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PubMed2004

Clinical, virologic, and immunologic response to efavirenz-or protease inhibitor-based highly active antiretroviral therapy in a cohort of antiretroviral-naive patients with advanced HIV infection (EfaVIP 2 study).

OBJECTIVE: To compare the clinical, immunologic, and virologic outcomes of efavirenz (EFV)-based versus protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) in severely immunosuppressed HIV-1-infected patients. DESIGN: Retrospective observational cohort study. METHODS: Responses were analyzed according to the intent-to-treat principle among antiretroviral-naive patients with < 100 CD4 cells/muL who started EFV (n = 92) or a PI (n = 218) plus 2 nucleoside reverse transcriptase inhibitors. The primary end point was time to treatment failure. Secondary end points were percentage of patients with a viral load < 400 copies/mL, time to virologic failure, time to CD4 lymphocyte count > 200 cells/microL, and incidence of opportunistic events or death. RESULTS: The median baseline CD4 cell count and viral load were 34 cells/microL and 5.54 log10 copies/mL (EFV group) and 38 cells/microL and 5.40 log10 copies/mL (PI group). Time to treatment failure was shorter with a PI-based regimen than with an EFV-based regimen (adjusted relative hazard [RH] = 2.19, 95% confidence interval [CI]: 1.23-3.89). After 12 months of therapy, a significantly higher proportion of patients receiving EFV reached a viral load < 400 copies/mL (69.4 vs. 45.1%; P < 0.05). The probability of virologic failure was higher with a PI than with EFV (adjusted HR = 2.52, 95% CI: 1.14-5.61; P = 0.024). There was no difference in time to CD4 cell count > 200 cells/microL or in incidence of opportunistic events or death. CONCLUSION: : In severely immunosuppressed, antiretroviral-naive, HIV-1-infected patients, treatment with an EFV-based regimen compared with a nonboosted PI-based regimen resulted in a superior virologic response with no difference in immunologic or clinical effectiveness.

Adult↗
PubMed2003

Adherence to prescribed antiretroviral therapy in human immunodeficiency virus-infected children in the PENTA 5 trial.

BACKGROUND: Most studies of adherence to highly active antiretroviral therapy in children have been retrospective or cross-sectional. Factors relating to the caregiver, the child and the medication are all considered to be important for good adherence. METHODS: Adherence with taking prescribed medication was assessed by questionnaires completed at 4, 12, 24 and 48 weeks by caregivers of previously untreated HIV-infected children participating in the PENTA 5 trial, which was designed to evaluate different dual nucleoside reverse transcriptase inhibitor therapy combinations with and without the protease inhibitor nelfinavir. The effects of several factors on adherence and the effect of adherence on virologic suppression were assessed by multivariate logistic regression. RESULTS: Caregivers returned 266 questionnaires including at least 1 for 108 (84%) children in the trial. Nelfinavir was reported to be the most difficult drug to take (38% of questionnaires), but the difficulty decreased over time, P = 0.02. Comments on difficulties in taking and remembering drugs related to fear of disclosure and to unpleasant characteristics of the drugs. Full adherence was reported in 74% of questionnaires, did not change over time and was reported more frequently in children older than 10 years and those with symptomatic HIV disease. More children reporting full adherence achieved HIV RNA <400 copies/ml (e.g. at 48 weeks 79% vs. 50% reporting some nonadherence; overall P = 0.01). CONCLUSION: Good adherence with taking prescribed medication was associated with virologic response. Social factors were important in explaining nonadherence.

Adolescent↗
PubMed2004

Host factors and efficacy of antiretroviral treatment.

It has been proposed that some host factors may affect the intracellular drug concentration leading to the inability of drug regimens to inhibit human immunodeficiency virus (HIV) replication in cells. Among them, two factors, whose description is the main aim of this review, have been considered during the last years with particular emphasis. They are: i) altered uptake and reduced activation of nucleoside reverse transcriptase inhibitors (NRTIs) in target cells, and ii) efflux of NRTIs and protease inhibitors (PIs) by cellular transporter molecules. In fact, several authors have shown that: changes in the activity of various purine and pyrimidine biosynthetic enzymes may occur in lymphocytes of HIV-infected patients; HIV-infected patients on prolonged treatment with nucleoside analogs, such as zidovudine, show significantly decreased activity of thymidine kinase compared to untreated HIV-infected persons; NRTI and PIs are substrates for the so-called multidrug membrane transporters. With regard to the latter issue, it is known that the ATP-binding cassette transporter proteins such as the P glycoprotein, and the newly discovered family of multidrug resistance-associated proteins (MRP 1-9) promote the active extracellular efflux of a wide variety of therapeutics and overexpression of some of them lowers intracellular concentration of PIs. In the very near future such mechanisms, called by most authors "cellular drug-resistance", might be taken into account, together with other immunological, virological and behavioral factors, to explain "drug failure" and/or the variability of response in HIV patients undergoing an antiretroviral treatment.

ATP-Binding Cassette Transporters↗
PubMed2001

Mitochondria in the pathogenesis of lipodystrophy induced by anti-HIV antiretroviral drugs: actors or bystanders?

Effective therapies are now available that can stop the progression of HIV infection and significantly delay the onset of AIDS. The "highly active antiretroviral therapy" (HAART) is a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, that has a variety of serious side effects, including lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance as well as fat wasting in face and limbs. There is still an open debate that concerns the precise responsibility of HAART as well as metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The similarities with multiple symmetric lipomatosis (MSL), in which mitochondria impairment plays a crucial role, lead to the hypothesis that drug-induced damages to mitochondrial DNA are able to alter mitochondria functionality to an extent that is similar to what occurs in MSL. In addition, several evidences indicate that HAART is also linked to a deregulated production of tumour necrosis factor-alpha, which uses mitochondria as intracellular targets. In this paper, we review data concerning the role of mitochondria in the pathogenesis of lipodystrophy, and advance a unifying hypothesis involving either direct or indirect effects of the drugs employed during HAART.

Adult↗
PubMedDate not supplied

HIV fusion and its inhibition in antiretroviral therapy.

The end of the twentieth century saw dramatic improvements in the prognosis of HIV infection brought about by the introduction of new agents (the protease inhibitors and the non-nucleoside reverse transcriptase inhibitors) and their use in highly active combinations. However, the durability of these combination treatments is limited by a number of factors including adverse effects and extensive intra-class cross-resistance so that new antiretrovirals acting on alternative targets and having improved systemic tolerability profiles are required. The HIV binding and entry process offers several potential targets for antiviral interaction. These include gp120 binding to CD4 and to chemokine co-receptor molecules as well as the fusion process itself, which involves interactions between two leucine zipper-like 4-3 repeat regions within gp41 known as heptad repeat (HR)1 and HR2. Peptides such as enfuvirtide (formerly DP178 or T-20), that mimic the HR2 region of gp41, inhibit HIV-1 by a mechanism that is thought to involve competitive binding to HR1. This review summarises the clinical development of enfuvirtide, providing an overview of the pharmacokinetic, efficacy and safety data in various patient populations, and also considers the evidence for the key role of genotypic changes in the HR1 region (amino acids 36-45) in determining viral susceptibility to inhibition by enfuvirtide.

Adolescent↗
PubMed2001

Transplantation in the HIV+ patient.

The historical exclusion from transplantation of HIV-infected people was based on the logical premise that immunosuppression required for organ transplantation would exacerbate an immunocompromised state. However, the prognosis for people with HIV infection has dramatically improved with the clinical use of highly active antiretroviral (ARV) therapy (HAART). Clinical trials of ARV agents have demonstrated significant virologic, immunologic and survival benefits associated with the use of protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) containing regimens, when combined with two nucleoside analogues. The incidence of opportunistic infections and hospitalizations has decreased with the use of HAART. In combination with historical data suggesting that a subpopulation of HIV+ transplant recipients tolerate immunosuppression and have allograft survival comparable to that of HIV- transplant recipients, these results indicate that the medical community should readdress HIV infection as a contraindication to transplantation.

Antiretroviral Therapy, Highly Active↗
PubMed2003

Determinants of adherence to highly active antiretroviral therapy (HAART) in Chinese HIV/AIDS patients.

OBJECTIVE: Drug adherence is crucial to the success of highly active antiretroviral therapy (HAART) in the treatment of HIV disease. Adherence to HAART and its determinants may, however, differ across HIV/AIDS populations. METHODS: We retrospectively studied drug adherence by self-report in HIV-1 infected Chinese patients who have been on HAART for at least 1 year as at the end of year 2000. HAART is defined as three or more antiretrovirals with at least one protease inhibitor or non-nucleoside analogue reverse transcriptase inhibitor. RESULTS: The last drug adherence level assessed by self-report in 161 Chinese patients were: grade A (100%) - 130, 80.7%; grade B (95-99%) - 25, 15.5%; grade C (90-94%) - three, 1.9% and grade D (< 90%) - three, 1.9%. Patients with full adherence were more likely to have undetectable (< 500 copies/mL) plasma virus level (adjusted OR, 4.22; 95% CI, 1.75-12.33). Patients' demographics, HIV disease status and antiretroviral regimen did not affect adherence. Partial drug adherence was, however, independently associated with the psychosocial factors of missing clinic appointments (adjusted OR, 3.13; 95% CI, 1.23-8.33), forgetfulness (adjusted OR, 4.55; 95% CI, 1.64-12.5) and a busy work life (adjusted OR, 6.67; 95% CI, 1.75-25). CONCLUSION: There were similarities and differences in determinants affecting HAART adherence in Chinese compared with other patients. Psychosocial factors rather than HIV disease or treatment were more important factors in our Chinese patients. The relevance of patient populations and care setting for adherence to HAART shall be further studied.

Adult↗
PubMed2003

Highly active antiretroviral therapy outcomes in a primary care clinic.

This paper compares antiretroviral outcomes of patients at a primary care clinic with those previously reported at HIV specialty clinics and examines risk factors for treatment failure. A retrospective medical record review was undertaken at an academic primary care practice in Baltimore, Maryland. One hundred and twenty-three patients were included who had not previously received HAART and who were started on a regimen that included a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor and at least one other new antiretroviral medication. HIV RNA levels, CD4 lymphocyte counts, missed appointment rate, HAART regimen, demographic variables, and their association with the achievement of a viral RNA of 500 or less at 7-14 months were analyzed. Forty-seven per cent of the patients had an HIV RNA level of 500 or less at 7-14 months after initiation of HAART. Factors associated with treatment failure included missed appointment rate, injection drug use and previous exposure to antiretroviral medication. On multivariate analysis, only missed appointment rate and lower baseline CD4 lymphocyte count were independently associated with treatment failure. The antiretroviral outcomes of patients started on HAART by experienced health care providers in this primary care practice were comparable to those reported in specialty clinics. As with previous reports, most patients did not maintain viral suppression. Missed appointment rate was the most important risk factor for treatment failure.

Adult↗
PubMed2005

Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection.

BACKGROUND: Maximum suppression of virus replication is often not achievable for persons infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). Available data suggest that lamivudine contributes to partial viral suppression, despite the presence of M184V mutations and high-level phenotypic lamivudine resistance. METHODS: Selective lamivudine withdrawal was studied in 6 subjects who had incomplete viral suppression during antiretroviral treatment for multidrug-resistant HIV-1 infection. RESULTS: Plasma levels of HIV-1 RNA increased to 0.5 log(10) copies/mL above baseline 6 weeks after the withdrawal of lamivudine treatment (P=.04), even though reversion of lamivudine resistance was not yet detected. Early increases in plasma levels of HIV-1 RNA after lamivudine withdrawal were associated with the presence of the T215Y/F mutation and broad phenotypic resistance to nucleoside reverse-transcriptase inhibitors at baseline. Genotypic and phenotypic reversion of lamivudine resistance was detected in 4 subjects 8-14 weeks after withdrawal of lamivudine therapy. The duration of lamivudine withdrawal ranged from 8 to 22 weeks; all subjects resumed lamivudine treatment. Plasma levels of HIV-1 RNA were 0.6 log(10) copies/mL above baseline (P=.03) when lamivudine therapy was resumed. After the resumption of lamivudine treatment, plasma HIV RNA levels decreased to baseline levels in 3 subjects but remained elevated in 3 subjects who had evolution of increased antiretroviral drug resistance during the period of lamivudine withdrawal. Safety concerns raised by this latter finding led to permanent closure of the study. CONCLUSIONS: In select cases of multidrug-resistant HIV-1 infection, lamivudine contributes to suppression of HIV-1 replication, despite the presence of M184V mutations and lamivudine resistance.

Adult↗
PubMed2006

Benefits and concerns of simplification strategies in HIV-infected patients.

Highly active antiretroviral therapies (HAART) provide sustained viral control in most patients, but many of these regimens are restricted by complex dosing, drug-drug interactions and toxicities. Numerous strategies of simplified treatment have been explored in order to improve patient quality of life and adherence to treatment, as well as to manage drug-related toxicities while maintaining viral suppression. The first simplification strategy involved switching from protease inhibitors (PIs) to non-nucleoside reverse transcriptase inhibitors (NNRTIs), with an additional benefit on lipid metabolism. The development of once-daily drugs or co-formulated combinations has successfully been used to further simplify treatment. However, studies assessing triple nucleoside regimens have shown a higher frequency of viral failure in comparison with standard HAART, mainly in patients with previous sequential suboptimal treatments. Finally, NRTI-sparing approaches, consisting of NNRTI+PI combinations or monotherapies with boosted PIs, are alternatives to avoid NRTI-related mitochondrial toxicities. An accurate analysis of each patient's history will be necessary in each case to determine whether a simplification strategy is appropriate.

Anti-HIV Agents↗
PubMed2000

Considerations in the choice of protease inhibitor-sparing regimens in initial therapy for HIV-1 infection.

The current standard of care for initial antiretroviral therapy is a combination of 2 nucleoside analogues with a third agent, a protease inhibitor (PI), a non-nucleoside reverse transcriptase inhibitor or a third nucleoside analogue. Recent data heralding the arrival of potent PI-sparing regimens for initial anti-retroviral therapy and concerns regarding PI-related metabolic disturbances have led to significant shifts in treatment practices. Protease inhibitor-sparing regimens with optimal antiviral activity may have several advantages over PI-based therapy for initial or prolonged therapy. These advantages include more convenient, non-food dependent dosing regimens, lower tablet volume, fewer drug interactions, central nervous system penetration and the maintenance of PIs as an option for second line therapy. However, no data currently exist directly comparing triple therapy regimens based on the three leading PI-sparing agents, efavirenz, nevirapine or abacavir. All these agents have been compared in randomized controlled studies in treatment naïve patients to triple therapy with the PI indinavir. In these studies, similar responses to indinavir were observed with nevirapine or abacavir regimens, whereas superiority was observed with efavirenz. Limited data in high viral load patients treated with nevirapine based regimens currently exist. However, the superiority of efavirenz over indinavir based regimens was also observed in comparative data in this patient subset. PI-sparing approaches appear generally well tolerated with few individuals discontinuing in clinical studies due to adverse drug events. The majority of adverse events with efavirenz and nevirapine occur within the first month, are predictable and are manageable without therapy interruption. Similarly, apart from a rare (3%) hypersensitivity reaction, which requires therapy cessation without rechallenge, adverse effects with abacavir are uncommon.

Journal Article↗
PubMed2002

HIV and antiretroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy.

OBJECTIVE: To determine HIV and antiretroviral drug distribution in plasma and fat tissue of HIV-infected patients with lipodystrophy. METHODS: Twenty-three consecutive HIV-infected patients (median age, 43 years; male:female ratio, 18:5; median CD4 cell count, 419 x 10(6)/l) undergoing Coleman's lipostructure were enrolled prospectively in this study. HIV-1 RNA and plasma concentration of antiretroviral drugs were determined blindly in plasma and adipocyte lysate samples. HIV-1 proviral DNA was detected by nested PCR in fresh frozen adipocytes. RESULTS: Mean plasma HIV-1 RNA was significantly higher than that in adipocyte lysate samples (this was below the limit of detection in all patients tested). HIV-1 proviral DNA was positive in two out of 18 adipocyte samples with a level between 2 and 5 copies; the distribution seemed to be specific and comparable within each therapeutic class--protease inhibitors (PI) or non-nucleoside reverse transcriptase inhibitors (NNRTI). NNRTI concentrations in adipocyte lysates were approximately 100-fold higher than those of PI. Efavirenz may accumulate in fat tissue as a function of treatment duration. CONCLUSION: Our results suggest that HIV does not replicate and does not integrate its genome in fat tissue in patients with fat redistribution abnormalities. In patients with effective nadir plasma concentrations of PI and NNRTI, determination of concentration in adipocyte lysates suggests that PI may diffuse in fat tissue with the same pattern of distribution for all structurally related components tested. NNRTI present a high affinity for fat tissue and may accumulate in this compartment.

Adipocytes↗
PubMed2001

Antiretroviral therapy-associated hyperlipidaemia in HIV disease.

Widespread utilization of highly active antiretroviral therapy (HAART) for HIV-infection, primarily protease inhibitors in combination with nucleoside analogue reverse transcriptase inhibitors, has recently led to a sustained reduction in the morbidity and mortality of this disease. However, administration of HAART is frequently associated with the development of lipid disorders. The severity and prevalence of dyslipidaemia vary, depending on the type of HAART, nutritional status, HIV disease stage, and concomitant presence of lipodystrophy and insulin resistance (two additional adverse effects of HAART). The mechanism that is responsible for HAART-associated dyslipidaemia remains incompletely understood. Recent data indicate that this effect may be, at least in part, accounted for by protease inhibitor-mediated inhibition of the proteasome activity and accumulation of the active portion of sterol regulatory element-binding protein-1c in liver cells and adipocytes. Whether lipid disorders in HIV-infected patients receiving HAART translate into an increased cardiovascular risk, and the indications for lipid-lowering interventions in this population, remain to be established.

Adipocytes↗
PubMed2006

Highly active anti-retroviral therapy (HAART)-induced maintenance of adaptive but not innate immune parameters is associated with protection from HIV-induced mortality.

Immunosuppression induced by the human immunodeficiency virus (HIV-1) increases the risk of death. We measured the influence of immunological and virological factors and the type of highly active anti-retroviral therapy (HAART) on this risk. Adaptive (lymphocyte) and innate (natural killer) immune correlates and maximum HIV viral loads were assessed for association with mortality using univariate and multivariate analyses. The protective effect of HAART regimens, containing protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTI) on mortality were also examined in a prospectively recorded cohort of 9621 HIV-infected individuals. From this entire cohort, 5873 HIV infected individuals (61%) have been followed-up in the HAART era and of these 499 (8.5%) have died. In multivariate analyses, CD4 counts below the 50th centile and CD8 and CD19 counts below the 25th centile were significantly associated with mortality, as was increased age (P < 0.001). Innate immune subset levels had no effect on mortality. A maximum HIV viral load greater than the 75th centile was also associated independently with mortality (P < 0.035). Exposure to either a PI or an NNRTI-containing HAART regimen, or both together, was protective against death compared with no anti-retrovirals (P < 0.001). Effective HAART-induced maintenance of the adaptive immune system (CD4, CD8 and CD19 counts) protects from HIV-related mortality.

Adult↗
PubMed2004

Antiretroviral treatment regimens and immune parameters in the prevention of systemic AIDS-related non-Hodgkin's lymphoma.

PURPOSE: Immunosuppression induced by HIV-1 increases the risk of developing non-Hodgkin's lymphoma (NHL). We measured the influence of immunologic factors and highly active antiretroviral therapy (HAART) on this risk. As there are no data demonstrating that specific antiretroviral regimens are effective at protecting from NHL, we compared different HAART regimens. PATIENTS AND METHODS: The protective effect of HAART regimens, containing protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the development of NHL was examined in a prospectively recorded cohort of 9,621 HIV-infected individuals. Lymphocyte and natural killer subset data were also entered in univariate and multivariate analyses to establish and stratify the risk of NHL. RESULTS: From this cohort of 9,621 patients, 102 have been diagnosed with systemic AIDS-related NHL since 1996, when HAART became freely available here. By univariate analysis, increased age, higher nadir CD4 and CD8 T-cell counts, CD19 B-cell count, CD16/56 natural killer count and exposure to NNRTI or PI containing HAART conferred significant protection against NHL (P <.05). In a multivariate analysis, age, nadir CD4 and CD8 T-cell counts, and exposure to HAART were independent predictors of risk of NHL (P <.02). NNRTI-based HAART (adjusted rate ratio, 0.4; 95% CI, 0.3 to 0.5) was as protective as PI-based HAART, and these were significantly more protective than nucleoside analogues alone (rate ratio, 0.5; 95% CI, 0.4 to 0.7) or no antiretrovirals (P <.001). CONCLUSION: Effective HAART-induced maintenance of CD4 and CD8 counts protects from systemic AIDS-related NHL.

Adult↗
PubMed2004

Emtricitabine: a new nucleoside analogue for once-daily antiretroviral therapy.

Highly active antiretroviral therapy has resulted in a dramatic decline in morbidity and mortality among patients infected with HIV. Nevertheless, this success has to be considered in the context of the current challenges and needs in this field. Adherence, toxicity, potency and resistance are still matters of intense research, which need to improve in order to overcome the current limitations of available drugs. Regarding needs, the improvement of convenience, tolerability and pharmacokinetics run in parallel with toxicity reduction, improvement of activity (both for wild-type and resistant virus), penetration into viral reservoirs and exploitation of new targets. The Food and Drug Administration approved emtricitabine in July 2003 for use in combination with other antiretroviral agents in adults with HIV-1 infection. Approval was based on the results of two Phase III clinical trials. The first was a double-blind study comparing the safety and efficacy of emtricitabine + didanosine + efavirenz to stavudine + didanosine + efavirenz as initial treatment in individuals who had not previously received antiretroviral therapy. At 24 and 48 weeks, patients receiving emtricitabine had significantly higher rates of virological suppression and greater increases in CD4+ counts than stavudine recipients. The second study was an open-label trial in treatment-experienced patients with HIV RNA < 400 copies/ml on a lamivudine-containing regimen in combination with either stavudine or zidovudine and either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor for at least 12 weeks. Patients were randomised either to continue lamivudine (150 mg b.i.d.) or to switch to emtricitabine 200 mg o.d. while maintaining the same background medications. In this study, the proportion of patients whose viral loads remained suppressed at the < 400 and < 50 copies/ml levels were similar in the two treatment groups. Potency, tolerability, convenient dosing and a low rate of side effects are some of the main characteristics of this new drug.

Anti-HIV Agents↗
PubMed1998

Combination therapy for HIV: towards long term control of disease progression.

The difficulty of curing HIV patients with currently available agents has now been demonstrated and the model of care has returned to the long-term use of antiretroviral therapy. As such, the current minimum standard of care is triple drug therapy, with two nucleoside analogues,along with either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRT). Such regimens induce long-term virologic suppression in only 50 - 67% cases, so new approaches are needed. The most promising of these includes the use of two protease inhibitors,particularly in drug-naive patients, with the addition of one or two nucleoside analogues. Newer agents that merit further study include hydroxyurea,abacavir, adefovir, amprenavir and efavirenz. Their role in clinical practice remains to be defined. More complex regimens (including six drugs) are also under consideration. Although they may be more effective, long-term adherence to therapy may be problematic, and such approaches may be more appropriate for short-term use to 'induce' a virologic remission that could then be 'maintained' using a much simpler regimen. Preliminary data generated using such an approach have been disappointing, but this may relate to the specific selection of patients and regimens rather than a basic conceptual flaw with the approach itself. Although much progress has been made in the field of antiretroviral therapy, there is still a long way to go. The insightful study of new combinations of older and newer agents will help us to get closer to our goal of long-term control of HIV infection in all patients.

Journal Article↗
PubMed1998

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 children infected with human immunodeficiency virus (HIV). The frequency and spectrum of neurologic impairment are greater in children than those reported for adults. In children, HIV is known to enter the central nervous 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 encephalopathy (eg, acquired microcephaly, pyramidal tract signs, and spasticity). It has been demonstrated that antiretroviral agents can improve or even reverse the course of neurologic impairment in children. These changes have been attributed to various degrees of central nervous system drug penetration. Increasingly, protease inhibitors and combination antiretroviral therapy using reverse transcriptase inhibitors are being used 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 combination therapy using two nucleoside analogues and a protease inhibitor on neurodevelopmental and neurologic function in children with HIV infection. 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 neurodevelopmental status has been conducted as part of his participation in longitudinal research protocols. For the first 51/2 years of life, his neurodevelopmental status was normal, with cognitive functioning as measured by standardized psychometric tools solidly in the average range. Speech and language skills were age-appropriate. Tests of gross and fine motor functioning as well as evaluation of overall neurodevelopmental status suggested normal development. Magnetic resonance imaging (MRI) of the brain was consistently normal. His family reported that adaptive functioning, peer and family relationships, and behavior were all within normal limits. School reports indicated consistently that the patient was performing at age and grade level, with respect to both academic achievement and behavior. Initial concerns regarding the patient's development were expressed by both his family and school at age 6 years, 6 months. These concerns included difficulty with classroom work, decreased attention, word-finding problems, fatigue, staring spells, and loss of strength. His family and school reported a marked loss of skills acquired previously. Results of formal psychological and speech and language evaluation reflected statistically significant drops in test scores from baseline, with both delayed and atypical skills evident. The patient's condition worsened rapidly. Within a few months, he was no longer able to use sentences to communicate. Cognitive testing was attempted, but he was unable to participate because of significant fatigue, limited attention, and inability to communicate verbally. His family described periods of disorientation and confusion, lethargy, and disinterest in age-appropriate activities. He became agitated and overstimulated easily both in small group settings and in crowds. He 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 and sulcii compared with baseline assessment. In addition to fatigue and neurologic symptoms, wasting syndrome was diagnosed, with loss of percentiles in both weight and height by age 71/2 years. Low-grade elevation of liver function tests and amylase was noted. Blood cultures for mycobacteria were negative, as were serologic tests for hepatitis. (ABSTRACT TRUN

AIDS Dementia Complex↗