George Beatty

Rapid emergence of enfuvirtide resistance in HIV-1-infected patients: results of a clonal analysis.

Objectives: To study the dynamics of enfuvirtide (T-20) resistance development in HIV-1-infected subjects. Patients and Methods: Clonal analysis of gp41 sequences was performed on serial samples obtained from HIV-1-infected subjects with early virologic failure of T-20-based regimens. Results: Enfuvirtide resistance mutations at codons 36 to 45 in the first heptad repeat of gp41 emerged within 2 weeks in most subjects and were associated with the return of plasma HIV-1 RNA level toward baseline by weeks 4 to 8. Mutations at codons 36 (G36E, G36D, or G36S) and 38 (V38A, V38G, or V38M) were the most commonly detected resistance mutations at week 2. Mutations at codons 40 (Q40H) and 43 (N43D) were more prevalent at week 4 than at week 2 and seemed to emerge more slowly than mutations at codons 36 and 38. Conclusions: The rapid emergence of mutations associated with T-20 resistance in the absence of a fully suppressive antiretroviral regimen demonstrates a low genetic barrier to resistance and underscores the importance of combining T-20 with other active drugs when constructing regimens for highly treatment-experienced patients.

Activity of a ritonavir plus saquinavir-containing regimen in patients with virologic evidence of indinavir or ritonavir failure

Objective:To evaluate the virologic activity of a ritonavir plus saquinavir–containing regimen in patients who have failed an indinavir or ritonavir–containing regimen. Design:Patients were identified through a retrospective study evaluating the incidence of indinavir or ritonavir failure in our clinic. Patients:Eighteen patients failing indinavir or ritonavir therapy and who switched to a ritonavir–saquinavir-containing regimen were evaluated. Indinavir or ritonavir failure was defined as a plasma viral load >1500 copies/ml (branched DNA) after 16 weeks of continuous therapy. Interventions:All patients switched to ritonavir (400 mg twice daily) plus saquinavir (400 mg twice daily) and received concurrent therapy with two nucleoside reverse transcriptase inhibitors (NRTI). Twelve of the 18 patients modified their NRTI regimen at the time ritonavir–saquinavir was initiated. Outcome measures:Plasma viral load was monitored using a branched DNA assay. Genotypic analysis was performed using a point mutation differential hybridization technique, and was confirmed with direct sequencing. Results:Fourteen out of 18 patients completed at least 24 weeks of therapy; the remaining four patients discontinued therapy after week 12 due to a lack of virologic response or intolerance. Plasma viral load decreased a median 1.4 log10 after 4 weeks of treatment with ritonavir–saquinavir. Only four patients had a greater than 0.5 log10 decrease in viral load after 24 weeks of therapy. In eight out of 10 patients evaluated, the V82A mutation was present at the time of the switch to ritonavir–saquinavir. Viral rebound on ritonavir–saquinavir was associated with the emergence of mutations at amino acids 46, 48, 54 and 90. Conclusion:The combination of ritonavir, saquinavir and two NRTI resulted in a moderate but transient suppression of viral replication in patients who have failed indinavir or ritonavir therapy. Failure of ritonavir–saquinavir may be associated with the emergence of mutations associated with resistance to ritonavir/saquinavir monotherapy, particularly the L90M mutation.

Interruption of Enfuvirtide in HIV-1-Infected Adults with Incomplete Viral Suppression on an Enfuvirtide-Based Regimen

Many antiretroviral drugs continue to exert an anti-human immunodeficiency virus (HIV) benefit in the presence of drug resistance mutations. The degree to which enfuvirtide exerts continued antiviral activity in the presence of incomplete viral suppression has not been defined. To address this question, 25 subjects interrupted enfuvirtide while remaining on a stable background regimen. Enfuvirtide interruption was associated with an immediate but limited increase in plasma HIV-1 RNA levels. Enfuvirtide resistance waned rapidly in the absence of drug pressure and was no longer detectable by week 16 in most individuals. These data indicate that enfuvirtide has measurable antiviral activity in the setting of incomplete viral suppression. Although enfuvirtide resistance mutations are associated with significant fitness defects in vivo, the clinical significance of these mutations remains undefined.

Survival in HIV-positive transplant recipients compared with transplant candidates and with HIV-negative controls.

Objectives:To evaluate the impact of liver and kidney transplantation on survival in HIV-positive transplant candidates and compare outcomes between HIV-positive and negative recipients. Design:Observational cohort of HIV-positive transplant candidates and recipients and secondary analysis comparing study recipients to HIV-negative national registry controls. Methods:We fit proportional hazards models to assess transplantation impact on mortality among recipients and candidates. We compared time to graft failure and death with HIV-negative controls in unmatched, demographic-matched, and risk-adjusted models. Results:There were 17 (11.3%) and 46 (36.8%) deaths among kidney and liver recipients during a median follow-up of 4.0 and 3.5 years, respectively. Transplantation was associated with survival benefit for HIV-infected liver recipients with model for end-stage liver disease (MELD) greater than or equal 15 [hazard ratio (HR) 0.1; 95% confidence interval (CI) 0.05, 0.01; P < 0.0001], but not for MELD less than 15 (HR 0.7; 95% CI 0.3, 1.8; P = 0.43) or for kidney recipients (HR 0.6; 95% CI 0.3, 1.4; P = 0.23). In HIV-positive kidney recipients, unmatched and risk-matched analyses indicated a marginally significant HR for graft loss [1.3 (P = 0.07) and HR 1.4 (P = 0.052)]; no significant increase in risk of death was observed. All models demonstrated a higher relative hazard of graft loss or death in HIV-positive liver recipients; the absolute difference in the proportion of deaths was 6.7% in the risk-matched analysis. Conclusion:Kidney transplantation should be standard of care for well managed HIV-positive patients. Liver transplant in candidates with high MELD confers survival benefit; transplant is a viable option in selected candidates. The increased mortality risk compared with HIV-negative recipients was modest. Trial Registration:ClinicalTrials.Gov; NCT00074386; http://clinicaltrials.gov/.

Untreated HIV infection is associated with higher blood alcohol levels

Background:Alcohol abuse has been associated with HIV/AIDS progression, but the effects of HIV infection and treatment on alcohol exposure have not been explored to date. This pilot study examines the relationship of untreated HIV infection to blood alcohol concentrations (BAC) relative to BAC after initiation of antiretroviral therapy (ART). Methods:Fifteen volunteers with untreated HIV/AIDS participated in 2 sets of alcohol or alcohol placebo administration studies before and after initiation of ART. Oral alcohol (1 g/kg) or alcohol placebo was administered, participants were followed for pharmacokinetics, subjective responses, and cognitive effects over 8 hours. After initial alcohol studies, the ART regimen selected by participant clinicians was instituted. Observed ART dosing took place for at least 2 weeks. Participants then returned for a second set of alcohol/placebo administration studies while on ART. Results:Participants had significantly higher BAC (P < 0.001) before ART than after ART administration. Alcohol area under the curve was significantly higher in untreated HIV disease (P = 0.011) with significantly higher Cmax (P = 0.015) and Cmin (P = 0.05). The elimination rate was not different between pre-ART and post-ART conditions. Despite declines in BAC after ART initiation, no differences in subjective responses were observed with alcohol administration. Conclusions:Untreated HIV infection is associated with risk for higher BAC than that observed after ART. These findings indicate that patients with untreated HIV disease who ingest alcohol are at greater risk for alcohol associated adverse events and toxicities and underscores the need for simultaneous treatment of alcohol use disorders and HIV in patients with co-occurring conditions.

Interactions between alcohol and the antiretroviral medications ritonavir or efavirenz.

Objective:Alcohol abuse occurs frequently in those with human immunodeficiency virus (HIV) infection. Alcohol has been linked to poor response to HIV treatment and more rapid progression of HIV. One possible contributor to such observations is drug interactions between alcohol and antiretroviral (ARV) medications. This study examined drug interactions between antiretroviral therapies (ARTs) containing either efavirenz or ritonavir with alcohol. Methods:Human immunodeficiency virus–infected individuals not currently receiving ARTs participated in a randomized, double-blind, placebo-controlled study in which alcohol (or placebo) was administered and followed by blood sampling for pharmacokinetics, subjective, cardiovascular, and neuropsychological responses obtained at predetermined times. Antiretroviral therapy was then initiated and alcohol (or placebo) sessions were repeated after at least 2 weeks of observed ART. Results:Blood alcohol concentrations (BAC) were lower after ART in a pattern consistent with decreased bioavailability. No effect of alcohol on ritonavir or efavirenz pharmacokinetics was observed. A pharmacodynamic interaction between alcohol and efavirenz was observed as evidenced by no change in intoxication or drowsiness before and after efavirenz ART despite lower BAC. Conclusions:These results show the effectiveness of implementing ART and its role in diminution of BAC, which could be associated with decreased risk of physiological toxicities related to alcohol consumption relative to those with untreated HIV infection. A potential pharmacodynamic interaction between alcohol and efavirenz was observed as demonstrated by a lack of decline in ratings of intoxication and drowsiness despite decreased BAC. Alcohol consumption did not alter the pharmacokinetics of ritonavir or efavirenz.

Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndrome (IRIS) must be considered in the differential diagnosis for any patient infected with HIV who has begun ART in the preceding months. Distinguishing between manifestations of IRIS and active infection is of paramount importance and poses a diagnostic challenge to the provider in the acute care setting. Presentations of IRIS are often atypical for the precipitating pathogen, and novel presentations are likely. Of the diseases associated with IRIS, mycobacteria and cryptococcal infections are commonly encountered, as are dermatologic symptoms in general. The most clinically significant complications of IRIS are those involving the central nervous system, lungs, and eye, and in many of these scenarios systemic steroids may be of benefit. Management should rarely include interruption of ART, except possibly in severe, life-threatening complications.

Quantification of insulin-mediated glucose disposal in HIV-infected individuals: comparison of patients treated and untreated with protease inhibitors.

To describe the distribution of insulin sensitivity and glucose tolerance in HIV-infected patients, the authors measured insulin-mediated glucose disposal (IMGD) in 51 subjects (24 protease inhibitor (PI)-treated subjects and 27 non-PI-treated subjects). IMGD was determined by measuring the steady-state plasma glucose (SSPG) concentration during the last 30 minutes of a 180-minute intravenous infusion of octreotide, glucose, and insulin. In addition, oral glucose tolerance testing was performed. SSPG concentrations varied six-fold in both groups, and the mean values +/- SEM did not differ between PI-treated and non-PI-treated groups (8.7 +/- 0.9 vs. 8.0 +/- 0.7 mmol/L, respectively). The mean fasting plasma glucose concentration +/- SEM was higher in the PI-treated subjects than in the non-PI-treated subjects (5.44 +/- 0.11 vs. 5.05 +/- 0.11 mmol/L, respectively; p =.01), whereas fasting plasma insulin concentrations did not differ. PI-treated patients also had significantly higher plasma glucose (p =.001) and insulin (p =.03) responses to the oral glucose challenge. However, whereas the incremental plasma glucose response during the first 30 minutes was significantly higher in PI-treated patients, the incremental insulin response in the two groups was identical. In conclusion, insulin sensitivity varies widely in HIV-infected patients irrespective of PI treatment, and the adverse effect of PIs on insulin sensitivity is likely to be of modest magnitude. Finally, PI treatment may have an inhibitory effect on insulin secretion.

Methods for quantifying insulin resistance in human immunodeficiency virus-positive patients ☆

Various indirect indices have been used in human immunodeficiency virus (HIV)-infected individuals to assess insulin resistance, but the validity of these measures has not been rigorously assessed by comparison with physiologic methods of quantifying insulin-mediated glucose uptake (IMGU). We directly measured IMGU in 50 nondiabetic HIV-positive subjects by determining the steady-state plasma glucose (SSPG) concentration in response to a 3-hour continuous infusion of insulin, glucose, and somatostatin. Because steady-state plasma insulin concentrations were similar (approximately 60 microU/mL) in all subjects, the SSPG concentrations provided direct assessments of insulin action. Relationships between SSPG levels and various surrogate measures of IMGU derived from the 75-g oral glucose tolerance test (OGTT) were determined. The indirect measure of IMGU most closely related to SSPG concentrations was the total integrated insulin response to a 75-g glucose load (r=0.78, P<.01), accounting for approximately two thirds of the variability in SSPG (r2=0.61). Other indirect measures of IMGU, including the homeostasis assessment for insulin resistance (HOMA-IR), were also significantly related to SSPG values, but had lower magnitudes of correlation (r=0.43 to 0.61), thereby possessing limited ability to predict SSPG variability (r2=0.18 to 0.37). In conclusion, indirect measures of IMGU need to be applied with caution when evaluating insulin action in HIV-infected patients.

Diarrhea in Patients Infected with HIV Presenting to the Emergency Department

Diarrhea is an exceedingly common complaint in patients with human immunodeficiency virus (HIV) infection, and the severity of symptoms ranges from mild, self-limiting diarrhea to debilitating disease that can result in malnutrition, volume loss, and shock. Up to 40% of patients with HIV infection report at least 1 episode of diarrhea in a given month, and approximately 1 quarter of patients experience chronic diarrhea at some point. The prevalence of diarrhea increases with decreasing CD4 counts. The clinical features, diagnosis, and management of diarrhea in patients with HIV are reviewed.