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Maintenance Antiretroviral Therapies in HIV-Infected Subjects with Undetectable Plasma HIV RNA after Triple-Drug Therapy

BACKGROUND Combination antiretroviral therapy with indinavir, zidovudine, and lamivudine can suppress the level of human immunodeficiency virus (HIV) RNA in plasma below the threshold of detection for two years or more. We investigated whether a less intensive maintenance regimen could sustain viral suppression after an initial response to combination therapy. METHODS HIV-infected subjects who had CD4 cell counts greater than 200 per cubic millimeter, who had been treated with indinavir, lamivudine, and zidovudine, and who had less than 200 copies of HIV RNA per milliliter of plasma after 16, 20, and 24 weeks of induction therapy were randomly assigned to receive either continued triple-drug therapy (106 subjects), indinavir alone (103 subjects), or a combination of zidovudine and lamivudine (107 subjects). The primary end point was loss of viral suppression, which was defined as a plasma level of at least 200 copies of HIV RNA per milliliter on two consecutive measurements during maintenance therapy. RESULTS During maintenance treatment, 23 percent of the subjects receiving indinavir and 23 percent of those receiving zidovudine and lamivudine, but only 4 percent of those receiving all three drugs, had loss of viral suppression (P<0.001 for the comparison between triple-drug therapy and the other two maintenance regimens). Subjects with greater increases in CD4 cell counts during induction therapy, higher viral loads at base line (i.e., at the beginning of induction therapy), and slower rates of viral clearance were at greater risk for loss of viral suppression. The presence of zidovudine-resistance mutations in HIV RNA at base line was strongly predictive of the loss of viral suppression in subjects treated with zidovudine and lamivudine. CONCLUSIONS The suppression of plasma HIV RNA after six months of treatment with indinavir, zidovudine, and lamivudine is better sustained by the continuation of these three drugs than by maintenance therapy with either indinavir alone or zidovudine and lamivudine.

A comparison of stavudine plus lamivudine versus zidovudine plus lamivudine in combination with indinavir in antiretroviral naive individuals with HIV infection : selection of thymidine analog regimen therapy (START I)

BackgroundNo clinical trial results directly comparing two nucleoside analog pairs in a drug regimen for HIV that includes a protease inhibitor are available. ObjectiveTo compare the safety and efficacy of stavudine (d4T) + lamivudine (3TC) with zidovudine (ZDV) + 3TC, each in combination with indinavir (IDV). DesignRandomized, open-label, multi-center. SettingFifteen HIV clinical research centers. PatientsTwo-hundred and four antiretroviral-naive HIV-1-infected-patients with CD4 cell counts ⩾ 200 × 106/l and HIV-1 RNA ⩾ 10 000 copies/ml (bDNA assay), modified to 5000 copies/ml. Interventiond4T 40 mg twice a day, 3TC 150 mg twice a day plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h (modified to 300 mg every 12 h) plus 3TC and IDV. MeasurementsPrimary endpoint: plasma HIV-1 RNA < 500 copies/ml. Additional endpoints: HIV-1 RNA ⩽ 50 copies/ml; change from baseline in HIV-1 RNA and CD4 cell counts; safety and adverse events. ResultsFor HIV-1 RNA, 62% of patients on d4T + 3TC + IDV and 54% of patients on ZDV + 3TC + IDV had < 500 copies/ml HIV RNA at weeks 40 through 48 [90% confidence interval, −0.204 to 0.036;P = 0.213], with 49% and 47% respectively achieving ⩽ 50 copies/ml at 48 weeks (90% CI, −0.134 to 0.096;P = 0.834). Median change in CD4 cell counts at 48 weeks was + 227 × 106/l and + 198 × 106/l for the d4T- and ZDV-containing arms, respectively. The median time-weighted average change from baseline in CD4 cell counts was significantly greater at 48 weeks in the d4T-containing arm (142 × 106/l versus 110 × 106/l;P = 0.033). Serious adverse events were not significantly different between treatment arms, but there were significant differences for frequency of adverse events of all severity with increased nausea and vomiting in the ZDV-containing arm, and increased diarrhea and rash in the d4T-containing arm. ConclusionsThese results support the choice of d4T + 3TC as a nucleoside analog pair in combination with a protease inhibitor in an initial HIV treatment regimen.

Resistance to penicillin and non-beta-lactam antibiotics of Streptococcus pneumoniae at a children's hospital.

During a 12-month period we tested all isolates of Streptococcus pneumoniae recovered from patients at St. Louis Childrens Hospital for resistance to penicillin and other antibiotics. Twenty-seven (20%) of 136 had relative penicillin resistance (minimum inhibitory concentration 0.1 to 1.0 microgram/ml) and 8 (6%) were fully resistant (minimum inhibitory concentration > or = 2.0 micrograms/ml). Sixteen percent from blood and cerebrospinal fluid were resistant, compared with 30% from other body sites. The resistant isolates were of diverse serotypes and included 38% intermediate and 6% resistant to cefotaxime, 40% resistant to trimethoprim-sulfamethoxazole and 20% resistant to erythromycin. Patients with resistant isolates were more likely to have taken antibiotics of the aminopenicillin class and to be of the white race. We conclude that penicillin-resistant pneumococci, including some with resistance to third generation cephalosporins and some with multidrug resistance to non-beta-lactam antibiotics, are widespread in the St. Louis area. The presence of these stains requires reconsideration of current approaches to the antibiotic therapy of a variety of infectious diseases in which pneumococci play a prominent role.

Progressive Multifocal Leukoencephalopathy in Patients with AIDS Receiving Highly Active Antiretroviral Therapy

Recent reports suggest that human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) may improve with highly active antiretroviral therapy (HAART). We observed three patients who developed PML while receiving HAART. All patients received HAART for 4-11 months and had low plasma levels of HIV-1 RNA before the onset of symptoms of PML. Antiretroviral therapy was changed in two patients, and their plasma HIV-1 RNA levels declined significantly. Despite this virologic response, PML did not improve in these patients. The third patients HIV-1 RNA level became undetectable while he was receiving HAART, and his symptoms of PML improved after the addition of interferon alpha. Our observations suggest that PML can develop in patients who have shown clinical response to HAART. Furthermore, PML may not improve despite an adequate virologic response to HAART. Definitive therapy is still needed for PML.

Effects of treatment intensification with hydroxyurea in HIV-infected patients with virologic suppression

BackgroundVirologic rebound can result from suboptimal antiviral potency in combination antiretroviral therapy. DesignMulticenter, partially blinded, prospective, randomized study of 202 HIV-infected subjects to determine whether therapy intensification improves long-term rates of virologic suppression. MethodsSubjects had plasma HIV RNA < 200 copies/ml, CD4 cell count of > 200 × 106 cells/l, and treatment with indinavir (IDV) + zidovudine (ZDV) + lamivudine (3TC) for at least 6 months before randomization to stay on this regimen or to receive IDV + didanosine (ddI) + stavudine (d4T) plus or minus hydroxyurea (HU) (600 mg twice daily). Treatment failure was defined as either confirmed rebound of HIV RNA level to > 200 copies/ml or a drug toxicity necessitating treatment discontinuation. ResultsTreatment failure occurred more frequently in subjects randomized to the HU-containing arm (32.4%), than in those taking IDV + ddI + d4T (17.6%) or IDV + ZDV + 3TC (7.6%). The time to treatment failure was shorter for the HU-containing arm compared with the IDV + ZDV + 3TC (P < 0.0001) or IDV + ddI + d4T arms (P = 0.032). Dose-limiting toxicities rather than virologic rebound accounted for the differences between treatment failure among the study arms. Pancreatitis led to treatment discontinuation in 4% of subjects in treatment arms containing ddI + d4T. Three subjects with pancreatitis died, all randomized to the HU-containing arm. ConclusionsSwitching to IDV + ddI + d4T + HU in patients treated with IDV + ZDV + 3TC was associated with a worse outcome, principally because of drug toxicity.

Emerging Bone Problems in Patients Infected with Human Immunodeficiency Virus

Recently, a high incidence of osteopenia and osteoporosis has been observed in individuals infected with human immunodeficiency virus (HIV). This problem appears to be more frequent in patients receiving potent antiretroviral therapy. Other bone-related complications in HIV-infected individuals, including avascular necrosis of the hip and compression fracture of the lumbar spine, have also been reported. People living with HIV have significant alterations in bone metabolism, regardless of whether they are receiving potent antiretroviral therapy. The underlying mechanisms to account for these observations remain unknown, although studies are underway to examine the relationship between the bone abnormalities and other complications associated with HIV and antiretroviral therapy. HIV-infected patients with osteopenia or osteoporosis should be treated similarly to HIV-seronegative patients with appropriate use of nutritional supplements (calcium and vitamin D) and exercise. Hormone replacement and antiresorptive therapies might be also indicated.

Use of the polymerase chain reaction in the diagnosis of herpes simplex encephalitis: a decision analysis model ∗

PURPOSE To evaluate the utility of an assay based on a polymerase chain reaction (PCR) of cerebrospinal fluid in the management of patients with suspected herpes simplex encephalitis. METHODS A decision model was constructed and used to compare a PCR-based approach with empiric therapy. Inputs required by the model included the sensitivity (96%) and specificity (99%) of PCR (derived from review of the literature), the prevalence of herpes simplex encephalitis (5%, based on the actual prevalence at Barnes Hospital among patients treated empirically with acyclovir), the outcomes for patients with and without herpes simplex encephalitis (derived from clinical studies of the Collaborative Antiviral Study Group and the actual experience at Barnes Hospital), and the average duration of empiric acyclovir therapy for patients with possible herpes simplex encephalitis (5.3 days based on actual experience at Barnes Hospital). RESULTS Using these input values, the decision model predicted better outcomes with empiric therapy. However, low rates of inappropriate discontinuation of empiric therapy in patients with herpes simplex encephalitis or improved diagnosis and outcome resulting from a negative PCR assay result in patients without herpes simplex encephalitis led to better outcomes with the PCR-based approach. The PCR-based approach was associated with 9.2 fewer doses of acyclovir per patient. CONCLUSION Based on the decision model using conservative assumptions, a PCR-based approach can yield better outcomes and reduced acyclovir use compared with empiric therapy.

Effect of prolonged discontinuation of successful antiretroviral therapy on CD4+ T cell decline in human immunodeficiency virus-infected patients: implications for intermittent therapeutic strategies.

This study evaluates the change in CD4(+) T cell counts among patients who achieved complete viral suppression and subsequently discontinued highly active antiretroviral therapy (HAART). We included 72 human immunodeficiency virus (HIV)-1-infected patients with plasma HIV RNA loads of <500 copies/mL for at least 3 months who then discontinued therapy for at least 12 weeks. The median CD4(+) T decay while off HAART was 16 cells/mm(3)/month (interquartile range, -6 to -34 cells/month). The mean follow-up after therapy ended was 45 weeks. The slope of the CD4(+) T cell decay was inversely correlated with the increase of CD4(+) T cells while receiving HAART, baseline virus load, CD4(+) T cell count at the time therapy was discontinued, age, and duration HIV RNA levels were undetectable. In a multiple regression analysis model, the increase of CD4(+) T cells while receiving therapy and age were independently associated with the rate of CD4(+) T cell loss.

Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients

ObjectivesTo evaluate plasma population pharmacokinetics and penetration into cerebrospinal fluid (CSF) by indinavir (IDV) in HIV-infected individuals receiving IDV, zidovudine and lamivudine. MethodsPlasma population pharmacokinetic analysis was performed on 805 IDV plasma values from 171 patients, using a non-linear mixed-effects modeling approach. CSF data from 19 patients were analyzed using an individual approach. ResultsMean individual Bayesian estimates for oral clearance (CL) and volume of distribution (V) by the final model that incorporated interoccasion variability were 0.75 l/h per kg [coefficient of variation (CV) 54.8%] and 1.74 l/kg (CV 82.7%), respectively. Mean model-predicted plasma IDV level at 8 h, maximal level, area under the plasma level–time curve up to 8 h and plasma half-life were 0.42 μmol/l (CV 57.5%), 9.51 μmol/l (CV 47.3%), 29.56 μmol/l⋅h (CV 46.9%) and 1.50 h (CV 20.9%), respectively. The mean IDV CSF level was 0.11 μmol/l (CV 49.7%) and the mean CSF:plasma concentration ratio was 0.017. ConclusionsPopulation estimates of pharmacokinetic parameters of IDV and its CSF penetration were in excellent agreement with previously reported data from individual analyses. Intraindividual interoccasion variability of IDV pharmacokinetics was estimated to be of similar order of magnitude to its interindividual variability, which may affect response to long-term antiretroviral therapy involving IDV. CSF levels of IDV exceeded its in vitro 95% inhibitory concentration of HIV replication. Given that CSF is virtually free of protein, viral suppression in the central nervous system should be achievable with an IDV-containing regimen.

Increasing prevalence of resistance mutations in antiretroviral-naïve individuals with established HIV-1 infection from 1996-2002 in St. Louis

Abstract BACKGROUND: Transmission of drug-resistant virus in HIV-1 infected individuals is well documented, particularly in patients with primary infection. Prevalence in chronically infected antiretroviral-naïve patients is reportedly low. Routine genotyping in this population is not recommended. PURPOSE: The purpose of this study was to evaluate resistance profiles in patients with established HIV infection in St. Louis. METHOD: We selected specimens from drug-naïve individuals (CD4 >300 cells/mL and VL >1000 copies/mL) with established HIV infection between 1996-2002. 62 of 75 specimens were available for genotyping. We excluded patients with evidence of acute HIV infection and long-term nonprogressors. RESULTS: The overall prevalence of resistance was 11% (7/62). From 1996 to 1998, a prevalence of 4% was observed (1/27 individuals). During the subsequent period from 1999 to 2002, the frequency increased to 17% (6/35 participants; p = .08; 95% CI 5-29%). CONCLUSION: The results suggest that the prevalence of primary resistance is increasing in our region to the point that it justifies genotypic testing in all individuals before the initiation of antiretroviral therapy. This has to be considered when designing antiretroviral clinical trials.