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Background: In BMS Study 045, once-daily (QD) atazanavir/ritonavir (ATV/RTV) demonstrated comparable efficacy and safety to twice-daily (BID) lopinavir/ritonavir (LPV/RTV) over 48 weeks in treatment-experienced patients. Results of extended follow-up to 96 weeks are presented., Methods: BMS Study 045 was an open-label, randomized, multi-national trial of HIV-infected patients with virologic failure on two or more prior HAART regimens designed to evaluate the efficacy and safety of ATV/RTV (300/100 mg) QD and LPV/RTV (400/100 mg) BID, each with tenofovir (300 mg) QD and one nucleoside reverse transcriptase inhibitor. The primary efficacy measure was the time-averaged difference (TAD) in reduction in HIV RNA from baseline. Secondary objectives included evaluation of safety and plasma lipid levels through week 96., Results: Over 96 weeks, the ATV/RTV regimen demonstrated similar virologic efficacy to the LPV/RTV regimen. Mean reductions from baseline in HIV RNA were -2.29 and -2.08 log10 copies/ml, respectively [TAD (97.5% confidence interval): 0.14 log10 copies/ml (-0.13, 0.41)]. The LPV/RTV regimen resulted in significant increases in total cholesterol (+9%) and fasting triglycerides (+30%) in comparison with the ATV/RTV regimen, which demonstrated decreases in these parameters [-7 and -2%, respectively, (P < 0.0001)]. Grade 2-4 diarrhoea occurred less frequently in ATV/RTV patients (3%) in comparison with LPV/RTV patients (13%) (P < 0.01). Grade 3-4 elevations in bilirubin were more common in ATV/RTV patients (53%) than LPV/RTV patients (< 1%) (P < 0.0001), with no resulting discontinuations., Conclusions: Regimens containing once-daily ATV/RTV demonstrated comparable efficacy and safety, with significant reductions in total cholesterol and fasting triglycerides and improved gastrointestinal-tolerability in comparison with twice-daily regimens containing LPV/RTV over 96 weeks in treatment-experienced patients.

HIV-1 Subtype D occurs mainly in East and Central African countries, especially Uganda, where the prevalence of HIV-1 infection is among the highest in the world. We present the phylogenetic analysis of one nonautochthonous and four autochthonous (including a near full-length genome) Brazilian HIV-1 subtype D strains identified in Rio de Janeiro State, where subtypes B, F1, and BF1 recombinants predominate. Phylogenetic inferences using maximum likelihood were applied on a near-full length genome and on concatenated gag, protease, reverse transcriptase, integrase, C2V3/env, gp41, and nef segments. Sequences from an Angolan immigrant showed close genetic similarity with a strain described in Finland, from an HIV patient of African origin, whereas all four autochthonous Brazilian sequences clustered with South African strains, where subtype D occurs only in isolated cases. Our results suggest the successful introduction and circulation in Brazil of closely related HIV-1 subtype D strains, possibly of South African origin.

Background: Recent studies have shown substantial increases in the survival of AIDS patients in developed countries and in Brazil as a result of antiretroviral therapy (ART) and prophylaxis for opportunistic infections. This study compares survival rates using the Brazilian Ministry of Health 2004 and Centers for Disease Control and Prevention (CDC) 1993 case definitions in a large HIV/AIDS referral centre in Rio de Janeiro., Methods: Survival after AIDS diagnosis was assessed in a clinic-based cohort of 1415 individuals using the Kaplan-Meier method and Cox proportional hazards models., Results: There were 393 (88%) deaths from AIDS-related causes and 52 (12%) from unrelated or unknown causes. A total of 205 patients (14%) were lost to follow-up and 765 patients (55%) remained alive until the end of the study. Three-quarters of patients (75%) were still alive 22 months [95% confidence interval (CI) 19-26] after the AIDS diagnosis according to the CDC case definition and 31 months (95% CI 26-36) according to the Ministry of Health case definition. Independent predictors of survival included AIDS defined by CD4 cell count and any use of highly active antiretroviral therapy, with either case definition, and initial stage of the case, with the Ministry of Health case definition., Conclusion: Survival observed in this reference centre is comparable or longer than other international studies, although the choice of case definition criterion influenced findings. Adoption of the Ministry of Health case definition may enhance the ability to track the use of and outcomes from ART among AIDS patients.

Objective: To evaluate atazanavir/ritonavir (ATV/RTV) (300/100 mg) once daily, atazanavir/saquinavir (ATV/SQV) (400/1200 mg) once daily, and lopinavir/ritonavir (LPV/RTV) (400/100 mg) twice daily, each with tenofovir (300 mg) once daily and a nucleoside reverse transcriptase inhibitor in treatment-experienced HIV-infected patients., Methods: Randomized, open-label, 48-week multicenter trial of 358 randomized adult patients who had failed two or more prior HAART regimens with baseline HIV RNA > or = 1000 copies/ml and CD4 cell count > or = 50 x 10(6) cells/l., Results: The primary efficacy endpoint [plasma HIV RNA reduction assessed by time-averaged difference (TAD)] was similar for ATV/RTV and LPV/RTV [TAD 0.13; 97.5% confidence interval, -0.12 to 0.39] at 48 weeks. Mean reductions from baseline for ATV/RTV and LPV/RTV were comparable at 1.93 and 1.87 log10 copies/ml, respectively. Mean CD4 cell count increases were 110 and 121 x 10(6) cells/l for ATV/RTV, and LPV/RTV, respectively. The efficacy of ATV/SQV was lower than LPV/RTV by both these parameters. Declines in total cholesterol and fasting triglycerides were greater with ATV/RTV and ATV/SQV than with LPV/RTV (P < or = 0.005). Lipids in the LPV/RTV arm at week 48 generally increased from baseline. Lipid-lowering agents were used more frequently in the LPV/RTV arm than in the ATV arms (P < 0.05 versus ATV/RTV), as were antidiarrheal agents (P < or = 0.04 versus both ATV treatments). No new or unique safety findings emerged., Conclusions: ATV boosted with RTV is as effective and well tolerated as LPV/RTV in treatment-experienced patients, with a more favorable impact on serum lipids. Pharmacokinetically enhanced ATV provides a suitable choice for therapy of treatment-experienced HIV-infected patients.

Background: A substantial number of patients start their first-line antiretroviral therapy at an advanced stage of an HIV-1 infection. Potential differences between specific drug regimens in antiviral efficacy and safety in these patients are of major importance., Methods: A post-hoc analysis within the randomized controlled 2NN trial comparing efficacy between regimes containing nevirapine (NVP), efavirenz (EFV), or both, in addition to stavudine and lamivudine., Primary Outcome: risk of virologic failure in different strata of baseline CD4 T-lymphocyte counts and plasma HIV-1 RNA concentrations (pVL). Virologic failure: never reaching a pVL < 400 copies/ml, or a rebound to two consecutive values > 400 copies/ml., Results: The risk of virologic failure was increased at very low CD4 counts (< 25 x 10(6) cells/l) compared to CD4 counts > 200 x 10(6) cells/l [hazard ratio (HR), 1.28; 95% confidence interval (CI), 0.93-1.77]. The same was seen for a pVL > or = 100,000 copies/ml compared to a lower pVL (HR, 1.20; CI, 0.96-1.50). There were no statistically significant differences between NVP and EFV in risk of virologic failure within any of the CD4 or pVL strata, although EFV performed slightly better in the low CD4 stratum. The incidence of rash in the NVP group was significantly higher in female patients with higher CD4 cell counts, while adverse events in the EFV group were not associated with CD4 cell count., Conclusions: Initial antiretroviral therapy including NVP or EFV is effective in patients with an advanced HIV-1 infection. A high baseline CD4 cell count is associated with the occurrence of rash in female patients using NVP.

The aim of this study was to characterize the immune system profile in the uterine cervix of 17 human papillomavirus (HPV)-infected women, compared with 17 whom were coinfected with HIV-1. Five histologically normal cervices in immunocompetent women were used as controls. HPV infection was associated with a marked increase in cells expressing interleukin (IL)-6, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha). Coinfection by HPV and HIV-1 led to decreased expression of IL-6, TNF-alpha, and IFN-gamma. However, coinfection led to increased numbers of cells expressing IL-4, IL-10, and IL-8. Compared with the histologically normal cervices, increased numbers of macrophages (CD68, RFD7) and T lymphocytes (CD4, CD8) were seen in HPV-infected cervices; coinfection with HIV-1 was associated with a higher number of CD8 cells and lower number of CD68 cells. HPV DNA localized exclusively to the dysplastic squamous cells, whereas HIV-1 RNA was detected mainly in CD68-positive stromal cells. In conclusion, this study shows differential expression of various cytokines and classes of inflammatory cells, relative to HIV-1 infection and HPV coinfection, which may relate to the risk of transmission of HIV-1 and increased risk of cervical cancer in these women.

A randomized, double-blind, double-dummy controlled, multicenter trial was conducted that involved 554 antiretroviral-naive human immunodeficiency virus-infected adults (plasma HIV type 1 [HIV-1] RNA level, >or=400 copies/mL; CD4(+) cell count, >100 cells/mm(3)) and compared a 300-mg once-daily (q.d.) regimen of lamivudine (3TC) versus a 150-mg twice-daily (b.i.d.) regimen of 3TC, combined with zidovudine (300 mg b.i.d.) and efavirenz (600 mg q.d.), during a 48-week period. Treatments were considered equivalent if the 95% confidence interval (CI) for the difference in proportions of patients achieving an HIV-1 RNA level of <400 copies/mL was within the bound of -12% to 12%. At week 48 of the study, an intent-to-treat analysis in which patients with missing data were considered to have experienced treatment failure showed that the 3TC q.d. and 3TC b.i.d. regimens were equivalent (HIV-1 RNA level <400 copies/mL, 178 [64%] of 278 vs. 174 [63%] of 276; treatment difference, 1% [95% CI, -7.1% to 8.9%]; HIV-1 RNA level <50 copies/mL, 165 [59%] of 278 vs. 168 [61%] of 276; treatment difference, 1.7% [95% CI, -9.7% to 6.6%]). Median increase above baseline in CD4(+) cell count was similar (q.d. group, +144 cells/mm(3); b.i.d. group, +146 cells/mm(3)), and the incidences of adverse events, disease progression, and HIV-associated conditions were comparable.

Replication of the human immunodeficiency virus type 1 (HIV-1) isolate MN in CEM cells was less neutralized by the plasma from the mothers of infected children (MIC) in comparison with the plasma from the mothers of uninfected children (MUC). Significantly higher neutralization titres were observed for the sera from MUCs compared with MICs, and only the sera from MUC showed 100% neutralization of the HIV-1 MN strain. We suggest that a simple neutralization assay as described here could be useful in prognostic analyses.

We evaluated, for the first time in Latin America, the performance of a commercial enzyme immunoassay (EIA) (Calypte Biomedical Corporation, Berkeley, Calif.) that detects human immunodeficiency virus type 1 (HIV-1)-specific antibodies in urine in comparison to standard serological assays (two commercial EIAs and a commercial Western blot [WB] assay). Paired serum and urine specimens were collected from two different groups of Brazilian patients: 225 drug users with unknown HIV status who attended drug treatment centers in Rio de Janeiro, Brazil, and 135 subjects with known HIV status. Patients showing positive results in the serum EIAs and/or in the urine EIA were serologically confirmed by WB assay. For 135 individuals with known HIV status, the urine EIA showed 100% sensitivity (74 positive samples) and 95.1% specificity (58 of 61 negative specimens). For 225 drug users, the test showed 100% sensitivity (2 positive samples) and 98.7% specificity (220 of 223 negative samples) compared to WB-confirmed serological EIA results. Thus, in a total of 360 samples, the urine EIA correctly identified all 76 HIV-positive samples and 278 of 284 negative samples (100% sensitivity and 97.9% specificity). Detailed analysis of the urine EIA results indicates that an increase of the recommended cutoff value might raise the specificity of the assay without affecting its sensitivity. Our results suggest that the HIV-1 urine EIA is a good screening test suitable for developing countries like Brazil. However, as for all other HIV screening tests on the market, it is not specific enough to be used as a one-step test and therefore requires confirmation.

Neutralization analyses were carried out with plasma from 132 volunteer human immunodeficiency virus (HIV)-1 infected women (76% pregnant, 24% with infants suspected for HIV-1 infection) collected between 1994 and 1998, against autologous and heterologous primary- and the reference HIV-1 MN isolates. A significantly lower percentage of HIV-1 transmissions was observed after 1996, parallel to a more intense antiretroviral treatment of infected pregnant women. HIV-1 isolation was significantly more frequent from peripheral blood mononuclear cells of mothers of infected children than mothers of uninfected children (P = 0.0065). Neutralization of autologous HIV-1 isolates was comparable for HIV-1 transmitters and nontransmitters' plasma, whereas neutralization of the reference isolate HIV-1 MN was more frequent at high titers for pregnant women who did not transmit HIV to their offspring compared to pregnant women who did. Although neutralization of heterologous primary HIV-1 isolates from HIV transmitters and non transmitters by transmitter plasma occurred with similar frequency, neutralization of isolates from transmitters was much more frequent when heterologous plasma from nontransmitters were used. Macrophage-tropic heterologous HIV-1 isolates were neutralized more frequently at higher titers by plasma from nontransmitters than from transmitters. The results obtained indicate that antiretroviral treatment, lack of success of HIV-1 isolation and high titers of antibodies able to neutralize macrophage-tropic viruses appear to be of importance for protection against HIV-1 vertical transmission for the group of patients studied.

We investigated whether the recurrence of tuberculosis in HIV-infected patients is due to an exogenous reinfection or relapses after antituberculosis chemotherapy. We reviewed clinical information on 32 patients at a Rio de Janeiro hospital from whom multiple Mycobacterium tuberculosis isolates were taken. All isolates were analysed by DRE-PCR fingerprinting technique, and those with identical DRE-PCR patterns were analysed by the RFLP method. Twenty patients had M. tuberculosis simultaneously isolated from different organs. These patients and nine others with sequential positive cultures after 2 months of therapy showed stable DRE-PCR and RFLP patterns. One patient's isolate became resistant to isoniazid, but the molecular pattern remained unchanged despite the development of drug resistance. In three patients, the DRE-PCR patterns of the isolates changed dramatically. Clinical and microbiological evidence was consistent with active tuberculosis caused by a new strain of M. tuberculosis. The exogenous reinfection of the three patients was not due to an outbreak, but the isolates from each patient showed unique patterns.

Objective: Disseminated Mycobacterium avium infection is an emerging opportunistic disease among patients with acquired immunodeficiency syndrome (AIDS) in Brazil. The mode of transmission of M. avium in a developing country setting needs to be better characterized., Methods: Mycobacterium avium strain collections in São Paulo and Rio de Janeiro were analyzed according to the strains' IS1245 DNA gel electrophoretic migration patterns. Medical records of the patients from whom M. avium isolates were available were reviewed, and their demographic characteristics were stratified according to the isolates' IS1245 DNA fingerprint patterns., Results: Of 105 patients, 33 (31%) with M. avium isolated between 1990 and 1994 had strains having IS1245 patterns identical in patterns seen in isolates from two or more patients (designated as cluster pattern strains). Cluster pattern strains were isolated from 21 (39%) of 54 patients with disseminated infection (defined as infection due to M. avium isolated from a sterile site in an adult patient). Six of the cluster pattern strains were isolated only from sterile sites. In São Paulo, cluster pattern strains were significantly more likely to be isolated from patients with disseminated disease., Conclusions: These preliminary observations suggest that in large cities of Brazil, a high proportion (at least 39%) of disseminated M. avium infections in patients with AIDS results from a recent transmission. Some strains of M. avium may be more likely to cause disseminated disease than others after an infection.

Susceptibility to autologous and heterologous neutralization of primary human immunodeficiency virus (HIV)-1 isolates belonging to subtype B, to the B"-variant of subtype B or to subtype F from infected individuals residing in Rio de Janeiro was assayed. A lower infectivity of the B"- and F isolates when compared to the classical B-subtype HIV-1 isolates was observed. Comparisons of neutralization susceptibilities were carried out for 19 B-subtype, 11 B"-variant and two F-subtype HIV-1 isolates with plasma from autologous and heterologous samples. Frequency of autologous neutralization was slightly lower for B-subtype isolates in comparison to B"-variant isolates. Heterologous intra-subtype neutralization was significantly lower for B-subtype than for the B"-variant or the F-subtype isolates. While B-subtype isolates were neutralized by most anti-F-subtype plasma, F-subtype isolates, although most susceptible to F-subtype antibodies, were highly susceptible to neutralization by anti-B-subtype antibodies. Cross-neutralization for B"-variant and B-subtype isolates was not as extensive as observed for B- and F-subtype isolates. However, the results presented indicate a quite extensive cross-neutralization between Brazilian HIV-1 isolates.

Efforts to characterize HIV-1 polymorphism and anti-HIV immune response are being made in areas where anti-HIV/AIDS vaccines are to be employed. Anti-HIV-1 humoral immune response is being studied in infected individuals residents in Rio de Janeiro, in distinct cohorts involving recent seroconvertors, pregnant women or intravenous drug users (IDU). Comparative analyses of specificity of antibody response towards epitopes important for anti-HIV-1 immune response indicate quantitative differences between cohorts, with an exceptionally strong response in IDUs and weakest response in pregnant women. However, a comparative analysis between pregnant women cohorts from Rio de Janeiro and Rio Grande do Sul indicated an even lower response (with exception of the anti-V3-C clade peptide recognition) for the southern cohort. Studies analysing the immune function of the humoral response indicate a quite elevated occurrence of antibodies capable for neutralizing heterologous primary HIV-1 isolates from Rio de Janeiro. Attempts to correlate seroreactivity with HIV-1 neutralization with respect to HIV-1 polymorphism were not very successful: while the Brazilian B clade B " variant could be recognized by binding assays, no significant distinction of HIV-1 clades/variants was observed in viral neutralization assays.

Background: Bacillemia is a key event in the pathogenesis of tuberculosis. Although current evidence indicates that Mycobacterium tuberculosis bacteremia is rare in patients seronegative for the human immunodeficiency virus, it has been increasingly reported in patients with the acquired immunodeficiency syndrome (AIDS)., Objective: To determine clinical and laboratory characteristics of patients with AIDS and tuberculosis with and without bacillemia., Methods: Fifty patients with AIDS with clinical suspicion of disseminated mycobacterial disease were prospectively selected. Three consecutive blood samples were collected for culture using a standardized protocol., Results: Mycobacterium was isolated from any body site in 42 patients (84%). Bacillemia was detected in 30 (71.4%) of these 42 patients: 11 (28.2%) caused by Mycobacterium avium-intracellulare complex and 19 (71.8%) caused by M tuberculosis. Blood culture was the only method used to confirm the diagnosis in 5 (15%) of the 33 tuberculosis cases. Tuberculosis in patients with AIDS developed with nonspecific insidious symptoms, a remarkable elevated alkaline phosphatase level, and without the classic miliary radiological pattern. We could demonstrate 2 previously unrevealed clinical characteristics of bacteremic tuberculosis in patients with AIDS: a shift to the left in the white blood cell count and abdominal lymph node enlargement. In patients with tuberculosis, the in-hospital mortality rate was higher among patients with bacillemia, although the posttreatment survival rate was comparable., Conclusions: Blood culture is a valuable tool to confirm the clinical diagnosis of disseminated tuberculosis in patients with AIDS and can distinguish patients with characteristic clinical findings and outcome. Abdominal ultrasonography may be an additional helpful tool to identify these patients.

With the development of the acquired immunodeficiency syndrome (AIDS) epidemic, the isolation of mycobacteria from blood has become a common problem for clinical laboratories. In this study two methods were used for the recovery of mycobacteria from blood specimens obtained from AIDS patients: (1) direct inoculation of a biphasic medium, and (2) a non-commercial lysis-centrifugation method. A total of 3 consecutive blood samples were taken at 15-minute intervals from each of 50 AIDS patients with clinical suspicion of disseminated mycobacterial disease. Mycobacterium growth was noted in 70/138 blood specimens from 30 (60%) patients. These cultures yielded Mycobacterium tuberculosis in 19 (63%) and Mycobacterium avium complex organisms in 11 (37%) patients. Cultures using the lysis-centrifugation method were positive in 54% of the patients while cultures using biphasic medium were positive in 44% (P > 0.05). The positivity for M. avium complex was higher with lysis-centrifugation (91%) than with biphasic medium (45.4%) (P < 0.05). However, the positivities for M. tuberculosis with the lysis-centrifugation method (89.5%) and direct inoculation in biphasic medium (100%) were similar (P > 0.05). The use of a non-commercial lysis-centrifugation technique is inexpensive, reliable, and can be an alternative method for the diagnosis of mycobacteraemia in developing countries.