Highly active antiretroviral therapy (HAART) may reduce the incidence of AIDS-related disease events even in patients with inadequate responses to treatment, according to an observational cohort study published in the 15th March edition of Clinical Infectious Diseases.
Investigators discovered that patients with a poor response to HAART were less likely to experience AIDS events than patients who had similar CD4 cell counts before powerful HIV drug combinations were available. AIDS events included diseases like Pneumocystis pneumonia (PCP) and oesophageal candidiasis or ‘thrush’.
The effect of HAART was even true when the investigators limited their analysis to patients who had high viral loads despite being on antiretroviral therapy. This suggests that HAART is still useful in preventing disease when the virological and immunological responses to treatment appear to be inadequate.
“Even in patients with advanced immunosuppression and inadequate CD4 cell count and viral load responses to HIV therapy, continuing HAART may reduce the incidence of new AIDS-related events,” they conclude.
The investigators, from the University of Michigan, analysed the rates of AIDS-related events in the medical records of 302 HIV-positive patients at the university’s HIV clinic. All of the patients had had CD4 cell counts below 200 cells/mm3 before starting HIV treatment.
Eighty-eight of the patients received single or dual nucleoside reverse transcriptase inhibitor (NRTI) therapy between 1990 and 1995. The remaining 214 patients were treated with HAART between 1996 and 2004, defined as a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI) with two NRTIs. The two groups had similar ages, ratios of men to women, risk factors for HIV transmission and CD4 cell counts before HIV treatment.
The investigators found that the rate of AIDS events was 39 per 100 person-years in the eleven patients with the worst response to HIV treatment while taking HAART, with CD4 cell counts below 50 cells/mm3 and viral loads above 100,000 copies/ml.
This was significantly lower than in the 'pre-HAART' patients with CD4 cell counts below 50 cells/mm3 (76 events per 100 person-years; p = 0.01). Viral load measurements were not available in the pre-HAART era.
They saw a similar pattern when they analysed AIDS event rates in patients with CD4 cell counts below 100 cells/mm3, with rates being higher in patients in the HAART era (18 vs. 65 events per 100 person-years; p = 0.001). This was also true when they restricted their analysis to those with viral loads above 100,000 copies/ml (30 events per 100 person-years; p = 0.01).
The same relationship was found in patients with CD4 cell counts between 100 and 200 cells/mm3 (8 vs. 35 events per 100 person-years; p = 0.001). Again, this was true in the patients with viral loads above 100,000 copies/ml (15 events per 100 person-years; p = 0.04).
The investigators looked for reports of AIDS event rates published in the medical literature between 1982 and 1995. The event rates seen in their pre-HAART patients were similar to those in the published reports, confirming their conclusions.
They also broke down AIDS rates into separate types of events, including Mycobacterium avium intracellulare (MAI), PCP, Kaposi’s sarcoma, oesophageal candidiasis and lymphoma. The rates for all of these types of event were higher in the HAART era, with the exception of lymphoma.
MAI was the commonest AIDS-related event in both pre-HAART and HAART eras (15 and 14 episodes, respectively), followed by PCP and candidiasis.
Since there were no differences between the two groups in the use of prophylaxis against opportunistic infections, the investigators conclude that the use of HAART is the most likely explanation for the difference in event rates.
Although their observational study cannot prove a causal link between use of HAART and reduced disease incidence, the investigators offer two possible explanations for the correlation they observed. Firstly, they suggest that patients treated with HAART but with persistent detectable HIV may harbour drug-resistant viruses that have a lower disease-causing potential than ‘wild type’ HIV.
Alternatively, they suggest that HAART-treated patients have a greater proportion of memory CD4 T-cells than the patients treated with NRTIs alone. These cells, they argue, may recognise disease-causing organisms to which the patient has been exposed in the past, resulting in a lower incidence of AIDS events despite overall CD4 cell counts remaining low.
The investigators point out that AIDS-related event rates in their unsuccessfully-treated patients are greater than those in patients with a successful response to HIV treatment. This was confirmed by lower event rates among HAART-treated patients with lower viral loads.
“Although our study suggests that there may be some value in maintaining HAART even for patients who have immunologic and virologic failure, it also stresses the need for development of new antiretroviral agents that have activity against drug-resistant HIV strains, in hope of sustaining the overall decrease in AIDS-associated illnesses that has been witnessed since the introduction of HAART,” they write.
Gandhi T et al. Effect of maintaining highly active antiretroviral therapy on AIDS events among patients with late-stage HIV infection and inadequate response to therapy. Clin Infect Dis 42: 878 – 884, 2006.