To the Editors:
It is unclear whether continued CD4 testing is necessary for patients with full HIV RNA suppression and high CD4 counts. In the MONET trial, 257 patients with HIV RNA less than 50 copies/mL at baseline received darunavir/ritonavir, with or without nucleoside analogues. During 144 weeks of treatment, of 208 patients with baseline CD4 counts more than 350 cells/μL, only one patient had a short-term reduction in CD4 count less than 200 cells/μL, which then rose back more than 350 cells/μL with no change in treatment. Monitoring based on HIV RNA only could save significant costs from large-scale treatment access programmes.
Since the first antiretrovirals were developed in the late 1980s, CD4 counts have been used to help decide which patients should be started on antiretroviral treatment. International HIV treatment guidelines documents include a CD4 threshold for the initiation of treatment of either less than 500 cells/μL1 or less than 350 cells/μL.2
During antiretroviral treatment, the CD4 count is a poor measure of success on treatment, with low sensitivity or specificity to detect virological failure or the emergence of drug resistance.3,4 However, patients with CD4 counts less than 200 cells/μL are at higher risk of opportunistic infections—this correlation is consistent across different antiretroviral classes.5 If CD4 counts are close to or less than the threshold of 200 cells/μL, continued monitoring for CD4 counts can help to identify those needing prophylaxis for opportunistic infections.6
When the CD4 counts increase more than 350 cells/μL, after full HIV RNA suppression, the value of continuing CD4 counts may be limited. European and US treatment guidelines are now recommending less frequent monitoring for CD4 counts (every 6–12 months) if patients have full HIV RNA suppression.1,2 Can we stop testing for CD4 counts for patients who have full HIV RNA suppression and high current CD4 counts?
In the PLATO cohort, patients with suppressed HIV RNA less than 10,000 copies/mL had no overall change in CD4 counts over time.7 A previous analysis of the Frankfurt HIV cohort showed that patients with CD4 counts more than 350 cells/μL and HIV RNA suppression less than 50 copies/mL were very unlikely to show falls in CD4 count less than 350 cells/μL during long-term follow-up.8
We reanalyzed the MONET trial9 to determine whether CD4 counts were maintained above safe thresholds for patients with HIV RNA suppression over 3 years. In this trial, 256 patients with HIV RNA less than 50 copies/mL at screening on current highly active antiretroviral therapy for at least 6 months and with no history of virological failure switched to darunavir/ritonavir 800/100 mg once daily, either as monotherapy (n = 127) or with 2 nucleoside analogues (n = 129). Patients were 81% male and 91% white with a median of 7 years prior treatment before the trial. CD4 counts were measured at a central laboratory at screening, at baseline, and then at visits every 12–16 weeks to week 144. As both arms did perform similarly in regard to virological suppression,9 pooled data from both arms were now assessed for CD4-strata development. We divided the patients into subgroups according to the mean of their CD4 counts at screening and at baseline: <200, 200–350, 350–500, and more than 500 cells/μL. Then, using data from the 231 patients with at least 48 weeks of follow-up, we assessed the lowest CD4 count measured on at least 2 consecutive visits during the trial, in the same categories.
During the MONET trial, the mean CD4 count increased from 571 cells/μL at baseline to 732 cells/μL at week 144 in the DRV/r monotherapy arm and from 579 cells/μL at baseline to 747 cells/μL at week 144 in the triple therapy arm, with no significant differences between the treatment arms.
The combined data from the 2 treatment arms are shown in Table 1. The one patient with CD4 counts less than 200 cells/μL at screening/baseline also had CD4 counts in this range during the trial. Of the 22 patients with CD4 counts in the range of 200–350 cells/μL at screening/baseline, one patient (4.5%) had a fall in CD4 count to less than 200 cells/μL during the trial (triple therapy arm). Of the 60 patients with CD4 counts in the range of 350–500 cells/μL at screening/baseline, one patient (1.7%) had a fall in CD4 count to less than 200 cells/μL during the trial. None of the 148 patients with CD4 counts more than 500 cells/μL had a reduction to less than 200 cells/μL during the trial.
The 2 patients with reductions in CD4 counts less than 200 cells/μL during the trial were both in the triple therapy arm. The first patient had a baseline CD4 count of 433 cells/μL, with a level of 325 cells/μL at week 72. There was a fall to 191 and 92 cells/μL at the week 84–96 visits and then a rebound to 453 cells/μL by week 144. Suppressed HIV RNA levels remained less than 50 copies/mL throughout this time, and the CD4 percentage remained in the range of 24%–30% throughout the trial. The second patient had a baseline CD4 count of 307 cells/μL, which remained level at 278 cells/μL at week 48. There were then 2 CD4 counts of 168 and 192 cells/μL at weeks 60–72, followed by CD4 counts consistently more than 300 cells/μL from week 84 to week 144. There were no confirmed elevations in HIV RNA in this patient; the CD4 percentage was in the range of 22%–27% throughout the trial, except for a single result of 17% when the absolute CD4 count was also low.
These results from the MONET trial suggest that there is limited benefit from continued measurement of CD4 counts in patients who have achieved full HIV RNA suppression and have high current CD4 counts—in the range of or more than 350 cells/μL. The risk of sustained CD4 cell count declines to lower levels and at elevated risk for clinical disease, progression was very low.
Even if CD4 counts do fall despite full HIV RNA suppression, no randomized trial has shown that patients with low CD4 counts on one antiretroviral, despite full HIV RNA suppression, can show significant rises in CD4 counts after switching to an alternative antiretroviral. There have been reports of slightly different effects on CD4 counts between treatments—for example, raltegravir versus efavirenz in the STARMRK trial,10 lopinavir/ritonavir versus efavirenz in the ACTG 5142-trial,11 or maraviroc versus efavirenz in the MERIT trial.12 However, these differences between antiretrovirals have generally been small—in the region of 20–40 cells/μL—and have not been correlated with different rates of clinical disease progression between antiretrovirals.
This analysis of the MONET trial could be repeated in larger cohort studies, to assess longer term results from a wide range of antiretroviral combinations. If confirmed, the results could justify a change in current monitoring of people with long-term HIV RNA suppression and CD4 counts more than 350 cells/μL. Continued full HIV RNA suppression could be used as an alternative surrogate marker for sufficient immunologic performance, up to the extent that CD4 cell monitoring is no longer necessary.
2. European AIDS Clinical Society (EACS). Guidelines for the Clinical Management of HIV Infected Adults in Europe. Version 6, October 2011. Paris, France: The European AIDS Clinical Society (EACS). Available at: http://www.europeanaidsclinicalsociety.org/
. Accessed July 17, 2012.
3. Mee P, Fielding K, Charalambous S, et al.. Evaluation of the WHO criteria for antiretroviral treatment failure among adults in South Africa. AIDS. 2008;22:1971–1977.
4. Reynolds S, Kakigozi G, Newell K, et al.. Failure of immunologic criteria to appropriately identify antiretroviral treatment failure in Uganda. AIDS. 2009;23:697–700.
5. Holkmann Olsen C, Gatell J, Ledergerber B, et al.. Risk of AIDS and death at given HIV-RNA and CD4 cell counts, in relation to specific antiretroviral drugs in the regimen. AIDS. 2005;19:319–330.
6. Centers for Disease Control and Prevention. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1–206.
7. The PLATO Collaboration. Predictors of trend in CD4 positive T-cell count and mortality among HIV-1 infected individuals with virological failure to all three antiretroviral drug classes. Lancet. 2004;364:51–62.
8. Phillips A, Youle M, Lampe F, et al.. CD4 cell count changes in individuals with counts above 500 cells/mm3
and viral loads below 50 copies/ml on antiretroviral therapy. AIDS. 2002;16:1073–1075.
9. Clumeck N, Rieger A, Banhegyi D, et al.. 96 week results from the MONET trial: a randomized comparison of darunavir/ritonavir with versus without nucleoside analogues, for patients with HIV RNA<50 copies/mL at baseline. J Antimicrob Chemother. 2011;6:1878–1885.
10. Rockstroh J, Lennox J, DeJesus E, et al.. STARTMRK RAL demonstrates durable virologic suppression and superior immunologic response with a favorable metabolic profile through 3 years of treatment: 156-week results from STARTMRK. 18th Conference on Retroviruses and Opportunistic Infections, March, 2011, Boston, MA. Abstract 542.
11. Riddler SA, Haubrich R, DiRienzo AG, et al.; AIDS Clinical Trials Group Study A5142 Team. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008;358:2095–2106.
12. Sierra-Madero J, Di Perri G, Wood R, et al.. Efficacy and safety of maraviroc versus efavirenz, both with zidovudine/lamivudine: 96-week results from the MERIT study. HIV Clin Trials. 2010;11:125–132.