Effect of gender and race on the week 48 findings in treatment-naïve, HIV-1-infected patients enrolled in the randomized, phase III trials ECHO and THRIVE.

OBJECTIVES: A week 48 efficacy and safety analysis with respect to gender and race was conducted using pooled data from the phase III, double-blind, double-dummy efficacy comparison in treatment-naïve, HIV-infected subjects of TMC278 and efavirenz (ECHO) and TMC278 against HIV, in a once-daily regimen versus efavirenz (THRIVE) trials. METHODS: Treatment-naïve, HIV-1-infected adults were randomized to receive rilpivirine (RPV; TMC278) 25 mg once a day (qd), or efavirenz (EFV) 600 mg qd, plus tenofovir/emtricitabine (ECHO) or tenofovir/emtricitabine, zidovudine/lamivudine or abacavir/lamivudine (THRIVE). RESULTS: A total of 1368 participants (76% male and 61% White, of those with available race data) were randomized and treated. No gender-related differences in response rate (percentage of patients with HIV-1 viral load < 50 HIV-1 RNA copies/mL, using an intent-to-treat, time-to-loss-of-virological-response algorithm) were observed (RPV: men, 85%; women, 83%; EFV: men, 82%; women, 83%). Response rates were lower in Black compared with Asian and White participants (RPV: 75% vs. 95% and 85%, respectively; EFV: 74% vs. 93% and 83%, respectively); this finding was mostly a result of higher discontinuation and virological failure rates in Black patients. Safety findings were generally similar across race and gender subgroups. However, nausea occurred more commonly in women than in men in both treatment groups. In men, diarrhoea was more frequent in the EFV group, and abnormal dreams/nightmares were more frequent in men in both the EFV and RPV groups. CONCLUSIONS: Overall response rates were high for both RPV and EFV. No gender differences were observed. However, response rates were lower among Black patients, regardless of treatment group. Gender appeared to influence the incidence of gastrointestinal adverse events and abnormal dreams/nightmares for both treatments.

Abacavir-lamivudine-zidovudine vs indinavir-lamivudine-zidovudine in antiretroviral-naive HIV-infected adults: A randomized equivalence trial.

CONTEXT: Abacavir, a nucleoside analogue, has demonstrated suppression of human immunodeficiency virus (HIV) replication alone and in combination therapy. However, the role of abacavir in a triple nucleoside combination regimen has not been evaluated against a standard protease inhibitor-containing regimen for initial antiretroviral treatment. OBJECTIVE: To evaluate antiretroviral equivalence and safety of an abacavir-lamivudine-zidovudine regimen compared with an indinavir-lamivudine-zidovudine regimen. DESIGN AND SETTING: A multicenter, phase 3, randomized, double-blind trial with an enrollment period from August 1997 to June 1998, with follow-up through 48 weeks at 73 clinical research units in the United States, Canada, Australia, and Europe. PATIENTS: Five hundred sixty-two antiretroviral-naive, HIV-infected adults with a plasma HIV RNA level of at least 10 000 copies/mL and a CD4 cell count of at least 100 x 10(6)/L. INTERVENTIONS: Patients were stratified by baseline HIV RNA level and randomly assigned to receive a combination tablet containing 150 mg of lamivudine and 300 mg of zidovudine twice daily plus either 300 mg of abacavir twice daily and indinavir placebo or 800 mg of indinavir every 8 hours daily plus abacavir placebo. After 16 weeks, patients with confirmed HIV RNA levels greater than 400 copies/mL were eligible to continue receiving randomized treatment or receive open-label therapy. MAIN OUTCOME MEASURE: Virologic suppression, defined as HIV RNA concentration of 400 copies/mL or less at week 48. RESULTS: The proportion of patients who met the end point of having an HIV RNA level of 400 copies/mL or less at week 48 was equivalent in the abacavir group (51% [133/262]) and in the indinavir group (51% [136/265]) with a treatment difference of -0.6% (95% confidence interval [CI], -9% to 8%). In patients with baseline HIV RNA levels greater than 100 000 copies/mL, the proportion of patients achieving less than 50 copies/mL was greater in the indinavir group than in the abacavir group with 45% (45/100) vs 31% (30/96) and a treatment diference of -14% (95% CI, -27% to 0%). The 2 treatments were comparable with respect to their effects on CD4 cell count. There was no difference between groups in the frequency of treatment-limiting adverse events or laboratory abnormalities. One death in the abacavir group was attributed to hypersensitivity reaction, which occurred following rechallenge with abacavir, approximately 3 weeks after initiating study treatment. CONCLUSIONS: In this study of antiretroviral-naive HIV-infected adults, the triple nucleoside regimen of abacavir-lamivudine-zidovudine was equivalent to the regimen of indinavir-lamivudine-zidovudine in achieving a plasma HIV RNA level of less than 400 copies/mL at 48 weeks.

Stereotactic biopsy of cerebral lesions in AIDS.

Stereotactic brain biopsy was used to establish diagnoses of conditions in patients with AIDS. Two hundred fifty stereotactic biopsies and one open resection were performed for 243 patients. Pathologically abnormal tissue was obtained in 246 (98%) of the procedures, and 16 patients (6%) had >1 diagnosis. Diagnoses included lymphoma in 82 (33%), progressive multifocal leukoencephalopathy in 73 (30%), and tumors not ordinarily associated with AIDS in 7 (3%). In one-third of the cases, the tissue diagnosis differed from the predicted diagnosis. Four of the first 32 patients (12%) developed intracranial bleeding hours after surgery, which was fatal in 3 (9%). Subsequently, all patients were treated with a coagulopathy protocol that included preoperative and postoperative administration of coagulation factors, and there were no further instances of delayed bleeding in the 218 subsequent patients. Among those later patients, there were 7 complications (3%), leading to 4 deaths (2%), a complication rate that compares favorably with that among patients without AIDS.

Efficacy of nelfinavir in patients switched from ritonavir/saquinavir combination antiretroviral therapy.

UNLABELLED: Based on available data and expert opinion, the IAS-USA treatment guidelines recommend "selective substitution" of the medication thought most likely to be causing a side effect for one that should have a different side effect profile. PURPOSE: This study evaluates the short-term virological efficacy of selective substitution with nelfinavir-nucleoside combination therapy in individuals with plasma viral RNA below 400 copies/mL. METHOD: This study involved a retrospective chart review at five large urban HIV Clinical practice settings and included 19 patients taking combination therapy including ritonavir with saquinavir. We performed selective substitution with a nelfinavir combination. Our main outcome measure was plasma HIV-1 RNA (Amplicor) obtained during the period between weeks 12 to 18. RESULTS: We identified 19 HIV-1-infected individuals with evidence of viral suppression as defined by a viral load below 400 copies/mL while taking dual nucleoside reverse transcriptase inhibitors with ritonavir/saquinavir. Reasons for switching included adverse effects (37%) or preference for nelfinavir due to the possibility of a better defined salvage regimen (63%). We defined a composite viral endpoint indicative of continued viral suppression using the first 12 to 18 weeks following the medication change. We found that 73% maintained undetectable viral loads (plasma HIV RNA below 400 copies/mL) during this period. CONCLUSION: These data suggest that any medication adjustment should be made cautiously, as there may be some potential risk in a substitution. Selective substitution of a medication that has undesirable side effects or other characteristics should be considered when the possible risks of the loss of viral suppression are outweighed by the potential benefits of that substitution.

Ethnic differences in hormone replacement prescribing patterns.

OBJECTIVE: To determine whether prescription patterns of hormone replacement therapy (HRT) differ in African-American, Asian, Latina, Soviet immigrant, and white women. DESIGN: Retrospective review of computerized medical records. SETTING: The general internal medicine, family medicine, and gynecology practices of an academic medical center. PATIENTS: Women aged 50 years or older with at least one outpatient visit from January 1, 1992, to November 30, 1995. MEASUREMENTS AND MAIN RESULTS: Use of HRT was defined as documentation of systemic estrogen use. The main predictor variable was self-identified ethnicity. Age, diagnosis (coronary heart disease, hypertension, diabetes, osteoporosis, or breast cancer), and median income were included in the analysis. Of the 8,968 women (mean age, 65.4 years) included, 50% were white, 20% Asian, 15% African American, 9% Latina, and 6% Soviet immigrants. Whites (33%) were significantly more likely to be prescribed HRT than Asians (21%), African Americans (25%), Latinas (23%), or Soviet immigrants (6.6%), p < 0.01 for each. Multivariate analysis, comparing ethnic groups and controlling for confounding variables, showed that Asians (odds ratio [OR] 0.56; 95% confidence interval [CI] 0.49, 0.64), African Americans (OR 0.70; 95% CI 0.60, 0.81), Latinas (OR 0.70; 95% CI 0.58, 0.84), and Soviet immigrants (OR 0.14; 95% CI 0.10, 0. 20) were each less likely to be prescribed HRT than were white women. Although women with osteoporosis were more likely to receive HRT (OR 2.28; 95% CI 1.71, 2.99), those with coronary heart disease were not (OR 0.88; 95% CI 0.68, 1.09). CONCLUSIONS: Physicians at this medical center were more likely to prescribe HRT for white women and women with osteoporosis. Further study is needed to address whether these differences in HRT prescribing result in different health outcomes.

Safety and antiretroviral effects of combined didanosine and stavudine therapy in HIV-infected individuals with CD4 counts of 200 to 500 cells/mm3.

The safety and antiretroviral effects of didanosine and stavudine in combination were evaluated in 86 people infected with HIV with CD4 counts between 200 and 500 cells/mm3 who had received <7 days of prior nucleoside analogue antiretroviral treatment. Patients were randomized to receive blinded treatments with one of five weight-adjusted, twice-daily regimens of didanosine and stavudine (100 + 10 mg, 100 + 20 mg, 100 + 40 mg, 200 + 20 mg, and 200 + 40 mg) for up to 1 year. Dosages were adjusted appropriately for patients weighing <60 kg and reduced in response to adverse effects. No clear dose-related differences among treatment groups were detected with regard to suppression of plasma HIV RNA level or reduction in infectious titers in peripheral blood mononuclear cells (PBMCs), improvement in CD4 count, or adverse effects. However, trends toward greater decreases in viral load and increases in CD4 count were detected when treatment groups containing the full recommended dosage of one or both agents (high-dose subgroup; arms 3, 4, and 5) were compared with the groups receiving lower dosages. At 28 weeks the mean log 10 HIV RNA decrease was 1.12 (n = 52) and at 52 weeks it was 0.97 (n = 32). Combination therapy was well tolerated, with no apparent dose-related adverse effects. Peripheral neuropathy occurred in 2 of 86 (2.3%) of patients. Didanosine and stavudine together appear to be a good nucleoside analogue foundation for aggressive triple- or quadruple-drug therapy. Full therapeutic doses of each of these two agents should be used to achieve optimal suppression of HIV replication.

Hormone replacement therapy for African American women: missed opportunities for effective intervention.

OBJECTIVES: Because of the potential benefits and risks of hormone replacement therapy (HRT), information about the efficacy of HRT in different groups of women is important to patients and providers. The objectives of this study were to review the evidence on the benefits and risks of HRT in African American women and to present a quantitative analysis of the potential reduction in mortality from osteoporotic fractures and coronary heart disease and the potential increase in risk of breast and endometrial cancer. METHODS: A MEDLINE search of English-language observational studies and clinical trials on the effects of HRT on osteoporotic fractures and coronary heart disease (CHD) was conducted for the time period from 1966 to September 1998. Using available CHD mortality data for African American women and white women, potential reductions in mortality with HRT were explored for African American and white women. RESULTS: In the 30 studies on CHD and HRT, African American women were known to comprise only 173 (0.1%) of 148,437 participants. In 11 studies of HRT and osteoporotic fractures, only 128 (0.4%) of 40,299 participants were known to be African American women. An analysis of CHD mortality by decade intervals indicated that African American women, aged 55 to 64, are more likely to die from CHD each year than white women. Despite a lower incidence of breast and endometrial cancer among African American women, the mortality rates of African American women with these cancers is higher compared with white women. CONCLUSIONS: With the higher underlying CHD mortality rate among African American women, HRT is an important potential preventive therapy. The absence of African American women and other non-white women from clinical studies of HRT makes it difficult to fully assess the risks and benefits of HRT in this group of women.

Improving patient adherence with antiretroviral therapy: evaluation of once-daily administration of didanosine.

One important goal of antiretroviral therapy should be simplification of treatment regimens whenever possible, in order to enhance adherence and potentially improve treatment outcome. While the nucleoside didanosine (ddI) has generally been dosed twice daily in clinical trials, the long intracellular half-life (>12 h) of its active metabolite, dideoxyadenosine triphosphate, should permit once-daily administration of this antiretroviral agent. The STADI trial evaluated this possibility by administering once-daily ddI and twice-daily stavudine (d4T) to antiretroviral-naive patients with human immunodeficiency virus type 1 (HIV-1) infection. This combination was well tolerated and at the end of 24 weeks of therapy, viral load was reduced by -1.48 log copies/ml and HIV-1 RNA was below the lower limit of quantification (500 copies/ml) in 62% of patients. Twenty-four weeks of treatment with d4T plus once-daily ddI increased average CD4 cell counts by 139/ml. The effectiveness of once-daily administration of ddI will be evaluated further in a new multinational clinical trial, AI454-148, in which it will be combined with d4T and the protease inhibitor, nelfinavir. The primary endpoint of this trial will be durable reduction of plasma HIV-1 RNA below 400 copies/ml. Such a change in the treatment regimen for this nucleoside has the potential to improve patient adherence and, thus, treatment outcome.