NEURODEVELOPMENTAL NEURORADIOLOGIC RECOVERY OF A CHILD INFECTED WITH HIV AFTER TREATMENT WITH COMBINATION ANTIRETROVIRAL THERAPY USING THE HIV-SPECIFIC PROTEASE INHIBITOR RITONAVIR/

Background. Neurodevelopmental impairment has been identified in child ren infected with human immunodeficiency virus (HIV). The frequency an d spectrum of neurologic impairment are greater in children than those reported for adults. In children, HIV is known to enter the central n ervous system early in the course of the disease. The presentation of pediatric neuro-acquired immune deficiency syndrome ranges from static (eg, nonprogressive developmental delay) to progressive encephalopath y (eg, acquired microcephaly, pyramidal tract signs, and spasticity). It has been demonstrated that antiretroviral agents can improve or eve n reverse the course of neurologic impairment in children. These chang es have been attributed to various degrees of central nervous system d rug penetration. Increasingly, protease inhibitors and combination ant iretroviral therapy using reverse transcriptase inhibitors are being u sed in the treatment of children infected with HIV. The addition of a protease inhibitor to nucleoside analogue therapy has been reported to delay disease progression and prolong life in adults with moderate to advanced HIV disease. No data currently exist on the impact of combin ation therapy using two nucleoside analogues and a protease inhibitor on neurodevelopmental and neurologic function in children with HIV inf ection. The following case report presents the effects of combination therapy using ritonavir in a child infected with HIV. Case Report. An 8-year, 2-month-old African-American boy was infected with HIV through vertical transmission. Regular monitoring of the patient's neurodevel opmental status has been conducted as part of his participation in lon gitudinal research protocols. For the first 5 1/2 years of life, his n eurodevelopmental status was normal, with cognitive functioning as mea sured by standardized psychometric tools solidly in the average range. Speech and language skills were age-appropriate, Tests of gross and f ine motor functioning as well as evaluation of overall neurodevelopmen tal status suggested normal development. Magnetic resonance imaging (M RI) of the brain was consistently normal. His family reported that ada ptive functioning, peer and family relationships, and behavior were al l within normal limits. School reports indicated consistently that the patient was performing at age and grade level, with respect to both a cademic achievement and behavior. Initial concerns regarding the patie nt's development were expressed by both his family and school at age 6 years, 6 months. These concerns included difficulty with classroom wo rk, decreased attention, word-finding problems, fatigue, staring spell s, and loss of strength. His family and school reported a marked loss of skills acquired previously. Results of formal psychological and spe ech and language evaluation reflected statistically significant drops in test scores from baseline, with both delayed and atypical skills ev ident. The patient's condition worsened rapidly. Within a few months, he was no longer able to use sentences to communicate. Cognitive testi ng was attempted, but he was unable to participate because of signific ant fatigue, limited attention, and inability to communicate verbally. His family described periods of disorientation and confusion, letharg y, and disinterest in age-appropriate activities. He became agitated a nd overstimulated easily both in small group settings and in crowds. H e demonstrated both fine and gross motor impairments. When frustrated, he displayed infantile and autistic-like behavior. MRI with contrast showed diffuse atrophy as well as mild prominence of the ventricles an d sulcii compared with baseline assessment. In addition to fatigue and neurologic symptoms, wasting syndrome was diagnosed, with loss of per centiles in both weight and height by age 7 1/2 years. Low-grade eleva tion of liver function tests and amylase was noted. Blood cultures for mycobacteria were negative, as were serologic tests for hepatitis. Pr evious antiviral treatment had included zidovudine monotherapy begun a t age 20 months through AIDS Clinical Trials Group protocol 128. This was changed to dideoxyinosine monotherapy through AIDS Clinical Trials Group protocol 144 at 4 years of age, which was discontinued at age 6 .5 years because of pancreatitis. A brief course of stavudine monother apy was associated with recurrence of pancreatitis. Zidovudine monothe rapy was reinstated at age 7 years. With the availability of new medic ations, at age 7 years, 9 months, the patient began combination therap y with ritonavir (350 mg/m(2) per dose twice a day), zidovudine (120 m g/m(2) per dose every 8 hours), and 3TC (4 mg/kg per dose twice a day) . In the 6 months since the initiation of combination therapy, we have observed significant changes in the patient's neurodevelopmental func tioning. Substantial improvements have occurred in both his cognitive and his language functioning. Improvements in laboratory measures were noted, as well as a three-log reduction in viral load and a significa nt increase in CD4+ T-lymphocyte percents and total counts. Repeat MRI of the brain was performed that demonstrated normal size of the ventr icular system and cerebral volume, compared with the earlier study, wh ich had shown diffuse atrophic changes. Signal intensity of the white matter was normal on all sequences, and no mass lesions were noted. Th ese changes were consistent with the resolution of all previous abnorm al findings.Discussion. In a short time, we have observed and document ed a dramatic recovery in our patient's virologic, hematologic, and ne urodevelopmental functioning as shown in neuroradiographic imaging aft er initiation of combination therapy. These positive changes suggest t hat the use of combination therapy not only significantly suppresses H IV replication, but can also lessen or even reverse some of the neurol ogic and neurodevelopmental sequelae of neuro-acquired immune deficien cy syndrome. If these findings are replicated in other HIV-infected ch ildren using combination therapy, it will reinforce the importance of aggressive, combination treatment for children.