Esteban Ribera

Severe Nucleoside-Associated Lactic Acidosis in Human Immunodeficiency Virus–Infected Patients: Report of 12 Cases and Review of the Literature

Lactic acidosis is a rare but often fatal complication reported in some human immunodeficiency virus (HIV)-infected patients treated with nucleoside-analogue reverse-transcriptase inhibitors. We report a series of 12 patients with HIV infection treated with nucleoside analogues who developed unexplained metabolic acidosis. We have also reviewed 60 additional published cases. The aim of the present study is to describe the clinical picture, prognostic factors, and final outcome for nucleoside-associated lactic acidosis. The mortality rate is high: 33% for our patients, and 57% for the patients described in the literature. In the multivariate analysis, a lactate serum level of >10 mM (odds ratio [OR], 13.23; 95% confidence interval [CI], 2.96-59.25) was the only factor associated with higher mortality. The administration of specific therapy with cofactors against acidosis was associated with a lower mortality (OR, 0.17; 95% CI, 0.04-0.73). We conclude that specific therapy with cofactors may improve the outcome for patients with this syndrome.

Effectiveness of Cloxacillin with and without Gentamicin in Short-Term Therapy for Right-Sided Staphylococcus aureus Endocarditis: A Randomized, Controlled Trial

Tricuspid valve endocarditis is a common infection in intravenous drug users and is caused by Staphylococcus aureus in more than 80% of cases [1-4]. Right-sided endocarditis is less aggressive than left-sided disease [5]. The prognosis for patients with isolated tricuspid valve endocarditis caused by S. aureus is generally favorable, and the condition promptly responds to medical therapy [6]. For this reason, and because of the difficulty of hospitalizing patients with right-sided endocarditis for 4 to 6 weeks [7], there has been considerable interest in short courses of intravenous treatment for managing this condition [8]. Several recent studies [9-11] have shown that a combination of a penicillinase-resistant penicillin and an aminoglycoside given for 2 weeks is useful in most patients with uncomplicated, right-sided S. aureus endocarditis. However, the efficacy of a penicillinase-resistant penicillin as single-agent therapy given for 2 weeks has not yet been evaluated. Thus, the benefit of adding an aminoglycoside to short-course regimens is only theoretical [8]. We did a randomized clinical trial to compare the efficacy of cloxacillin alone with that of cloxacillin plus gentamicin as short-course therapy for right-sided S. aureus endocarditis in intravenous drug users. Methods Patients All patients who were suspected of having right-sided staphylococcal endocarditis, who were hospitalized at our institution between March 1988 and February 1993, and who admitted that they used intravenous drugs were considered for inclusion in our study. Patients who presented with tricuspid endocarditis caused by S. aureus according to the criteria shown in Table 1 were eligible. The institutional review board of our hospital approved the study, and all patients gave informed consent. Table 1. Diagnostic Criteria for Tricuspid Valve Infective Endocarditis Patients were excluded if they had any of the following: allergy to study medications, infection with methicillin-resistant S. aureus, confirmed or suspected left-sided endocarditis shown by clinical examination (indicated by characteristic regurgitation murmur or systemic embolization) or echocardiography (indicated by vegetation or valvular insufficiency), vegetation on the pulmonic valves shown by echocardiography, systemic complications requiring prolonged therapy (osteomyelitis, abscesses that could not be drained surgically), or antibiotic therapy given for longer than 48 hours before hospitalization. Clinically significant hemodynamic compromise, extensive pulmonary embolism, and large tricuspid vegetations were not considered exclusion criteria. Study Design and Treatment Our study was an open, randomized trial. Consecutive patients were randomly assigned to receive cloxacillin, 2 g intravenously every 4 hours for 14 days, alone or combined with gentamicin, 1 mg/kg of body weight intravenously every 8 hours for the first 7 days. Randomization was done using a random-number table in sets of 10: In each consecutive set, 5 patients received cloxacillin alone and 5 received combination therapy. A sealed envelope labeled with the randomization number was opened at the start of treatment. The decision to start treatment was based on microbiological criteria (positive blood cultures) or clinical criteria (fever and evidence of pulmonary embolism or poor general condition attributable to the infection). Thus, some patients were randomly assigned to treatment before the results of some procedures (echocardiography and isolation of microorganism) that might have uncovered exclusion criteria were available. Follow-up Initial patient assessment included medical history, physical examination, chest radiography, radionuclide body scanning with technetium pyrophosphate, electrocardiography, and the following laboratory tests: complete blood count, standard blood chemistries, urinalysis, serologic testing for human immunodeficiency virus (HIV), and lymphocyte subpopulation counts (when the HIV test result was positive). Standard laboratory tests and chest radiography were done every week. Two-dimensional transthoracic echocardiography was done within 4 days of hospital admission and at the end of treatment. Blood cultures were done at the time of hospital admission, 3 days after the initiation of treatment, and 2 days after the end of treatment. Aerobic and anaerobic cultures were done by using the BACTEC NR 660 System (Becton Dickinson, Mountain View, California). Follow-up visits were scheduled at 2 weeks and at 1, 3, and 6 months after the end of therapy. At the 2-week visit, a physical examination, standard laboratory tests, chest radiography, and two blood cultures were done. Subsequent blood cultures were done only if evidence suggested infection. Nine patients did not attend a follow-up visit; outcome information for these patients was obtained by telephone. Evaluation Criteria In all patients who met the exclusion criteria after random assignment, treatment was modified accordingly. In the intention-to-treat analysis, these patients were considered to have had treatment failure. Three primary end points were considered to indicate treatment failure: 1) death during treatment, 2) continued clinical or microbiological evidence of active infection after 2 weeks of therapy, and 3) relapse of staphylococcal infection. Clinical recovery was defined as the disappearance of clinical evidence of infection and the absence of radiologic abnormalities (pleural effusion or active pulmonary abscesses) at 14 days of treatment. Bacteriologic recovery was defined as a negative blood culture obtained 48 hours after the end of treatment. Successful therapy was defined as clinical and microbiological recovery without subsequent relapse. Patients who showed signs of active infection after 14 days of treatment continued to receive cloxacillin for 2 more weeks. Relapses were treated with cloxacillin alone for 4 weeks. To differentiate between relapse and reinfection, we considered clinical criteria (resumption of drug use and duration of symptom-free interval after stopping treatment) and comparison of S. aureus isolates by phage-typing. Phage-typing was done at the National Reference Center of Microbiology, Virology and Immunology, Majadahonda, Madrid, by using the international set of phages applied sequentially at the standard test dilution and a 1:100 test dilution; typing was also done after heat treatment. Reverse phagotyping was done as described elsewhere [12]. The duration of fever and appearance of complications during treatment were also evaluated. In patients without previous renal dysfunction, acute renal insufficiency was defined as a serum creatinine level greater than 176.8 mol/L. In patients with previous renal dysfunction, renal insufficiency was defined as an increase in the serum creatinine level of more than 50%. Statistical Analysis We did two analyses. An intention-to-treat analysis was done for all randomly assigned patients, and an efficacy analysis was done after we excluded patients who were found, after treatment began, to have met an exclusion criterion. We used the Fisher exact test to compare categorical baseline characteristics and outcomes of the two groups, and we used the Student t-test or the Mann-Whitney U test to compare continuous characteristics and outcomes. In the primary efficacy analysis, we compared the rates of successful treatment. Because we assumed that treatment would be successful in 95% of patients who received combination therapy [9], we estimated that almost 38 evaluable patients had to receive each regimen in order for us to detect a difference in efficacy of 20% or more, with a power of 80% at a one-sided level of 0.05. Because we anticipated that 10% to 15% of patients might have to be excluded after random assignment, 45 patients were assigned to each group. Two-tailed P values were used for all calculations; thus, the power of the study to find no differences in the efficacy of the two regimens was 70%. Results Patients During the 5-year study period, 45 patients were randomly assigned to each treatment group. Of these 90 patients, 6 (13%) of those assigned to receive cloxacillin alone and 8 (18%) of those assigned to receive combination therapy were later excluded for the following reasons. Three patients (1 receiving cloxacillin alone and 2 receiving combination therapy) had endocarditis caused by Streptococcus viridans; 7 patients (3 receiving cloxacillin alone and 4 receiving combination therapy) had involvement of the mitral, aortic, or pulmonic valves; 3 patients (1 receiving cloxacillin alone and 2 receiving combination therapy) were allergic to penicillin or had methicillin-resistant S. aureus infection; and 1 patient receiving cloxacillin alone had osteomyelitis. Two patients (1 in each group) refused further in-hospital treatment 5 and 8 days after enrollment, respectively. Thus, 74 patients (38 receiving cloxacillin alone and 36 receiving combination therapy) remained available for the efficacy analysis. Clinical, radiologic, and echocardiographic findings and laboratory values were similar in the two groups. The exclusion of 16 patients from the efficacy analysis after randomization did not change these similarities (Table 2). Table 2. Selected Baseline Characteristics of 74 Patients Evaluable for the Efficacy Analysis* Efficacy of Therapy Table 3 shows the outcome of all patients randomly assigned to treatment, as determined by the intention-to-treat analysis. A successful overall outcome was seen in 34 of the 45 patients (76% [95% CI, 61% to 87%]) assigned to receive cloxacillin only and 31 of the 45 patients (69% [CI, 53% to 82%]) assigned to receive combination therapy (P > 0.2). Table 3. Outcome of All Randomly Assigned Patients according to Treatment Regimen (Intention-to-Treat Analysis) Table 4 shows the outcomes for the 74 patients that were available for the efficacy analysis. Treatment was successful in 34 of the

Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients with tuberculosis

To determine whether rifampicin reduces serum concentrations of nevirapine and whether nevirapine modifies serum concentrations of rifampicin, levels of these agents were determined at steady state by high-performance liquid chromatography in 10 HIV-infected patients with tuberculosis. The median area under the curve (AUC) 0-12h of nevirapine before and after rifampicin was 56.2 and 32.8 microg/ml per hour, respectively ( p =.04). This represents a 31% reduction in serum nevirapine concentrations. The C(max) decreased from 5.6 to 4.5 microg/ml ( p =.04), which represented a 36% reduction. A 21% decrease in the C(min) was not statistically significant. Exposure to rifampicin did not significantly differ between those patients who were receiving and were not receiving nevirapine. However, our study shows that rifampicin reduces serum exposure to nevirapine. The clinical implications for this reduction remain to be established. Given that the lowest trough serum concentration of nevirapine exceeded by more than 40 times the protein binding adjusted median infective dose (IC(50)) of wild-type HIV in all patients, we suggest that there is no need to increase nevirapine dosage when it is given with rifampicin.

Less lipoatrophy and better lipid profile with abacavir as compared to stavudine: 96-week results of a randomized study.

Objective:To assess lipoatrophy, other toxicities, and efficacy associated with abacavir as compared with stavudine in HIV-infected antiretroviral-naive patients. Methods:This was a prospective, randomized, open trial, stratified by viral load and CD4 cell count, conducted January 2001 to July 2004. Two hundred thirty-seven adult patients with HIV infection initiating antiretroviral therapy were assigned to receive abacavir (n = 115) or stavudine (n = 122), both combined with lamivudine and efavirenz. The primary endpoint was the proportion of patients with lipoatrophy as assessed by physician and patient observation at 96 weeks. Results:A lower proportion of patients assigned to abacavir developed clinical signs of lipoatrophy (4.8% vs. 38.3%; P < 0.001). These observations were confirmed by anthropometric data. Dual energy x-ray absorptiometry (DEXA) scans performed in 57 patients showed significantly greater total limb fat loss in the stavudine arm (−1579 vs. 913 g; P < 0.001). The lipid profile in abacavir patients presented more favorable changes in the levels of triglycerides (P = 0.03), high-density lipoprotein cholesterol (HDLc; P < 0.001), and apolipoprotein A1 (P < 0.001) as well as in the ratio between total cholesterol and HDLc (P = 0.005). Throughout the study, a higher proportion of patients in the stavudine group received lipid-lowering agents as compared to the abacavir group (17% vs. 4%; P = 0.002). Similar virologic and immunologic responses were observed. Conclusions:Assuming the limitations inherent to clinical assessment, this study shows a notably weaker association of abacavir with lipoatrophy than stavudine. DEXA scans and anthropometric measurements supported the clinical findings. In addition, the lipid changes that occurred were more favorable in patients receiving abacavir.

Metabolic benefits 24 months after replacing a protease inhibitor with abacavir, efavirenz or nevirapine.

Objective:To evaluate the 24-month metabolic and morphological benefits obtained from replacing the protease inhibitor (PI) in a regimen with nevirapine, efavirenz or abacavir. Design and methods:NEFA was a randomized study designed to compare the efficacy of nevirapine, efavirenz or abacavir as substitutes for PI. A subset of 90 patients [abacavir (n = 29), efavirenz (n = 32), nevirapine (n = 29)] formed the metabolic study. Fasting total cholesterol (TC), high density lipoprotein cholesterol (HDL-c) and triglycerides levels were determined. Glucose homeostasis parameters were also collected. Lipodystrophy was evaluated by clinical examination and morphological measurements. Results:Treatment simplification led to overall lipid profile improvements. At 24 months, the two non-nucleoside reverse transcriptase inhibitors produced similar lipid benefits: HDL-c levels increased [efavirenz, 15% (P = 0.001); nevirapine, 21% (P < 0.001)] and TC to HDL-c ratios decreased [efavirenz, 14% (P < 0.001); nevirapine, 19% (P < 0.01)], an effect not observed in the abacavir arm. Non-HDL-c levels decreased by 10% in both the abacavir (P = 0.001) and efavirenz (P < 0.05) arms. Significant decreases in the levels of triglycerides occurred for the first year in all treatments; however, at 24 months most of the initial loss had been regained. Patients with baseline moderate or severe lipodystrophy obtained less-pronounced lipid benefits. Several insulin resistance markers showed a trend towards improvement. Conversely, no improvements in morphological abnormalities were observed. Conclusions:Replacing PI with efavirenz, nevirapine or abacavir improved the lipid profile, with more marked results in non-lipodystrophic patients. In contrast, this strategy does not seem to be effective for reversing body fat abnormalities.

Clinical Course and Prognostic Factors of Progressive Multifocal Leukoencephalopathy in Patients Treated with Highly Active Antiretroviral Therapy

We analyzed survival rates, neurologic function, and prognostic factors for 118 consecutive patients with acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy (PML) treated with highly active antiretroviral therapy (HAART) in 11 hospitals throughout Spain. Seventy-five patients (63.6%) remained alive for a median of 114 weeks (2.2 years) after diagnosis of PML. Neurologic function of the survivors was categorized as cure or improvement in 33, stabilization or worsening in 40, and unknown in 2. The baseline CD4+ cell count was the only variable found with prognostic significance. The odds ratio of death was 2.71 (95% confidence interval, 1.19-6.15) for patients with CD4+ cell counts of <100 cells/microL, compared with patients who had CD4+ cell counts of > or =100 cells/microL. One-third of patients with PML died despite receipt of HAART; neurologic function improved in approximately one-half of the survivors. A CD4+ cell count of <100 cells/microL was associated with higher mortality.

A simplification trial switching from nucleoside reverse transcriptase inhibitors to once-daily fixed-dose abacavir/lamivudine or tenofovir/emtricitabine in HIV-1-infected patients with virological suppression.

Background:Data comparing abacavir/lamivudine versus tenofovir/emtricitabine in antiretroviral-naive patients are controversial. We compared 48-week efficacy and safety of these combinations as substitutes of nucleosides in patients with virological suppression. Methods:We randomly assigned 333 HIV-1-infected patients on lamivudine-containing triple regimens with <200 copies per milliliter for at least 6 months to switch their nucleosides to either abacavir/lamivudine (n = 167) or tenofovir/emtricitabine (n = 166). The primary outcome was treatment failure [“switching = failure” intention to treat (ITT) analysis, noninferiority margin 12.5%]. Secondary outcomes were time to treatment failure, virological failure, adverse events, and changes in CD4 count, fasting plasma lipids, lipodystrophy, body fat, bone mineral density, and renal function. Results:Treatment failure occurred in 32 patients (19%) on abacavir/lamivudine and 22 patients (13%) on tenofovir/emtricitabine [difference 5.9%; (95% confidence interval −2.1% to 14.0%), P = 0.06]. Four patients in the abacavir/lamivudine group versus none in the tenofovir/emtricitabine group developed virological failure [difference 2.4; (95% confidence interval 0.05 to 6.0), P = 0.04]. Twenty-three patients (14%) assigned to abacavir/lamivudine and 10 (6%) to tenofovir/lamivudine experienced grade 3 or 4 adverse effects (P = 0.03). CD4 counts and plasma lipids showed higher increments in the abacavir/lamivudine group than in the tenofovir/emtricitabine group. Conclusions:In HIV-1-infected patients with virological suppression, abacavir/lamivudine did not meet the noninferiority outcome for treatment efficacy compared with tenofovir/emtricitabine.

Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment

Stavudine is a nucleoside analogue used for the treatment of HIV-1 infection, as part of highly active antiretroviral treatment. In developing countries, stavudine is used widely, owing to low cost and inclusion in generic fixed-dose combinations. In developed countries, stavudine is now rarely used, although it is highly effective. This is because newer drugs show lower rates of mitochondrial toxicities, such as lipoatrophy, peripheral neuropathy and lactic acidosis. In the development of stavudine, there was evidence that a dosage of 20 – 30 mg b.i.d. was effective, but the 40-mg b.i.d. dose gained regulatory approval. This review analyses the clinical trials conducted before and after the regulatory approval of stavudine, and shows that the dose of 30 mg b.i.d. has equivalent antiviral efficacy (given the caveats of meta-analysis), with some evidence of lower rates of peripheral neuropathy and lipoatrophy. With limited resources for HIV-1 treatment in developing countries, and only 25% of eligible patients receiving highly active antiretroviral treatment, low-cost treatment options such as stavudine still need to be pursued, if safety can be improved by dose optimisation.

Role of Structured Treatment Interruption before a 5-Drug Salvage Antiretroviral Regimen: The Retrogene Study

We evaluated the efficacy of a 5-drug salvage regimen, preceded by a 12-week, structured treatment interruption (STI), in 46 multidrug-treated, human immunodeficiency virus type 1-infected patients with detectable viremia. Patients were randomly assigned to receive a 5-drug salvage regimen immediately (noninterruption [NI] group; n=24 patients) or after 12 weeks of STI (interruption [I] group; n=22 patients). At week 48, 45% of patients in the I group and 46% of patients in the NI group had virus loads <50 HIV-1 RNA copies/mL (P=.619). No differences in CD4 cell counts were seen between groups at week 48 (P=.734). A complete reversion to wild-type genotype was detected in 35% of patients in the I group, but this phenomenon did not affect the virological response. The only overall baseline factor associated with ensuing virus suppression was a lower number of nucleoside reverse-transcriptase inhibitor-resistant mutations (relative risk, 0.66; 95% confidence interval, 0.47-0.93; P=.021). A prior STI seems to confer no additional benefit to subsequent virological or immunological outcomes of a salvage regimen.

Body composition changes after switching from protease inhibitors to raltegravir: SPIRAL-LIP substudy.

Objective:To compare 48-week changes in body fat distribution and bone mineral density (BMD) between patients switching from a ritonavir-boosted protease inhibitor (PI/r) to raltegravir (RAL) and patients continuing with PI/r. Design:Substudy of the prospective, randomized, open-label, multicenter SPIRAL study. Methods:Patients were randomized (1 : 1) to continue with the PI/r-based regimen or switch to RAL, maintaining the rest of the treatment unchanged. Dual-energy X-ray absorptiometry and computed tomography scans were performed at baseline and after 48 weeks to measure body fat and bone composition, analyzing intragroup and intergroup differences. Results:Eighty-six patients were included and 74 patients (39 RAL, 35 PI/r) completed the substudy. Significant increases in median [interquartile range (IQR)] visceral adipose tissue (VAT) [20.7 (−2.4 to 45.6) cm2, P = 0.002] and total adipose tissue (TAT) [21.4 (−1.3 to 55.4) cm2, P = 0.013] were seen within the PI/r group. No significant changes in body fat were seen with RAL or between treatment groups. Regarding bone composition, total BMD [0.01 (0 to 0.02) g/cm2, P = 0.002], total hip BMD [0.01 (0 to 0.03) g/cm2, P = 0.015] and total hip T score [0.12 (−0.05 to 0.21) SD, P = 0.004] significantly increased with RAL, with no significant changes within the PI/r group. Differences between treatment groups were significant in femoral neck BMD [0.01 (−0.02 to 0.02) g/cm2, P = 0.032] and T score [0.01 (−0.18 to 0.18) SD, P = 0.016]. Conclusion:Although there were no significant changes in body fat between groups, maintaining a PI/r-based regimen was associated with a significant increase in VAT and TAT. Switching to RAL led to a significant increase in femoral neck BMD when comparing between groups.