Short Communication: CD4 Cell Count Increases During Successful Treatment of Graves' Disease with Methimazole in HIV-Infected Patients on Antiretroviral Therapy

A ntiretroviral therapy (ART) induces a dramatic decrease in plasma HIV RNA and an increase in CD4 cell count, ^1,2 leading to decreased morbidity and mortality in HIV-infected patients. ³ Graves' disease (GD) may occur after ART initiation and in some cases is thought to be a late phenomenon of the immune reconstitution inflammatory syndrome (IRIS). Since the first report by a French group in 1998, ⁴ 47 cases of GD after ART initiation have been reported in HIV-infected patients. ^{4 –12} Among them 15 had a low CD4 cell count prior to ART initiation, with a marked increase on ART. ⁵ However, the change in CD4 cell count after antithyroid therapy was not mentioned in any of the previous reports. Here, we describe two cases of dramatic CD4 cell count increase after administration of methimazole (MMI; 1-methyl-2-mercaptimidazole) and compare them with those reported previously.

Case 1 is a 39-year-old HIV-infected white male who was transferred to Ebara Hospital (Tokyo, Japan) in February 2007. His CD4 cell count had reached a nadir of 50 cells/μl, with a plasma HIV RNA level of 7700 copies/ml. He was found to have esophageal candidiasis and was started on an ART regimen of zidovudine/lamivudine (ZDV/3TC) plus lopinavir/ritonavir (LPV/r). Fifteen months after ART initiation, tenofovir/emtricitabine (TDF/FTC) was substituted for ZDV/3TC because of anemia and to avoid lipoatrophy. Twenty-eight months after ART initiation, his viral load was undetectable (<50 copies/ml), and his CD4 cell count rose to 238 cells/μl. His CD4 cell count remained less than 300 cells/μl for 15 months after suppression of plasma viremia. His body weight was 70–71 kg and subsequently decreased despite an unchanged oral intake.

Thirty-nine months after ART initiation, he began to suffer from dizziness, right-handed numbness, tremor, fatigue, and palpitations. A brain MRI revealed no neurological findings. His body weight had decreased by 10 kg in the previous 5 months, reaching 57–58 kg. No evidence of malignancy was found by computed tomography. CD4 cell count was 354 cells/μl and viral load was undetectable. Forty-four months after ART initiation, he was evaluated at Johns Hopkins University Hospital (Baltimore, MD) and was found to have thyroid-stimulating hormone (TSH)<0.02 μU/ml (normal range 0.5–4.5 μIU/ml), a free T₄ of 4.0 ng/dl (normal range 0.7–1.8 ng/dl), and a T₃ of 4.65 ng/ml (normal range 0.8–2.0 ng/ml), and the clinical diagnosis of Graves' disease was made. He began MMI 30 mg daily and atenolol 50 mg daily. After 2 weeks, free T₄ levels had decreased to 1.84 ng/dl (normal range 0.7–1.8 ng/dl) measured at Ebara Hospital, and the anti-TSH receptor was revealed to be at 84.7% (normal range≤15%). His CD4 cell count increased from 354 to 482 cells/μl during this period. Seven months after administration of MMI, TSH and free T₃ and free T₄ levels were in a normal range, 0.96 μU/ml (normal range 0.3–4.5 μU/ml), 3.46 pg/ml (normal range 2.0–4.5 pg/ml), and 0.68 ng/dl (normal range 0.7–1.8 ng/dl), respectively. His CD4 cell count reached 570 cells/μl. No symptoms of hyperthyroidism were present.

Case 2 is a 41-year-old HIV-infected Japanese male who was admitted to Ebara Hospital in September 2006. His CD4 cell count had reached a nadir of 7 cells/μl with a plasma HIV RNA level of 51,000 copies/ml. He was diagnosed with AIDS based on esophageal candidiasis and intestinal cryptosporidiosis and was started on an ART regimen of ZDV/3TC and efavirenz. Six months after ART initiation, he had improved clinically with no sign of opportunistic infection. Twenty-two months after ART initiation, because of his increasing HIV RNA level (420 copies/ml), the regimen was switched to TDF/FTC and LPV/r. Thirty-one months after ART initiation, his HIV RNA level was undetectable and his CD4 cell count was 205 cells/μl. His CD4 cell count remained less than 300 cells/μl for 14 months. Forty-seven months after ART initiation, he began to complain of double vision, hand tremor, weakness of voice, and amnesia. Physical examination revealed enlargement of the thyroid without tenderness and slight exophthalmos with decreased extraocular movement. TSH and free T₃ and T₄ levels were <0.05 μU/ml (normal range 0.3–4.5 μU/ml), 26.91 pg/ml (normal range 2.0–4.5 pg/ml), and 6.97 ng/dl (normal range 0.7–1.8 ng/dl), respectively. His anti-TSH receptor level was 73.3% (normal range≤15%), confirming the diagnosis of GD. He was started on MMI 30 mg and propranolol 30 mg daily. At this time, his CD4 cell count was 329 cells/μl and viral load was undetectable; LPV/r was changed to raltegravir (RAL) because of hypercholesterolemia. After 4 weeks, his TSH and free T₃ and T₄ levels had improved dramatically to <0.05 μU/ml (normal range 0.3–4.5 μU/ml), 6.33 pg/ml (normal range 2.0–4.5 pg/ml), and 1.51 ng/dl (normal range 0.7–1.8 ng/dl), respectively, with symptomatic improvement. His CD4 cell count increased to 622 and 712 cells/μl after 3 and 6 months, respectively. The MMI dose was tapered to 5 mg daily after 6 months.

GD, an autoimmune disease involving production of anti-TSH receptor antibodies, has been described as a late immune reconstitution phenomenon in the setting of ART initiation. ¹³ The immunological mechanism underlying IRIS-related GD remains to be elucidated. To our knowledge, 47 cases of GD during ART have been reported in HIV-infected patients. ^{4 –12} A statistical analysis of 28 of these cases by Crum and colleagues indicated that the mean duration from the initiation of ART to the diagnosis of GD was 20.7 months (range 9–48), whereas the mean CD4 cell count at the development of GD was 411 cells/μl (range 138–841). ⁶ In the present study, cases 1 and 2 were diagnosed with GD 44 and 47 months after ART initiation, at which time their CD4 cell counts increased to 354 and 329 cells/μl, respectively (Fig. 1A and 1B). Because of this relatively long period between ART initiation and the development of GD, as compared to those previously reported, it is unclear whether these cases are a result of IRIS.

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FIG. 1.

Viral load and CD4 cell count profile during antiretroviral therapy and administration of antithyroid drugs in case 1 (A) and case 2 (B). Periods of drug administration are indicated by horizontal bars.

Our cases were similar to those previously described in the degree of immunosuppression prior to ART initiation and the extent of CD4 cell count increase with fully suppressive ART (Fig. 1A and 1B). For example, Chen and colleagues reported lower CD4 cell counts prior to ART (mean 66.6 cells/μl) and larger CD4 cell increases following ART (mean 355 cells/μl) in those who developed autoimmune thyroid disease, including GD, compared with their respective controls. ⁵

One intriguing finding of the present study is that the CD4 cell count increased dramatically soon after administration of MMI in both cases (Fig. 1A and 1B). One possible explanation is that MMI affects the Th1/Th2 balance and consequently may induce the expansion of CD4 cells. Although GD has been considered to be a Th2-dominant autoimmune disease, several studies demonstrated Th1 dominance during early stages and Th2 dominance in later stages. ¹⁴ A previous report showed a decreased number of peripheral helper T cells (i.e., CD4 cells), an increased number of circulating suppressor T cells, and activated intrathyroidal T cells during administration of MMI. ¹⁵ Moreover, intervention by MMI promotes the shift from Th1 to Th2 dominance in patients with GD. ¹⁴ Because HIV-specific CD4 Th1 cells, producing interferon-gamma and interleukin (IL)-2, play a crucial role in the maintenance of HIV infection, ¹⁶ the deletion of Th1 by the shift to Th2 is thought to be compensated for by recruitment of Th1. For this reason, proliferation of Th1 is vigorously activated, and as a result, the CD4 cell count expands. Another possibility is that thyroid hormones (i.e., free T₄ and T₃) have a direct inhibitory effect on lymphocyte proliferation. CD4 cells may be released from inhibition by thyroid hormones after administration of MMI, resulting in acceleration of proliferation. Further functional studies are required to elucidate the relationship between thyroid hormones and cell proliferation.

Among the 47 previous reported cases of GD after ART initiation, 36 were treated with antithyroid drug (ATD) (i.e., MMI, carbimazole, and propylthiouracil). ^{4 –12} Furthermore, thyroidectomy or radioactive iodine administration was performed in four refractory cases with ATD. However, none of the studies reported the change in CD4 cell count during successful treatment of hyperthyroidism with ATD or compared the changes in CD4 cell count in cases with successful treatment of GD with ATD to refractory cases whose hyperthyroidism persisted despite ATD. This would help distinguish between the potential direct effects of MMI on CD4 cell count recovery and the control of hyperthyroidism.

Thyroid dysfunction, including GD, has been reported in the ART era. Vigilance with regard to these complications should be maintained, especially when a patient's CD4 cell count increases to greater than 300 cells/μl. The mechanisms underlying the CD4 cell count increase with successful treatment of Graves' hyperthyroidism with MMI require further investigation.