Coinfection with HBV and HIV are common globally; the estimated prevalence is 7-11% [19
]. HBV genotypes exhibit distinctive geographical distribution [6
]. HBV genotype A and D are predominant in Europe and North America, B and C in East Asia, D in North Africa, E in West Africa, and F and H in Latin America [21
]. In Japan as East Asia, HBV has principally spread through mother-to-child infection; its genotypes C (85%) and B (12%) are primarily native to Japan [18
]. In a recent report of HBV genotypes co-infected with HIV in Japan, genotype A (80%) and C (19%) were predominant and were postulated to be transmitted by sexual contact [22
]. These prevalent developmental changes in HBV genotypes in HIV carriers indicate that universal vaccination for juveniles against HBV in Japan is warranted. Our patient exhibited mixed genotypes HBV (A/E). To the best of our knowledge, this is the first combined genotype A and E carrier co-infected with HIV. A recent report from Sri Lankan revealed a high proportion of mixed genotype infections among B, C and D [20
]. In another report from Laos, HBV mixed infections led to frequent recombinations in the same donor [19
]. However, there are no previous reports concerning HBV genotypes not only in HAL but also in malignant lymphoma. Therefore, the associations among HBV genotypes, development, characteristics, and chemosensitivity of HAL remain unknown. These issues should be addressed in future large scaled-studies.
HIV-associated AKI is clinically, etiologically, and morphologically divers [11
]. The histological findings in our renal biopsy specimen are compatible with acute interstitial nephritis (AIN). In previous reports, pathogenetic factors involved in AIN with HIV infection are drugs, such as NSAIDs and antiretroviral drugs, IRIS, and infections including HIV itself [11
]. Possible pathogenetic factors in our case were NSAIDs or HIV or both because he was treated with NSAIDs for one month and rapidly recovered from AIN concomitantly with cART. Although the biopsy specimen did not exhibit a diffuse infiltration of lymphoma cells into the renal cortex or a small number of cells in the renal interstitium, but clusters of lymphoma cells in the sub-capsule, we could not dismiss the contribution of lymphoma to renal dysfunction. In general, involvement of lymphoma in the kidney is morphologically classified as interstitial type or intra-glomerular type, and the interstitial infiltration type shows minimal proteinuria and bilateral enlargement of the kidneys on imaging [13
]. In our case, in addition to enlargement of the kidneys, the CT showed low or heterogeneous lesions in the pelvis and irregular capsular swelling lesions. These findings suggest that a number of lymphoma cells potentially infiltrated the kidney in our case. Moreover, the clinical course that the enlargement of the kidneys resolved within a few days after chemotherapy suggests lymphoma as a potential cause of AKI. Thus, we could not eliminate the possibility of sampling error in our case. We hypothesized that in an early phase of AKI, NSAIDs or HIV or both may play a major role in renal dysfunction, and in the later phase, lymphoma may play a role in renal impairment. Treatment of AKI primarily depends on the pathogenic factors. However, we could not determine which factors were dominant or concomitant in this patient’s renal dysfunction before initiation of treatment. Fortunately, the drugs administered for the treatment of HAL combatted the postulated pathogenetic factors of AKI in our case. However, we did not detect any infectious agents inducing AKI, except for HIV itself.
IRIS is a well-known complication in HIV-infected patients after cART, but uncertainty exists with regards to its pathogenesis, management, and definition [23
]. A number of case definitions for IRIS have been proposed [16
], but there is no gold standard definition of IRIS. Even so, the minimum criteria are; 1) temporal association between cART and subsequent development of symptoms, 2) evidence of immune restoration by a decrease in HIV-RNA level by more than 1 log copy/mL and an increase in CD4+ count from baseline, and 3) existence of clinical symptoms and signs consistent with inflammatory process. The immunopathogenesis of IRIS is unclear, but is believed to result from a dysregulated immune response to various antigenic stimuli including innate antigens as well as infectious organisms after cART. In our case, pneumonia following the first cycle CHOP with cART fulfilled the described minimum criteria of IRIS, although underlying infectious agents were not detected. His pneumonia rapidly resolved after the second cycle of CHOP (including prednisolone). Therefore, these clinical improvements potentially reveal the efficacy of prednisolone for IRIS presenting with pneumonia. In general, the majority of patients with IRIS exhibit a self-limiting disease course. Thus, management of IRIS relies on watchful observation. However, the incidence of IRIS during treatment of HAL remains unknown. There have been only two previous reports of IRIS with HAL [16
]. They said that IRIS should be differentiated from relapse or regrowth of HAL, and that it may be difficult for physicians to make the differential diagnosis [16
]. We suggest that a number of cases of IRIS may develop during treatment for HAL, but may be frequently overlooked because of spontaneous improvement.
The patient developed ptosis due to the left oculomotor and abducens nerve palsy. It was difficult to determine the pathogenesis of the patients’ neurological symptoms, especially to differentiate possible pathogens from lymphoma or others. In previous studies, a 3-8% incidence of ocular nerve palsy in patients with HIV infection was reported [25
]. In one report, toxoplasmosis and cryptococcosis were the most commonly detected pathogens inducing palsy, but HIV itself was not excluded [25
]. In our case, extensive examinations did not detect any presumed pathogens in his CNS. He had been always treated with FCZ and ST as prophylactic agents for toxoplasmosis and cryptococcosis. Furthermore, his palsies gradually improved without any additional specific infectious therapies. These clinical course and laboratory findings suggest that infectious pathogens were unlikely to induce his cranial nerve palsies. In recent reports, 10-20% of lymphoma patients with HIV-infection had meningeal involvement [27
]. The incidence rate of meningeal involvement may rely on the methods of evaluation [27
]. In our case, repeated CSF studies by FCM exhibited only mild protein elevation, and detected no specific monoclonal B-cell population in his CSF. His systemic manifestations, except for palsies, remained stable or slowly improved, and moreover, the laboratory findings improved; thus, his lymphoma appeared not to relapse. Previous reports have suggested that all patients with HIV-infection lymphoma receive IT for prophylaxis of CNS involvement [1
], and demonstrated that the incidence rate of CNS involvement decreased by combination with cART [29
]. We treated the patient with both prophylactic IT and cART. Although it was unclear whether he responded to high-dose chemotherapy including MTX and AraC, known to easily penetrate the CNS wall, his neurological symptoms eventually, gradually improved. In our case, a repeat brain MRI showed patchy high signal intensity lesions in the white matter, but no gadolinium-enhancing lesions in the left oculomotor nerve. The gold standard of diagnosis for leptomeningeal lymphoma is both CSF cytology and FCM [2
]. On the other hand, MRI imaging exhibited positive findings in only 50% of patients with CNS involvement of lymphoma [30
]. However, false negative MRI could not be excluded in our case. NeuroIRIS was less likely to induce ptosis in our case because of the obscure causal association between cART and its onset, or no evidence of inflammatory reactions by brain MRI [31
In conclusion, we report the first case of mixed HBV genotypes (A/E) with AKI, IRIS, and left-ptosis in HAL. We suggest that this study may be valuable in assessing HBV genotypes in lymphoma; our case study indicates that it is possible to identify the characteristics between a specific HBV genotype and lymphoma, and to provide the most appropriate treatment for lymphoma patients co-infected with HBV.