Fehmida Visnegarwala

Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy.

Background:There is little systematic information regarding the immune reconstitution inflammatory syndrome (IRIS). Objective:To determine the incidence, risk factors, and long-term outcome of IRIS in HIV-infected patients receiving highly active antiretroviral therapy (HAART) who were coinfected with one of three common opportunistic pathogens. Design:A retrospective cohort identified through a city-wide prospective surveillance program. Methods:A retrospective chart review was performed for 180 HIV-infected patients who received HAART and were coinfected with Mycobacterium tuberculosis, Mycobacterium avium complex, or Cryptococcus neoformans between 1997 and 2000. Medical records were reviewed for baseline demographics, receipt and type of HAART, response to antiretroviral therapy, development of IRIS, and long-term outcome. Results:In this cohort, 31.7% of patients who received HAART developed IRIS. Patients with IRIS were more likely to have initiated HAART nearer to the time of diagnosis of their opportunistic infection (P < 0.001), to have been antiretroviral naive at time of diagnosis of their opportunistic infection (P < 0.001), and to have a more rapid initial fall in HIV-1 RNA level in response to HAART (P < 0.001). Conclusions:IRIS is common among HIV-infected persons coinfected with M. tuberculosis, M. avium complex, or C. neoformans. Antiretroviral drug-naive patients who start HAART in close proximity to the diagnosis of an opportunistic infection and have a rapid decline in HIV-1 RNA level should be monitored for development of this disorder.

Immune reconstitution inflammatory syndrome. Emergence of a unique syndrome during highly active antiretroviral therapy

The discovery of effective therapy for human immunodeficiency virus (HIV) infection has improved the outlook for patients with the acquired immunodeficiency syndrome (AIDS) (75, 88, 115, 121, 134). Since the introduction of highly active antiretroviral therapy (HAART), there has been a decrease in the incidence of opportunistic infections among HIVinfected patients along with a corresponding reduction in the mortality rate (7, 30, 45, 102, 117). The basis for these improvements appears to be a result of partial recovery of the host’s immune system. Suppression of viral replication by antiretroviral therapy allows for the reappearance of immune effector cells, that in turn, provide vital protection against opportunistic pathogens (15, 32, 92, 95, 132). However beneficial HAART has been, experience during the past several years has disclosed the emergence, in a small proportion of cases, of a unique set of complications. Soon after treatment is begun, some patients experience clinical deterioration due to restoration of their capacity to mount an inflammatory immune response against both infectious and noninfectious antigens. This phenomenon which carries such labels as the immune reconstitution syndrome (IRS) and immune restoration disease (IRD), has been described for a wide variety of infectious pathogens (26, 36, 46). The manifestations of this syndrome are diverse and depend on the particular infectious agent involved. Given that an increased inflammatory response underlies its presentation, we propose the name immune reconstitution inflammatory syndrome (IRIS). Autoimmune diseases that occur following institution of HAART may also be considered as part of the same process. For the purpose of this review, IRIS is defined as a paradoxical deterioration in clinical status attributable to the recovery of the immune system during HAART. Recognition of this entity is crucial, for successful treatment relies on alleviation of the patient’s symptoms without compromising antiretroviral or antimicrobial therapy. In this article, we review the present understanding of the basic science underlying IRIS, with illustrative examples from our case series, and review the existing clinical literature.

The Role of Immune Reconstitution Inflammatory Syndrome in AIDS-Related Cryptococcus neoformans Disease in the Era of Highly Active Antiretroviral Therapy

This study of human immunodeficiency virus (HIV)-infected patients coinfected with Cryptococcus neoformans found that 30% of patients who initiated highly active antiretroviral therapy developed immune reconstitution inflammatory syndrome (IRIS). Patients with C. neoformans-related IRIS had higher cerebrospinal fluid opening pressures, glucose levels, and white blood cell counts, compared with patients with typical HIV-associated C. neoformans meningitis.

Effects of HIV disease on lipid, glucose and insulin levels: results from a large antiretroviral‐naïve cohort

With the use of potent antiretroviral therapy in patients with HIV disease, changes in lipid parameters and glucose homeostasis have been noted. However, these effects have been difficult to interpret because of the varied demographic and treatment characteristics of the cohorts and the complexity of differentiating the effect of HIV disease from that of the drugs used in its treatment. This study was designed to explore these issues.

Continuous antiretroviral therapy decreases bone mineral density.

Objectives:To assess the effects of antiretroviral therapy (ART) on bone mineral density (BMD) Design:Randomized comparison of continuous ART (viral suppression group; VS) with intermittent ART (drug conservation group; DC) Setting:Outpatient clinics in the United States, Australia, and Spain. Participants:Participants in the Strategies for Management of Antiretroviral Therapy (SMART) Body Composition substudy. Main outcome measures:Annual hip and spine BMD by dual-energy radiographic absorptiometry (DXA) and spine BMD by quantitative computed tomography (qCT). Methods:Comparisons were by intention-to-treat analysis, using longitudinal models for change in BMD. Risk factors for BMD loss were evaluated. Results:The 214 participants (median 44 years, 19% female participants, 73% on ART; median T-scores −0.5 total hip, −0.7 spine DXA, −0.9 spine qCT; 98 randomized to VS and 116 to DC) were followed for a mean 2.4 years. With continuous ART, BMD declined per year by 0.8% (hip), 0.4% (spine DXA), and 2.4% (spine qCT). BMD declined significantly less with intermittent ART. Estimated DC minus VS group differences in mean BMD change through follow-up were 1.4% [hip; 95% confidence interval (CI) 0.6–2.3; P = 0.002], 1.3% (spine DXA; 95% CI 0.1–2.4, P = 0.03), and 3.0% (spine qCT; 95% CI 0.8–5.2, P = 0.007). No consistent drug-specific association with BMD decline was found. In the parent study, 10 of 2753 participants in the VS group and two of 2720 in the DC group reported serious fractures (hazard ratio 4.9; 95% CI 1.1–22.5; P = 0.04). Conclusion:Continuous ART is associated with decline in BMD and possibly more fractures relative to intermittent, CD4 cell count-guided ART.

Patients referred to an urban HIV clinic frequently fail to establish care: factors predicting failure

Abstract To measure the success with which patients newly entering outpatient care establish regular care, and assess whether race/ethnicity was a predictive factor, we conducted a medical record review of new patients seen 20 April 1998 to 31 December 1998 at The Thomas Street Clinic, a county clinic for uninsured persons. Patients were considered ‘not established’ if they never saw a physician in the 6 months after intake (the ‘initial period’), ‘poorly established’ if seen but a > 6-month gap in care began in the initial period, and ‘established’ if there were no such gaps. Of 404 patients, 11% were ‘not established’, 37% ‘poorly established’, and 53% ‘established’. Injection drug use as HIV risk factor (IDU), admitted current alcohol and drug use, age < 35 years, and CD4 count > / = 200 cells/mm3 were most common in the ‘not established’ group and least common in the ‘established’ group. In multivariate ordinal logistic regression, difficulty establishing care was associated with IDU, admitted current alcohol use, and admitted former drug use. Age > 35 years was protective. Half the indigent patients entering care in this single-site study fail to establish regular care. Substance use and younger age are predictors of failure to establish care.

Severe diabetes associated with protease inhibitor therapy.

TO THE EDITOR: Protease inhibitors block the action of aspartate protease, which is required to produce new virions. We describe a patient in whom symptomatic hyperglycemia was associated with the protease inhibitor nelfinavir, perhaps as a result of inhibition of the protease that converts proinsulin to insulin. A 46-year-old man with advanced-stage AIDS was receiving didanosine and lamuvidine. His viral load was 380 000 RNA copies/mL, and his CD4+ count was 20 cells/mm3. Treatment was changed to nelfinavir, zidovudine, and lamivudine. Other medications were trimethoprim-sulfamethoxazole, ciprofloxacin, clarithromycin, ethambutol, itraconazole, megestrol acetate, phenytoin, amitryptyline, and carbamazepine. The patients mother had type 2 diabetes, but the patient was repeatedly euglycemic (Figure 1). Figure 1. Serum glucose levels in a patient with AIDS before and after therapy with the protease inhibitor nelfinavir began. Two weeks after starting nelfinavir therapy, the patient noticed polyuria, blurred vision, oral thrush, dysphagia, and fever. On physical examination, he was thin, weak, and febrile with marked oral thrush. His lung, heart, and abdomen were normal. His leukocyte count was 2200 cells/mm3. The serum glucose level was 657 mg/dL, and the sodium level was 123 mEq/L; results of other laboratory tests were normal. No enzymatic or radiologic evidence showed pancreatitis. All blood cultures were negative, as was the result of an ophthalmoscopic examination for cytomegalovirus. Glucose levels were controlled with neutral protamine Hagedorn insulin (40 U/d), vision improved, and oral thrush responded to fluconazole. In this case, treatment with a protease inhibitor was rapidly followed by new-onset, symptomatic diabetes mellitus. Megestrol acetate [1] was not thought to be responsible because hyperglycemia began with initiation of nelfinavir therapy and continued for 2 months after megestrol acetate therapy had been discontinued. No pancreatitis was present. Before initiation of nelfinavir therapy, the patient was euglycemic; however, a familial predisposition may have played a role. It is estimated that more than 100 000 patients are taking protease inhibitors. The U.S. Food and Drug Administration has received 83 reports of new-onset or worsening diabetes (ranging from mild hyperglycemia to diabetic ketoacidosis) associated with each of the four protease inhibitors used to treat HIV infection [2]. The mechanism by which protease inhibitors cause diabetes is unknown. The proteolytic processing of prohormones within neuroendocrine cells is needed to generate biologically active peptides [3-5]. Three families of proteases, including an aspartate protease, have been localized to the chromaffin granules that process prohormones [3]. Human processing of proinsulin to cleave C-peptide requires serine endopeptidases PC1/PC3 and PC2 [3, 4]. Genetic deficiency of endopeptidases has recently been implicated as a cause of hyperglycemia [4]. In patients who are functionally deficient in these endopeptidases, the mammalian homologue of yeast aspartic protease (YAP3p) may play a more critical role in processing proinsulin and other prohormones [5]; as a result, it may be subject to inhibition by nelfinavir, an aspartic protease, inhibitor. The mechanism of this effect is under further study. Since this case, we have documented new-onset diabetes in two more patients, both of whom developed diabetes while receiving indinavir.

Factors associated with the use of highly active antiretroviral therapy in patients newly entering care in an Urban clinic

Ethnic minority, female, and drug-using patients may be less likely to receive highly active antiretroviral therapy (HAART), despite its proven benefits. We reviewed the medical records of a consecutive population of 354 patients entering care in 1998 at the Thomas Street Clinic, an academically affiliated, public, HIV-specialty clinic in Houston, to determine the factors associated with not receiving HAART as recorded in pharmacy records. Ninety-two patients (26.0%) did not receive HAART during at least 6 months of follow-up. Patients who did not receive HAART were more likely to be women and to have missed more than two physician appointments and were less likely to have a CD4 count <200 cells/microL or a viral load > or = 10 copies/mL. In multivariate logistic analysis, missed appointments (OR = 5.85, p<.0001), female sex (OR = 2.53, =.001), and CD4 count > or = 200 cells/microL (OR = 2.50, p=.001) were independent predictors of not receiving HAART. More than half the patients who never received HAART never returned to the clinic after their first appointment. Among patients new to care, women and those with poor appointment adherence were less likely to receive HAART. Efforts to improve clinic retention and further study of the barriers to HAART use in women are needed.

Body composition and metabolic changes in antiretroviral-naive patients randomized to didanosine and stavudine vs. abacavir and lamivudine.

Comparisons of body composition and metabolic changes among antiretroviral-naive patients randomly assigned to didanosine and stavudine- (ddI + d4T) vs. abacavir and lamivudine- (ABC + 3TC) containing regimens were assessed in a nested substudy of an ongoing multicenter randomized trial. At baseline and every 4 months, body cell mass and total body fat were calculated, anthropometric measurements were performed, and fasting metabolic parameters were obtained. The rates of change (unit/mo) estimated using the slopes of regression lines and overall mean changes from baseline were compared by study assignment. Among 96 patients enrolled, 46 received ddI + d4T- and 50 received ABC + 3TC-containing regimens with a median follow-up of 32.4 months. For both study arms, an overall increase in the rates of change was seen for body cell mass. For ddI + d4T, after an initial increase, the rates of change declined for regional fat and total body fat compared with an increase for ABC + 3TC, with the 2 arms being significantly different (P < 0.05). For high-density lipoprotein cholesterol rates of change, ddI + d4T decreased, while ABC + 3TC increased. For both arms, low-density lipoprotein cholesterol decreased, while triglycerides increased. Early and sustained increases in insulin and insulin resistance were seen only for ddI + d4T. In this prospective study, metabolic and body composition changes varied according to whether subjects received ddI + d4T or ABC + 3TC.

Long-term body composition and metabolic changes in antiretroviral naive persons randomized to protease inhibitor-, nonnucleoside reverse transcriptase inhibitor-, or protease inhibitor plus nonnucleoside reverse transcriptase inhibitor-based strategy

Objective:To assess changes in metabolic parameters and body composition among 422 antiretroviral-naive patients randomized to 3 antiretroviral therapy (ART) strategies: protease inhibitor (PI; n = 141)-, nonnucleoside reverse transcriptase inhibitor (NNRTI; n = 141)-, or PI + NNRTI (n = 140)-based strategies with a median follow-up of 5 years. Methods:At baseline and 1-month (metabolic parameters only) and 4-month follow-up intervals, fat-free mass (FFM) and total body fat were calculated, anthropometric measurements were performed, and fasting metabolic parameters were obtained. Rates of change and mean change were compared. Results:The PI + NNRTI strategy resulted in greater increases in triglycerides and low-density lipoprotein cholesterol compared with the PI and the NNRTI strategies (P < 0.005), with no differences between the PI and NNRTI strategies. High-density lipoprotein cholesterol increased significantly more in the NNRTI strategy than in the PI strategy (P < 0.005). Insulin and insulin resistance increased similarly with all 3 strategies. Changes in total and regional body composition (loss of subcutaneous tissue area and gains in FFM, nonsubcutaneous tissue area, and visceral tissue area) were observed but did not differ by strategy. Conclusions:Long-term follow-up of participants initiating 3 ART strategies demonstrated similar changes in total and regional fat, with no differences by ART strategy. The differential effects on lipid metabolism by strategy and the overall increases in insulin and insulin resistance with all 3 strategies necessitate close monitoring of patients on ART.