Joseph B. Quinn

Treatment with Lamivudine, Zidovudine, or Both in HIV-Positive Patients with 200 to 500 CD4+ Cells per Cubic Millimeter

BACKGROUND The reverse-transcriptase inhibitor lamivudine has in vitro synergy with zidovudine against the human immunodeficiency virus (HIV). We studied the activity and safety of lamivudine plus zidovudine as compared with either drug alone as treatment for patients with HIV infection, most of whom had not previously received zidovudine. METHODS Three hundred sixty-six patients with 200 to 500 CD4+ cells per cubic millimeter who had received zidovudine for four weeks or less were randomly assigned to treatment with one of four regimens: 300 mg of lamivudine every 12 hours; 200 mg of zidovudine every 8 hours; 150 mg of lamivudine every 12 hours plus zidovudine; or 300 mg of lamivudine every 12 hours plus zidovudine. The study was double-blind and lasted 24 weeks, with an extension phase for another 28 weeks. RESULTS Over the 24-week period, the low-dose and high-dose regimens combining lamivudine and zidovudine were associated with greater increases in the CD4+ cell count (P = 0.002 and P = 0.015, respectively) and the percentage of CD4+ cells (P < 0.001 for both) and with greater decreases in plasma levels of HIV-1 RNA (P < 0.001 for both) than was treatment with zidovudine alone. Combination therapy was also more effective than lamivudine alone in lowering plasma HIV-1 RNA levels and increasing the percentage of CD4+ cells (P < 0.001 for all comparisons), and these advantages persisted through 52 weeks. Adverse events were no more frequent with combination therapy than with zidovudine alone. CONCLUSIONS In HIV-infected patients with little or no prior antiretroviral therapy, treatment with a combination of lamivudine and zidovudine is well tolerated over a one-year period and produces more improvement in immunologic and virologic measures than does treatment with either agent alone.

Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults.

AimTo estimate the effectiveness of triple combination therapy in antiretroviral-naive adults. MethodsA systematic overview of results from clinical trials involving triple combination therapy with dual nucleoside reverse transcriptase inhibitors (NRTI) and: a protease inhibitor (PI triple); a non-nucleoside reverse transcriptase inhibitor (NNRTI triple); or a third NRTI (triple NUC). Data from 23 clinical trials involving 31 independent treatment groups, 19 unique antiretroviral regimens, and 3257 enrolled patients were included in this study. ResultsMedian log10 baseline plasma HIV RNA and CD4 cell count over all trials averaged 4.69 (49 329 copies/ml) and 375 × 106 cells/l, respectively. The overall estimated percentage of patients with plasma HIV RNA ⩽ 400 copies/ml at 24 weeks was 64% [95% confidence interval (CI), 60 to 67%]. The percentages of patients with plasma HIV RNA ⩽ 50 copies/ml at 48 weeks by drug class were: PI triple, 46% (95% CI, 41 to 52%); NNRTI triple, 51% (95% CI, 43 to 59%); triple NUC, 45% (95% CI, 36 to 54%). The CD4 cell count increase over all trials at 24 and 48 weeks averaged +123 × 106 cells/l (95% CI, 111 × 106 to 135 × 106 cells/l) and +160 × 106 cells/l (95% CI, 146 × 106 to 175 × 106 cells/l), respectively and did not differ between drug classes. In multivariable regression analysis, neither baseline plasma HIV RNA level and CD4 cell count nor treatment regimen predicted plasma HIV RNA ⩽ 50 copies/ml at week 48. However, pill count was significantly negatively associated with plasma HIV RNA ⩽ 50 copies/ml at week 48 (P = 0.0085). ConclusionsThe results suggest that three drug regimens containing two NRTI with a PI, a NNRTI, or a third NRTI may provide comparable activity, and practical issues such as daily pill burden should be considered when choosing a treatment regimen.

Severe Hepatotoxicity Associated with Nevirapine Use in HIV-Infected Subjects

Human immunodeficiency virus (HIV)-infected South African patients (n=468) received blinded lamivudine or emtricitabine, stavudine, and either nevirapine or efavirenz (based on screening viral load). Baseline characteristics were analyzed in univariate and multivariate regression, to identify risk factors for hepatotoxicity (grade 3 or greater increase in serum aminotransferase levels). The occurrence of early hepatotoxicity was 17% in the nevirapine group and 0% in the efavirenz group and was balanced between the lamivudine and emtricitabine arms. Two subjects died of hepatic failure. Independent risk factors were body-mass index (BMI) <18.5, female sex, serum albumin level <35 g/L, mean corpuscular volume >85 fL, plasma HIV-1 RNA load <20,000 copies/mL, aspartate aminotransferase level <75 IU/L, and lactate dehydrogenase level <164 IU/L. The use of nevirapine in female patients with a low BMI should be discouraged.

Drug resistance and virologic response in NUCA 3001, a randomized trial of lamivudine (3TC) versus zidovudine (ZDV) versus ZDV plus 3TC in previously untreated patients.

Objective:To study the effect of HIV-1 resistance to lamivudine (3TC) and zidovudine (ZDV), and syncytium-inducing (SI) phenotype on virologic response to treatment with ZDV, 3TC, or ZDV plus 3TC in previously untreated individuals with HIV-1 infection. Design:A prospective virologic substudy of GlaxoWellcome protocol NUCA 3001. Methods:HIV-1 isolates obtained at study entry and at week 12 were expanded in peripheral blood mononuclear cell (PBMC) culture, titered, and assayed for phenotypic and genotypic evidence of resistance to ZDV and 3TC, and for syncytium formation on MT-2 cells. Results:Phenotypic and genotypic resistance to 3TC was detected in the majority of HIV-1 isolates from patients who received 3TC alone or in combination with ZDV. Despite showing 3TC resistance, subjects who received 3TC in combination with ZDV had significantly greater decreases in plasma HIV-1 RNA levels compared with those who received ZDV alone. Occurrence of the K70R ZDV resistance mutation was significantly reduced in patients who received the 3TC/ZDV combination as compared with patients on ZDV monotherapy. Plasma HIV-1 RNA returned to near-baseline levels more quickly in patients with SI isolates at study entry. Conclusions:Despite the rapid emergence of 3TC resistance, combination therapy with 3TC plus ZDV resulted in greater reduction in plasma HIV-1 RNA levels over 24 weeks as compared to ZDV monotherapy. Prevention of ZDV resistance may contribute to the sustained activity of the combination therapy.

Poor immunogenicity of the H1N1 2009 vaccine in well controlled HIV-infected individuals.

Objective:To evaluate the safety and immunogenicity of the H1N1 2009 vaccine in HIV-positive individuals. Design:A single-arm study. Setting:Clinic at the Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA. Participants:HIV-infected adults with an indication for H1N1 vaccination. Intervention:Single intramuscular 15 μg dose of the monovalent, unadjuvanted, inactivated, split virus H1N1 vaccine. Main outcomes:Immunogenicity, safety and tolerability. Results:A total of 120 participants were enrolled, 71% men, 68% African–American, with median age of 46 years. All of them but one were on antiretroviral treatment, with a median current CD4 cell counts of 502 cells/μl, and a nadir CD4 cell counts of 132 cells/μl. The HIV RNA level was below 400 copies/ml in 92% of participants. All participants completed the 3 weeks of follow-up. Thirty of the 120 (25%) participants had antibody hemagglutination-inhibition assay titers equal or greater than 1: 40 at baseline. Among participants without evidence of previous exposure, only 61% develop protective titers by week 3 of the study. Nonresponders had lower current and nadir CD4 cell counts than responders. Only four of nine participants with detectable HIV viral load at baseline developed protective antibody titers. Age and race were not predictors of the response to the vaccine. The vaccine was well tolerated. Conclusion:These results suggest that only 60% of well controlled HIV-infected individuals without preexisting immunity to H1N1 develop protective antibody titers after immunization. Alternative vaccines, dosing, adjuvants or schedule strategies are needed to achieve effective immunization of this vulnerable population.

Lamivudine Plus Zidovudine Compared with Zalcitabine Plus Zidovudine in Patients with HIV Infection: A Randomized, Double-Blind, Placebo-Controlled Trial

For the treatment of human immunodeficiency virus (HIV) type 1 infection, five nucleoside reverse transcriptase inhibitors are currently available: zidovudine, didanosine, zalcitabine, stavudine, and lamivudine. The results of clinical trials to date [1-7] suggest that the effectiveness of monotherapy with these agents is time limited. This may be because the regimens incompletely suppress viral burden and allow the emergence of drug-resistant virus populations and because of the dynamic nature of HIV infection. Combinations of anti-HIV agents in vitro provide more thorough viral suppression and may limit the emergence of drug resistance [8]. Numerous clinical trials of zidovudine plus zalcitabine or zidovudine plus didanosine [9-13] have suggested that suppression of HIV replication and increases in absolute CD4+ cell counts are greater with combination therapy than with monotherapy. Several recent trials [3, 14] have shown improved clinical outcomes for patients receiving combination therapy, including those who had previously received zidovudine monotherapy. These results have encouraged further evaluation of antiretroviral drug combinations for the treatment of HIV infection. Lamivudine ([minus]-2,3-dideoxy-3-thiacytidine; 3TC) is a nucleoside reverse transcriptase inhibitor and a potent, relatively nontoxic, selective inhibitor of HIV replication [15, 16]. It is active against zidovudine-resistant HIV isolates and is synergistic with zidovudine in vitro [17, 18]. Lamivudine is well tolerated and effectively improves prognostic virologic and immunologic markers during the treatment of HIV-infected patients [19-21]. Lamivudine-resistant HIV isolates have been identified both in vitro and in vivo during therapy in association with the development of a mutation at codon 184 in the HIV pol gene [22-27]. In vitro studies have shown that inserting the lamivudine resistance-conferring codon 184 mutation into zidovudine-resistant viruses restores phenotypic zidovudine sensitivity in tissue culture [22, 27]. Despite the rapid appearance of lamivudine-resistant viruses in clinical trials of lamivudine monotherapy or therapy with lamivudine-containing drug combinations, sustained reductions in viral burden have been seen [26, 27]. Therefore, the combination of lamivudine and zidovudinebecause of its in vitro synergy; its potential reversal of zidovudine resistance; its antiretroviral activity, seen in vivo despite the emergence of lamivudine resistance; and its favorable safety profilemay be particularly promising as therapy for HIV-infected patients previously treated with zidovudine. This NUCA 3002 study was designed to compare the safety and activity of two doses of lamivudine plus zidovudine with the safety and activity of zalcitabine plus zidovudine in patients with moderately advanced HIV infection who had previously received zidovudine. Methods Study Sample To be eligible for the study, patients had to meet all of the following criteria: age at least 18 years; documented HIV infection; absolute CD4+ cell count between 100 and 300 cells/mm3; at least 6 months of previous zidovudine therapy, including current zidovudine use at time of study entry; either no experience with didanosine, zalcitabine, or investigational antiretroviral drugs or a maximum of 4 weeks of previous treatment with didanosine; Karnofsky score of at least 60; hemoglobin concentration of at least 92 g/L for men and 88 g/L for women; absolute neutrophil count of at least 1000 cells/mm3; platelet count of at least 5 107/L; hepatic aminotransferase and alkaline phosphatase levels no greater than five times the upper limit of normal; serum bilirubin level less than 25.65 mg/L; serum creatinine concentration less than 132.6 mg/L; and total serum amylase level no greater than 1.5 times the upper limit of normal. Patients receiving chemoprophylaxis for Pneumocystis carinii pneumonia, candidiasis, or herpes simplex infections and those receiving erythropoietin or granulocyte colony-stimulating factor were eligible for inclusion. Exclusion criteria were evidence of active acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections for which therapy had not been completed; current peripheral neuropathy of mild to moderate or greater severity; significant cardiac, hepatic, renal, or neurologic disease; active cancer; or intractable diarrhea or severe malabsorption. Patients were also ineligible if they were pregnant, were breastfeeding, or had childbearing potential and were not using adequate contraception. Study Design Our study was a multicenter, randomized, double-blind (the use of zidovudine was open-label) clinical trial designed to compare the safety and activity of two different doses of lamivudine plus zidovudine with the safety and activity of zalcitabine plus zidovudine. The study was originally intended to last 24 weeks, but the duration was amended during the course of the trial so that all patients who completed 24 weeks of study therapy could continue their assigned treatment in a double-blind manner through at least 52 weeks. The study was done at 21 sites in the United States, Canada, and Puerto Rico. The institutional review board at each institution approved the study, and all patients gave written consent. Glaxo Wellcome, Inc., collected and analyzed the primary study data, and the study investigators reviewed and interpreted the results. Treatment Regimens Patients were randomly assigned to receive one of three treatment regimens: 150 mg of lamivudine every 12 hours, 200 mg of zidovudine every 8 hours, and zalcitabine placebo every 8 hours (low-dose lamivudine group); 300 mg of lamivudine every 12 hours, 200 mg of zidovudine every 8 hours, and zalcitabine placebo every 8 hours (high-dose lamivudine group); or 0.75 mg of zalcitabine and 200 mg of zidovudine every 8 hours and lamivudine placebo every 12 hours (zalcitabine group). Each dose of zidovudine (Retrovir; Glaxo Wellcome, Inc., Research Triangle Park, North Carolina) was given as two 100-mg capsules; each dose of zalcitabine (Hivid; Hoffman-La Roche, Inc., Nutley, New Jersey) was given as two 0.375-mg tablets; and each dose of lamivudine (Epivir; Glaxo Wellcome, Inc.) was given as two 75-mg tablets or as one 300-mg tablet with a matching placebo. All adjustments of medications for management of adverse events were made by each study center in a standardized and blinded manner. Adverse events and abnormal laboratory results were graded according to a toxicity rating scale developed by the Division of AIDS, National Institutes of Health. Study Assessments The primary outcome measure was the change from baseline in absolute CD4+ cell counts during the first 24 weeks of the study. The secondary outcome measures were the change in log10 plasma HIV RNA levels, clinical progressions of HIV disease, percentages of cells that were CD4+ cells, serum 2-microglobulin and neopterin levels, and serum immune complex-dissociated p24 antigen levels. Each patient was evaluated within 14 days of randomization, at least 72 hours before randomization, at the time of randomization (day 1), at study weeks 2 and 4, and every 4 weeks thereafter. Safety of the study regimens was evaluated through medical histories and physical examinations, clinical laboratory tests, and the reporting of adverse events. All laboratory studies were done by the Laboratory Corporation of America (formerly Roche Biomedical Laboratories, Research Triangle Park, North Carolina, and Raritan, New Jersey). Virologic activity was evaluated through the measurement of plasma HIV RNA levels by reverse transcriptase quantitative polymerase chain reaction (PCR) (Roche Quantiplex PCR, Laboratory Corporation of America) and the measurement of serum immune complex-dissociated p24 antigen levels (Coulter Corp., Hialeah, Florida) in all patients. The lower limit of detection for the reverse transcriptase PCR assay was 200 copies of HIV RNA per mL. Human immunodeficiency virus isolates were banked for future drug-resistance studies. Immunologic activity was evaluated through the measurement of T-lymphocyte subsets, 2-microglobulin levels, and neopterin levels in all patients. T-lymphocyte subsets were determined three times before therapy with study medications was initiated, and the baseline absolute CD4+ cell count was defined as the mean of the final two values obtained at the last visit made before and at the time of randomization. Clinical progressions of HIV disease were classified according to the criteria from the Centers for Disease Control and Prevention (CDC); these criteria consist of commonly recognized AIDS-related events (class B conditions) and AIDS-defining events (class C conditions) [28]. All diagnoses were reviewed by clinical research personnel who were blinded to treatment assignments. The criteria for the discontinuation of assigned treatment included serious adverse events; a 50% decline from baseline in absolute CD4+ cell counts on two consecutive occasions at least 28 days apart or a new AIDS-indicator illness (at the discretion of the center); pregnancy; unreliable follow-up (at the discretion of the center); or noncompliance. Patients who discontinued treatment were asked to return for monitoring of CD4+ cell counts every 4 weeks until study week 52. Statistical Analysis An equal number of patients was randomly assigned to the three treatment regimens through the use of permuted blocks at each study center. A sample size of 75 participants per treatment group was chosen to allow 80% power to detect a difference of 25 CD4+ cells/mm3 between the mean CD4+ cell counts of the three groups at the 0.05 level of significance. A summary metric [29] was used to characterize the HIV disease marker profile during the first 24 weeks of the study for the analyses of primary study outcomes. The time-weighted area under the curve (trapezoidal rule) minus the baseline value (DAVGT) was used to compare the profi

Prospective Randomized Trial of Emtricitabine versus Lamivudine Short-Term Monotherapy in Human Immunodeficiency Virus-Infected Patients

We conducted a randomized, open-label, 10-day study that compared the antiretroviral activity of emtricitabine (FTC) 25, 100, and 200 mg once daily and lamivudine (3TC) 150 mg 2 times/day in 82 human immunodeficiency virus (HIV)-infected patients with virus loads >5000 and <100,000 copies/mL who were naive for 3TC and abacavir. All FTC doses demonstrated potent antiretroviral activity. Significantly greater virus suppression was seen at the 200 mg/day dose of FTC than with the lower FTC doses and/or 3TC (P=.02, P=.04, and P=.04, respectively). At the 200 mg/day dose, FTC produced a 1.7-log10 mean reduction in virus load. Trough FTC levels at the 200 mg/day dose exceeded the in vitro 90% inhibitory concentration dose for FTC by 5-fold. The long plasma half-life and the superior antiviral activity versus 3TC of the 200 mg/day FTC dose confirmed the results of other studies and led to the selection of this dose for subsequent therapeutic trials.

A randomized study of emtricitabine and lamivudine in stably suppressed patients with HIV

Background: Once daily (QD) dosing facilitates regimen simplification and adherence to antiretroviral therapy. Emtricitabine (FTC) QD is a newly approved nucleoside reverse transcriptase inhibitor compared in this study to twice daily lamivudine (3TC BID). Methods: Controlled, open label equivalence trial of 440 HIV-1-infected patients with plasma HIV-1 RNA stably suppressed on a regimen of 3TC 150 mg BID, stavudine or zidovudine, and a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Patients were randomized to continue their current regimen or replace 3TC with FTC 200 mg QD. If HIV-1 RNA levels were ⩽ £ 400 copies/ml at 48 weeks in Protocol 303, patients could continue on FTC in Protocol 350. The primary analysis was based on virologic failure and response defined by plasma HIV-1 RNA suppression below 400 copies/ml. Results: At baseline, the mean CD4 cell count was 525 (FTC) and 533 × 106 cells/l (3TC). At week 48 in Protocol 303, the probability of virologic failure was low, 7% (FTC) and 8% (3TC), and the probability of sustained viral suppression at week 48 was equivalent between treatment arms at both the 50 and 400 copies/ml thresholds. The mean increase in CD4+ T-cell percentage was 2.5% (FTC) and 1.7% (3TC). In Protocol 350, the probability of virologic failure was 11% after 4 years on FTC-containing highly active antiretroviral therapy (HAART). Conclusion: In stably suppressed patients, 200 mg emtricitabine QD was equivalent to 150 mg lamivudine BID. Emtricitabine-containing HAART was associated with a high rate of sustained virologic suppression during 4 years of follow-up.

Comparative Efficacy of Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Combination with Efavirenz: Results of a Systematic Overview

Abstract Background: Many trials of antiretroviral therapy in treatment-naïve subjects have investigated the relative efficacy of the third drug in a treatment regimen. However, the nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) components may also affect efficacy. Method: A systematic overview of clinical trials studying initial treatment in naïve subjects receiving efavirenz-containing regimens and providing week 48 time to loss of virologic response (TLOVR) results was undertaken to compare results with different NRTI combinations. Results: Seven trials studying 3,807 subjects were identified that met the inclusion criteria. Baseline characteristics were similar across studies. Using the week 48 TLOVR results as the primary method of comparison, combinations of tenofovir and lamivudine or emtricitabine appeared to provide improved virologic responses. Similar results were obtained when the proportions of subjects with plasma HIV RNA levels <50 copies/mL were examined.

A Placebo-Controlled Trial of Ranitidine in Patients with Early Human Immunodeficiency Virus Infection

Previous uncontrolled reports have suggested that H2-antagonists may possess immunomodulatory activity in human immunodeficiency virus (HIV)-infected patients. Such trials reported improvements in HIV-related symptoms, increased absolute CD4 cell numbers, and improvements in other measures of host immunity. The present trial was a randomized, placebo-controlled, double-blind trial of ranitidine 300 mg (orally twice daily) in subjects with early HIV infection (absolute CD4 cells, 400-700/mm3). Eighty-one subjects entered the trial and 73 completed 16 weeks on study medications. There were no significant differences in the time-weighted average change from baseline between the 2 treatment groups in absolute CD4 cell number, plasma HIV RNA level, or most other surrogate markers of HIV infection. Serum beta2-microglobulin levels were significantly lower in placebo than ranitidine recipients. Ranitidine should not be recommended for the treatment of HIV-infected patients unless it is used for established indications.