Long-term efficacy and safety of once-daily fosamprenavir 1400 mg boosted by ritonavir 100 mg: the BOLD100 study.

In a retrospective database study at two HIV treatment centres, medical records were accessed to evaluate long-term efficacy and safety parameters in all HIV-infected adults who had achieved HIV-1 RNA <50 copies/mL following the initiation of fosamprenavir (FPV)/ritonavir (RTV) 1400 mg/100 mg once-daily (QD)-containing regimens between January 2004 and January 2006. Data were available for 20 antiretroviral (ARV)-naïve patients (baseline median HIV-1 RNA 5.0 log(10) copies/mL; CD4+ cell count 307 cells/mm(3)), 30 protease inhibitor (PI)-naïve, ARV-experienced patients (HIV-1 RNA 3.6 log(10) copies/mL; CD4+ count 348 cells/mm(3)) and 25 PI-experienced patients switching to FPV/RTV100 for reasons other than virological failure (HIV-1 RNA 2.7 log(10) copies/mL; CD4+ count 328 cells/mm(3)). HIV-1 RNA <50 copies/mL was achieved in 100% of the ARV-naïve cohort (median monitoring period, 2.4 years; range, 1.4-3.2 years), 87% of the PI-naïve cohort (2.4 years; range, 1.2-3.4 years) and 88% of the PI-experienced cohort (2.2 years; range, 1.0-3.2 years). Virological failure occurred in 0%, 7% and 8% of the cohorts, respectively, and median CD4+ count increased above baseline by 224, 155 and 115 cells/mm(3), respectively. Change from baseline in median fasting lipids was: total cholesterol +12, -6, -2 mg/dL; low-density lipoprotein-cholesterol 0, -5, +12 mg/dL; high-density lipoprotein-cholesterol +4, +2, +7 mg/dL; triglycerides +9, -21, -65 mg/dL, respectively. In conclusion, FPV/RTV 1400/100 mg QD-containing regimens remained effective long-term in all ARV-naïve and most PI-naïve and PI-experienced HIV-infected patients.

Lowering the dose of hydroxyurea minimizes toxicity and maximizes anti-HIV potency.

The goal of this study was to optimize the hydroxyurea dosage in HIV-infected patients, and to minimize the toxicity and maximize the antiviral efficacy of the hydroxyurea-didanosine combination. In a randomized, open-label study (RIGHT 702, a multicenter trial performed in private and institutional practices), three daily doses (600 microg, 800-900 microg, and 1200 microg) of hydroxyurea were administered in combination with didanosine and stavudine to 115 chronically HIV-infected patients, one-third antiretroviral drug naive, with viremia between 5000 and 200,000 copies/ml regardless of CD4+ cell count. The primary efficacy end point was the proportion of patients with plasma HIV-1 RNA levels below 400 copies/ml after 24 weeks of therapy. In the RIGHT 702 intent-to-treat population the lowest (600 mg) dose of hydroxyurea was better tolerated, associated with fewer adverse events, and more potent by all efficacy parameters, including the primary end point (76 versus 60% patients with viremia<400 copies/ml at week 24 for the 600-mg and 800- to 900-mg dose groups, respectively; p=0.027), the mean area under the curve (60.3 versus 65.8; p=0.016), and the mean log10 decrease (-1.95 versus -0.77; p=0.001). Patients receiving 600 mg of hydroxyurea daily also had the highest CD4+ cell count, CD4+/CD8+ cell ratio, and lowest CD8+ cell count and percentage (p=0.035). The RIGHT 702 trial provides an explanation for the increased toxicity and decreased efficacy of hydroxyurea when it was used at high dosage (1200 mg daily). At the optimal dosage of 600 mg daily, hydroxyurea, in combination with didanosine, deserves reevaluation for the long-term management of HIV/AIDS worldwide, because of its excellent resistance profile, durability, and affordability.

Passive immunotherapy in advanced HIV infection and therapeutic plasmapheresis in asymptomatic HIV-positive individuals: a four-year clinical experience.

We have been treating patients with advanced HIV disease using passive immunotherapy (PIT). Earlier studies of PIT which have been published concerned relatively short periods of treatment: our study is by far the longest and reports also on the long-term effects of plasmapheresis on healthy HIV-infected individuals. Fifty-nine patients with an average CD4+ T-cell count of 55 per cu.mm. at baseline were transfused at monthly intervals with 500 ml of hyperimmune plasma. No disease progression or death occurred among the 8 asymptomatic patients under the treatment, which lasted for 36.25 months on average. Seven of the 15 ARC patients progressed to AIDS but none died in an average period of 25.9 months. Seven of the 36 symptomatic AIDS patients with advanced disease died in an average period of 19.6 months. PIT appears to be nontoxic and to have beneficial effects lasting at least four years under continuous treatment. It probably delays disease progression in ARC and AIDS patients, and almost certainly does so in asymptomatic late HIV infection with a very low CD4+ T-cell count. None of the 51 donors suffered adverse effects, nor did any progress to ARC or AIDS in an average period of 30.1 months. Their laboratory parameters indicated a nearly stable condition: in particular, their average CD4+ T-cell count rose from 478 to 498. The study of our plasma donors indicated that repeated and frequent plasma donation by asymptomatic HIV-infected individuals could delay disease progression, although further studies are needed to investigate this.

Safety and efficacy of thymopentin in zidovudine (AZT)-treated asymptomatic HIV-infected subjects with 200-500 CD4 cells/mm3: a double-blind placebo-controlled trial.

Thymopentin, 50 mg subcutaneously (s.c.) 3 times per week, was evaluated in a double-blind, randomized, placebo-controlled trial of zidovudine (AZT)-treated asymptomatic human immunodeficiency virus (HIV)-infected subjects with 200-500 CD4 cells/mm3 at entry. The 352 subjects were prestratified by prior AZT use into stratum I (235 subjects, > 6 months AZT at entry) and stratum II (117 subjects, < or = 6 months AZT at entry). Clinical end points, CD4 cell counts, serum p24, serum immune complex dissociated (ICD) p24, and safety variables were evaluated through 48 weeks, using an intent-to-treat analysis. The two strata were analyzed individually because they yielded different clinical outcomes, with a statistically significant treatment-by-stratum interaction. In stratum I (mean, 16 months AZT at entry) two AIDS or death events occurred in thymopentin and 10 in placebo recipients (p = 0.024; relative risk (RR) estimate, 4.9 [95% confidence limit (CI), 1.1 to 22.2]). There were three AIDS-related complex (ARC), AIDS, or death events in thymopentin and 18 in placebo recipients [p = 0.001; RR estimate, 5.9 (95% CI, 1.7 to 20.0)]. In stratum II (mean, 3 months AZT at entry), four AIDS or death events occurred in thymopentin and none in placebo recipients (p = 0.11), and four ARC, AIDS, or death events occurred in thymopentin and two in placebo recipients (p = 0.79). The treatment groups did not differ significantly with respect to changes in CD4 counts or p24 antigen levels or with respect to clinical adverse experiences or laboratory abnormalities. Thus, AZT-experienced placebo-treated subjects had relatively high progression rates to AIDS or death and to ARC, AIDS, or death, and these rates were reduced by thymopentin treatment. In contrast, placebo-treated subjects with little prior AZT experience had low progression rates; these were not significantly changed by thymopentin treatment. There was no increase in the incidence of adverse reactions with thymopentin.

Alteration of prostaglandin biosynthesis in rat chloroleukemic tumor.

Data from our present studies demonstrate the capability of a 105,000 X g pellet from rat normal bone marrow, turpentine-induced hyperplastic bone marrow, and chloroma tumor to transform precursor arachidonic acid into prostaglandins. The activity of the prostaglandin synthetase systems in these tissues is inhibited by the known nonsteroid antiinflammatory drug indomethacin and by two unsaturated fatty acids previously demonstrated in other tissues. Although the overall biosynthesis of prostaglandin E2 (PGE2) was higher in the hyperplastic bone marrow than in the chloroma tumor, the PGF2alpha:PGE2 ratio was markedly higher (8-fold) in the chloroma tissue. This latter increase was probably due to the increased transformation of PGE2 into PGF2alpha by the NADPH-dependent PGE2 9-ketoreductase (an enzyme that catalyzes the transformation of PGE2 and PGF2alpha). These results indicate the greater capability of the malignant chloroma tissue to form PGF2alpha than of nonmalignant hyperplastic bone marrow. Although the role of PGF2alpha in the malignant myelogenous leukemic tumor is presently unclear, its increased formation in this tissue suggests that this substance may play a role in the hyperproliferative process.