Tumour control in ion beam radiotherapy with different ions in the presence of hypoxia: an oxygen enhancement ratio model based on the microdosimetric kinetic model.

Few attempts have been made to include the oxygen enhancement ratio (OER) in treatment planning for ion beam therapy, and systematic studies to evaluate the impact of hypoxia in treatment with the beam of different ion species are sorely needed. The radiobiological models used to quantify the OER in such studies are mainly based on the dose-averaged LET estimates, and do not explicitly distinguish between the ion species and fractionation schemes. In this study, a new type of OER modelling, based on the microdosimetric kinetic model, taking into account the specificity of the different ions, LET spectra, tissues and fractionation schemes, has been developed. The model has been benchmarked with published in vitro data, HSG, V79 and CHO cells in aerobic and hypoxic conditions, for different ion irradiation. The model has been included in the simulation of treatments for a clinical case (brain tumour) using proton, lithium, helium, carbon and oxygen ion beams. A study of the tumour control probability (TCP) as a function of oxygen partial pressure, dose per fraction and primary ion type has been performed. The modelled OER depends on both the LET and ion type, also showing a decrease for an increased dose per fraction with a slope that depends on the LET and ion type, in good agreement with the experimental data. In the investigated clinical case, a significant increase in TCP has been found upon increasing the ion charge. Higher OER variations as a function of dose per fraction have also been found for low-LET ions (up to 15% varying from 2 to 8 Gy(RBE) for protons). This model could be exploited in the identification of treatment condition optimality in the presence of hypoxia, including fractionation and primary particle selection.

Women experience higher rates of adverse events during hepatitis C virus therapy in HIV infection: a meta-analysis.

BACKGROUND: In HIV/ hepatitis C virus (HCV) coinfection, adverse events (AEs) during HCV therapy account for 12%-39% of treatment discontinuations. It is unknown whether sex influences complications. METHODS: Meta-analysis to study the effect of sex and other predictors of AEs in 3 randomized trials, ACTG 5071, APRICOT, and ANRSHCO2-RIBAVIC of Interferon (IFN) and Pegylated IFN (PEG), both with and without Ribavirin, in HIV/HCV coinfection. Primary endpoints were AEs requiring treatment discontinuation (AETD) or first dose modification (AEDM). Multi-covariate stratified logistic regression was used to study predictors and assess interactions with sex. RESULTS: Twenty-one percent of 1376 subjects were women; 61% had undetectable HIV RNA; 14% were antiretroviral (ARV) therapy naive at entry; median CD4 was 485 cells per cubicmillimeter. Seventeen percent had an AETD and 50% AEDM; women had more AETD than men (24% vs. 16% P = 0.003) and AEDM (61% vs. 48% P < 0.0001). AETD and AEDM occurred earlier in women; but the types of AETD and AEDM were similar between sexes. Seventy-four percent of AETDs and 49% of AEDMs involved constitutional AEs; 18% of AETD depression; and 26% of AEDM neutropenia. We identified interactions with sex and body mass index (BMI) (P = 0.04, continuous) and nonnucleoside reverse transcriptase inhibitor (P = 0.03); more AETDs were seen in men with lower BMI (P = 0.01) and in women on nonnucleoside reverse transcriptase inhibitors (P = 0.009). More AEDMs were seen with PEG [odds ratio (OR) = 2.07]; older age (OR = 1.48 per 10 years); decreasing BMI (OR = 1.04 per kg/m); HCV genotype 1, 4 (OR = 1.31); Ishak 5, 6 (OR = 1.42); decreasing Hgb (OR = 1.23 per g/dL); and decreasing absolute neutrophil count (1.04 per 500 cells/mm). Interactions between sex and ARV-naive status (P = 0.001) and zidovudine (P = 0.001) were identified: There were more AEDMs in ARV-naive women (P = 0.06) and ARV-experienced men (P = 0.001) and higher AEDMs in women with zidovudine (P = 0.0002). CONCLUSIONS: Although there was no difference in type of AE, AETD and AEDM were more frequent and occurred earlier in women. In women, ARV regimen may be an important predictor of AETDs during HCV therapy and should be explored as a predictor of AEs in HIV/HCV coinfection trials.

Degree of viral decline early in treatment predicts sustained virological response in HCV-HIV coinfected patients treated with peginterferon alfa-2a and ribavirin.

BACKGROUND: In hepatitis C virus (HCV) monoinfection, the on-treatment virological response at Weeks 4 and 12 is a strong predictor of treatment outcomes. METHODS: In a retrospective analysis, we examined these responses in 289 HIV-HCV coinfected patients treated with Peg-IFN alfa-2a /ribavirin for 48 weeks in a large randomized, multinational trial (APRICOT). RESULTS: Overall, 21% of patients achieved a rapid virological response at Week 4 and, of these, 88% achieved a sustained virological response. An early virological response at Week 12 was achieved in 71% of patients, and 56% of these patients achieved a sustained virological response. These results are similar to the sustained virological response rates obtained in monoinfected patients who achieve a rapid or early virological response. Patients who did not achieve a rapid virological response but who had unquantifiable HCV RNA or > 3 log10 drop over baseline also had high sustained virological response rates. A total of 46% of patients achieved undetectable HCV RNA (<50 IU/mL) at Week 12. Multiple logistic regression analysis showed that infection with HCV genotype 2/3, low baseline HCV RNA level, and lower age predicted rapid virological response. Infection with HCV genotype 2/3 and low baseline HCV RNA level predicted early virological response. CONCLUSION: A rapid virological response is the best predictor of a sustained virological response, and lack of an early virological response is the best predictor of no sustained virological response. Such results are consistent with findings in HCV monoinfected patients.

Pharmacodynamics of peginterferon alpha-2a and peginterferon alpha-2b in interferon-naïve patients with chronic hepatitis C: a randomized, controlled study.

BACKGROUND: Peginterferon alpha-2a and alpha-2b, the two commercially available pegylated interferons, have different pharmacokinetic properties that produce differing abilities to suppress replication of the hepatitis C virus. AIM: To compare the pharmacodynamics of peginterferon alpha-2a and peginterferon alpha-2b in interferon-naive patients with chronic hepatitis C. METHODS: Patients were randomized to receive peginterferon alpha-2a, 180 microg (n = 10) or peginterferon alpha-2b 1.0 microg/kg (n = 12) once weekly. The enzymatic activity of 2'5'-oligoadenylate synthetase and levels of neopterin and beta(2)-microglobulin were measured at baseline and at 24, 48, 120 and 168 h. RESULTS: Oligoadenylate synthetase activity and serum neopterin and beta(2)-microglobulin concentrations did not differ significantly between the two patient groups at any time point, nor was there a significant correlation between the serum area under the concentration-time curve of either peginterferon and the area under the concentration-time curve for 2',5'-oligoadenylate synthetase, neopterin and beta(2)-microglobulin. The area under the concentration-time curves calculated for these three markers did not correlate with body mass index stratified at <25 and >or=25 kg/m(2) for either peginterferon. CONCLUSIONS: Despite pharmacokinetic differences between peginterferon alpha-2a and peginterferon alpha-2b, the pharmacodynamic profiles of the two formulations appear to be comparable.

Occult hepatitis B virus infection in the setting of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection: clinically relevant or a diagnostic problem?

The clinical relevance of occult hepatitis B virus (HBV) infection, defined as detectable HBV DNA serum/liver, in the absence of hepatitis B surface antigen (HBsAg), is unclear. We determined the prevalence of serum occult HBV infection in HIV/HCV co-infected patients enrolled in APRICOT, a randomized multinational trial that investigated the efficacy and safety of peginterferon alfa-2a (40 kDa) plus ribavirin for treatment of HCV. We also examined the effect of prior HBV exposure to liver histology at baseline. Only HBsAg-negative patients were eligible. At screening, serum HBV DNA was assessed by commercial assay (detection limit = 200 copies/mL). Patients were divided into four serological groups: anti-HBs+/anti-HBc+; anti-HBs-/anti-HBc+; anti-HBs+/ anti-HBc-; anti-HBs-/anti-HBc-. Baseline liver biopsy grade and stage were compared among groups. Serum HBV DNA was undetectable in all patients, (n = 866). Results of anti-HBs and anti-HBc was available for 176 patients: 60 (34.1%) anti-HBs+/anti-HBc+; 60 (34.1%) anti-HBs-/anti-HBc+; 11 (6.3%) anti-HBs+/anti-HBc-; 45 (25.6%) anti-HBs-/anti-HBc-. There were no differences among the groups in the histological grade or stage at baseline liver biopsies. Occult HBV infection in serum was not detected in this large immunocompetent cohort. Moreover, prior exposure to HBV did not appear to have any affect on baseline liver histology.

Effect of ribavirin on intracellular and plasma pharmacokinetics of nucleoside reverse transcriptase inhibitors in patients with human immunodeficiency virus-hepatitis C virus coinfection: results of a randomized clinical study.

The intracellular triphosphorylation and plasma pharmacokinetics of lamivudine (3TC), stavudine (d4T), and zidovudine (ZDV) were assessed in a pharmacokinetic substudy, in 56 human immunodeficiency virus-hepatitis C virus (HIV-HCV) coinfected patients receiving peginterferon alfa-2a (40KD) 180 microg/week plus either placebo or ribavirin (RBV) 800 mg/day in the AIDS PEGASYS Ribavirin International Coinfection Trial. There were no significant differences between patients treated with RBV and placebo in plasma pharmacokinetics parameters for the nucleoside reverse transcriptase inhibitors (NRTIs) at steady state (weeks 8 to 12): ratios of least squares mean of area under the plasma concentration-time curve (AUC(0-12 h)) were 1.17 (95% confidence interval, 0.91 to 1.51) for 3TC, 1.44 (95% confidence interval, 0.58 to 3.60) for d4T and 0.85 (95% confidence interval, 0.50 to 1.45) for ZDV, and ratios of least squares mean plasma C(max) were 1.33 (95% confidence interval, 0.99 to 1.78), 1.06 (95% confidence interval, 0.68 to 1.65), and 0.84 (95% confidence interval, 0.46 to 1.53), respectively. Concentrations of NRTI triphosphate (TP) metabolites in relation to those of the triphosphates of endogenous deoxythymidine-triphosphate (dTTP) and deoxcytidine-triphosphate (dCTP) were similar in the RBV and placebo groups. Differences (RBV to placebo) in least squares mean ratios of AUC(0-12 h) at steady state were 0.274 (95% confidence interval, -0.37 to 0.91) for 3TC-TP:dCTP, 0.009 (95% confidence interval, -0.06 to 0.08) for d4T-TP:dTTP, and -0.081 (95% confidence interval, -0.40 to 0.24) for ZDV-TP:dTTP. RBV did not adversely affect HIV-1 replication. In summary, RBV 800 mg/day administered in combination with peginterferon alfa-2a (40KD) does not significantly affect the intracellular phosphorylation or plasma pharmacokinetics of 3TC, d4T, and ZDV in HIV-HCV-coinfected patients.

The safety of discontinuation of maintenance therapy for cytomegalovirus (CMV) retinitis and incidence of immune recovery uveitis following potent antiretroviral therapy.

BACKGROUND: Reconstitution of immune function during potent antiretroviral therapy can prompt discontinuation of maintenance cytomegalovirus (CMV) therapy but has also been associated with sight-threatening inflammatory conditions including immune recovery uveitis (IRU). METHOD: Patients with inactive CMV retinitis and a CD4+ cell count above 100/mm3, receiving CMV therapy and stable combination antiretroviral therapy, were assigned to one of two groups based on willingness to discontinue CMV therapy. RESULTS: Thirty-eight participants were enrolled: 28 discontinued anti-CMV therapy (Group 1) and 10 continued CMV treatment (Group 2). Median on-study follow-up was 16 months. One Group 1 participant who experienced an increase in plasma HIV viral load and a decline in CD4+ cell count developed confirmed progression of CMV retinitis. Progression or reactivation CMV retinitis was not observed among Group 2. IRU was present at study entry in 3 participants. Six participants in Group 1 and 3 participants in Group 2 developed IRU on-study. CMV viremia was not detected in any participants, and urinary shedding of CMV was intermittent. CONCLUSION: Recurrence of CMV retinitis following discontinuation of anti-CMV therapy among patients with antiretroviral-induced increases in CD4+ cell count was rare. However, IRU was common in both those who maintained and discontinued anti-CMV therapy.

A prospective study of discontinuing primary and secondary Pneumocystis carinii pneumonia prophylaxis after CD4 cell count increase to > 200 x 106 /l.

OBJECTIVE: To assess the incidence of Pneumocystis carinii pneumonia (PCP) after discontinuation of either primary or secondary prophylaxis. DESIGN: This was a prospective, non-randomized, non-blinded study. SETTING: Twenty-five University-based AIDS Clinical Trials Group units. PARTICIPANTS: Participants either had a CD4 cell count < or = 100 x 106/l at any time in the past and no history of confirmed PCP (group I; n = 144), or had a confirmed episode of PCP > or = 6 months prior to study entry (group II; n = 129). All subjects had sustained CD4 cell counts > 200 x 106/l in response to antiretroviral therapy. INTERVENTIONS: Subjects discontinued PCP prophylaxis within 3 months or at the time of study entry. Evaluations for symptoms of PCP and CD4 cell counts were performed every 8 weeks. Prophylaxis was resumed if two consecutive CD4 cell counts were < 200 x 106/l. MAIN OUTCOME MEASURE(S): The main outcome was development of PCP. RESULTS: No cases of PCP occurred in 144 subjects (median follow-up, 82 weeks) in group I or in the 129 subjects (median follow-up, 63 weeks) in group II (95% upper confidence limits on the rates of 1.3 per 100 person-years and 1.96 per 100 person-years for groups I and II, respectively). Eight subjects (five in group I and three in group II) resumed PCP prophylaxis after two consecutive CD4 cell counts < 200 x 106/l. CONCLUSIONS: The risk of developing initial or recurrent PCP after discontinuing prophylaxis is low in HIV-infected individuals who have sustained CD4 cell count increases in response to antiretroviral therapy. Neither lifelong primary nor secondary PCP prophylaxis is necessary.

Cytomegalovirus (CMV)-specific CD4+ T lymphocyte immune function in long-term survivors of AIDS-related CMV end-organ disease who are receiving potent antiretroviral therapy.

To better understand the relation of cytomegalovirus (CMV)-specific CD4+ T lymphocyte immunity and clinical outcome in AIDS-related CMV end-organ disease, 2 patient groups were prospectively studied: patients recently diagnosed with active CMV end-organ disease and survivors of CMV retinitis who had responded to highly active antiretroviral therapy and had quiescent retinitis when anti-CMV therapy was discontinued. Most patients with active CMV disease had negative CMV-specific CD4+ T lymphocyte responses at diagnosis, as measured by lymphoproliferation (7/7) or cytokine flow cytometry (3/5) assays. In contrast, all 10 subjects with quiescent retinitis and >150 absolute CD4+ T lymphocytes/microL whose anti-CMV therapy was discontinued during 6 months of follow-up had positive CMV-specific immune responses at least once by each assay. However, 6 of these 10 subjects also had negative CMV-specific immune responses > or =1 time. Such patients may be at risk for future CMV disease progression and should be closely monitored.

Immune recovery vitritis and uveitis in AIDS: clinical predictors, sequelae, and treatment outcomes.

PURPOSE: To determine 1) clinical predictors of an inflammatory syndrome associated with cytomegalovirus (CMV) retinitis (immune recovery vitritis or uveitis [IRV or IRU]); 2) clinical sequelae of IRV; and 3) the effect of corticosteroid treatment on visual acuity. METHODS: A cohort study from the AIDS Ocular Research Unit of the University of California, San Diego, and a case series from the Cleveland Clinic consisted of patients who had acquired immunodeficiency syndrome and inactive CMV retinitis who responded to highly active antiretroviral therapy (HAART) with CD4 T-lymphocyte levels >60 cells/mm3. The cohort was followed for a median of 13.5 months following increase in CD4 count. The authors studied the occurrence of IRV, defined as symptomatic (vision decrease and/or floaters) vitritis of 1+ or greater severity associated with inactive CMV retinitis. Macular edema or epiretinal membrane formation was determined by clinical examination and fluorescein angiography. Five eyes were treated with sub-Tenon corticosteroid injections. RESULTS: In the cohort study, 19 (63%) of 30 HAART responders developed IRV (26 eyes). The clinical spectrum of inflammation included vitritis, papillitis, macular edema, and epiretinal membranes. Eyes with CMV surface area >30% of the retina were at the highest risk (relative risk = 4.5) of developing IRV (P = 0.03). During follow-up, inflammation persisted without treatment for a median of 20 weeks and 14 patients (16 eyes) developed macular changes. Treatment resulted in vision improvement without reactivation of retinitis. Histology and immunohistochemistry of associated epiretinal membranes showed evidence of chronic inflammation with a predominant T-lymphocyte cell population. In the case series, 3 (38%) of 8 HAART responders developed IRV (4 eyes). All four eyes were treated and resulted in visual acuity improvement of one line. CONCLUSIONS: Symptomatic IRV or IRU develops in a significant number of patients with CMV retinitis following successful HAART. Eyes with CMV surface area >30% of the retina are at the greatest risk. Eyes with IRV respond favorably to antiinflammatory therapy without reactivation of retinitis. Immune recovery vitritis may be the result of an immunologic reaction to latent CMV antigens in the eye in which T-lymphocytes play a role.

Serum interleukin-6 (IL-6), IL-10, tumor necrosis factor (TNF) alpha, soluble type II TNF receptor, and transforming growth factor beta levels in human immunodeficiency virus type 1-infected individuals with Mycobacterium avium complex disease.

To characterize changes in serum cytokine levels in human immunodeficiency virus type 1 (HIV-1)-infected persons with Mycobacterium avium complex (MAC) bacteremia, the levels of IL-1alpha (interleukin-1alpha), IL-6, IL-10, tumor necrosis factor alpha (TNF-alpha), soluble type II TNF receptor (sTNF-RII), and transforming growth factor beta (TGF-beta) in serum were measured in two cohorts of HIV-1-infected persons with MAC bacteremia. The first cohort was part of a MAC prophylaxis study. Patients with bacteremia were matched with controls without bacteremia. Elevated IL-6, IL-10, TNF-alpha, sTNF-RII, and TGF-beta levels were noted at baseline for all subjects, a result consistent with advanced HIV-1 disease. IL-1alpha was not detected. No differences in cytokine levels in serum were noted at baseline and at the time of bacteremia between patients with MAC and controls. In the second cohort, subjects had serum samples collected at the time of MAC bacteremia and thereafter while on macrolide therapy. Serum samples at time of bacteremia were collected from HIV-1-infected persons at a time when neither highly active antiretroviral therapy (HAART) nor MAC prophylaxis was used routinely. MAC treatment resulted in decreased levels of IL-6 and TNF-alpha in serum, which were evident for IL-6 by 4 to 6 weeks and for TNF-alpha by 8 to 16 weeks. Thus, antibiotic treatment for MAC results in decreased levels of IL-6 and TNF-alpha in serum in HIV-1-infected persons who are not on HAART.

Effect of potent antiretroviral therapy on immune responses to Mycobacterium avium in human immunodeficiency virus-infected subjects.

To characterize the influence of highly active antiretroviral therapy (HAART) on cell-mediated immunity (CMI) to Mycobacterium avium complex (MAC), we measured immune responses to M. avium in human immunodeficiency virus (HIV)-infected individuals before and during HAART, in subjects with a history of disseminated MAC (DMAC), and in HIV-uninfected control subjects. Forty-seven percent of untreated HIV-infected patients and 78% of control subjects exhibited in vitro proliferative responses to M. avium (P=.03). Proliferative responses to M. avium increased after HAART for 3 months and were present in 77% of subjects after 6 months. Mean interferon-gamma production increased from 199 to 1156 pg/mL after HAART (P=.06). Proliferative responses to M. avium occurred in 76% of DMAC subjects receiving HAART. CD4 and CD8 but not gammadelta T cells expanded in response to M. avium. CMI to M. avium reconstitutes rapidly after HAART and appears sustained even with partial viral suppression.

Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group.

Dyslipidemia is a prevalent condition that affects patients infected with human immunodeficiency virus (HIV) who are receiving antiretroviral therapy. These preliminary recommendations summarize the current understanding in this area and propose guidelines for management. Existing guidelines for the management of dyslipidemia in the general population formed the general basis for our recommendations. Data on the prevalence and treatment of dyslipidemia of HIV-infected patients, implications of treatment-related dyslipidemia in other chronically ill populations, and pharmacokinetic profiles for the available hypolipidemic agents in non-HIV populations were considered. Although the implications of dyslipidemia in this population are not fully known, the frequency, type, and magnitude of lipid alterations in HIV-infected people are expected to result in increased cardiovascular morbidity. We propose that these patients undergo evaluation and treatment on the basis of existing guidelines for dyslipidemia, with the caveat that avoidance of interactions with antiretroviral agents is paramount.

Highly active antiretroviral therapy-related immune recovery in AIDS patients with cytomegalovirus retinitis.

OBJECTIVE: To characterize cytomegalovirus (CMV) retinitis in human immunodeficiency virus (HIV)-infected patients who demonstrate immune recovery while receiving highly active antiretroviral therapy (HAART). DESIGN: Consecutive, noncomparative case series. PARTICIPANTS: Twenty-two HIV-positive patients, from two institutions, with a history of CMV retinitis, and with elevated CD4 cell counts after HAART. MAIN OUTCOME MEASURES: Duration of healed CMV retinitis without anti-CMV therapy, CD4 cell count, and HIV viral load. INTERVENTION: Discontinuation of anti-CMV therapy after persistent elevation of CD4 cell count over 50 cell/mm3 (median, 161/mm3; range, 85-408/mm3). RESULTS: The median period of healed CMV retinitis without anti-CMV therapy was 72 weeks (range, 33-116 weeks). Nineteen of 22 patients were still healed without anti-CMV therapy at study end. The three patients with CMV retinitis progression simultaneously had HAART, fail with CD4 cell counts of 37, 35, and 47/mm3. CONCLUSIONS: HIV-positive patients with CMV retinitis, who demonstrate a sustained HAART-induced elevation of CD4 cell count on two consecutive counts 3 months apart and whose retinitis remains healed on anti-CMV therapy for greater than 4 months, are likely to remain healed if the anti-CMV therapy is withdrawn. It is important to monitor these patients with indirect ophthalmoscopy because HAART failure may occur and allow CMV retinitis reactivation.

CMV retinitis recurs after stopping treatment in virological and immunological failures of potent antiretroviral therapy.

OBJECTIVES: To determine predictors of clinical relapse of cytomegalovirus (CMV) end-organ disease in a cohort of 17 HIV-infected patients with healed and treated CMV retinitis (CMVR) who responded to HAART with an increase in CD4 cell counts to above 70 cells/mm3 and discontinued CMV maintenance therapy (MT). DESIGN: Seventeen patients were monitored for reactivation of retinitis. The CD4 cell counts, HIV RNA and peripheral blood mononuclear cell (PBMC) lymphoproliferative assays to CMV at 3 month intervals were compared between patients with and without reactivation of CMVR. Positive lymphoproliferative responses were defined as a stimulation index of 3 or greater. RESULTS: Five out of 17 (29%) patients experienced a recurrence of CMVR a mean of 14.5 months after stopping CMV MT and between 8 days and 10 months after CD4 cell counts fell below 50 cells/mm3. Median CD4 cell counts and plasma HIV RNA at reactivation were 37 cells/mm3 and 5.3 log10 copies/ml. Three patients recurred at a previously active site of the retina, one had contralateral CMVR, and one a recurrence of retinitis and pancreatitis simultaneously. Mean lymphoproliferative responses to CMV were 2.4 in patients with reactivation versus 21.0 stimulation index (SI) in patients without reactivation (P= 0.01). A model incorporating four variables (CD4 cell counts and HIV RNA at maintenance discontinuation, highest CD4 cell count, nadir HIV RNA and median lymphoproliferative responses) identified correctly 88% of patients with and without reactivation. CONCLUSION: CMV disease recurs after virological and immunological failure of HAART if CD4 cell counts drop below 50. In this situation, anti-CMV agents should be resumed before clinical reactivation ensues, because of the risk of contralateral retinal involvement and systemic disease.

Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy.

This study was conducted to determine the likelihood of the development of a new ocular inflammatory syndrome (immune recovery vitritis, IRV), which causes vision loss in AIDS patients with cytomegalovirus (CMV) retinitis, who respond to highly active antiretroviral therapy (HAART). We followed 30 HAART-responders with CD4 cell counts of >/=60 cells/mm3. Patients were diagnosed with IRV if they developed symptomatic vitritis of >/=1+ severity associated with inactive CMV retinitis. Symptomatic IRV developed in 19 (63%) of 30 patients and in 26 (59%) of 44 eyes over a median follow-up from HAART response of 13.5 months. The annual incidence of IRV was 83/100 person-years. Excluding patients with previous cidofovir therapy did not significantly alter the time course of IRV (P=.79). These data suggest that IRV develops in a significant number of HAART-responders with CMV retinitis and is unrelated to previous cidofovir therapy.

Successful short-term suppression of clarithromycin-resistant Mycobacterium avium complex bacteremia in AIDS. California Collaborative Treatment Group.

During a randomized study of clarithromycin plus clofazimine with or without ethambutol in patients with AIDS and Mycobacterium avium complex (MAC) bacteremia, eight participants received additional antimycobacterial drugs following the detection of a clarithromycin-resistant isolate (MIC, > 8 micrograms/mL). A macrolide (seven received clarithromycin, one azithromycin) and clofazimine were continued; additional treatment included various combinations of ethambutol, ciprofloxacin, amikacin, and rifabutin. After the detection of a resistant isolate and before receipt of additional antimycobacterials, the median peak MAC colony count in blood was 105 cfu/mL (range, 8-81,500 cfu/mL). After additional antimycobacterials, the median nadir MAC colony count was 5 cfu/mL (range, 0-110 cfu/mL). Five (63%) of eight patients had a > or = 1 log10 decrease, including two who achieved negative blood cultures; all of these responses occurred in patients originally assigned to clarithromycin plus clofazimine. Treatment of clarithromycin-resistant MAC bacteremia that emerges during clarithromycin-based treatment can decrease levels of bacteremia and transiently sterilize blood cultures.

Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS.

We compared the efficacy of a 400-mg once-weekly dosage versus a 200-mg daily dosage of fluconazole for the prevention of deep fungal infections in a multicenter, randomized, double-blind trial of 636 human immunodeficiency virus-infected patients to determine if a less intensive fluconazole regimen could prevent these serious but relatively infrequent complications of AIDS. In the intent-to-treat analysis, a deep fungal infection developed in 17 subjects (5.5%) randomly assigned to daily fluconazole treatment and in 24 (7.7%) given weekly fluconazole during 74 weeks of follow-up (risk difference, 2.2%; 95% confidence interval [CI], -1.7% to 6.1%). Thrush occurred twice as frequently in the weekly versus daily fluconazole recipients (hazard ratio, 0.59; 95% CI, 0.40-0.89), and in a subset of patients evaluated, fluconazole resistance was infrequent. Fluconazole administered once weekly is effective in reducing deep fungal infections in patients with AIDS, but this dosage is less effective than the 200-mg-daily dosage in preventing thrush.

Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy.

The suppression of human immunodeficiency virus (HIV) replication and elevation in CD4 cells observed with protease inhibitor combination regimens known as HAART (highly active antiretroviral therapy) may allow AIDS patients to undergo an immune recovery that allows them to suppress the progression of cytomegalovirus (CMV) retinitis. Eleven AIDS patients receiving HAART with healed CMV retinitis in whom CMV-specific maintenance therapy was discontinued were studied. Median CD4 cell counts were 42 before the initiation of HAART and 183 at discontinuation of anti-CMV therapy. While a median 1.1 log10 drop in plasma HIV-1 RNA was obtained between starting HAART and withdrawal of maintenance therapy for CMV, only 3 of 11 patients maintained plasma HIV RNA below the limits of detection. Reactivation of CMV retinitis after withdrawal of anti-CMV therapy did not occur in any of the patients observed for a median of 156 days (range, 92-558).