TMC114/ritonavir substitution for protease inhibitor(s) in a non-suppressive antiretroviral regimen: a 14-day proof-of-principle trial

OBJECTIVE: To evaluate antiviral activity, tolerability, and safety of the protease inhibitor (PI) TMC114 boosted with low-dose ritonavir (RTV). DESIGN: A randomized, open-label, controlled, phase IIA clinical trial in 15 sites in Europe with 50 HIV-1-infected patients who had taken multiple PIs. METHODS: At entry, PIs in non-suppressive regimens were replaced with TMC114/RTV (300/100 or 600/100 mg twice daily, or 900/100 mg once daily) or left unchanged for 14 days. The time-averaged difference (DAVG) in HIV-1 RNA from baseline, change in HIV-1 RNA from baseline, proportions achieving plasma HIV-1 RNA < 400 copies/ml and > or = 0.5 and > or = 1.0 log10 copies/ml reductions in HIV-1 RNA, and safety were assessed. RESULTS: DAVG responses in all TMC114/RTV groups (range, -0.56 to -0.81 log10 copies/ml) were significantly greater (P < 0.001) than in the controls (-0.03 log10 copies/ml). Median change at day 14 was -1.38 and +0.02 log10 copies/ml for all TMC114/RTV groups and the control group, respectively. A reduction of > or = 0.5 and > or = 1.0 log10 copies/ml was attained by 97% and 76% of patients, respectively, in all TMC114/RTV groups and by 25% and 17%, respectively, in the control group. HIV-1 RNA < 400 copies/ml at any time during treatment was achieved by 40% in the TMC114/RTV groups and 8% in the control group. Most common reported adverse events were gastrointestinal and central nervous system disorders (mild to moderate severity). No dose relationship was observed. Biochemical, haematological and electrocardiographic parameters showed no significant changes. CONCLUSIONS: TMC114/RTV demonstrated a potent antiretroviral effect over 14 days in multiple-PI-experienced patients and was generally well tolerated.     

Atovaquone maintenance therapy prevents reactivation of toxoplasmic encephalitis in a murine model of reactivated toxoplasmosis

Acute therapy with pyrimethamine plus sulfadiazine is the treatment of choice for reactivated toxoplasmic encephalitis (TE). Acute therapy is followed by lifelong maintenance therapy (secondary prophylaxis) with the same drugs at lower dosages. The use of pyrimethamine plus sulfadiazine is hampered by severe side effects including allergic reactions and hematotoxicity. Alternative treatment regimens with pyrimethamine plus clindamycin or other antiparasitic drugs are less efficacious. Atovaquone nanosuspensions show excellent therapeutic effects for "acute" intravenous (i.v.) treatment of reactivated TE in a murine model. In the present study, the therapeutic efficacy of atovaquone for oral "maintenance" therapy was investigated. Mice with a targeted mutation in the interferon regulatory factor 8 gene were latently infected with Toxoplasma gondii, developed reactivated TE, and received acute i.v. therapy with atovaquone nanosuspensions. Mice were then treated orally with atovaquone suspension or other antiparasitic drugs to prevent relapse of TE. Maintenance therapy with atovaquone at daily doses of 50 or 100 mg/kg (body weight) protected mice against reactivated TE and death. This maintenance treatment was superior to standard therapy with pyrimethamine plus sulfadiazine. The latter combination was superior to the combination of pyrimethamine plus clindamycin. Inflammatory changes in the brain parenchyma and meninges, as well as parasite numbers, in the brains of mice confirmed the therapeutic efficacy of atovaquone for maintenance therapy. Atovaquone was detectable in sera, brains, livers, and lungs of infected mice by high-performance liquid chromatography and/or mass spectrometry. In conclusion, atovaquone appears to be superior to the standard maintenance therapy regimens in a murine model of reactivated TE. The therapeutic efficacy of atovaquone for maintenance therapy against TE should be further investigated in clinical trials.     

Acquired immunodeficiency syndrome-related lymphoma: simultaneous treatment with combined cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy and highly active antiretroviral therapy is safe and improves survival--results of the German Multicenter Trial

BACKGROUND: Highly active antiretroviral therapy (HAART) has improved the survival of patients with acquired immunodeficiency syndrome-related lymphoma (ARL). The German ARL Study Group investigated whether HAART administered concomitantly with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy compromised the course of immune parameters during and after chemotherapy and exerted a positive effect on remission and survival. METHODS: From 1997 to 2001, 72 patients with ARL were stratified prospectively into a standard-risk group (n = 48 patients) and a high-risk group (n = 24 patients) with either 0-1 or 2-3 of the following risk factors: CD4 < 50/microL, prior opportunistic infection, and/or a World Health Organization performance status > or = 3. Patients in the high-risk group received > or =75% of the CHOP regimen. RESULTS: In the standard-risk group (CD4 = 223/muL; age-adjusted International Prognostic Index [aaIPI], 38% > or = 2), the complete remission (CR) rate was 79%, and median survival was not reached after a median 47 months of follow-up. CD4 counts did not change from baseline to 4 weeks after the end of chemotherapy (206/microL). In the high-risk group (CD4 = 34/muL; aaIPI, 88% > or = 2), the CR rate was 29%, and the median survival was 7.2 months (3 patients survived for > 3 yrs). Toxicity was moderate: Leukopenia Grade 3 or 4 occurred in 100 of 249 chemotherapy cycles (40%) in the standard-risk group and in 70 of 102 cycles (69%) in the high-risk group. CONCLUSIONS: Based on the aaIPI, the survival of patients in the standard-risk group was very similar to that achieved by nonhuman immunodeficiency virus-infected patients who had aggressive lymphomas. Concurrent CHOP plus HAART can be administered in an outpatient setting. Thus, the authors recommend using this modality as first-line therapy for patients with ARL.     

Pharmacokinetics, safety, and efficacy of tipranavir boosted with ritonavir alone or in combination with other boosted protease inhibitors as part of optimized combination antiretroviral therapy in highly treatment-experienced patients (BI Study 1182.51)

BACKGROUND: Given the limited treatment options for patients with high-level resistance, antiretroviral (ARV) regimens based on concomitant use of 2 ritonavir (RTV)-boosted protease inhibitors (PIs) were considered a therapeutic option. METHODS: Boehringer Ingelheim (BI) study 1182.51 examined the pharmacokinetic profile, safety, and efficacy of RTV-boosted tipranavir (TPV/r), alone and in combination with comparator PIs (CPIs) in 315 triple-class-experienced, HIV-infected patients. RESULTS: Two weeks after single PI therapy, the addition of TPV/r reduced plasma trough levels 52%, 80%, and 56% for lopinavir (LPV), saquinavir (SQV), and amprenavir (APV) recipients, respectively. After 2 weeks, a TPV/r-only regimen reduced HIV viral load (VL) by a median of 1.06 log(10) copies/mL. VL reductions at 2 weeks between single-boosted CPIs were difficult to compare, because the numbers of patients maintaining their previous failing PI after randomization were different. At week 4, patients initiating treatment with TPV-containing regimens sustained VL reduction (median decrease of 1.27 log(10) copies/mL). Patients adding TPV to regimens at week 2 achieved median reductions from a baseline of 1.19 log(10), 0.96 log(10), and 1.12 log(10) copies/mL at week 4 in dual-boosted LPV, SQV, and APV groups, respectively. At 24 weeks, VL reductions (median: -0.24 to -0.47 log(10) copies/mL) were comparable between treatment groups. CONCLUSIONS: The efficacy of a dual PI regimen depended on the presence of TPV, with additional recycled CPIs having limited activity, even in drug-resistant patient populations with plasma trough concentrations regarded as likely to be adequate in this study. No clear guidelines exist about ARV plasma trough concentrations in treatment-experienced patients, however.     

Disseminated toxoplasmosis with sepsis in AIDS

Summary A 24-year-old woman with acquired immunodeficiency syndrome was admitted with septic fever of unknown origin and a 2-week history of diarrhea. Clinical diagnostic procedures did not reveal the cause of sepsis. Broad-spectrum antibiotics and intensive symptomatic therapy could not prevent progressive deterioration. The patient developed septic shock and consumptive coagulopathy and died 6 days after admission. Autopsy revealed disseminated infection with toxoplasma gondii and multiple organ manifestations. We conclude that disseminated toxoplasmosis should be considered in AIDS patients with septic disease of unknown origin. Extremely elevated lactate dehydrogenase may suggest disseminated toxoplasma gondii infection. New procedures such as polymerase chain reaction for detection of toxoplasmosis may be helpful diagnostic tools.Abbreviations AIDS acquired immunodeficiency syndrome     

Evaluation of IS1245-based PCR for detection of mycobacterium avium bacteraemia in AIDS patients.

A PCR method based on the repetitive IS1245 sequence was evaluated for the detection of Mycobacterium avium bacteraemia in AIDS patients. Two blood preparation methods were applied: lysis of erythrocytes using a hypotonic buffer and Ficoll density centrifugation. Results were compared with culture and PCR amplification of the non-repetitive pMav22 sequence. Fifty-one of 251 tested samples grew M. avium. Bacterial densities lower than 10 cfu/ml blood were frequent, they occurred in 59% of blood samples from patients with mycobacteraemia. Inhibitory substances were detected more frequently with the lysis method (36%) than the Ficoll processed samples (19%). While specificity of PCR was high, sensitivities varied according to the methods used and the load of infection in the bloodstream. False-negative PCR results were attributable to low level bacteraemia and inhibition of PCR. Moreover, 1 of 186 and 9 of 51 M. avium strains investigated lacked the IS1245 and the pMav22 sequence, respectively. Sensitivities of culture, IS1245- and pMav22-based PCR were 88, 64 and 58%, within the lysis processed samples and 95, 86 and 50% using Ficoll prepared samples, respectively. Thus, we conclude that IS1245-based PCR is a rapid and specific method for diagnosing M. avium bacteraemia and shows a higher sensitivity than single copy gene targets, but that the sensitivity is inferior to culture.