Urine assay for tenofovir to monitor adherence in real time to tenofovir disoproxil fumarate/emtricitabine as pre-exposure prophylaxis.

OBJECTIVES: Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is approved for pre-exposure prophylaxis (PrEP) against HIV infection. Adherence is critical for the success of PrEP, but current adherence measurements are inadequate for real-time adherence monitoring. We developed and validated a urine assay to measure tenofovir (TFV) to objectively monitor adherence to PrEP. METHODS: We developed a urine assay using high-performance liquid chromatography coupled to tandem mass spectrometry with high sensitivity/specificity for TFV that allowed us to determine TFV concentrations in log10 categories between 0 and 10 000 ng/mL. We validated the assay in three cohorts: (1) HIV-positive subjects with undetectable viral loads on a TDF/FTC-based regimen, (2) healthy HIV-negative subjects who received a single dose of TDF/FTC, and (3) HIV-negative subjects receiving daily TDF/FTC as PrEP for 24 weeks. RESULTS: The urine assay detected TFV with greater sensitivity than plasma-based measures and with a window of measurements within 7 days of the last TDF/FTC dose. Based on the urine log-linear clearance after the last dose and its concordance with all detectable plasma levels, a urine TFV concentration > 1000 ng/mL was identified as highly predictive of the presence of TFV in plasma at > 10 ng/mL. The urine assay was able to distinguish high and low adherence patterns within the last 48 h (> 1000 ng/mL versus 10-1000 ng/mL), as well as nonadherence (< 10 ng/mL) extended over at least 1 week prior to measurement. CONCLUSIONS: We provide proof of concept that a semiquantitative urine assay measuring levels of TFV could be further developed into a point-of-care test and be a useful tool to monitor adherence to PrEP.

High IP-10 levels decrease T cell function in HIV-1-infected individuals on ART.

HIV-1-infected subjects, despite control of viral replication with ART, have an altered immune cytokine/chemokine milieu. Changes in systemic cytokines and chemokines can alter immune responses. IP-10, in particular, has been associated with pathogenesis in a number of conditions, and we found that IP-10 is increased in serum in subjects who are HIV-1 infected and on stable ART compared with HIV-1-uninfected individuals. In a series of in vitro studies, we found that PBMCs exposed to IP-10 showed a significant decrease in the number of cells capable of secreting IFN-γ, as well as other cytokines, when stimulated with recall antigens. Furthermore, treatment with IP-10 led to decreased antigen-specific calcium signaling and MAPK38 phosphorylation. Importantly, the cytokines, as well as proliferative responses, could be enhanced with an IP-10 Nab. Our findings suggest that IP-10-modulating drugs may potentially enhance T cell responses to vaccination and HIV-1 in HIV+ subjects on ART.

Effect of statin therapy in reducing the risk of serious non-AIDS-defining events and nonaccidental death.

BACKGROUND: Excessive inflammation persists despite antiretroviral treatment. Statins decrease cardiovascular (CV) disease risk by reducing low-density lipoprotein cholesterol and inflammation. We performed an exploratory analysis to evaluate whether statin therapy decreased risk of non-AIDS-defining events and nonaccidental death. METHODS: A total of 3601 subjects not on a statin from the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort were included. Outcome was time to first clinical event (CV event, renal or hepatic disease, incident diabetes, thrombotic/embolic event, nontraumatic fracture, non-AIDS-defining malignancy, serious bacterial infection, or nonaccidental death); event categories were also analyzed separately. Inverse probability of treatment and censoring weighted Cox proportional hazard models were used to assess the causal statin effect. Differential statin effects by baseline covariates were evaluated. RESULTS: Over 15 135 person-years (PY) of follow-up, 484 subjects initiated statins; 616 experienced an event (crude event rate, 4.4/100 PY on a statin and 4.1/100 PY not on a statin); the unadjusted hazard ratio (HR) was 1.17 (95% confidence interval [CI], .91-1.50). In a final weighted model, the adjusted HR (AHR) was 0.81 (95% CI, .53- 1.24). Results for other clinical events were similar, except for malignancies (AHR, 0.43 [95% CI, .19-.94]) and bacterial infections (AHR, 1.30 [95% CI, .64-2.65]). No differential statin effects by baseline covariates were detected. CONCLUSIONS: Although statin therapy was not associated with a reduction in time to all non-AIDS-defining event or nonaccidental death, it was associated with a statistically significant 57% reduction in non-AIDS-defining malignancies. Confirmatory studies are needed to evaluate statin-associated reduction in risk of cancer and non-AIDS-associated morbidities.

Peripheral and visceral fat changes following a treatment switch to a non-thymidine analogue or a nucleoside-sparing regimen in HIV-infected subjects with peripheral lipoatrophy: results of ACTG A5110.

BACKGROUND: Switching a thymidine analogue to a non-thymidine analogue or changing to a nucleoside-sparing regimen has been shown to partially reverse peripheral lipoatrophy. The current study evaluated both approaches. METHODS: Subjects at 15 AIDS Clinical Trial Group sites receiving thymidine analogue stavudine- or zidovudine-containing regimens with plasma HIV RNA < or =500 copies/mL and lipoatrophy were prospectively randomized to: (i) switch the thymidine analogue to abacavir; (ii) discontinue all antiretrovirals and switch to lopinavir/ritonavir plus nevirapine (LPV/r+NVP); or (iii) delay switching for 24 weeks (ClinicalTrials.gov identifier: NCT00028314). Single-slice computer tomography of mid-thigh and abdominal fat and metabolic and virological/immunological parameters were measured at baseline and weeks 24 and 48. RESULTS: Among the 101 patients enrolled, there were significant subcutaneous thigh fat and subcutaneous abdominal tissue (SAT) increases over time and decreases in visceral adipose tissue to total adipose tissue (VAT:TAT) ratios for both interventions, and a decrease in VAT for abacavir. CD4 increased in the LPV/r+NVP arm. LPV/r+NVP had a significantly shorter time to grade 3 or higher toxicity (P = 0.007), but discontinuation rates were similar. Glucose levels did not change, but insulin decreased in the LPV/r+NVP arm. Lipids tended to increase in the LPV/r+NVP arm. CONCLUSIONS: Switching stavudine or zidovudine to a non-thymidine analogue or changing to a nucleoside reverse transcriptase inhibitor-sparing regimen is associated with qualitatively similar improvements in thigh fat, SAT and VAT:TAT ratio at 48 weeks. Abacavir also resulted in VAT reductions and LPV/r+NVP resulted in CD4 count increases.

Hyperhomocysteinaemia in HIV-infected patients: determinants of variability and correlations with predictors of cardiovascular disease.

OBJECTIVE: We evaluated hyperhomocysteinaemia (HHcy) in a cohort of HIV-infected patients in order to assess its relation to cardiovascular risk (CVR) and identify determinants of HHcy variability. METHODS: Cross-sectional observational study. HIV-infected patients on stable highly active antiretroviral therapy (ART) were evaluated for the presence of the metabolic syndrome, lipodystrophy and traditional CVR factors. Plasma homocysteine levels were measured using high-performance liquid chromatography. RESULTS: Five hundred and sixty-seven patients (38% female) with a median age of 44 years were included in the study. Homocysteine (Hcy) was significantly higher in patients with the metabolic syndrome and lipodystrophy. No significant association was found between Hcy levels and the use of ART. However, Hcy was associated with higher blood pressure, waist circumference and waist-to-hip ratio, total lean body mass, visceral adipose tissue (VAT), VAT/total adipose tissue, homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides, high-density lipoprotein cholesterol, apolipoprotein A1, B, and creatinine. All 10-year CVR assessment scores were significantly associated with Hcy. In a multivariate regression model, systolic blood pressure, vitamin supplementation and HOMA-IR were significantly and independently related to Hcy. CONCLUSIONS: Hcy is elevated in HIV-infected patients and is significantly associated with increased CVR. Measurement of Hcy might be useful in identifying particularly high-risk populations at whom therapeutic interventions could be targeted.

Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy.

Changes in fat distribution, dyslipidemia, disordered glucose metabolism, and lactic acidosis have emerged as significant challenges to the treatment of human immunodeficiency virus (HIV) infection. Over the past decade, numerous investigations have been conducted to better define these conditions, identify risk factors associated with their development, and test potential therapeutic interventions. The lack of standardized diagnostic criteria, as well as disparate study populations and research methods, have led to conflicting data regarding the diagnosis and treatment of metabolic and body shape disorders associated with HIV infection. On the basis of a review of the medical literature published and/or data presented before April 2006, we have prepared a guide to assist the clinician in the detection and management of these complications.

Increasing prevalence of resistance mutations in antiretroviral-naïve individuals with established HIV-1 infection from 1996-2001 in St. Louis.

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 1996-2001. 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 2001, 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.

Randomized, double-blind comparison of two nelfinavir doses plus nucleosides in HIV-infected patients (Agouron study 511).

OBJECTIVE: To evaluate the safety and antiretroviral activity of nelfinavir mesylate at two doses as part of a combination regimen in HIV-infected, antiretroviral-naive patients. DESIGN: Phase III, multicenter, double-blind, placebo-controlled trial. PATIENTS AND METHODS: Two-hundred and ninety-seven patients were randomized to one of three treatment groups: nelfinavir 750 mg three times daily (tid), nelfinavir 500 mg tid, or matching placebo, each in combination with open-label zidovudine (ZDV) 200 mg tid and lamivudine (3TC) 150 mg twice daily (bid). Data were analyzed on an intent-to-treat basis. RESULTS: Sixty-seven percent of patients receiving nelfinavir 750 mg tid, and 50% receiving nelfinavir 500 mg tid in combination with ZDV/3TC achieved HIV RNA < 400 copies/ml compared to 7% receiving ZDV/3TC plus placebo (P < 0.001); 55% and 30% of patients in the nelfinavir-containing arms achieved HIV RNA < 50 copies/ml at week 24. This compared with 4% in the placebo-containing arm. For patients continuing nelfinavir treatment (750 mg or 500 mg tid as treated) for a further 6 months, the proportions achieving < 400 copies/ml at week 48 were 75% and 54% (P = 0.001) and < 50 copies/ml 61% and 37%, respectively (P = 0.004). The mean increases from baseline in CD4 cell counts were also durable in patients receiving the triple combination nelfinavir therapy. The range and incidence of adverse events was similar for the two nelfinavir-containing arms, with diarrhea being the most common adverse event. CONCLUSIONS: Nelfinavir plus ZDV/3TC was superior to ZDV/3TC/placebo. In addition, the 750 mg tid nelfinavir dose was better than the 500 mg tid dose. Virologic responses were sustained over 12 months.

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

BACKGROUND: Virologic rebound can result from suboptimal antiviral potency in combination antiretroviral therapy. DESIGN: Multicenter, partially blinded, prospective, randomized study of 202 HIV-infected subjects to determine whether therapy intensification improves long-term rates of virologic suppression. METHODS: Subjects had plasma HIV RNA < 200 copies/ml, CD4 cell count of > 200 x 10(6) 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. RESULTS: Treatment 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. CONCLUSIONS: Switching to IDV + ddI + d4T + HU in patients treated with IDV + ZDV + 3TC was associated with a worse outcome, principally because of drug toxicity.

Prevalence and predictive value of intermittent viremia with combination hiv therapy.

CONTEXT: In HIV-infected patients having virologic suppression (plasma HIV RNA <50 copies/mL) with antiretroviral therapy, intermittent episodes of low-level viremia have been correlated with slower decay rates of latently infected cells and increased levels of viral evolution, but the clinical significance of these episodes is unknown. OBJECTIVE: To determine if HIV-infected patients with intermittent viremia have a higher risk of virologic failure (confirmed HIV RNA >200 copies/mL). DESIGN AND SETTING: Retrospective analysis of subjects in well-characterized cohorts, the AIDS Clinical Trials Group (ACTG) 343 trial of induction-maintenance therapy (August 1997 to November 1998) and the Merck 035 trial (ongoing since March 1995). PATIENTS: Two hundred forty-one ACTG 343 patients, of whom 101 received triple-drug therapy throughout the study, and a small group of 13 patients from Merck 035 having virologic suppression after 6 months of indinavir-zidovudine-lamivudine. MAIN OUTCOME MEASURES: Association of intermittent viremia (plasma HIV RNA >50 copies/mL with a subsequent measure <50 copies/mL) with virologic failure (2 consecutive plasma HIV RNA measures >200 copies/mL) in both study groups; evidence of drug resistance in 7 patients from the small (n = 13) study group with long-term follow-up. RESULTS: Intermittent viremia occurred in 96 (40%) of the 241 ACTG 343 patients of whom 32 (13%) had 2 consecutive HIV RNA values >50 copies/mL during the median 84 weeks of observation (median duration of observation after first intermittent viremia episode was 46 weeks). Of the 101 individuals receiving triple-drug therapy throughout, 29% had intermittent viremia; the proportion of episodes occurring during the maintenance period was 64% for the entire cohort and 68% for the group not receiving triple-drug therapy throughout vs 55% for those who did (P =.25). Intermittent viremia did not predict virologic failure: 10 (10.4%) of 96 patients with and 20 (13.8%) of 145 patients without intermittent viremia had virologic failure (relative risk, 0.76; 95% confidence interval [CI], 0.29-1.72). In a Cox proportional hazards model, the risk for virologic failure was not significantly greater in the ACTG 343 patients with intermittent viremia (hazard ratio, 1.28; 95% CI, 0.59-2.79). Median viral load in 10 ACTG 343 patients assessed between 24 and 60 weeks of therapy using an ultrasensitive 2.5-copies/mL detection level assay was 23 copies/mL in those with intermittent viremia vs <2.5 copies/mL in those without (P =.15). Intermittent viremia occurred in 6 of 13 patients from the small study group assessed after 76 to 260 weeks of therapy (using the 2.5-copies/mL detection level assay) and was associated with a higher steady state of viral replication (P =.03), but not virologic failure over 4.5 years of observation. Viral DNA sequences from 7 patients did not show evolution of drug resistance. CONCLUSIONS: Intermittent viremia occurred frequently and was associated with higher levels of replication (Merck 035), but was not associated with virologic failure in patients receiving initial combination therapy of indinavir-zidovudine-lamivudine (ACTG 343 and Merck 035). In this population, treatment changes may not be necessary to maintain long-term virologic suppression with low-level or intermittent viremia.

Timing of antiretroviral therapy. Use of Markov modeling and decision analysis to evaluate the long-term implications of therapy.

BACKGROUND: The timing of initiation of antiretroviral therapy is controversial. Current guidelines are heavily based on the principle of 'hit early, hit hard', although the long-term implications of this approach are unknown. METHODS: Using Markov modeling and decision analysis we modeled the virologic outcomes over 10 years in a hypothetical population of 10 000 HIV-infected patients in which therapy (with the possibility of three sequential regimens before the development of multidrug-resistant virus) is started immediately versus starting progressively at rates of 5, 10, 15, 20 or 30% of the original population each year. The model used inputs from available clinical trial data: virologic success rate and durability of the response of the first and subsequent regimens. We performed one-way and two-way sensitivity analysis to evaluate changes in the input variables. RESULTS: If therapy is started immediately in all patients, by 10 years 57% would be undetectable, but 38% would have detectable multidrug-resistant virus. In contrast, the population as a whole would have had better virologic outcomes if one waited before starting treatment at any progression rate; for example, initiating therapy in 10% of the subjects per year results in 64% of patients being undetectable and 24% with multidrug-resistant virus. Two-way sensitivity analysis demonstrates that immediate initiation should be at least 15 to 20% better than delayed antiretroviral therapy to justify immediate initiation of therapy over a wide range of success rates of the delayed start. CONCLUSION: Our analysis, utilizing optimistic outcomes based on short-term clinical trials, provides a theoretical basis for questioning the current aggressive early use of therapy and should help prompt studies that look at when and how to start antiretroviral therapy.

Elevated lactate levels in hospitalized persons with HIV infection.

Lactic acidosis has been described in persons with HIV infection particularly in association with the use of nucleoside reverse transcriptase inhibitors (NRTIs). Little is known about the epidemiology of this problem. We reviewed the records of all HIV-infected adults with elevated lactate levels admitted to Barnes-Jewish hospital from 1996 to 1998. There were 37 patients identified with elevated lactate levels. The annual rate of elevated lactate levels was 22.6, 33.9, and 30.8 per 1,000 admissions in 1996, 1997, and 1998, respectively. The median age of the patients was 40.4 years; median CD4(+) count was 148 cells/mm(3); and the median HIV-1 RNA level was 4,401 copies/ml. The median lactate level was 4.5 mmol/liter (range, 2.2-19 mmol/liter). Twenty-nine patients (78%) had elevated lactate levels at admission. Elevated lactate levels were associated with sepsis (48.7%), pancreatitis (13.5%), liver failure (8.1%), multiorgan failure (8.1%), and other conditions. Five patients had lactic acidosis associated with the use of antiretroviral medications; one patient with unexplained lactic acidosis and four patients with pancreatitis. The mortality rate was 45.9% (17/37). Higher lactate levels were associated with increased mortality. In conclusion, elevated lactate levels were uncommon but not rare in hospitalized patients with HIV infection. Sepsis was the most commonly associated condition and antiretroviral medications were the second most frequently associated factor. There was no significant increase in the annual rate of lactic acidosis during this 3-year period.

Resistance exercise training reduces hypertriglyceridemia in HIV-infected men treated with antiviral therapy.

Hypertriglyceridemia, peripheral insulin resistance, and trunk adiposity are metabolic complications recently recognized in people infected with human immunodeficiency virus (HIV) and treated with highly active antiretroviral therapy (HAART). These complications may respond favorably to exercise training. Using a paired design, we determined whether 16 wk of weight-lifting exercise increased muscle mass and strength and decreased fasting serum triglycerides and adipose tissue mass in 18 HIV-infected men. The resistance exercise regimen consisted of three upper and four lower body exercises done for 1-1.5 h/day, 4 days/wk for 64 sessions. Dual-energy X-ray absorptiometry indicated that exercise training increased whole body lean mass 1.4 kg (P = 0.005) but did not reduce adipose tissue mass (P = NS). Axial proton-magnetic resonance imaging indicated that thigh muscle cross-sectional area increased 5-7 cm(2) (P < 0.005). Muscle strength increased 23-38% (P < 0.0001) on all exercises. Fasting serum triglycerides were decreased at the end of training (281-204 mg/dl; P = 0.02). These findings imply that resistance exercise training-induced muscle hypertrophy may promote triglyceride clearance from the circulation of hypertriglyceridemic HIV-infected men treated with antiviral therapy.

Dynamics of HIV-1 viral load rebound among patients with previous suppression of viral replication.

OBJECTIVE: To model the dynamics of HIV-1 rebound in patients receiving suboptimal therapy after suppression of plasma viremia to < 200 copies/ml by triple combination therapy. DESIGN: Mathematical modeling of data from 23 patients switched to indinavir maintenance therapy after viral replication was suppressed with a combination of indinavir, zidovudine and lamivudine. Modeling of HIV-1 rebound among 24 patients on zidovudine/lamivudine maintenance was also performed for comparison. METHODS: Evaluation of slopes of rebound and of their heterogeneity; calculation of the basic reproductive number (Ro, the number of newly infected cells arising from each productively infected cell); regression analyses for predictors of the slope of rebound. RESULTS: Rebound of plasma HIV RNA followed a sigmoid curve with an initial exponential phase. There was significant heterogeneity in the slopes of rebound for individual patients (P < 0.001). In the indinavir maintenance rebounds, the average initial slope was estimated to be 0.587/day (doubling time 1.2 days). The slopes of rebound in patients on zidovudine/lamivudine maintenance tended to be less steep on average (P = 0.025). Among patients taking indinavir maintenance, the average Ro for the initial rebound of viremia was 4.3; in multivariate regressions, the slope of rebound was steeper during early rebound and in patients with higher viral load at the start of triple therapy or a higher CD4 cell count when indinavir monotherapy was initiated. The slope was less steep in patients with a greater increase in the number of CD4 cells during triple therapy. CONCLUSIONS: The rates of viral load increase among patients with viral rebound while receiving less than triple therapy are similar to those reported in patients interrupting therapy. Variability among patients may depend on viral fitness, target cell availability and extent of immune reconstitution.

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).

BACKGROUND: No clinical trial results directly comparing two nucleoside analog pairs in a drug regimen for HIV that includes a protease inhibitor are available. OBJECTIVE: To compare the safety and efficacy of stavudine (d4T) + lamivudine (3TC) with zidovudine (ZDV) + 3TC, each in combination with indinavir (IDV). DESIGN: Randomized, open-label, multi-center. SETTING: Fifteen HIV clinical research centers. PATIENTS: Two-hundred and four antiretroviral-naive HIV-1-infected-patients with CD4 cell counts > or = 200 x 10(6)/l and HIV-1 RNA > or = 10,000 copies/ml (bDNA assay), modified to 5000 copies/ml. INTERVENTION: d4T 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. MEASUREMENTS: Primary endpoint: plasma HIV-1 RNA < 500 copies/ml. Additional endpoints: HIV-1 RNA < or = 50 copies/ml; change from baseline in HIV-1 RNA and CD4 cell counts; safety and adverse events. RESULTS: For 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 < or = 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 x 10(6)/l and +198 x 10(6)/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 x 10(6)/l versus 110 x 10(6)/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. CONCLUSIONS: These results support the choice of d4T + 3TC as a nucleoside analog pair in combination with a protease inhibitor in an initial HIV treatment regimen.

Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy.

BACKGROUND: The use of highly active antiretroviral therapy (HAART) has been associated with multiple metabolic complications whose pathogenesis is poorly understood at the present time. METHODS: We performed a cross-sectional analysis of whole-body, lumbar spine (L1-L4) and proximal femur bone mineral density in 112 male subjects (HIV-infected patients on HAART that included a protease inhibitor, HIV-infected patients not receiving a protease inhibitor and healthy seronegative adults) using dual energy x-ray absorptiometry. RESULTS: Men receiving protease inhibitors had a higher incidence of osteopenia and osteoporosis according to World Health Organization definitions: relative risk = 2.19 (95% confidence interval 1.13-4.23) (P = 0.02). Subjects receiving protease inhibitors had greater central: appendicular adipose tissue ratios than the other two groups (P < 0.0001). There was no relationship between the central: appendicular fat ratio and the lumbar spine or proximal femur bone mineral density t- or z- scores, suggesting that osteoporosis and body fat redistribution are independent side effects of HAART. CONCLUSIONS: Osteopenia and osteoporosis are unique metabolic complications associated with protease inhibitor-containing potent antiretroviral regimens, that appear to be independent of adipose tissue maldistribution.

Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens.

CONTEXT: Loss of viral suppression in patients infected with human immunodeficiency virus (HIV), who are receiving potent antiretroviral therapy, has been attributed to outgrowth of drug-resistant virus; however, resistance patterns are not well characterized in patients whose protease inhibitor combination therapy fails afterachieving viral suppression. OBJECTIVE: To characterize drug susceptibility of virus from HIV-infected patients who are failing to sustain suppression while taking an indinavir-containing antiretroviral regimen. DESIGN AND SETTING: Substudy of the AIDS Clinical Trials Group 343, a multicenter clinical research trial conducted between February 1997 and October 1998. PATIENTS: Twenty-six subjects who experienced rebound (HIV RNA level > or =200 copies/mL) during indinavir monotherapy (n = 9) or triple-drug therapy (indinavir, lamivudine, and zidovudine; n = 17) after initially achieving suppression while receiving all 3 drugs, and 10 control subjects who had viral suppression while receiving triple-drug therapy. MAIN OUTCOME MEASURE: Drug susceptibility, determined by a phenotypic assay and genotypic evidence of resistance assessed by nucleotide sequencing of protease and reverse transcriptase, compared among the 3 patient groups. RESULTS: Indinavir resistance was not detected in the 9 subjects with viral rebound during indinavir monotherapy or in the 17 subjects with rebound during triple-drug therapy, despite plasma HIV RNA levels ranging from 10(2) to 10(5) copies/mL. In contrast, lamivudine resistance was detected by phenotypic assay in rebound isolates from 14 of 17 subjects receiving triple-drug therapy, and genotypic analyses showed changes at codon 184 of reverse transcriptase in these 14 isolates. Mean random plasma indinavir concentrations in the 2 groups with rebound were similar to those of a control group with sustained viral suppression, although levels below 50 ng/mL were more frequent in the triple-drug group than in the control group (P = .03). CONCLUSIONS: Loss of viral suppression may be due to suboptimal antiviral potency, and selection of a predominantly indinavir-resistant virus population may be delayed for months even in the presence of ongoing indinavir therapy. The results suggest possible value in assessing strategies using drug components of failing regimens evaluated with resistance testing.

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

OBJECTIVES: To evaluate plasma population pharmacokinetics and penetration into cerebrospinal fluid (CSF) by indinavir (IDV) in HIV-infected individuals receiving IDV, zidovudine and lamivudine. METHODS: Plasma 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. RESULTS: Mean 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 micromol/l (CV 57.5%), 9.51 micromol/l (CV 47.3%), 29.56 micromol/l x h (CV 46.9%) and 1.50 h (CV 20.9%), respectively. The mean IDV CSF level was 0.11 micromol/l (CV 49.7%) and the mean CSF:plasma concentration ratio was 0.017. CONCLUSIONS: Population 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.