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Joseph J Eron

Publications and source records attributed to Joseph J Eron.

At least 19 recordsLinked to original sources
PubMed2026

Effect of inhaled interferon-β1a on SARS-CoV-2 diversity and evolution.

Interferon resistance has been implicated in SARS-CoV-2 escape from innate immunity, but exogenous interferon's impact on viral evolution and diversity is unknown. SNG001, an inhaled interferon-β1a treatment, was evaluated in the ACTIV-2/A5401 randomized controlled trial of therapeutics for COVID-19. We measured viral kinetics and performed whole-genome sequencing on longitudinal nasal swabs collected from ACTIV-2 participants who received either SNG001 or placebo to assess viral sequence diversity. No difference in nasal viral load decay was detected between study arms when stratifying by SARS-CoV-2 variant or by viral culture conversion. Compared to placebo participants, the SNG001-treated participants displayed significantly lower nonsynonymous amino acid average pairwise distance, indicating lower sequence diversity. Similarly, SNG001-treated individuals also developed numerically fewer nonsynonymous mutations during their infection in ORF1a, ORF1b, Spike, and Nucleocapsid. No specific emerging SARS-CoV-2 nonsynonymous amino acid changes indicating signatures of viral escape were enriched in those receiving SNG001. These in vivo data provide an intriguing signal that exogenous interferon-β1a may restrict SARS-CoV-2 viral diversity and add to growing evidence that interferon levels play a critical role in antiviral responses during COVID-19.IMPORTANCESARS-CoV-2 encodes several genes which can antagonize the interferon signaling cascade, preventing it from activating antiviral responses and thereby facilitating viral establishment and dissemination. It is unknown how the administration of exogenous interferon might affect viral evolution and immune escape. ACTIV-2/A5401 represents a unique opportunity to study the virologic effects of interferon treatment in a rigorous randomized, placebo-controlled clinical trial setting. Our characterization of longitudinal nasal samples shows that interferon-treated individuals had lower viral diversity and no evidence of viral escape mutations.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04518410.

Humans↗
PubMed2007

Psychiatric illness and virologic response in patients initiating highly active antiretroviral therapy.

BACKGROUND: Mental illness (MI) and substance abuse (SA) are common in HIV-positive patients. MI/SA consistently predict poorer antiretroviral adherence, suggesting that affected patients should be at higher risk of poor virologic and immunologic response to highly active antiretroviral therapy (HAART). PARTICIPANTS: 198 HAART-naive patients initiated HAART at an academic medical center serving a heterogeneous population. METHODS: Participants were assigned a predicted probability from 0 to 1 of having each of the following: (1) any mood, anxiety, or substance use disorder; (2) clinically relevant depression; (3) alcohol abuse/dependence; and (4) drug abuse/dependence. Probabilities were based on responses to questions on an MI/SA screening instrument (Substance Abuse and Mental Illness Symptoms Screener [SAMISS]) and other clinical and sociodemographic characteristics and were derived using predictive logistic regression modeling from a separate validation study of the SAMISS compared with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnoses. Using survival analysis techniques, we assessed baseline predicted probability of psychiatric illness as a predictor of time from HAART initiation to virologic suppression (first viral load [VL] <400 copies/mL), from HAART initiation to overall virologic failure (first VL >or=400 copies/mL after suppression, time set to 0 for patients never achieving suppression), from virologic suppression to virologic rebound (first VL >or=400 copies/mL), and from HAART initiation to immunologic failure (first CD4 cell count lower than baseline). RESULTS: A higher predicted probability of any psychiatric disorder was associated with a slower rate of virologic suppression (adjusted hazard ratio [aHR] = 0.86 per 25% increment, 95% confidence interval [CI]: 0.75 to 0.98) and a faster rate of overall virologic failure (aHR = 1.22, 95% CI: 1.06 to 1.40). Associations with other outcomes were consistent in direction but not statistically significant. Predicted probability of depression was associated with slower virologic suppression (aHR = 0.79, 95% CI: 0.63 to 0.98), and predicted probabilities of alcohol and drug abuse/dependence was associated with faster overall virologic failure (aHR = 1.37, 95% CI: 1.08 to 1.74 and aHR = 1.18, 95% CI: 1.00 to 1.39, respectively). CONCLUSIONS: These results are consistent with an inferior virologic response to first HAART among patients with concurrent mood, anxiety, and substance use disorders, suggesting a clinical benefit to identification and treatment of psychiatric illness among patients initiating antiretroviral therapy.

Adult↗
PubMed2006

Evidence that intermittent structured treatment interruption, but not immunization with ALVAC-HIV vCP1452, promotes host control of HIV replication: the results of AIDS Clinical Trials Group 5068.

BACKGROUND: The ability to control human immunodeficiency virus (HIV) replication in vivo in the absence of antiretroviral therapy (ART) is a measure of the efficiency of antiviral immunity. In a study of patients with chronic, ART-suppressed HIV infection, AIDS Clinical Trials Group 5068 investigated the effects of immunization with an exogenous HIV vaccine and pulse exposure to the subject's unique viral epitopes, by means of structured treatment interruptions (STIs), on the dynamics of viral rebound during a subsequent analytical treatment interruption (ATI). METHODS: Ninety-seven subjects receiving stable ART with an HIV-1 RNA load <50 copies/mL and CD4(+) T lymphocyte count >400 cells/mm(3) were randomized to undergo continued ART, STIs, ALVAC-HIV vCP1452 immunization, or STIs and ALVAC-HIV vCP1452 immunization. RESULTS: Subjects in the 2 STI arms had a significantly longer median doubling time in the period of the initial rise of viral load, a significantly lower median peak viral load, a significantly lower median end-of-ATI viral load set point, and a greater proportion of subjects with an end-of-ATI viral load set point <1,000 copies/mL, compared with the subjects in the 2 arms without STIs. With an immunization schedule of 3 sets of 3 weekly injections, ALVAC-HIV vCP1452 did not affect viral load measures. CONCLUSIONS: In this randomized, controlled study of intermittent STI as a therapeutic autoimmunization strategy, evidence of enhanced immunologic control of HIV replication was demonstrated.

AIDS Vaccines↗
PubMed2006

Neurocognitive functioning and HAART in HIV and hepatitis C virus co-infection.

OBJECTIVES: This study examined the effects of HAART on neurocognitive functioning in persons with hepatitis C virus (HCV) and HIV co-infection. DESIGN: A prospective study examining neurocognitive performance before and after HAART initiation. METHOD: Participant groups included a mono-infected group (45 HIV+/HCV- participants) and a co-infected group (20 HIV+/HCV+ participants). A neuropsychological battery (attention/concentration, psychomotor speed, executive functioning, verbal memory, visual memory, fine motor, and gross motor functioning) was used to evaluate all participants. After 6 months of HAART, 31 HIV+ mono-infected and 13 HCV+/HIV+ co-infected participants were reevaluated. RESULTS: Neurocognitive functioning by domain revealed significantly worse performance in the co-infected group when compared to the monoinfected group on domains of visual memory and fine motor functioning. Assessment of neurocognitive functioning after antiretroviral therapy revealed that the co-infected group was no longer performing worse than the monoinfected group. CONCLUSIONS: The findings of the current study suggest that persons with HCV+/HIV+ co-infection may have greater neurocognitive declines than persons with HIV infection alone. HCV+/HIV+ co-infection may accelerate the progression of HIV related neurocognitive decline.

Adult↗
PubMed2006

Pharmacodynamics of antiretroviral agents in HIV-1 infected patients: using viral dynamic models that incorporate drug susceptibility and adherence.

We developed a novel HIV-1 dynamic model with consideration of pharmacokinetics, drug adherence and drug susceptibility to link plasma drug concentration to the long-term changes in HIV-1 RNA observation after initiation of therapy. A Bayesian approach is proposed to fit this model to clinical data from ACTG A5055, a study of two dosage regimens of indinavir (IDV) with ritonavir (RTV) in subjects failing their first protease inhibitor treatment. The HIV RNA testing was completed at days 0, 7, 14, 28, 56, 84, 112, 140, and 168. An intensive pharmacokinetic (PK) evaluation was performed on day 14 and multiple trough concentrations were subsequently collected. Pill counts were used to monitor adherence. IC(50) for IDV and RTV were determined at baseline and at virologic failure. Viral dynamic model fitting residuals were used to assess the significance of covariate effects on long-term virologic response. As univariate predictors, none of the four PK parameters C(trough), C(12 hour), C(max), and AUC was significantly related to virologic response (p > 0.05). By including drug susceptibility (IC(50)), or IC(50) and adherence measured by pill counts together, C(trough), C(12 hour), C(max) and AUC were each significantly correlated to long-term virologic response (p = 0.0055,0.0002,0.0136,0.0002 with IC(50) and adherence measured by pill counts considered). The IC(50) and adherence measured by pill counts alone were not related to the virologic response. In predicting virologic response adherence measured by pill counts did not provide any additional information to PK parameters (p = 0.064), to drug susceptibility IC(50) (p = 0.086), and to their combination (p = 0.22). Simple regression approaches did not detect any significant pharmacodynamic (PD) relationships. Any single factor of PK, adherence measured by pill counts and drug susceptibility did not contribute to long-term virologic response. But their combinations in viral dynamic modeling significantly predicted virologic response. The HIV dynamic modeling can appropriately capture complicated nonlinear relationships and interactions among multiple covariates.

Algorithms↗
PubMed2006

Advanced immunosuppression at entry to HIV care in the southeastern United States and associated risk factors.

In this study we characterized factors associated with the late initiation of HIV care in the southeastern United States. At initiation of care, antiretroviral therapy was indicated for 75% of patients, 50% had a CD4 cell count of less than 200 cells/mul, and 27% presented with an AIDS-defining illness. Male sex was an independent predictor in multivariable analysis. These results indicate an urgent need to increase HIV testing for earlier diagnosis in the southeastern USA.

Adult↗
PubMed2006

Effect of hepatitis C coinfection on discontinuation and modification of initial HAART in primary HIV care.

OBJECTIVES: To estimate the effect of hepatitis C (HCV) coinfection on time to first occurrence of either discontinuation or modification of initial HAART among previously antiretroviral therapy-naive HIV-infected patients. METHODS: The analysis included antiretroviral therapy-naive patients who initiated HAART prior to November 2003 and were participating in the University of North Carolina Center for AIDS Research, HIV/AIDS observational clinical cohort. The effect of HCV status on time to first occurrence of either HAART discontinuation or modification was assessed using Kaplan-Meier survival estimates and multivariable proportional hazards regression was used to estimate hazard ratios. RESULTS: Of 296 patients initiating HAART, 22% were coinfected with HCV. During a median follow-up of 473 days [interquartile range (IQR), 167-940] from HAART initiation, 104 (35%) patients discontinued and 91 (31%) modified their first regimen. Reasons for discontinuation and modification were comparable by HCV serostatus and included treatment failure (12%), toxicity (41%), and barriers to adherence (47%). The median time to first occurrence of either discontinuation or modification among HCV-infected patients was 401 days (IQR, 128-821), and among HCV-uninfected patients was 493 days (IQR, 204-952) (P = 0.22). After adjustment for baseline demographic and clinical characteristics, the hazard ratio contrasting HCV-infected with HCV-uninfected patients was 1.39 (95% confidence interval, 0.95-2.03; P = 0.09). CONCLUSION: HCV coinfection was only marginally associated with a shorter duration of an initial HAART regimen, suggesting optimization of a first HAART regimen may not appreciably depend on HCV serostatus.

Adult↗
PubMed2006

Factors associated with fewer visits for HIV primary care at a tertiary care center in the Southeastern U.S.

In this study we sought to evaluate sociodemographic and clinical characteristics associated with decreased access to HIV outpatient care in a University-based clinic in the Southeastern U.S. The number of HIV outpatient clinic visits per person-year was estimated among 1,404 HIV-infected individuals participating in a large observational clinical cohort study. On average, participants attended 3.38 visits per person-year (95% CI = 3.32, 3.44), with 71% attending fewer than 4 visits per year. Younger persons, of Black race/ethnicity, with less advanced HIV disease, and a shorter time from entry to HIV care, had poorer access to care, as did participants without health insurance and residing a greater distance from care. Vulnerable subgroups of HIV-infected patients in the South have decreased access to ongoing HIV health care. Interventions including more intensive counseling and active outreach for newly HIV diagnosed individuals and support with obtaining health insurance and transportation may lead to improved outcomes.

Academic Medical Centers↗
PubMed2006

Prevalence of DSM-IV-defined mood, anxiety, and substance use disorders in an HIV clinic in the Southeastern United States.

BACKGROUND: Mood and anxiety disorders, particularly depression, and substance abuse (SA) commonly co-occur with HIV infection. Appropriate policy and program planning require accurate prevalence estimates. Yet most estimates are based on screening instruments, which are likely to overstate true prevalence. SETTING: Large academic medical center in Southeast. PARTICIPANTS: A total of 1,125 patients, representing 80% of HIV-positive patients seen over a 2.5-year period, completed the Substance Abuse-Mental Illness Symptoms Screener, a brief screening instrument for probable mood, anxiety, and SA disorders. Separately, 148 participants in a validation study completed the Substance Abuse-Mental Illness Symptoms Screener and a reference standard diagnostic tool, the Structured Clinical Interview for DSM-IV. METHODS: Using the validation study sample, we developed logistic regression models to predict any Structured Clinical Interview for DSM-IV mood/anxiety disorder, any SA, and certain specific diagnoses. Explanatory variables included sociodemographic and clinical information and responses to Substance Abuse-Mental Illness Symptoms Screener questions. We applied coefficients from these models to the full clinic sample to obtain 12-month clinic-wide diagnosis prevalence estimates. RESULTS: We estimate that in the preceding year, 39% of clinic patients had a mood/anxiety diagnosis and 21% had an SA diagnosis, including 8% with both. Of patients with a mood/anxiety diagnosis, 76% had clinically relevant depression and 11% had posttraumatic stress disorder. CONCLUSIONS: The burden of psychiatric disorders in this mixed urban and rural clinic population in the southeastern United States is comparable to that reported from other HIV-positive populations and significantly exceeds general population estimates. Because psychiatric disorders have important implications for clinical management of HIV/AIDS, these results suggest the potential benefit of routine integration of mental health identification and treatment into HIV service sites.

Adult↗
PubMed2006

Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers.

OBJECTIVE: The effect of lopinavir/ritonavir (LPV/r) administration on cytochrome P450 (CYP) enzyme activity was quantified using a phenotyping biomarker cocktail. Changes in CYP2C9, CYP2C19, CYP3A, CYP1A2, N-acetyltransferase-2 (NAT-2), and xanthine oxidase (XO) activities were evaluated using warfarin (WARF) + vitamin K, omeprazole (OMP), intravenous (IV) and oral (PO) midazolam (MDZ), and caffeine (CAF). DESIGN: : Open-label, multiple-dose, pharmacokinetic study in healthy volunteers. METHODS: Subjects (n = 14) simultaneously received PO WARF 10 mg, vitamin K 10 mg, OMP 40 mg, CAF 2 mg/kg, and IV MDZ 0.025 mg/kg on days (D) 1 and 14, and PO MDZ 5 mg on D2 and D15. LPV/r (400/100 mg twice daily) was administered on D4-17. CYP2C9 and CYP2C19 activities were quantified by S-WARF AUC0-inf and OMP/5-hydroxy OMP ratio, respectively. CYP1A2, NAT-2, and XO activities were quantified by urinary CAF metabolite ratios. Hepatic and intestinal + hepatic CYP3A activities were quantified by IV (CL) and PO (CL/F) MDZ clearance, respectively. RESULTS: After LPV/r therapy, CYP2C9, CYP2C19, and CYP1A2 activity increased by 29%, 100%, and 43% (P = 0.001, 0.046, and 0.001), respectively. No changes were seen in NAT-2 or XO activity. Hepatic and intestinal + hepatic CYP3A activity decreased by 77% (P < 0.001) and 92% (P = 0.001), respectively. CONCLUSION: LPV/r therapy results in modest induction of CYP1A2 and CYP2C9 and potent induction of CYP2C19 activity. Increasing doses of concomitant medications metabolized by these enzymes may be necessary. LPV/r inhibited intestinal CYP3A to a greater extent than hepatic CYP3A activity. Doses of concomitant CYP3A substrates should be reduced when combined with LPV/r, although intravenously administered compounds may require less of a relative dose reduction than orally administered compounds.

Administration, Oral↗
PubMed2006

Immunosuppression, hepatitis C infection, and acute renal failure in HIV-infected patients.

BACKGROUND: Low CD4 cell counts predict HIV-related morbidity and mortality and may be associated with acute renal failure (ARF). OBJECTIVE: To estimate the effect of CD4 cell count on the incidence rate (IR) of ARF in ambulatory HIV-infected patients with access to highly active antiretroviral therapy. METHODS: Observational clinical cohort of HIV-infected patients recruited from a university-based infectious diseases clinic, between 2000 and 2002, and followed up until December 31, 2002. Poisson log-linear regression models were used to calculate ARF IRs, IR differences, and IR ratios. RESULTS: The mean age of the 705 study participants was 40 years, two thirds were male, and 61% were African American. Incidence rates of ARF were higher at lower CD4 cell counts and among patients who were coinfected with hepatitis C. Patients with hepatitis C coinfection who also had low CD4 cell counts had the highest adjusted IR of ARF. CONCLUSION: Immunosuppression and hepatitis C virus coinfection are associated with increased IRs of ARF in ambulatory HIV-1-infected patients.

Acute Kidney Injury↗
PubMed2006

Dose separation does not overcome the pharmacokinetic interaction between fosamprenavir and lopinavir/ritonavir.

Previous investigations have shown a significant negative two-way drug interaction between fosamprenavir (FPV) and lopinavir/ritonavir (LPV/RTV) in both human immunodeficiency virus (HIV)-infected patients and seronegative volunteers. This randomized, nonblinded, three-way crossover study of HIV-seronegative adult volunteers investigated dose separation and increased doses of RTV as a means to overcome the interaction between FPV and LPV/RTV. Eleven HIV-seronegative volunteers were given FPV plus LPV/RTV at 700 mg plus 400/100 mg every 12 hours (q12h) simultaneously for 10 days and then randomized to receive each of three 7-day treatments in one of six possible sequences, as follows: FPV plus LPV/RTV at 700 mg plus 400 mg/100 mg q12h simultaneously, FPV/RTV at 700 mg/100 mg q12h plus LPV/RTV at 400 mg/100 mg q12h, with doses separated by 4 h, and FPV/RTV at 1,400 mg/200 mg in the morning plus LPV/RTV at 800 mg/200 mg in the evening. Pharmacokinetic sampling was performed on day 8 of each treatment, and samples were analyzed for FPV, amprenavir (APV), LPV, and RTV concentrations by high-performance liquid chromatography-tandem mass spectrometry. Geometric mean ratios (GMR [with 95% confidence intervals]) for the 4- and 12-h dose separation strategies compared to simultaneous administration were calculated for the areas under the concentration-time curves from 0 to 24 h. Compared to simultaneous administration, RTV exposures increased with both 4-h and 12-h dose separation strategies (GMR, 5.30 [3.66 to 7.67] and 4.45 [3.09 to 6.41], respectively). LPV exposures also significantly increased with both 4-h and 12-h dose separation strategies (GMR, 1.76 [1.34 to 2.32] and 1.43 [1.02 to 2.01], respectively). However, both the 4- and 12-h strategies resulted in greater reductions in APV exposure (0.67 [0.54 to 0.83] and 0.77 [0.59 to 0.99], respectively) compared to simultaneous administration. Additional investigations are warranted to determine the optimal dosing of FPV with LPV/RTV.

Adolescent↗
PubMed2005

Validation of a brief screening instrument for substance abuse and mental illness in HIV-positive patients.

BACKGROUND: Substance abuse (SA) and mental illness (MI) commonly co-occur with HIV infection in the United States and have important implications for clinical management of HIV/AIDS. Yet SA/MI often go untreated due in part to a lack of practical, validated screening tools. SETTING: HIV clinic in academic medical center. METHODS: The 16-item SA/MI Symptoms Screener (SAMISS) targets SA/MI in HIV-positive patients. Consecutive consenting HIV-positive patients completed the SAMISS and then a reference standard diagnostic tool, SCID, the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). RESULTS: Twenty percent of participants (29/148) had an SA diagnosis and 41% (59/143) had an MI diagnosis in the past year on the SCID; 48% (68/143) had 1 or both. Thirty-seven percent (55/148) screened positive for SA and 69% (99/143) screened positive for MI on the SAMISS. The SAMISS had 86% (95% CI: 68%-96%) sensitivity and 75% (66%-82%) specificity for SA and 95% (86%-99%) sensitivity and 49% (38%-60%) specificity for MI. Patients with SA were likely to show up as false positives for MI and vice versa. CONCLUSION: The SAMISS functioned well as a first-line screening tool for SA/MI in this HIV clinic population. It missed few cases and was easily incorporated into a busy clinical setting. Persons screening positive require a more rigorous confirmatory psychiatric evaluation.

Adult↗
PubMed2005

Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks.

BACKGROUND: Antiretroviral tolerability is a critical factor contributing to treatment outcome. The T-20 Versus Optimized Background Regimen Only (TORO) studies assessed the safety and efficacy of enfuvirtide in treatment-experienced HIV-1-infected patients. METHODS: A total of 997 patients were randomized at a 2:1 ratio to an optimized background antiretroviral regimen plus enfuvirtide (n = 663) or an optimized background regimen alone (control group; n = 334). Control patients could switch to enfuvirtide on virologic failure. RESULTS: In total, 26.5% of patients randomized to enfuvirtide and 36.6% to the control group discontinued study treatment before week 48; the percentage of patients withdrawn for safety reasons (including adverse events [AEs], deaths, and laboratory abnormalities) was 14.0% in the enfuvirtide group and 11.6% in the control group. Injection site reactions (ISRs) occurred in 98% of enfuvirtide patients and led to treatment discontinuation in 4.4%. Treatment-related (defined as possibly, probably, or remotely) AE rates per 100 patient-years were lower with enfuvirtide (96.2) than in the control group (149.9); diarrhea, nausea, and fatigue, the most frequently reported AEs, were significantly less frequent with enfuvirtide than in the control group. Pneumonia was significantly more frequent in patients treated with enfuvirtide (6.7 vs. 0.6 events per 100 patient-years), although the incidence was within expected ranges for this population. Lymphadenopathy was also higher in enfuvirtide-treated patients (7.1 vs. 1.2 events per 100 patient-years) for control patients. CONCLUSION: The addition of enfuvirtide to an optimized background regimen does not exacerbate AEs commonly associated with antiretrovirals. ISRs limited treatment in <5% of patients.

Adult↗
PubMed2005

Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials.

BACKGROUND: The T-20 Versus Optimized Background Regimen Only (TORO) 1 and TORO 2 clinical trials are open-label, controlled, parallel-group, phase 3 studies comparing enfuvirtide plus an optimized background (OB) of antiretrovirals (n = 661) with OB alone (n = 334) in treatment-experienced HIV-1-infected patients. METHODS: The primary objective at week 48 was to investigate durability of efficacy, as measured by the percentage of patients maintaining their week 24 response or improving. Efficacy analyses used the intent-to-treat population. RESULTS: A total of 73.7% of patients randomized to the enfuvirtide group remained on treatment through week 48 versus 21.3% originally randomized to the control group. At week 48, a higher proportion of week 24 responders maintained their response or were new responders in the enfuvirtide group than in the control group in each responder category: HIV-1 RNA level > or =1.0 log(10) change from baseline, <400 copies/mL and <50 copies/mL (37.4%, 30.4%, and 18.3% in the enfuvirtide group vs. 17.1%, 12.0%, and 7.8% in the control group, respectively; P < 0.0001 for all comparisons). CD4 cell count increases from baseline were twice as great in the enfuvirtide group as in the control group. CONCLUSION: These data demonstrate durable efficacy of enfuvirtide plus OB over 48 weeks.

Adolescent↗
PubMed2005

Short-term safety and pharmacodynamics of amdoxovir in HIV-infected patients.

OBJECTIVES: To evaluate the pharmacodynamics and safety of escalating doses of amdoxovir (DAPD) monotherapy administered to treatment-naive and experienced HIV-1-infected patients over 15 days. DESIGN: Ninety patients with plasma HIV-1 RNA levels between 5000 and 250,000 copies/ml were randomized to DAPD 25, 100, 200, 300 or 500 mg twice daily or 600 mg once daily monotherapy [antiretroviral therapy (ART)-naive and ART-experienced] or to add DAPD 300 or 500 mg twice daily to existing ART. After 15 days of dosing, patients were followed for an additional 7 days. METHODS: Antiviral activity was compared between treatment arms using log10 HIV-1 RNA based on average area under the curve minus baseline to day 15. Safety and tolerability was analyzed by incidence of grade 1 to 4 clinical and laboratory adverse events. RESULTS: In ART-naive patients receiving short-term DAPD monotherapy, a median reduction in plasma HIV-1 RNA of 1.5 log10 copies/ml at the highest doses was observed. In ART-experienced patients, the reduction in viral load observed at each dose was less than that observed in treatment-naive patients (reduction of 0.7 log10 at 500 mg twice daily). The incidence of adverse events was similar across groups with the majority of adverse events reported as mild or moderate in severity. Steady-state plasma concentrations of DAPD and dioxolane guanosine followed linear kinetics. CONCLUSIONS: DAPD was well tolerated and produced antiviral activity in treatment-naive and in some treatment-experienced patients. In ART-experienced patients, the antiviral activity was significant in those with no thymidine-analogue mutations and higher baseline CD4+ cell counts.

Adult↗