Predictors of unstructured antiretroviral treatment interruption and resumption among HIV-positive individuals in Canada.

OBJECTIVES: Sustained optimal use of combination antiretroviral therapy (cART) has been shown to decrease morbidity, mortality and HIV transmission. However, incomplete adherence and treatment interruption (TI) remain challenges to the full realization of the promise of cART. We estimated trends and predictors of treatment interruption and resumption among individuals in the Canadian Observational Cohort (CANOC) collaboration. METHODS: cART-naïve individuals ≥ 18 years of age who initiated cART between 2000 and 2011 were included in the study. We defined TIs as ≥ 90 consecutive days off cART. We used descriptive analyses to study TI trends over time and Cox regression to identify factors predicting time to first TI and time to treatment resumption after a first TI. RESULTS: A total of 7633 participants were eligible for inclusion in the study, of whom 1860 (24.5%) experienced a TI. The prevalence of TI in the first calendar year of cART decreased by half over the study period. Our analyses highlighted a higher risk of TI among women [adjusted hazard ratio (aHR) 1.59; 95% confidence interval (CI) 1.33-1.92], younger individuals (aHR 1.27; 95% CI 1.15-1.37 per decade increase), earlier treatment initiators (CD4 count ≥ 350 vs. <200 cells/µL: aHR 1.46; 95% CI 1.17-1.81), Aboriginal participants (aHR 1.67; 95% CI 1.27-2.20), injecting drug users (aHR 1.43; 95% CI 1.09-1.89) and users of zidovudine vs. tenofovir in the initial cART regimen (aHR 2.47; 95% CI 1.92-3.20). Conversely, factors predicting treatment resumption were male sex, older age, and a CD4 cell count <200 cells/µL at cART initiation. CONCLUSIONS: Despite significant improvements in cART since its advent, our results demonstrate that TIs remain relatively prevalent. Strategies to support continuous HIV treatment are needed to maximize the benefits of cART.

Low urine pH is associated with reduced indinavir crystalluria in indinavir-treated HIV-infected individuals.

Indinavir is a potent HIV-1 protease inhibitor included in current antiretroviral therapeutic regimens. It is associated with renal and urological complications ascribed to indinavir crystalluria. We have previously reported that indinavir crystalluria is frequently observed soon after initiation of therapy. In a cohort of 54 asymptomatic indinavir-naive HIV-1-infected individuals during their first year of treatment with indinavir, approximately 25% of urinalyses (U/A) contained indinavir crystals. Because the determinants of the crystalluria are unknown, we examined the relationship between urine specific gravity (SG) and pH, singly and in combination, and indinavir crystalluria in these subjects. A total of 579 U/A were obtained from the study subjects at their scheduled monthly outpatient medical assessments. The frequency of indinavir crystalluria was lower in U/A with lower pH, irrespective of the SG. Conversely, U/A with high pH (> or = 6.0) had a higher frequency of indinavir crystalluria, which was further influenced by the urine SG. As a result, nearly half of the U/A (46.7%) with high pH (> or = 6.0) and intermediate-high SG (> or = 1.015) contained indinavir crystals. In conclusion, the frequency of indinavir crystalluria in asymptomatic HIV-1 infected individuals during their first year of treatment with indinavir was markedly influenced by the urine pH and SG. Our findings suggest that low urine pH may have a protective effect against indinavir crystalluria across the entire range of urine SG.

Selection of molecular descriptors with artificial intelligence for the understanding of HIV-1 protease peptidomimetic inhibitors-activity.

Quantitative Structure Activity Relationship (QSAR) techniques are used routinely by computational chemists in drug discovery and development to analyze datasets of compounds. Quantitative numerical methods like Partial Least Squares (PLS) and Artificial Neural Networks (ANN) have been used on QSAR to establish correlations between molecular properties and bioactivity. However, ANN may be advantageous over PLS because it considers the interrelations of the modeled variables. This study focused on the HIV-1 Protease (HIV-1 Pr) inhibitors belonging to the peptidomimetic class of compounds. The main objective was to select molecular descriptors with the best predictive value for antiviral potency (Ki). PLS and ANN were used to predict Ki activity of HIV-1 Pr inhibitors and the results were compared. To address the issue of dimensionality reduction, Genetic Algorithms (GA) were used for variable selection and their performance was compared against that of ANN. Finally, the structure of the optimum ANN achieving the highest Pearson's-R coefficient was determined. On the basis of Pearson's-R, PLS and ANN were compared to determine which exhibits maximum performance. Training and validation of models was performed on 15 random split sets of the master dataset consisted of 231 compounds. For each compound 192 molecular descriptors were considered. The molecular structure and constant of inhibition (Ki) were selected from the NIAID database. Study findings suggested that non-covalent interactions such as hydrophobicity, shape and hydrogen bonding describe well the antiviral activity of the HIV-1 Pr compounds. The significance of lipophilicity and relationship to HIV-1 associated hyperlipidemia and lipodystrophy syndrome warrant further investigation.

A phase I study of letrazuril in AIDS-related cryptosporidiosis.

OBJECTIVE: The intestinal parasite Cryptosporidium is a common cause of chronic diarrhoea in AIDS patients and is responsible for significant morbidity and mortality. No effective treatment is currently available for this condition. Here we aim to determine the safety, tolerance, and clinical effect of letrazuril in the treatment of AIDS-related Cryptosporidiosis. DESIGN: A prospective, open-label study of letrazuril was performed. SETTING: The study was conducted at the Immune Deficiency Treatment Centre (IDTC) of Montreal General Hospital, a tertiary-care centre with inpatient and outpatient facilities. PARTICIPANTS: All HIV-positive patients presenting to the IDTC between November 1991 and January 1993 who had symptomatic intestinal Cryptosporidiosis were enrolled in this protocol. Sixteen participants entered the study and 15 were available for evaluation, having completed at least 2 weeks on the study medication. INTERVENTIONS: Patients received letrazuril daily in escalating doses of 50 to 100 mg orally for 6 weeks. Clinical and laboratory evaluations were performed weekly during the treatment phase, with a follow-up evaluation 4 weeks after the end of this phase, for a total study period of 10 weeks. MAIN OUTCOME MEASURES: Response to letrazuril was assessed by eradication of Cryptosporidial oocysts from the stool and symptomatic improvement in diarrhoea and abdominal pain. Haematological, biochemical, and electrocardiographic parameters were also studied to evaluate potential toxicities of the treatment. RESULTS: Fourteen evaluable patients had baseline CD4 lymphocyte counts ranging from 3 to 99 x 10(6)/l cells (mean, 30 x 10(6)/l cells). (The fifteenth evaluable patient had a CD4 count 235 x 10(6)/l.) Of these 14 patients, five showed a major response (symptomatic improvement and eradication of Cryptosporidial oocysts from the stool), two had a minor response (symptomatic improvement with persistence of oocysts in stool), and seven had no response to therapy with letrazuril. Seven patients developed a transient drug-related rash. CONCLUSION: Fifty per cent of the AIDS patients in this study experienced an improvement in their Cryptosporidial disease while receiving letrazuril. No serious dose-related toxicities were observed. Larger Phase II trials are needed to evaluate the safety and efficacy of letrazuril in AIDS-associated intestinal Cryptosporidiosis.

HIV-specific cytotoxic T-lymphocyte activity in immunologically normal HIV-infected persons.

BACKGROUND: CD8+ T-cell counts usually increase soon after infection with HIV, whereas CD4+ cell counts decrease. The result of these changes in T-cell subpopulation subsets in most HIV-infected subjects is inversion of the CD4 : CD8 ratio from greater than 1.0 typical of uninfected persons to less than 1.0 after infection. SUBJECTS: Six HIV-infected individuals were identified in whom the CD4 : CD8 ratio remained normal throughout follow-up (4.0-11.25 years). They all maintained levels of CD4+ cells above 500 x 10(6)/l and had never received antiretroviral therapy. Because HIV-specific cytotoxic T lymphocytes (CTL) have been implicated in control of HIV during the asymptomatic phase of disease, we screened these individuals for the presence of HIV-specific CTL activity. METHODS: CTL activity was assessed in freshly isolated peripheral blood mononuclear cells (PBMC) and in phytohaemagglutinin-stimulated interleukin-2 expanded cell lines established from PBMC. Cytotoxicity to HIV-1 env, gag, pol and nef gene products was surveyed in a 4 h 51Cr-release assay using autologous Epstein-Barr virus (EBV) transformed B cells infected with vaccinia constructs expressing each of these HIV genes. The immunodominant CTL epitope and MHC class I antigen restriction specificity of HIV-specific CTL was mapped when present. Plasma viral load was assessed by branched DNA assay. Attempts were made to isolate virus from these individuals by the PBMC coculture assay. RESULTS: None of the six immunologically normal HIV-infected (INHI) subjects exhibited direct HIV-specific CTL activity in their freshly isolated PBMC compared with 16 (47%) out of 34 HIV disease progressors (P = 0.03, chi2 test) and one out of 10 seronegative subjects. Three of the six INHI subjects had detectable memory HIV-specific precursor CTL (pCTL) activity in in vitro-activated T-cell lines compared with 25 (73.5%) out of 34 HIV-1 disease progressors and in none out of 10 seronegative individuals. All three INHI subjects had Gag-specific pCTL, and none had reverse transcriptase-specific pCTL. Plasma HIV viraemia in all six INHI subjects was below the level of detection by branched DNA assay (< 500 copies/ml). Virus could not be isolated from four of these individuals despite multiple attempts to do so by PBMC coculture assays. CONCLUSION: Direct HIV-specific CTL activity mediated by activated circulating PBMC was undetectable in six INHI individuals under conditions where it is frequently observed in HIV disease progressors. Despite the absence of cells activated for killing HIV-infected targets in the circulation of these individuals, they appeared able to control their HIV infection by maintaining normal levels of CD4 and CD8 cells and low viral load.

Activity of the soft gelatin formulation of saquinavir in combination therapy in antiretroviral-naive patients. NV15355 Study Team.

OBJECTIVE: A Phase II, open-label, randomized, parallel-arm, multicentre trial to compare the antiviral activity and safety of two formulations of saquinavir (SQV), soft gelatin (SQV-SGC) and hard gelatin (SQV-HGC) capsules, in combination with two nucleoside reverse transcriptase inhibitors (NRTI), in antiretroviral-naive, HIV-1-infected individuals. PARTICIPANTS: A total of 171 people of > or = 13 years, with plasma HIV-1 RNA levels > or = 5000 copies/ml, who had received no protease inhibitor therapy, < or = 4 weeks NRTI therapy and no antiretroviral treatment within 28 days of screening. Eighty-one people were randomized to the SQV-HGC group and 90 to the SQV-SGC group. A total of 148 patients completed 16 weeks of therapy. INTERVENTION: Therapy for 16 weeks with either SQV-SGC 1200 mg or SQV-HGC 600 mg, both three times a day, in combination with two NRTI. RESULTS: Using an on-treatment analysis, patients taking SQV-SGC had a larger reduction in plasma HIV-1 RNA than those taking SQV-HGC (-2.0 versus -1.6 log10 copies/ml). Eighty per cent of those on SQV-SGC had < 400 copies HIV RNA/ml, compared with 43% in the SQV-HGC group (P = 0.001). A statistically significant difference in the area under the curve (AUC) values between the SQV-SGC and SQV-HGC arms (-1.7 versus -1.5 log10 copies/ml, respectively; P = 0.0054) was observed when withdrawals prior to week 12, major protocol violators and patients with < 75% compliance were excluded from the analysis; however, the difference between the values for the intent-to-treat population was not significant (P = 0.1929). Adverse events (mostly mild) included diarrhoea and nausea. CONCLUSIONS: SQV-SGC was generally well tolerated and gave significantly more potent suppression of plasma HIV-1 RNA in antiretroviral-naive patients than SQVHGC.

N-acetylation among HIV-positive patients and patients with AIDS: when is fast, fast and slow, slow?

BACKGROUND: The discrepancy between genotype and expressed phenotype of the polymorphic N-acetyltransferase (NAT2) has been suggested by separate genotypic and phenotypic studies in populations with human immunodeficiency virus (HIV). Only one study has examined both genotype and phenotype in the same population, and no discrepancies were observed. METHODS: In a cross-sectional study, 105 HIV-positive patients and patients with acquired immunodeficiency syndrome (AIDS) were phenotyped for NAT2 activity with use of caffeine as an in vivo probe; 50 of these patients were also genotyped by restriction mapping and allele-specific amplification. In a longitudinal study, 23 patients were phenotyped at least twice during the 2-year study. RESULTS: The distribution of the NAT2 phenotype among the 105 patients was unimodal and skewed toward slow acetylators as opposed to the bimodal distribution observed in healthy white populations. The genotype distribution was 26:24 slow:fast. There were 18 discrepancies between genotype and phenotype: 12 slow acetylators with fast genotypes and six fast acetylators with slow genotypes. No drug-related effects on NAT2 activity were apparent, but the role of disease progression was evident. Among the slow acetylators whose genotype was fast, the incidence of AIDS was higher (six of 12) than that among the fast acetylators whose genotype was fast (two of 14). Among patients phenotyped more than once (mean time between samples, 10.4 months) changes in phenotype from fast to slow were associated with progression of HIV infection. CONCLUSIONS: Disease progression in HIV infection and AIDS may alter expression of the NAT2 gene. The genotype and the phenotype are not interchangeable measurements. In the HIV population, to know the genotype is useful only if the phenotype is also known and vice versa.

Lack of transmission of HIV through human bites and scratches.

To examine the relative risk of transmission of the human immuno-deficiency virus (HIV) through bites and scratches, we studied 198 health care workers, 30 of whom were traumatized in this fashion while caring for an aggressive AIDS patient. This violent patient frequently bit or scratched others, his mouth had blood and saliva, while his fingernails were at times soiled with semen, feces, and urine. He was HIV antibody and antigen positive. Although HIV was recovered from his peripheral blood lymphocytes, after 2.5 years of serial follow-up, all traumatized personnel were clinically normal, no HIV was cultured from their blood, and all were HIV antibody and P24 antigen negative. We conclude that this viremic AIDS patient, while producing copious amounts of body fluids, failed to infect those caring for him through bites and scratches. The risk of transmission of HIV through this route under similar conditions should be low.

Improvement of HIV-specific immunity in HIV-infected twins treated with highly active antiretroviral therapy, interleukin 2, and syngeneic adoptively transferred cells.

Five HIV-seropositive twins were treated with HAART and given cycles of treatment consisting of adoptive cellular therapy from their HIV-seronegative identical twins followed by a 5-day course of intravenous IL-2. Changes in absolute and percent CD4(+) and CD8(+) cell count were monitored and compared with changes in these parameters occurring in seven age-, sex-, and disease stage-matched HIV-infected patients treated with HAART alone. Increase in the magnitude and breadth of HIV-specific immune responses was monitored in three twin subjects who received multiple treatment cycles. Absolute and percent CD4(+) cell counts rose dramatically and to significantly higher levels in the recipient twins than in control subjects treated with HAART only. The subjects who received multiple cycles of treatment developed new and increased levels of HIV-specific activated and memory cytotoxic T lymphocyte responses, and interferon gamma-secreting effector cells. Treatment consisting of HAART, adoptive cellular therapy, and IL-2 was superior to treatment with HAART alone for improving absolute and percent CD4(+) cell counts and inducing new, or increasing the magnitude of, HIV-specific immune responses in HIV infected patients.

Active immunization of patients with HIV infection: a study of the effect of VaxSyn, a recombinant HIV envelope subunit vaccine, on progression of immunodeficiency.

Infection with the human immunodeficiency virus (HIV) leads to a progressive immunodeficiency characterized by decreasing levels of CD4+ T lymphocytes. VaxSyn, a vaccine based on the recombinant envelope glycoprotein subunit (rgp160) of HIV-1IIIB, was used to immunize HIV-infected patients to determine whether its administration was beneficial with respect to slowing disease progression. A 3-year multicenter, randomized, placebo-controlled, double-blinded, efficacy and safety trial of repeated immunization with VaxSyn was used to evaluate the long-term impact on the progression of immunodeficiency. VaxSyn in alum, or alum alone, was given to 278 HIV-infected asymptomatic individuals with initial CD4 counts of > or =500 cells/mm3. Clinical findings, the CD4 count, and both virological and immunological parameters were followed. No significant differences were observed between the treatment and placebo control groups in rate of CD4 T cell decline, time to initiation of antiretroviral therapy, incidence of opportunistic infections, HIV RNA plasma viremia, HIV viral infectivity as measured by quantitative HIV coculture assay, and death. This study revealed no effect on either clinical or laboratory virological parameters from the administration of VaxSyn.

Prospective study of urinalysis abnormalities in HIV-positive individuals treated with indinavir.

Indinavir is a potent protease inhibitor widely used in combination with reverse-transcriptase inhibitors to treat human immunodeficiency virus (HIV) disease. Individuals treated with indinavir are prone to develop urinary complications, including renal colic, renal calculi, lower urinary tract symptoms, and indinavir crystalluria. Although renal stones secondary to indinavir have been described and characterized, little is known about the onset, frequency, and significance of the crystalluria. To document the longitudinal characteristics of indinavir crystalluria and associated urine abnormalities, 54 asymptomatic indinavir-naive HIV-positive individuals had urinalysis testing initially weekly and then monthly during the first year of indinavir treatment. Six hundred eight urinalyses were performed (11 +/- 2 urinalysis/subject), including 579 microscopy examinations performed by a nephrologist (10 +/- 2 examinations/subject). Baseline urinalysis results were essentially normal. After the start of treatment, indinavir crystalluria was frequently observed (67% of subjects). After the first 2 weeks, indinavir crystalluria remained constant at a frequency of approximately 25% of urine sediments examined at each test point. Other urine abnormalities, principally leukocytes (>/=10/high-power field) and casts, were observed in 39% of subjects. These abnormalities were more severe in five subjects, with concomitant increasing serum creatinine levels in three of them. Additional urine findings include the predominance of low pH (/=1.025 in 66% of urinalyses). In conclusion, abnormal urinalysis results were noted frequently during the first year of treatment with indinavir. The main findings were the high proportion of subjects with crystalluria and the relatively high frequency of crystalluria observed consistently throughout. These findings may occasionally be associated with other urine abnormalities, presumably secondary to indinavir crystalluria.

Effect of splenectomy on slowing human immunodeficiency virus disease progression.

BACKGROUND: Lymphoreticular tissue is the most important site for human immunodeficiency virus (HIV) replication in HIV-infected individuals. OBJECTIVE: To compare the long-term effect of splenectomy on survival and time to development of acquired immunodeficiency syndrome in subjects who had undergone splenectomy with subjects who had not undergone splenectomy. DESIGN: A cohort study with a follow-up of up to 13.4 years. SETTING: Subjects were recruited from a hospital outpatient clinic population and a multicenter study of patients with hemophilia. PARTICIPANTS: Forty-five HIV-infected individuals were observed prospectively for up to 13.4 years (17 had undergone splenectomy and 28 had not undergone splenectomy). Five subjects underwent splenectomy before acquiring HIV infection and 12 underwent splenectomy during the asymptomatic phase of HIV infection. The group who did not undergo splenectomy consisted of HIV-infected individuals who were asymptomatic at study enrollment. MAIN OUTCOME MEASURES: A Cox proportional hazards model was used to test the effects of splenectomy on survival and time to development of acquired immunodeficiency syndrome when adjusting for potential confounders (age, initial CD4+ cell count, and treatment with antiretroviral drugs). Splenectomy was treated as a time-dependent covariate to account for the variation in its timing. RESULTS: During the average follow-up of 8.6 years, 9 (53%) of the 17 subjects who underwent splenectomy and 23 (82%) of the 28 subjects who did not undergo splenectomy died; acquired immunodeficiency syndrome developed in 6 (35%) of the subjects who underwent splenectomy and 23 (82%) of the subjects who did not undergo splenectomy. Splenectomy was associated with a significant reduction of risk of developing acquired immunodeficiency syndrome (adjusted relative risk [RR] <0.4, P<.05), whereas the effect on risk of mortality approached, although it did not reach, significance (adjusted RR approximately 0.5, P approximately .10). CONCLUSION: The absence of a spleen during the asymptomatic phase of HIV infection seems to have a beneficial effect on HIV disease progression.

Symptomatic and health status outcomes in the Canadian randomized MAC treatment trial (CTN010). Canadian HIV Trials Network Protocol 010 Study Group.

Our objective was to compare the effect of 2 regimens for treatment of Mycobacterium avium complex (MAC) bacteraemia in an HIV-positive population on symptoms and health status outcomes using a substudy of an open-label randomized controlled trial. The study was conducted in 24 hospital-based human immunodeficiency virus (HIV) clinics in 16 Canadian cities. Patients had HIV infection and MAC bacteraemia and were given either rifampin 600 mg, ethambutol 15 mg/kg daily, clofazimine 100 mg daily and ciprofloxacin 750 mg twice daily (4-drug arm) or rifabutin 600 mg daily (amended to 300 mg daily in mid-trial), ethambutol 15 mg/kg daily and clarithromycin 1000 mg twice daily (3-drug arm). The primary health status outcome was the change on the 8-item symptom subscale of the Medical Outcome Study (MOS)-HIV Health Survey adapted for MAC. Changes on other MOS-HIV subscales and on the Karnofsky score were also evaluated. Patients on the 3-drug arm had better outcomes on the MOS-HIV symptom subscale at 16 weeks (P=0.06), with statistically significant differences restricted to night sweats and fever and chills (P < 0.001). The proportion of patients improving on the symptom subscale relative to baseline was 55% on the 3-drug arm and 40% on the 4-drug arm. Patients on the 3-drug arm also had better Karnofsky score at 16 weeks (P < 0.001) and better outcomes on the social function, mental health, energy/fatigue, health distress and cognitive function subscales of the MOS-HIV. The 3-drug arm is superior to the 4-drug arm in terms of impact on MAC-associated symptoms, functional status and other aspects of health status.

Neural networks morbidity and mortality modeling during loss of HIV T-cell homeostasis.

Despite the proven clinical benefits of HAART, mortality may still occur; particularly in those with less than 50 CD4+ cells/mL and, in some cases, with a viral burden below detectable plasma levels of HIV-1 RNA. Multiple factors may predict mortality including initial response to therapy, viral factors and host immune parameters. Due to the complexity of this problem, we developed Artificial Intelligence based tools/Neural Network (NN) to optimally evaluate outcomes of therapy and predict morbidity and mortality. To further validate the accuracy of these tools, we challenged their performance with that of Cox regression modeling (RM). Our study population involved 116 HIV+ individuals who consistently maintained CD4+ count < 50 cells/mL for over 6 months. All patients were treated with antiretrovirals. To assess clinical outcomes, we developed a feedforward back-propagation Neural Network. We then compared the performance of this network to a Cox regression model. The Neural Network outscored the Cox regression model in the ROC curve areas: 0.888 vs 0.760 (HIV+ first Seropositivity to AIDS), 0.901 vs 0.758 (HIV+ first Seropositivity to Last Assessment incl. death) and 0.832 vs 0.799 (AIDS to Last Assessment incl. death), for the NN & Cox, respectively. In patients with a history of AIDS defining events and with severe T-Cell depletion, mortality occurs despite therapy. Although Neural Networks and Cox modeling were successful in predicting mortality, the Neural Network was superior in assessing risk in this population.

Markers predicting progression of human immunodeficiency virus-related disease.

Human immunodeficiency virus (HIV) interacts with the immune system throughout the course of infection. For most of the disease process, HIV activates the immune system, and the degree of activation can be assessed by measuring serum levels of molecules such as beta 2-microglobulin and neopterin, as well as other serum and cell surface phenotype markers. The levels of some of these markers correlate with clinical progression of HIV disease, and these markers may be useful as surrogate markers for development of clinical AIDS. Because the likelihood and timing of development of clinical AIDS following seroconversion, for any particular individual, are not readily predictable, the use of nonclinical disease markers has become critically important to patient management. Surrogate markers of HIV infection are, by definition, measurable traits that correlate with disease progression. An ideal marker should identify patients at highest risk of disease progression, provide information on how long an individual has been infected, help in staging HIV disease, predict development of opportunistic infections associated with AIDS, monitor the therapeutic efficacy of immunomodulating or antiviral treatments, and the easily quantifiable, reliable, clinically available, and affordable. This review examines the current state of knowledge and the role of surrogate markers in the natural history and treatment of HIV infection. The clinical usefulness of each marker is assessed with respect to the criteria outlined for the ideal surrogate marker for HIV disease progression.

Effect of splenectomy on T-cell subsets and plasma HIV viral titers in HIV-infected patients.

OBJECTIVE: In previous studies we have shown that removal of the spleen in HIV-infected people during the asymptomatic phase of disease results in slower time to AIDS and may also result in improved survival. In this paper, we examine whether splenectomy affects lymphocyte counts, T-cell subsets, and HIV plasma viremia in a manner that could explain the clinical benefits associated with this intervention. METHODS: 10 HIV-infected patients who underwent splenectomy and 23 HIV-infected controls with idiopathic thrombocytopenia purpura who did not undergo splenectomy were studied. These groups were compared for changes in cell subpopulations and HIV plasma viremia. RESULTS: Splenectomy resulted in increases in absolute lymphocyte numbers with rises in both CD4 and CD8 counts, whereas CD4 and CD8 percentage levels remained unchanged. In controls, absolute and percentage CD4+ T-cell counts declined with time from date of HIV infection. Plasma viremia decreased more than threefold, the limit of biologic variation, after splenectomy in 4 of 9 subjects and in only 1 of 18 controls. The proportion of subjects exhibiting reduced viremia following splenectomy was greater than that in HIV-infected patients that did not undergo splenectomy (chi 2 test, P = .015). CONCLUSIONS: Improved survival and time to AIDS in splenectomized HIV-infected patients is associated with temporary reduction of plasma viremia and increase in absolute CD4 and CD8 counts. These effects could not be attributed to antiretroviral therapy because subjects were either untreated or treated with antiretroviral monotherapy during the observation period. These observations may have importance in the understanding of T-cell dynamics and the potential for splenectomy as an HIV reservoir-debulking procedure.

The use of oral ganciclovir in the treatment of cytomegalovirus retinitis in patients with AIDS.

OBJECTIVE: To recommend the appropriate use of oral ganciclovir as an alternative to intravenous (i.v.) maintenance therapy for cytomegalovirus (CMV) retinitis in patients with AIDS. OPTIONS: i.v. infusion of ganciclovir and foscarnet have been the only approved choices for maintenance therapy until the introduction of oral ganciclovir. OUTCOMES: Ease of administering maintenance therapy and improved quality of life for patients with AIDS. VALUES: The medical advisory group comprised physicians treating patients with AIDS therapy. Ease of administration of maintenance therapy and quality of patients' lives were considered important. BENEFITS, HARMS AND COSTS: Oral ganciclovir is a safe and convenient alternative to i.v. maintenance therapy for patients with CMV retinitis. However, its low bio-availability precludes its use for induction therapy and necessitates careful monitoring for compliance. Compared with i.v. administration of ganciclovir, oral maintenance therapy is cost effective. EVIDENCE: Evidence for the guidelines was gathered from data presented at a symposium on CMV retinitis and oral ganciclovir, clinical trials of oral ganciclovir and input from a visiting expert. It was presented at a meeting of the advisory board whose members are involved in the care of patients with AIDS and the management of CMV retinitis. The guidelines were approved by each member of the advisory board. RECOMMENDATIONS: Diagnosis, treatment and follow-up of CMV retinitis should always be in consultation with an ophthalmologist who is experienced in treating this disease. The patient should be fully informed about the limitations of the oral form of ganciclovir; he or she should be involved in decision making and carefully monitored. Oral ganciclovir should not be used for induction therapy or for maintenance therapy in high-risk patients. VALIDATION: Similar guidelines have been produced in England where the drug has been available since January 1995. SPONSOR: The deliberations of the advisory board and the preparation of this report were funded through an educational grant from Hoffmann-La Roche (Canada).

A density functional study of the hydrogen-bond network within the HIV-1 protease catalytic site cleft.

The relative energy between two different protonation sites of the Asp25' catalytic site residue is computed and analyzed for various HIV-1 Protease/inhibitor complexes and compared to the wild-type structure. By comparing calculations of negatively charged fragments of gradually increasing size up to 105 atoms we show that correct modeling of the HIV-1 Protease active site requires much larger models than the commonly used acetic acid/acetate moieties. The energy difference between the two proposed protonation sites decreases as the size of the system increases and tends to converge only when the entire catalytic triad of both monomers is taken into account. The importance of the Gly27 backbone amine groups in the stabilization of the negative charge within the catalytic site cleft is revealed. Comparison of the wild-type structure with the structures from various Pr/drug complexes indicates that the HIV-1 protease has a particular catalytic site flexibility.

Hepatitis C virus is related to progressive liver disease in human immunodeficiency virus-positive hemophiliacs and should be treated as an opportunistic infection.

The hypothesis was investigated that hepatitis C virus (HCV) infection behaves like an opportunistic infection in which progressive liver disease (PLD) is the principal manifestation. PLD in 81 hemophiliacs coinfected with HCV and human immunodeficiency virus (HIV) was compared with 53 HIV-seronegative HCV-infected hemophiliacs. Progression to AIDS and death in 22 HCV/HIV-coinfected hemophiliacs with PLD was also compared with 59 coinfected hemophiliacs who did not develop PLD. The risk of PLD occurrence associated with an HIV-positive status was 7.4 (95% confidence interval [CI], 2.2-25.5; Cox model). In the coinfected group, the risk of PLD occurrence was higher in subjects with severe AIDS-defining immunodeficiency than in those without (odds ratio, 3. 6; 95% CI, 1.3-10). Persons with PLD also had a faster progression to AIDS (P=.03, log rank test) than those without PLD. Thus, as with other chronic resident human viruses, HCV should be considered another opportunistic pathogen in HIV disease.