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Patients Experiencing Early Virologic Failure on a Protease Inhibitor- or Nonnucleoside Reverse Transcriptase Inhibitor-Based Initial Regimen Containing a Thymidine Analogue and Lamivudine Can Be Successfully Treated With a Quadruple-Nucleoside Regimen

Rodriguez, Allan MD*; Hill-Zabala, Christina PharmD; Sloan, Louis MD; Jefferson, Thomas MD§; Yau, Linda PhD; Watson, Maria PhD; Irlbeck, David; Shaefer, Mark PharmD

JAIDS Journal of Acquired Immune Deficiency Syndromes: January 1st, 2006 - Volume 41 - Issue 1 - p 127-129
doi: 10.1097/01.qai.0000191999.77658.6e
Letters to the Editor

*University of Miami, Miami, FL, †GlaxoSmithKline, Research, Triangle Park, NC, ‡North Texas IDC, Dallas, TX, §Health for Life, Little Rock, AR

To the Editor:

The virologic goal of HIV management with antiretroviral therapy (ART) is to achieve durable suppression of HIV-1 RNA to undetectable levels.1 However, no single ART regimen has been proven to provide life-long viral suppression in all patients. Currently there is not a consensus as to how to treat patients with low-level virologic rebound. A recognized approach has been to allow low-level detectable viremia up to an arbitrary level prior to changing therapy. However, ongoing viral replication in the presence of antiretroviral drugs promotes the selection of drug resistance mutations that may compromise future treatment options.2,3 Other approaches include intensifying therapy or changing the entire regimen to include 3 active drugs.1,4 A single-class compact (3 pills/day) quadruple combination of abacavir (ABC)/lamivudine (3TC)/zidovudine (ZDV) (TZV; Trizivir, GlaxoSmithKline, Research Triangle Park, NC) and tenofovir (TDF; Viread, Gilead Sciences, Foster City, CA) offers an attractive strategy for the treatment of patients experiencing early virologic failure. Quadruple-nucleoside/tide therapy with TZV + TDF has been proven to have similar efficacy and tolerability to nonnucleoside reverse transcriptase inhibitor (NNRTI)-based therapy (3TC/ZDV + efavirenz) in treatment-naive individuals5 and it may preserve future options in other ART classes.

We conducted ESS30005 to investigate the safety and efficacy of a quadruple-nucleoside/tide therapy (TZV twice daily + TDF once daily) in HIV-1-infected patients experiencing early virologic failure on a thymidine analogue-containing protease inhibitor (PI)- or NNRTI-based regimen. HIV-1-infected adults were eligible for enrollment if they were on an initial ART regimen containing a thymidine analogue (ZDV or stavudine [d4T]) in combination with 3TC and a PI or NNRTI and were experiencing early virologic failure (defined as confirmed HIV-1 RNA between 400-10,000 copies/mL following a reduction to <400 copies/mL). At baseline, all patients substituted TDF for the NNRTI or PI, a thymidine analogue (ZDV) and 3TC were maintained, and ABC was added to the second-line regimen.

Our single-arm, open-label, evaluative study was conducted at 56 sites in the United States, with 23 sites enrolling 51 patients. The study was approved by institutional review boards and all patients provided written informed consent. The target enrollment for this study was 100 patients; however, finding patients experiencing early virologic failure on a regimen that included ZDV or d4T plus 3TC was more difficult than anticipated. The majority of screen failures (76%, 68/89) were due to HIV-1 RNA <400 copies/mL at the screening visit following an elevation >400 copies/mL prior to screen.

Patients were predominantly male (78%) and nonwhite (61%). Baseline median HIV-1 RNA was 3.295 log10 copies/mL and median CD4 cell count was 436 cells/mm3. At entry all patients were taking 3TC and either ZDV (61%) or d4T (39%) per protocol requirements; 61% were taking a PI-based regimen, with the remainder taking an NNRTI.

Reasons for premature discontinuation from study were adverse events (4 patients; nausea, fatigue, cancer), lost to follow-up (4), virologic failure (2), protocol violation (2), and site closure (1). The most common drug-related adverse events were nausea (16; 31%), fatigue (12; 24%), headache (4; 8%), vomiting (4; 8%), diarrhea (3; 6%), and insomnia (3; 6%). No drug-related serious adverse events or hypersensitivity reactions to ABC occurred in this ABC-naive population.

Potential patients were excluded if viral genotype at screen indicated >2 NRTI-associated mutations (M41L, A62V, D67N, T69D/S, K70R, L74V/I, V75I, F77L, Y115F, F116Y, Q151M, M184V, L210W, T215Y/F, K219Q/E) or the K65R mutation. Only 1.4% (2/140) of patients screened were excluded owing to genotypic restrictions. At study entry, the majority of patients (80%) had virus containing M184V mutation, as expected in a population exposed to 3TC (Fig. 1). Other common mutational patterns included primary PI mutations (45%) and NNRTI mutations (35%). About ¼ (24%) had a detectable thymidine-associated mutation (TAM), usually in addition to the M184V mutation.



Overall, a high proportion of patients experiencing early virologic failure on an initial ART regimen containing a thymidine analogue, 3TC, and a PI or NNRTI achieved viral suppression with the quadruple-nucleoside regimen of TZV + TDF over 48 weeks (Fig. 2). Similar results were observed in a modified per-protocol analysis, which excluded 4 of 51 patients with HIV-1 RNA <400 copies/mL at baseline. The proportions of patients with HIV-1 RNA <50 copies/mL at week 48 (per protocol analysis) were 75% (27/36, Obs) and 57% (24/47, M = F). Virologic response was also similar between patients with and without TAMs at screen. At week 48, among patients who had TAMs at screen, 7/9 (78%, intention-to-treat, Obs) achieved HIV-1 RNA <50 copies/mL, compared with 23/30 (77%, intention-to-treat, Obs) for those without TAMs at screen. The median CD4 change from baseline at week 48 was an increase of 71 cells/mm3.



Virologic failure in this study was defined as failure to achieve HIV-1 RNA <400 copies/mL by week 24 or confirmed rebound of HIV-1 RNA ≥1265 copies/mL (0.5-log10 increase over 400 copies/mL) following a reduction to <400 copies/mL. Virologic failure was rare (2/51) despite the presence of M184V or limited TAMs at entry. One patient without resistance mutations at baseline acquired M184V and TAMs (D67N + K70R + K219Q) at the time of confirmed virologic failure (week 32). This patient reported incomplete adherence at multiple prior visits. The other patient did not develop treatment-emergent mutations and had evidence of nonadherence. The low rate of virologic failure supports the efficacy of a quadruple-NRTI regimen composed of Trizivir and tenofovir in patients experiencing early virologic failure.

Data from a patient-completed adherence questionnaire suggest that the simplicity of TZV + TDF may have contributed to the virologic efficacy. Of 33 patients with adherence data at week 48, 85% reported perfect adherence over the prior 3 days and prior weekend. The same assessment conducted at baseline revealed that only 68% of these patients were perfectly adherent to their previous failing regimen.

In conclusion, our study demonstrates that patients experiencing early virologic failure on an NNRTI- or PI-based thymidine analogue-containing regimen can be effectively treated with a simple, compact, quadruple regimen of Trizivir and tenofovir even in the presence of M184V and limited TAMs. In the second-line regimen, 3TC and the thymidine analogue were maintained, ABC and tenofovir were added, and the PI or NNRTI from the initial regimen was removed. The quadruple-nucleoside regimen TZV + TDF may help preserve other ART classes for future treatment while offering an effective, tolerable, and simple (3 pills/day) alternative for patients experiencing early virologic failure.

Allan Rodriguez, MD*

Christina Hill-Zabala, PharmD†

Louis Sloan, MD‡

Thomas Jefferson, MD§

Linda Yau, PhD†

Maria Watson, PhD†

David Irlbeck†

Mark Shaefer, PharmD†

*University of Miami, Miami, FL †GlaxoSmithKline, Research Triangle Park, NC ‡North Texas IDC, Dallas, TX §Health for Life, Little Rock, AR

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© 2006 Lippincott Williams & Wilkins, Inc.