepatitis A were measured as were delayed-type hypersensitivity to candida and response to mumps skin test antigen. Where appropriate, patients were vaccinated against tetanus and hepatitis A and had their response to these vaccines measured.
Patients had received a median of 40 weeks of HAART when they entered the study, and 64% had an undetectable HIV viral load (below 500 copies/mL). At the time of entry to the study the patients’ median CD4 cell count was 226 cells/mm3 and by week 144, the end of the study, median CD4 cell count was 336 cells/mm3.
Nevertheless, the investigators found evidence of impaired immune reconstitution. A total of 80.2% of individuals lacked anergy – defined as a negative response to the delayed type hypersensitivity test for the candida antigen, mumps skin test antigen, and tetanus toxin test.
Further, 86% of individuals who received a tetanus vaccine had an impaired antibody response to it, as did 54% of patients who received the hepatitis A vaccine.
The investigators found, however, that patients who received azithromycin prophylaxis had higher rates of delayed-type hypersensitivity reaction to the tetanus toxin test (25% versus 15%, p=0.009), and the mumps skin test antigen (29% versus 17%, p=0.001).
Even though the investigators found evidence of impaired immune reconstitution, this did not translate into a higher incidence of AIDS-defining illnesses. There was no significant difference between the rates of opportunistic infections occurring in individuals with positive test results for delayed hypersensitivity reaction and antibody response, indicating immune reconstitution, and those with negative results, indicative of immune impairment,
An editorial in the same edition of the journal says that it is time to “move beyond” an examination of the markers examined in the study. Clinicians should “rely on CD4 cell counts, plasma HIV RNA levels, and clinical clues of immunodeficiency, such as persistent fever or unexplained oropharyngeal candidiasis, to guide antiretroviral therapy and opportunistic infection prophylaxis.”
Further information on this website
Starting HAART at low CD4 count can mean that functional immune response blunted - news story
When to start HIV therapy - menu of resources
The immune system and HIV - menu of resources
HIV therapy - award winning booklet in the information for HIV-positive people series (pdf)
Lederman HM et al. Incomplete immune reconstitution after the initiation of highly active antiretroviral therapy in HIV-infected patients with severe CD4 cell count depletion. Journal of Infectious Diseases 188: 1794 – 1803, 2003.
Hengel RL et al. Surrogate markers of immune function in HIV-infected patients: what are they surrogates for? Journal of Infectious Diseases 188: 1791 – 93, 2003