Judy Johnson

Early Virologic Nonresponse to Tenofovir, Abacavir, and Lamivudine in HIV-Infected Antiretroviral-Naive Subjects

BACKGROUND Antiretroviral combinations that reduce the number of pills and dosing frequency have the potential to simplify therapy. We compared 2 regimens dosed as 2 pills once daily. METHODS This was a randomized, open-label, multicenter study of tenofovir disoproxil fumarate versus efavirenz, both administered once daily with the abacavir/lamivudine fixed-dose combination in treatment-naive human immunodeficiency virus type 1 (HIV-1)-infected subjects. After reports of early nonresponse, an unplanned interim analysis was performed. Virologic nonresponse was defined as (1) a <2.0-log(10) copies/mL decrease in HIV-1 RNA level by week 8, (2) an HIV-1 RNA rebound of > or =1.0 log(10) copies/mL above the nadir, or (3) for subjects with 2 consecutive HIV-1 RNA measurements <50 copies/mL, a subsequent increase to >400 copies/mL on 2 consecutive occasions. RESULTS We randomized 340 subjects. Median baseline HIV-1 RNA level and CD4+ cell count were 4.7 log(10) copies/mL and 251 cells/mm3, respectively; 194 subjects with HIV-1 RNA data from > or =8 weeks were included in the interim analysis. Virologic nonresponse occurred in 50 (49%) of 102 subjects in the tenofovir disoproxil fumarate arm, compared with 5 (5%) of 92 of subjects in the efavirenz arm (P<.001). Within 12 weeks, viral genotypes for nonresponders in the tenofovir disoproxil fumarate arm showed M184V or I/M/V mixtures in 40 (98%) of 41 subjects and K65R and M184V or mixtures in 22 (54%) of 41 subjects. The protocol was immediately amended to modify the tenofovir disoproxil fumarate arm. The efavirenz arm continued unchanged; after 48 weeks, 120 (71%) of 169 subjects achieved HIV-1 RNA levels <50 copies/mL. CONCLUSION The tenofovir disoproxil fumarate/abacavir/lamivudine regimen resulted in an unexpected and unacceptably high rate of nonresponse and incidence of K65R and M184V/I. This 3-drug regimen should not be used.

Long-term results of initial therapy with abacavir and lamivudine combined with efavirenz, amprenavir/ritonavir, or stavudine

Objective:To compare alternative class-sparing antiretroviral regimens in treatment-naive subjects. Design:Open-label, multicenter, randomized trial of up to 3 consecutive treatment regimens over 96 weeks. Methods:Two hundred ninety-one subjects received abacavir (ABC) and lamivudine and efavirenz (nonnucleoside reverse transcriptase inhibitors [NNRTIs]), ritonavir-boosted amprenavir (protease inhibitor [PI]), or stavudine (nucleoside reverse transcriptase inhibitor [NRTI]) by random assignment. The primary end points were the percentages of subjects with plasma HIV-1 RNA levels <400 copies/mL and time to treatment failure over 96 weeks. Results:Ninety percent of subjects completed 96 weeks of follow-up, and 79% remained on study treatment. At week 96, there were no differences between arms in the percentages of subjects with plasma HIV-1 RNA levels <400 and <50 copies/mL, mean changes in plasma HIV-1 RNA levels, time to treatment failure, time to first or second virologic failure, or CD4+ cell counts. The NNRTI arm had a greater percentages of subjects with RNA levels ≤50 copies/mL at weeks 24 and 48 and a greater overall duration of plasma HIV-1 RNA levels <400 copies/mL. Three subjects in the NNRTI arm had treatment failure on their first regimen and switched therapy compared with 16 in the NRTI arm and 13 in the PI arm. Twenty-one subjects had hypersensitivity reactions attributed to ABC (7.3%). Fewer drugs were used by subjects in the NNRTI arm, and fewer subjects in the NNRTI arm used 3 drug classes. Conclusions:All treatment regimens demonstrated excellent 96-week results. Secondary analyses favored the NNRTI regimen over the PI and NRTI regimens.

Reductions in Hiv-1 disease progression for zidovudine/lamivudine relative to control treatments: a meta-analysis of controlled trials

Objectives:Four randomized double-blind trials have demonstrated that zidovudine/lamivudine (ZDV/3TC) reduces HIV RNA and raises CD4 counts relative to control treatments [ZDV or ZDV/zalcitabine (ddC)]. A meta-analysis of the clinical events in these trials was conducted to determine whether treatment with ZDV/3TC was also associated with a clinical benefit. Design:The four trials, ZDV/3TC versus ZDV (NUCA3001, NUCB3001, NUCB3002) or versus ZDV/ddC (NUCA3002), were run concurrently, using the same doses of ZDV and 3TC. Setting:Investigational sites in Europe and North America. Patients:The trials recruited 972 HIV-1-positive, male and female patients aged ≥ 18 years, with CD4 counts of 100–500 cells × 106/l. Two trials were for ZDV- naive patients and two were for ZDV pre-treated patients. Main outcome measures:Progression to first new Centers for Disease Control and Prevention (CDC) B or C event was compared between all ZDV/3TC arms and all control (ZDV, ZDV/ddC) arms. Results:A total of 118 patients progressed to a first new CDC B/C event during the four trials, while 28 progressed to a new CDC C event. Meta-analysis of the trials showed a 49% reduction in progression to new CDC B/C events (relative risk, 0.509; 95% confidence interval, 0.365–0.710; P < 0.0001) and a 66% reduction in progression to new CDC C events (relative risk, 0.344; 95% confidence interval, 0.169–0.700; P= 0.003) for the ZDV/3TC patients relative to the control patients. Reductions in progression to CDC B/C disease were seen in subgroups of naive and pre-treated patients, those with high and low CD4 counts and symptomatic and asymptomatic patients. Conclusions:ZDV/3TC combination treatment delays the progression of CDC B/C disease compared with control treatments. In view of the low incidence of CDC C events, the results for progression to CDC C disease should be interpreted with caution.

virologic and Immunologic Effect of Antiretroviral Therapy on Hiv-1 in Gut-associated Lymphoid Tissue

Objectives: We evaluated virologic and immunologic responses to antiretroviral therapy in gut‐associated lymphoid tissue (GALT) compared with those found in peripheral blood. Methods: Eight HIV‐1‐infected individuals were treated with three reverse transcriptase inhibitors and one protease inhibitor. Endoscopic biopsies were performed at baseline, and at months 1, 2, and 6. We measured the level of cell‐associated multiply spliced and unspliced HIV‐1 mRNA in GALT and in peripheral blood mononuclear cells. Immunologic responses were assessed by flow cytometry. Results: Levels of multiply spliced HIV‐1 mRNA declined in parallel fashion both in peripheral blood and GALT. After 6 months of therapy, unspliced HIV‐1 mRNA in the GALT was below assay detection although it persisted in peripheral blood mononuclear cells in 4 study subjects. Although the percentage of CD4+ lymphocytes increased significantly in peripheral blood, only modest increases occurred in GALT. The percentage of activated CD8+ T cells decreased significantly in peripheral blood whereas only modest reductions occurred in GALT. Conclusions: Antiretroviral therapy effectively suppressed HIV‐1 replication in GALT. The percentage of CD4+ T cells in peripheral blood uniformly increased in all study subjects, whereas it was more variable in the GALT.

emergence of Dual Resistance to Zidovudine and Lamivudine in Hiv-1-infected Patients Treated With Zidovudine Plus Lamivudine as Initial Therapy

Summary: Presence of mutations associated with resistance to zidovudine or lamivudine was determined in isolates of HIV‐1 obtained after long‐term follow‐up of 64 infected individuals who received zidovudine, lamivudine, or both drugs as initial antiretroviral therapy. Zidovudine resistance mutations were less frequent in isolates from patients treated with combination lamivudine plus zidovudine compared with zidovudine alone, but these mutations accumulated over time. Phenotypic resistance to both drugs was found in isolates from 3 of 23 patients. In 3 other patients, lamivudineresistant virus detected at week 12 was replaced by wild‐type virus after longer follow‐up, which correlated with a return to baseline levels of plasma HIV‐1 RNA. These results show that dual resistance to zidovudine and lamivudine develops over time despite the delayed emergence of zidovudine‐resistant mutations. These results also suggest a selective advantage in vivo for HIV‐1 species that are wild‐type at RT codon 184.

Persistent antiretroviral activity of nucleoside analogues after prolonged zidovudine and lamivudine therapy as demonstrated by rapid loss of activity after discontinuation.

Antiretroviral (ARV) treatment decisions are difficult for HIV-1-infected patients on complex treatment regimens who have partial suppression of HIV-1 replication and limited treatment options. Information on the ARV activity of the components of a complex regimen would be useful. Sixteen subjects who had received prolonged therapy with zidovudine (ZDV) and lamivudine (3TC), with a median duration of 32.5 months, were discontinuing this dual-nucleoside regimen and volunteered to have plasma HIV-1 RNA levels monitored over the 2 weeks after discontinuation. All subjects experienced an increase in HIV-1 RNA after discontinuation, with a median increase of 0.54 log10 copies/mL over 2 weeks (range: 0.31-1.71; P < 0.001). An inverse correlation existed between the decline in HIV-1 RNA levels over 2 to 3 years on nucleoside analogue therapy and the increase over the 10 to 14 days off therapy (Spearman r = −0.53; P = 0.036). Over the 2-week period, a subset of individuals who had genotype testing at multiple reverse transcriptase codons associated with ZDV and 3TC resistance had no changes in genotype off therapy. Nucleoside analogue reverse transcriptase inhibitors may have continued ARV activity despite long durations of partially suppressive therapy and the presence of resistant HIV-1.

Correspondence between the effect of zidovudine plus lamivudine on plasma HIV level/CD4 lymphocyte count and the incidence of clinical disease in infected individuals

Objectives:To investigate whether apparently beneficial changes in plasma HIV RNA level and CD4 lymphocyte count that are induced by antiretroviral therapy are associated with a corresponding clinical benefit. Methods:For 620 patients in two randomized, double-blind trials of lamivudine (3TC) and zidovudine (ZDV) plasma HIV RNA and CD4 lymphocyte count changes were compared in patients randomized to 3TC plus ZDV and patients randomized to other treatment arms. The effect of therapy on the HIV RNA level and CD4 count was compared with the effect of therapy on clinical endpoints over the same time period. Results:Median baseline values for all subjects were 42 420 copies/ml for HIV RNA and 277 × 106/l for CD4 count. During the trial a significantly lower HIV RNA level and higher CD4 count was sustained in the ZDV/3TC group compared with the other group, with a difference in the median area under the curve from baseline per month of follow-up of 0.38 log10 copies/ml HIV RNA and 0.18 log2 × 106/l CD4 cells (P < 0.001 in each case). For patients who were initially asymptomatic or in CDC stage B, the adjusted relative hazard (RH) of AIDS for a twofold lower CD4 count was 3.14 [95% confidence interval (CI), 1.44–6.83] and for a 10-fold higher HIV RNA level was 3.22 (1.20–8.59). The RH of progression to AIDS expected with ZDV/3TC compared with the control treatments, given the observed effects of treatment on CD4 cell counts and HIV RNA levels, is 0.52, whereas the observed value was 0.16 (0.03–0.74). After adjustment for HIV RNA and CD4 changes over time the observed RH of progression to AIDS for ZDV/3TC treatment compared with controls was increased to 0.36 and was no longer significant (95% CI, 0.07–1.85). Conclusion:In this analysis of two trials, the effects of ZDV/3TC in reducing plasma HIV RNA and raising peripheral blood CD4 counts were associated with concurrent clinical benefits and the effect of treatment on these markers could account for at least part of the clinical benefits of therapy that were observed.

Pharmacodynamic Effects of Zidovudine 600 mg Once/Day versus 300 mg Twice/Day in Therapy‐Naïve Patients Infected with Human Immunodeficiency Virus

Study Objective. To compare the virologic activity of zidovudine monotherapy administered as 600 mg once/day versus 300 mg twice/day.

Abacavir Expanded Access Program for Adult Patients Infected with Human Immunodeficiency Virus Type 1

Expanded access programs (EAPs) provide medication to patients with life-threatening, treatment-refractory illnesses before regulatory approval and allow the acquisition of safety information. A 2-part, multisite EAP to evaluate abacavir, a carbocyclic nucleoside reverse-transcriptase inhibitor for use in combination antiretroviral therapy, was conducted. The EAP involved >13,000 adults infected with human immunodeficiency virus type 1 (HIV-1) who no longer responded to commercially available treatment regimens. Part A (open-label trials) examined the efficacy, safety, and tolerance of abacavir, and part B (provision of abacavir through expanded access) assessed only the occurrence of serious adverse events. By month 2 of abacavir-containing treatment, plasma HIV-1 RNA levels decreased by > or =0.5 log(10) in 31.4% of patients, and 5.6% of the patients had HIV-1 RNA levels decrease to <400 copies/mL. Drug-related serious adverse events were reported by 7.7% of patients, the most common of which were nausea, skin rash, diarrhea, malaise or fatigue, and fever. Approximately 4.6% of patients experienced a hypersensitivity reaction that was possibly drug related. Overall, the types and incidences of adverse events reported in the abacavir EAP were similar to those reported in phase 2 and 3 clinical trials evaluating abacavir.

Lamivudine 300 mg QD Versus Continued Lamivudine 150 mg BID with Stavudine and a Protease Inhibitor in Suppressed Patients

Abstract Purpose: To compare the efficacy (sustained virologic suppression) and safety/tolerability of a switch to lamivudine 300 mg once daily (QD) versus continued lamivudine 150 mg twice daily (BID) in virologically suppressed patients (HIV-1 RNA <400 copies/mL for ≥3 months) on stable (≥6 months) therapy with lamivudine 150 mg BID plus stavudine and either indinavir or nelfinavir. Method: Eighty-nine suppressed patients ≥18 years old with CD4 counts >50 cells/mm3 were enrolled in this phase II, open-label, multicenter, randomized, stratified (by pretrial protease inhibitor [PI]), parallel-group clinical trial. Eighty-one patients received either lamivudine 300 mg QD (n = 39) or 150 mg BID (n = 42) with their pretrial stavudine/PI regimens for 24 weeks. Results: A high rate of virologic suppression was sustained with both regimens throughout the trial. At week 24, intent-to-treat:exposed (missing = failure) analyses showed no statistically significant differences in the percentage of patients with HIV-1 RNA <400 copies/mL (95% [QD] vs. 90% [BID]) or <50 copies/mL (82% [QD] vs. 81% [BID]) or in the median change from baseline in CD4 counts (+42 cells/mm3 [QD] vs. +22 cells/mm3 [BID]). Both regimens were well tolerated. No patient experienced virologic failure, clinical disease progression, or a drug-related serious adverse event during the trial. Self-reported medication adherence was high in both groups. Conclusion: Patients who experience virologic suppression with a regimen of lamivudine 150 mg BID in combination with stavudine/PI can maintain that suppression by continuing their regimen or switching to lamivudine 300 mg QD and continuing the other components. Adverse event profiles were comparable among treatment regimens, and no new safety concerns were raised.PURPOSE To compare the efficacy (sustained virologic suppression) and safety/tolerability of a switch to lamivudine 300 mg once daily (QD) versus continued lamivudine 150 mg twice daily (BID) in virologically suppressed patients (HIV-1 RNA <400 copies/mL for > or =3 months) on stable (> or =6 months) therapy with lamivudine 150 mg BID plus stavudine and either indinavir or nelfinavir. METHOD Eighty-nine suppressed patients > or =18 years old with CD4 counts >50 cells/mm(3) were enrolled in this phase II, open-label, multicenter, randomized, stratified (by pretrial protease inhibitor [PI]), parallel-group clinical trial. Eighty-one patients received either lamivudine 300 mg QD (n = 39) or 150 mg BID (n = 42) with their pretrial stavudine/PI regimens for 24 weeks. RESULTS A high rate of virologic suppression was sustained with both regimens throughout the trial. At week 24, intent-to-treat:exposed (missing = failure) analyses showed no statistically significant differences in the percentage of patients with HIV-1 RNA <400 copies/mL (95% [QD] vs. 90% [BID]) or <50 copies/mL (82% [QD] vs. 81% [BID]) or in the median change from baseline in CD4 counts (+42 cells/mm(3) [QD] vs. +22 cells/mm(3) [BID]). Both regimens were well tolerated. No patient experienced virologic failure, clinical disease progression, or a drug-related serious adverse event during the trial. Self-reported medication adherence was high in both groups. CONCLUSION Patients who experience virologic suppression with a regimen of lamivudine 150 mg BID in combination with stavudine/PI can maintain that suppression by continuing their regimen or switching to lamivudine 300 mg QD and continuing the other components. Adverse event profiles were comparable among treatment regimens, and no new safety concerns were raised.