Lower peripheral blood CD14+ monocyte frequency and higher CD34+ progenitor cell frequency are associated with HBV vaccine induced response in HIV infected individuals.

We evaluated immunologic predictors of response to HBV vaccine administered in the presence or absence of GM-CSF in HIV infected individuals. We measured peripheral blood hematopoietic progenitor, monocyte and myeloid-derived suppressor cell (MDSC) frequencies, and expression of GMCSF receptor on monocytes and MDSCs, at baseline and 4weeks after immunization in relation to antibody response. We observed higher baseline progenitor and lower monocyte frequencies among week 16 antibody responders. Week 4 decline in MDSC frequency was associated with week 16 antibody response, while administration of GM-CSF was associated with preservation of these cells. No significant differences in GM-CSF receptor expression were observed in the presence vs. absence of GM-CSF. These findings are consistent with a positive role of progenitor cells and a potential negative role of monocytes in vaccine response. Additionally, GM-CSF augmented the preservation of peripheral blood MDSC, which may contribute to the lack of improved vaccine responses.

Immune response to hepatitis B vaccine in HIV-infected subjects using granulocyte-macrophage colony-stimulating factor (GM-CSF) as a vaccine adjuvant: ACTG study 5220.

HIV-infected persons are at risk for HBV co-infection which is associated with increased morbidity and mortality. Unfortunately, protective immunity following HBV vaccination in HIV-infected persons is poor. This randomized, phase II, open-label study aimed to evaluate efficacy and safety of 40 mcg HBV vaccine with or without 250 mcg GM-CSF administered at day 0, weeks 4 and 12. HIV-infected individuals >or=18 years of age, CD4 count >or=200 cells/mm(3), seronegative for HBV and HCV, and naïve to HBV vaccination were eligible. Primary endpoints were quantitative HBsAb titers and adverse events. The study enrolled 48 subjects. Median age and baseline CD4 were 41 years and 446 cells/mm(3), 37 were on ART, and 26 subjects had undetectable VL. Vaccination was well tolerated. Seven subjects in the GM-CSF arm reported transient grade >or=2 signs/symptoms (six grade 2, one grade 3), mostly aches and nausea. GM-CSF had no significant effect on VL or CD4. Four weeks after vaccination, 26 subjects (59%) developed a protective antibody response (HBsAb >or=10 mIU/mL; 52% in the GM-CSF arm and 65% in the control arm) without improved Ab titer in the GM-CSF vs. control arm (median 11 mIU/mL vs. 92 mIU/mL, respectively). Response was more frequent in those with CD4 >or=350 cells/mm(3) (64%) than with CD4 <350 cells/mm(3) (50%), though not statistically significant. GM-CSF as an adjuvant did not improve the Ab titer or the development of protective immunity to HBV vaccination in those receiving an accelerated vaccine schedule. Given the common routes of transmission for HIV and HBV, additional HBV vaccine research is warranted.

Safety and tolerability of sequential pegylated IFN-alpha2a and tenofovir for hepatitis B infection in HIV(+) individuals.

Chronic hepatitis B virus infections are a major cause of morbidity and mortality in HIV co-infected patients. The standard of care for treating HCV co-infection has been guided by major clinical trials, but the treatment of HBV co-infection has not been as thoroughly studied and the standard of care remains largely untested. The single pill formulation of tenofovir with emtricitabine has become a standard treatment approach in HBV co-infected patients. WU114 was a phase 1 clinical trial that examined the safety and tolerability of sequential treatment of HBV with pegylated interferon-alpha2a plus delayed-initiation tenofovir in HIV co-infected individuals. We postulated that initial HBV viral load reduction with pegylated interferon prior to initiation of nucleoside/nucleotide therapy would increase seroconversion events and durability of HBV virologic suppression. No severe pegylated IFN-alpha2a drug toxicities were seen in either the monotherapy or delayed tenofovir arms. Sequential pegylated interferon and tenofovir-based therapy was tolerable and should be compared with dual nucleoside/nucleotide suppression to determine relative frequencies of seroconversion and durability of HBV suppression in co-infected patients.

Presence of macrolide resistance in respiratory flora of HIV-Infected patients receiving either clarithromycin or azithromycin for Mycobacterium avium complex prophylaxis.

Clarithromycin 500 mg po bid or azithromycin 1200 mg po weekly is recommended as first line prophylaxis for Mycobacterium avium complex (MAC) in patients with HIV infection whose CD4 counts are <50 cells/microL. HIV-infected patients with CD4+ T-cell counts <200 cells/microL were randomized to receive either clarithromycin 500 mg po bid or azithromycin 1200 mg po weekly for 12 weeks. Nasopharyngeal swabs for Streptococcus pneumoniae and Haemophilus influenzae plus an anterior nare culture for Staphylococcus aureus were obtained at pretreatment, at 6 weeks, and at 12 weeks. A throat culture for oral flora was obtained for susceptibility testing against erythromycin. Minimum inhibitory concentrations (MICs) for clarithromycin and azithromycin were performed on all S. pneumoniae, H. influenzae, and S. aureus isolates. The study was terminated after respiratory flora, from all participants, revealed macrolide resistance. Because results of recent randomized trials indicate minimal efficacy of continuing MAC prophylaxis in patients who respond to potent combination antiretroviral therapy, the observed high incidence of macrolide-resistant bacterial colonization of the respiratory tract in this trial supports the discontinuation of macrolide prophylaxis in all AIDS patients whose CD4 counts have risen above 100 cells/microL.

HIV and cardiovascular risk factors.

There is growing concern that the metabolic complications associated with HIV and antiretroviral therapy may lead to accelerated coronary artery disease (CAD). Traditional cardiovascular risk factors, such as hypertension, hyperlipidemia, diabetes mellitus, and visceral fat accumulation, are increasingly seen in HIV patients receiving HAART. These factors are in addition to nonreversible risk factors, such as male sex, age greater than 40 years, and family history of premature CAD. Patients may also be smokers and may have a sedentary lifestyle, both of which predispose to significant CAD. In older patients and those with other risk factors, there may be an accentuation of these risk factors by HAART, although these factors also occur in young patients with no other risk factors. It is still unknown whether the factors predispose HIV patients to accelerated cardiovascular disease. Short-term studies, including 2 large cross-sectional studies, do not show an increased risk of cardiovascular complications or cardiac death, but longer follow-up is needed to answer such questions effectively. Even if patients are not at increased risk for cardiovascular disease, they are at least at the same risk as HIV-negative, age-matched persons with similar risk factors. It is, therefore, pertinent to identify and effectively manage those risk factors that can be modified.

Invasive fungal sinusitis and meningitis due to Arthrographis kalrae in a patient with AIDS.

We report the first described case of Arthrographis kalrae pansinusitis and meningitis in a patient with AIDS. The patient was initially diagnosed with Arthrographis kalrae pansinusitis by endoscopic biopsy and culture. The patient was treated with itraconazole for approximately 5 months and then died secondary to Pneumocytis carinii pneumonia. Postmortem examination revealed invasive fungal sinusitis that involved the sphenoid sinus and that extended through the cribiform plate into the inferior surfaces of the bilateral frontal lobes. There was also an associated fungal meningitis and vasculitis with fungal thrombosis and multiple recent infarcts that involved the frontal lobes, right caudate nucleus, and putamen. Post mortem cultures were positive for A. kalrae.

Sex differences in nevirapine rash.

Nevirapine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that has the most common treatment limiting side effect of rash. Severe rash has been observed in 3% of patients taking nevirapine in clinical trials, 85% of whom were men. In a multicenter, retrospective cohort study of all patients who received nevirapine over a 5-year period, severe rash was noted in 9 of 95 women and 3 of 263 men (risk ratio [RR], 8.31; 95% confidence interval [CI], 2.3-30.0; P=.005). Women were more likely to discontinue nevirapine therapy because of rash (RR, 4.5; 95% CI, 1. 9-10.5; P=.0005). After adjusting for age and baseline CD4 cell count in multivariate analysis, women had a 7-fold increase in risk for severe rash and were 3.5 times more likely to discontinue nevirapine therapy. In women of reproductive age for whom contraception may occur, nevirapine remains the NNRTI of choice. Recognition of sex differences in this severe adverse event will be important in prescribing nevirapine.

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.

Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count. A randomized, double-blind, placebo-controlled trial. AIDS Clinical Trials Group 362 Study Team.

BACKGROUND: Patients infected with HIV who experience increases in CD4(+) cell counts are at reduced risk for opportunistic infections. However, the safety of discontinuing prophylaxis against Mycobacterium avium complex has been uncertain. OBJECTIVE: To compare the rate of M. avium complex infection in patients with increased CD4(+) cell counts who receive azithromycin and those receiving placebo. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 29 university-based clinical centers in the United States. PARTICIPANTS: 643 HIV-1-infected patients with a previous CD4(+) cell count less than 0.05 x 10(9) cells/L and a sustained increase to greater than 0.10 x 10(9) cells/L during antiretroviral therapy. INTERVENTION: Azithromycin, 1200 mg once weekly (n = 321), or matching placebo (n = 322). MEASUREMENTS: Mycobacterium avium complex cultures, CD4(+) cell counts, and clinical evaluations for AIDS-defining illnesses and bacterial infections were done every 8 weeks. Plasma HIV-1 RNA levels were measured at 16-week intervals. RESULTS: During follow-up (median, 16 months), 2 cases of M. avium complex infection were reported among the 321 patients assigned to placebo (incidence rate, 0.5 event per 100 person-years [95% CI, 0.06 to 1.83 events per 100 person-years]) compared with no cases among the 322 patients assigned to azithromycin (CI, 0 to 0.92 events per 100 person-years), resulting in a treatment difference of 0.5 event per 100 person-years (CI, -0.20 to 1.21 events per 100 person-years) for placebo versus azithromycin. Both cases were atypical in that M. avium complex was localized to the vertebral spine. Patients receiving azithromycin were more likely than those receiving placebo to discontinue treatment with the study drug permanently because of adverse events (8% vs. 2%; hazard ratio, 0.24 [CI, 0.10 to 0.57]). CONCLUSIONS: Prophylaxis against Mycobacterium avium complex can safely be withdrawn or withheld in adults with HIV infection who experience increases in CD4(+) cell count while receiving antiretroviral therapy.

Reconstitution of immunity against opportunistic infections in the era of potent antiretroviral therapy.

Critical questions remain unanswered regarding the safety and efficacy of withdrawing primary and secondary prophylaxis in the context of HAART-associated immune reconstitution. What are the mediators of first phase cellular increases? Will continued HIV suppression result in continued immune restoration? And what are the immunological consequences of viral rebound despite HAART in patients whose CD4 counts remain elevated? Can immunity, once lost, be restored by reintroduction of antigens such as by tetanus or pneumococcal vaccination? Can immunoassays predict who will relapse or reactivate an OI? Is it possible to eradicate infections such as MAC, cryptococcosis, and histoplasmosis? Certainly, one can never eradicate CMV infection but can immunoassays predict who will have disease-reactivate? Unfortunately, various studies have reported contradicting results regarding the immunological response in vitro to specific antigens. Until these immunoassays become standardized and validated, it is unclear if immunoassays will be predictive of who would be at risk of development of disease or relapse. Therefore, until such time, clinicians may want to initiate and maintain primary prophylaxis in HIV-infected individuals as recommended by the USPHS/IDSA guidelines based on the nadir CD4+ T-cell count at least until studies have clearly demonstrated whether the increased CD4+ T-cell response attributed to HAART does in fact confer protection against these pathogens. Although for some OIs it does appear safe to withdraw primary prophylaxis and probably secondary prophylaxis, the decision to stop prophylaxis or maintenance therapy should be a joint decision by the patient and clinician based on the risks and benefits of stopping the therapy and the availability of close clinical monitoring for evidence of disease.

Clinical utility of monitoring serum cryptococcal antigen (sCRAG) titers in patients with AIDS-related cryptococcal disease.

PURPOSE: The purpose of our study was to define the time course and clinical role of monitoring serum cryptococcal antigen titers (sCRAG) in patients with AIDS-related cryptococcal disease. METHOD: A retrospective chart review was conducted. The medical records for all HIV-infected patients with positive cryptococcal antigen (CRAG) tests from January 1993 to May 1998 at San Francisco General Hospital (SFGH) were reviewed for sCRAG titer levels and clinical outcomes. RESULTS: Out of the 314 patients found to have positive antigen tests, 136 met the inclusion criteria. Twelve (8.8%) had no change in titer from baseline, 6 (4.4%) had an increase, and 118 (86.8%) had a decrease. Examining the association of sCRAG with time to relapse using a variety of Cox models produced largely null results. Rate of change in sCRAG over time (slope) was not significantly predictive of time to relapse nor of time to definite relapse/probable relapse/persistent disease. CONCLUSION: Although in the majority of patients, the sCRAG titers appeared to decrease over time, we could not detect a significant correlation between sCRAG titer results of patients who had a clinical response to treatment and sCRAG titers in patients who experienced persistent disease, probable relapse, or definitive relapse of cryptococcal disease. We conclude that follow-up monitoring of the sCRAG titer is not useful in the management of patients with AIDS-related cryptococcal disease on treatment.

Pulmonary cryptococcosis in patients without HIV infection.

PURPOSE: To further elucidate the diagnostic and therapeutic approaches to patients with pulmonary cryptococcosis who are not HIV-infected. SUBJECTS: All of the patients without HIV infection who received care at two Midwest hospitals between January 1986 and February 1996 and had a respiratory isolate of Cryptococcus neoformans. METHODS: The medical records of the study patients were reviewed for demographic data, host immune status, respiratory symptoms, diagnostic studies, treatment, and follow-up. RESULTS: Forty-two patient presentations comprised the overall study group. Thirty-six patients (85.7%) had no evidence of dissemination, and six patients (14.3%) had disseminated disease. Seven of the 36 patient presentations were definitive pulmonary cryptococcosis, 15 were presumptive disease, and 14 were colonization with C neoformans. Neither the baseline demographic parameters nor the immune status appeared to discriminate the patients with disease from the patients with colonization. A serum cryptococcal antigen (sCRAG) was positive for 7 of 18 patients, 3 of whom were proven by culture to have a disseminated infection. A negative sCRAG was observed in 11 patients, one of whom had proven dissemination. Fifteen patients underwent a lumbar puncture as part of their evaluation, and cryptococcal meningitis was diagnosed in three of these patients, all of whom had positive blood cultures for C neoformans. The majority of the patients did not receive antifungal therapy. CONCLUSION: In the majority of the patients, the lung appeared to be the sole organ involved, and a workup for systemic infection was rarely helpful. A positive sCRAG was not specific for dissemination. Antifungal therapy should be reserved for symptomatic patients, for patients with a positive sCRAG, and for patients with underlying immunosuppression.

Eradication of AIDS-related disseminated mycobacterium avium complex infection after 12 months of antimycobacterial therapy combined with highly active antiretroviral therapy.

To determine if microbiologic cure of AIDS-related disseminated Mycobacterium avium complex (MAC) is possible in patients receiving highly active antiretroviral therapy (HAART), 4 patients with a history of disseminated MAC received >/=12 months of macrolide-based antimycobacterial therapy. All were asymptomatic and had absolute CD4 cell count >100/microL (range, 137-301) and <10,000 copies/mL of human immunodeficiency virus RNA (range, <500-1250). A bone marrow aspirate and peripheral blood were obtained for mycobacterial culture. Follow-up blood cultures were obtained routinely at 4 weeks and every 8 weeks thereafter. All 4 patients had negative bone marrow and blood cultures and then discontinued antimycobacterial therapy. All patients' subsequent cultures remain sterile and all are clinically asymptomatic (range, 8-13 months follow-up). It appears that disseminated MAC infection can be cured by prolonged antimycobacterial therapy in some persons who experience sustained CD4 lymphocyte increases while receiving HAART.

Immunoglobulin G immunosuppression of multiple sclerosis. Suppression of all three major lymphocyte subsets.

Six patients with relapsing chronic progressive multiple sclerosis were treated on 2 consecutive days with large amounts of IgG to induce immunosuppression. Peripheral blood lymphocyte subsets were monitored for 5 weeks after IgG treatment to determine immunosuppression. Decreased numbers of B, T, and natural killer lymphocytes were detected after treatment. Lymphocyte numbers were at a nadir 1 week after treatment, but an immunosuppressive effect continued to be present after 5 weeks. Although clinical efficacy was not evident in this brief open trial, the decrease of peripheral lymphocyte numbers and the apparent safety of the procedure warrant further study.

Prostaglandin production in chronic progressive multiple sclerosis.

Peripheral blood monocytes have been implicated in the immune reactions that accompany demyelination in patients with multiple sclerosis (MS). We measured prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) release from peripheral monocytes exposed in vitro to complement. Our studies suggest that there is a significantly higher production of PGE2 in monocytes from patients with chronic progressive MS than in those with exacerbation or remitting MS and healthy controls. No significant differences in TxB2 release were noted between the three groups.