CD4 Count Improvement Following Tenofovir to Abacavir Switch in a Patient With Persistent Lymphopenia Despite an Undetectable Viral Load

August 1, 2008

Many different antiretroviral regimens can be used as initial therapy for infection with HIV.

In 2008, initial treatment of HIV infection can be managed with many different antiretroviral regimens, all of which are highly ef­fective, are generally well tolerated, and produce substantial increases in CD4+ cell counts. Both tenofovir disoproxil fumarate and abacavir are commonly used reverse transcriptase inhibitors. A number of studies have shown that regimens containing ten­ofovir may not produce as robust a CD4+ cell count recovery as those containing abacavir.1,2 We report significant CD4+ cell count recovery, with continued virological suppression, following the switch from tenofovir to abacavir in a patient with pronounced lymphopenia despite persistent nondetectable viremia.

CASE SUMMARY
A 51-year-old HIV-positive African American woman presented for treat­ment of a rectovaginal fistula in April 2006. Her CD4+ cell count was below 20/µL (1%), and her HIV RNA level was 631,341 copies/mL. The patient’s HIV infection had been diagnosed in 1995 following heterosexual contact, but she had never sought treatment.

Antiretroviral therapy was initiated with a boosted protease inhib­itor (PI) regimen of a lopinavir/ ritonavir (LPV/r) coformulation 400/100 mg given twice daily plus a fixed-dose combination of tenof­o­vir/emtricitabine 300/200 mg given once daily. Over the next 2 months, her HIV RNA level became undetectable and remained suppressed for the next 12 months (less than 50 copies/mL). Despite her persistent undetectable viral load, her CD4 count never improved (Figure). The patient continued to experience recurring rectovaginal fistulas, which surgeons were reluctant to operate on given her significant immune dysfunction.

Figure.Virological and immunological response in a 51-year-old HIV-positive African American woman following a switch from ten­ofovir/emtricitabine to abacavir/lamivudine in a boosted protease inhibitor regimen. (TDF, tenofovir disoproxil fumarate; FTC, emtri­citabine; LPV/r, lopinavir/ritonavir; ABC, abacavir; 3TC, lamivudine.)


In May 2007, in the hope of improving the patient’s CD4 count, her NRTI backbone was switched from tenofovir/emtricitabine to a fixed-dose combination of abacavir/la­miv­­­udine 600/300 mg given once daily while continuing the LPV/r. The patient’s concurrent medications included trimethoprim/sulfa­methoxazole, rosuvastatin, flucon­azole, hydrochlorothiazide, oxycodone/acetaminophen, clopidrogel, megesterol, amlodipine, valacyclovir, and azithromycin. At the time of the drug regimen change, no additional medications were started or discontinued.

Over the next 9 months, the patient’s HIV RNA levels remained below 50 copies/mL; however, her CD4+ cell counts increased from less than 20/µL (3%) to 133/µL (15%) (Figure). In addition, her absolute lymphocyte count increased from 672/µL to 1400/µL, CD8+ cell count increased from 284/µL (52%) to 432/µL (50%), and CD4:CD8 ratio increased from 0.06 to 0.30. At various time points after her NRTI backbone was switched to abacavir/lamivudine, changes were made to her concomitant medications: potassium tablets, pregablin, nitrofurantoin, and metoclopramide were started, and hydrochlorothiazide, amlodipine, fluconazole, rosuvastatin, and megesterol were discontinued. The patient did not receive any immuno­modulator therapy before or after her NRTIs were switched. As of July 2008, the patient is stable.

DISCUSSION
While highly effective, a tenofovir-containing antiretroviral regimen may cause either a blunted or suppressed CD4 response in a small subset of patients. When tenofovir/emtricitabine was compared with abacavir/lamivudine in the HEAT trial (with LPV/r-based therapy as the initial regimen), at 48 weeks, tenofovir/emtricitabine-treated patients had smaller increases in CD4+ cell counts than abacavir/lamiv­udine-treated patients (median increase from baseline of 173/µL and 201/µL, respectively).1

In the BICOMBO trial, patients receiving stable antiretroviral therapy had their NRTI backbones replaced with either tenofovir/emtricitabine or abacavir/lamivudine.2 At 48 weeks, the patients whose NRTI backbone was switched to abacavir/ lamivudine had a median CD4+ cell count increase of 44/µL, and patients whose NRTI backbone was switched to tenofovir/emtricitabine had a median CD4+ cell count decrease of 2.7/µL.

Finally, in the SWEET trial, patients who were receiving the NNRTI efavir­enz with zidovudine/ lamivudine were randomized to either continue zidovudine/lamivudine or switch their NRTI backbone to teno­fo­vir/emtricitabine.3 At 24 weeks, the patients who continued zidovudine/lamivudine had a median CD4+ cell count increase of 21/µL, and those whose NRTI backbone was switched to tenofovir/emtricitabine had a decrease in CD4+ cell count of 8/µL.

Tenofovir has been shown to produce pronounced lymphopenia when used in combination with didanosine,4 possibly as a result of an inhibition of purine nucleoside phosphorylase, leading to increases in intracellular purines and lymphocyte depletion. We previously reported 9 cases of CD4 count declines among patients with undetectable viral loads who were receiving tenofovir-containing highly active antiretroviral therapy without didanosine5 and hypothesize that some patients may be highly sensitive to tenofovir inhibition of purine nucleoside phosphorylase per se.

The patient described here may represent such a case. No changes other than the substitution of abacavir/lamivudine for tenofovir/emtricitabine were made before the increases in CD4+ cell counts. In addition, the patient experienced continued CD4 suppression for 12 months while on a tenofovir/emtricitabine-containing regimen. This was followed by CD4 count increases within 2 months of switching the NRTI backbone to abacavir/lamivudine.

A number of new concomitant medications were initiated after the NRTI backbone was switched to abacavir/lamivudine; however, none have previously been shown to alter lymphocyte counts. While trimethoprim/sulfamethoxazole can cause myelosuppression, it should be recognized that it was administered both before and after the switch to abacavir/lamivudine and therefore is unlikely to be the cause of the lymphopenia.

In conclusion, we describe a case of an improved CD4 count following the substitution of abacavir/lamivudine for tenofovir/emtricitabine in a patient with persistent lymphopenia despite having an undetectable viral load. Among patients experiencing similar clinical circumstances, a trial switch from tenofovir/emtricitabine to abacavir/lamivudine may help improve the patient’s CD4 count.

References:

References1. Smith K, Fine D, Patel P, et al. Efficacy and safety of abacavir/lamivudine compared to tenofovir/emtricitabine in combination with once-daily lopinavir/ritonavir through 48 weeks in the HEAT study. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston. Abstract 774.
2. Martinez E, Arranz JA, Podzamczer D, et al. Efficacy and safety of NRTIs switch to tenofovir plus emtricitabine (Truvada) vs abacavir plus lamivudine (Kivexa) in patients with virologic suppression receiving a lamivudine containing HAART: the BICOMBO study. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WESS102.
3. Moyle G, Fisher M, and the SWEET Study Group. A randomized comparison of continued zidovudine plus lamivudine BID (AZT/3TC) vs switching to tenofovir DF plus emtricitabine (FTC/TDF) each plus efavirenz (EFV) in stable HIV infected persons: 48 week study-results of a planned 24-week analysis. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract WEPEB028.
4. Barrios A, Rendón A, Negredo E, et al. Paradoxical CD4+ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine. AIDS. 2005;19:569-575.
5. Condoluci D, Luber A, Folino M, Andrews M. CD4 cell count declines among patients with non-detectable viral load measurements receiving non-didanosine (ddI) containing tenofovir DF (TDF) based HAART. 6th International Workshop on Clinical Pharmacology of HIV Therapy; April 28-30, 2005; Quebec City, Quebec. Abstract 53.