Antiretroviral therapy has clear benefits in terms of reduced disease progression, even among patients who start treatment late, achieve smaller than expected CD4 cell gains, and do not achieve full HIV suppression, according to research presented at the recent 9th International Congress on Drug Therapy in HIV Infection (HIV9) in Glasgow, Scotland.

Starting HAART Late

In the first report, investigators studying the German ClinSurv cohort presented an analysis of risk factors for the development of AIDS-defining events in patients who begin fully suppressive antiretroviral therapy with a low baseline CD4 cell count.

The analysis included data from 1576 treatment-naive patients who started HAART after January 1, 1996 (as protease inhibitors came into widespread use) with a CD4 count < 200 cells/mm3. Participants had fairly advanced disease, with a mean pre-treatment CD4 count of about 60 cells/mm3 and about half having an AIDS diagnosis.

Patients were followed from the time of full viral suppression (< 50 copies/mL) until virological failure, the occurrence of a new AIDS-defining event, loss to follow-up, or December 31, 2007, whichever came first.

The researchers assessed the relationship between AIDS-defining events and discordant immunological response, defined as failure to achieve a CD4 count > 200 cells/mm3 despite viral suppression. They counted events occurring more than 30 days after starting therapy, to give treatment some time to work.

Results

• During the first year on therapy, a total of 42 new AIDS-defining events were reported, about one-third of them in patients with discordant immunological response.

• During year 1 the incidence rate ratio (IRR) for AIDS-defining events was 5.57 for patients with a discordant immunological response (P < 0.001).

• 9 AIDS-defining events occurred during the second year and 8 occurred during the third year of virological suppression.

• During these years, there was a non-significant trend toward a smaller influence of discordant immunological response (IRR 1.03, P = 0.98 for year 2; IRR 2.02, P = 0.51 for year 3).

• Risk factors for development of a new AIDS-defining event included having a latest CD4 count below 50 cells/mm3 (hazard ratio [HR] 6.36; P < 0.001) or 50-100 cells/mm3 (HR 3.84; P = 0.001).

• Patient sex, age, HIV transmission risk factor, CD4 count at initiation of HAART, latest CD4 measurement of 100-200 cells/mm3, and history of AIDS-defining events prior to HAART had no significant effect on AIDS-defining events after starting therapy.

"Immune discordance is a risk factor for a new AIDS-defining event while on HAART during the first year of suppressed viremia," the investigators concluded. "After this time, the incidence of AIDS-defining events decreases dramatically even in patients with prolonged immunodeficiency."

The risk is greatest, they added, for patients who do not achieve a CD4 count above 100 cells/mm3.

Strategies to raise or maintain a CD4 count above at least 100 cells/mm3, they suggested, "could prevent most AIDS-defining events in this patient group."

The study also raises the prospect that OI prophylaxis might be discontinued after a year of full viral load suppression, even if the CD4 count remains low; however, further study is needed to verify the safety of this approach.

University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Robert Koch Institute, Berlin, Germany.

Unsuppressed Viral Load

In a related study, researchers with the large EuroSIDA study looked at the incidence of opportunistic infections (OIs) and death in immunocompromised patients with a CD4 count ? 200 cells/mm3, comparing those who achieved a viral load < 500 copies/mL while on combination antiretroviral therapy (n = 3164), those whose viral load remained > 500 copies/mL despite HAART (n = 3537), and those with a viral load > 500 copies/mL while off therapy (n = 1601).

Combination therapy was considered to be a 3-drug regimen containing a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or abacavir (Ziagen) in a NRTI-only regimen.

Treated patients with viral load < 500 copies/mL had started HAART a median 1.5 years prior to the start of the study. Of the patients with viral load > 500 copies/mL despite combination therapy, about one-third had previously achieved virological suppression before study entry. About one-third of the untreated patients had never been on combination therapy.

Results

• OIs were less common in treated patients with viral load < 500 copies/mL than in treated patients with > 500 copies/mL or the untreated patients (5 vs 13 vs 53 events per 100 person-years, respectively).

• After adjusting for other factors (including patient demographics, current CD4 count, antiretroviral treatment history, hepatitis B or C coinfection, and use of OI prophylaxis), patients on HAART with a viral load > 500 copies/mL had a 2-fold increased incidence of OIs compared with treated patients who achieved < 500 copies/mL (P < 0.001).

• The untreated patients, however, had a 4-fold increased risk compared with treated patients who achieved virological suppression (P < 0.001).

• The untreated patients with viral load > 500 copies/mL had a higher crude overall death rate than treated patients with or without viral suppression.

• Treated patients without virological suppression had a higher risk of AIDS-related death than treated patients with viral load < 500 copies/mL, though the reverse was true for non-AIDS-related deaths.

• After adjusting for other factors, rates of both HIV-related and non-HIV-related death in the untreated group remained about 10 times higher than that of the treated patients with viral load < 500 copies/mL (P < 0.001).

Based on these findings, the researchers concluded, "Achieving virological suppression in immunocompromised patients is important for reducing the risk of OIs."

Furthermore, they continued, "Patients on [combination antiretroviral therapy] have a much lower risk of death than those not receiving [therapy], regardless of viral suppression."
These data, they added, suggest that treatment confers a beneficial effect "over and above what can be explained by suppression of viral load and increases in CD4 count."

Royal Free and University College Medical School, London, UK; Copenhagen HIV Programme, Panum Institute, Copenhagen, Denmark; Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam, Netherlands; Istituto Di Clinica Malattie Infettive e Tropicale, Milan, Italy; Hospital Clinic i Provincial, Barcelona, Spain; Royal Sussex County Hospital, Brighton, UK; Medical University, Gdansk, Poland; Medical Academy Botkin Hospital, St Petersburg, Russian Federation

11/25/08

References

A Zoufaly, C Kreuzberg, M An der Heiden, and others. O423 Risk of new AIDS-defining events in patients with advanced immunodeficiency during suppressive HAART: results from the German ClinSurv cohort. 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008. Journal of the International AIDS Society 11(Suppl 1):O423. November 10, 2008.

WP Bannister, A Mocroft, O Kirk, and others. Opportunistic infections in immunocompromised but virologically suppressed HIV-1 infected patients. 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008. Journal of the International AIDS Society 11(Suppl 1):O332. November 10, 2008.