Raltegravir, the first in class integrase inhibitor from Merck, will be presented with an update of phase 2 and 3 clinical trials, and an update on PK, drug - drug interaction data, and resistance data, obtained to date. 96 week phase two data in naïve patients shows a sustained virological suppression of viral load with TNF+FTC+RAL similar to the control arm of TNF+FTC+EFV with all four doses of RAL studied - 100 mg, 200 mg, 400 mg and 600 mg bid. Drug related clinical adverse events with RAL at 48%, were less then with EFV - 71%. RAL had a neutral effect on serum lipids. Suppression of viral load with RAL was somewhat more rapid initially with RAL than with EFV although the relevance of this finding is unknown. 48 week data in two phase three studies with RAL and OBR (BENCHMRK) show sustained virological suppression to <50 copies/mL in 62% of patients versus 33% with OBR alone. Side effects for patients treated with OBR+RAL were similar as for those treated with OBR alone suggesting RAL added little to toxicity. PK with RAL is highly variable and no relationship between blood levels and results has so far been determined. RAL is metabolized by glucuronidation by the enzyme UGT1A1. Studies to date show no significant drug level alterations with different UGT1A1 polymorphisms - and few concerning drug drug interaction with drugs that induce or inhibit UGT1A1. Tipranavir lowers RAL levels by 55% and rifampin lowers levels by 61%. Phase 3 data suggests tipranavir's effect is not significant - no data yet exists for use with rifampin. Resistance to RAL usually follows one of two pathways with primary mutations at either position Q148 or N155, which are usually rapidly followed by the development of secondary mutations which increase resistance and return fitness to the virus.

When fully suppressive regimens are not available, incompletely suppressive regimens also provide immunologic benefits. In this study, with stable background therapy, human immunodeficiency virus (HIV)-infected patients who were randomized to receive atazanavir or boosted atazanavir, compared with those who continued boosted protease inhibitor therapy, maintained similar virologic and immunologic control, resistance-mutation patterns, and replication capacities with reduced use of lipid-lowering medication.

Central nervous system opportunistic infections (CNS-OI) are a significant cause of morbidity and mortality in AIDS. While current interventions are increasingly successful in treating CNS-OI, little information exists regarding long-term behavioral outcomes among survivors. In this exploratory study we examined neurocognitive data among three groups of adults with different AIDS-related CNS-OI: 15 with past cryptococcal meningitis (CM), 8 with toxoplasmosis encephalitis (TE), and 8 with progressive multifocal leukoencephalopathy (PML). A group of 61 individuals with AIDS, but without CNS-OI, was used as a comparison group. A battery of standardized neuropsychological tests assessing a variety of cognitive domains was administered upon entry. Results indicate that individuals with a history of CNS-OI were most impaired on measures of cognitive and psychomotor speed relative to the HIV+ comparison group. Among the CNS-OI groups, individuals with history of TE had the most severe and varied deficits. The results are discussed in relation to what is known about the neuropathological consequences of the various CNS-OIs. While this is the first systematic group study of residual CNS-OI effects on neurocognitive function, future studies employing more participants, perhaps focusing on specific CNS-OIs, will further characterize the long-term outcomes in AIDS-related CNS-OI.

Background The continuing, randomised, multinational, phase IIB POWER 1 and 2 studies aim to evaluate efficacy and safety of darunavir in combination with low-dose ritonavir in treatment-experienced HIV-1-infected patients. We did a pooled subgroup analysis to update results at week 48 for patients receiving the recommended dose Of darunavir-ritonavir compared with those receiving other protease inhibitors (PIS).Methods After 24-week dose-finding phases and primary efficacy analyses, patients randomised to receive darunavir-ritonavir were given 600/100 mg twice daily, and patients receiving control PIs continued on assigned treatment into the longer-term, open-label phase; all patients continued on optimised background regimen. We assessed patients who had reached week 48 or discontinued earlier at the time of analysis; for the darunavir-ritonavir group, only patients who received 600/100 mg twice daily from baseline were included. Analyses were intention-to-treat. The POWER 2 study (TMC114-C202) is registered with ClinicalTrials.gov (NCT00071097).Findings At week 48, 67 of 110 (61%) darunavir-ritonavir patients compared with 18 of 120 (15%) of control PI patients had viral load reductions of 1 log(10) copies per mL or greater from baseline (primary endpoint; difference in response rates 46%,95% Cl 35%-57%, p < 0.0001). Based on a logistic regression model including stratification factors (baseline number of primary PI mutations, use of enfuvirtide, baseline viral load) and study as covariates, the difference in response was 50% (odds ratio 11.72, 95% CI 5.75-23.89). In the darunavir-ritonavir group, rates of adverse events were mostly lower than or similar to those in the control group when corrected for treatment exposure. No unexpected safety concerns were identified.Interpretation Efficacy responses with darunavir-ritonavir 600/100 mg twice daily plus optimised background regimen were greater than those with control PI and were sustained to at least week 48, with favourable safety and tolerability in treatment-experienced patients. This regimen could expand the treatment options available for such patients.

Findings At week 48, 67 of 110 (61%) darunavir-ritonavir patients compared with 18 of 120 (15%) of control PI patients had viral load reductions of 1 log10 copies per mL or greater from baseline (primary endpoint; diff erence in response rates 46%, 95% CI 35%-57%, p<0·0001). Based on a logistic regression model including stratifi cation factors (baseline number of primary PI mutations, use of enfuvirtide, baseline viral load) and study as covariates, the diff erence in response was 50% (odds ratio 11·72, 95% CI 5·75-23·89). In the darunavir-ritonavir group, rates of adverse events were mostly lower than or similar to those in the control group when corrected for treatment exposure. No unexpected safety concerns were identifi ed. Interpretation Effi cacy responses with darunavir-ritonavir 600/100 mg twice daily plus optimised background regimen were greater than those with control PI and were sustained to at least week 48, with favourable safety and tolerability in treatment-experienced patients. This regimen could expand the treatment options available for such patients.

A randomized 2-group medication adherence intervention is evaluated with HIV-infected adults (N = 141) assessed at baseline, 3-, and 9-month follow-ups. Cognitive (self-efficacy, behavioral intent), mental health (depression, well-being), and substance use indicators were the outcome measures. In addition, a posttest-only analysis from 3 to 9 months evaluates intervention impact on antiretroviral adherence, measured through Medication Event Monitoring System and pill counts. Compared to the standard care group, the intervention group showed significant increases in adherence self-efficacy and behavioral intent at 3 and 9 months and marginal improvements in mental health. Although the standard care group had higher adherence at 3 months (no baseline data were available prior to intervention), intervention group patients showed significant increases in adherence from 3 to 9 months. Although adherence levels achieved by intervention patients may not be sufficient for virological control, this is one of the first studies to provide promising results of longer term effectiveness of a behavioral adherence intervention.

Background: GS-9137 is a potent low-nanomolar strand transfer inhibitor of HIV-1 integrase.Methods: The antiviral activity, tolerability, pharmacokinetics, and pharmacodynamics of GS-9137 were evaluated in a randomized, double-blind, placebo-controlled monotherapy study in 40 HIV-1-infected patients not receiving antiretroviral therapy with an HIV-1 RNA between 10;000 and 300,000 copies/mL and a CD4 count of 200 cells/mu L or greater. GS-9137 or matching placebo was administered with food for 10 days at 5 dosage regimens (200, 400, or 800 mg BID, 800 mg QD, or 50 mg + 100 mg ritonavir QD; 6 active, 2 placebo per dose level). The primary end point was the maximum reduction from baseline in logo HIV-1 RNA.Results: Forty patients were enrolled, with a mean baseline viral load of 4.75 log(10) copies/mL and a CD4 count of 442 cells/mu L. Each GS-9137 dosing regimen exhibited significant. exposure-dependent (mean reductions. -0.98 to -1.99 logo copies/mL) antiviral activity compared with placebo (P < 0.01). Twice-daily administrations of GS-9137 at doses of 400 or 800 mg or once-daily dosing of 50 mg with ritonavir demonstrated mean reductions from baseline in HIV-1 RNA of 1.91 log(10) copies/mL or greater, with all patients exhibiting 1 log(10) or greater and 50% having 2 log(10) or greater reductions. No patient developed evidence of integrase resistance. GS-9137 showed an adverse event profile similar to placebo, and there were no study drug discontinuations.Conclusions: GS-9137 demonstrated substantial short-term antiviral activity and was well tolerated as monotherapy, thus warranting further study.

AIDS Patient Care and STDsVol. 20, No. 9 Letter to the EditorLong-Term Follow-Up of Patients with Initial Early Virologic Failure After Being Treated with Once-Daily Tenofovir/Abacavir/LamivudineHomayoon Khanlou and Charles FarthingHomayoon KhanlouSearch for more papers by this author and Charles FarthingSearch for more papers by this authorPublished Online:20 Sep 2006https://doi.org/10.1089/apc.2006.20.604AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail "Long-Term Follow-Up of Patients with Initial Early Virologic Failure After Being Treated with Once-Daily Tenofovir/Abacavir/Lamivudine." , 20(9), pp. 604–605FiguresReferencesRelatedDetails Volume 20Issue 9Sep 2006 InformationCopyright 2006, Mary Ann Liebert, Inc.To cite this article:Homayoon Khanlou and Charles Farthing.Long-Term Follow-Up of Patients with Initial Early Virologic Failure After Being Treated with Once-Daily Tenofovir/Abacavir/Lamivudine.AIDS Patient Care and STDs.Sep 2006.604-605.http://doi.org/10.1089/apc.2006.20.604Published in Volume: 20 Issue 9: September 20, 2006PDF download

To the Editor The authors thank Dr. Guiard-Schmid and colleagues for their interest in our article.2 In our study, the drug levels were obtained before the next dose due time and we eliminated nonadherent patients by interview. Atazanavir (ATV) absorption is clearly altered by administration of acid-modifying agents; the degree to which this occurs is dependent on the potency of acid-suppressing agents.3-5 Current recommendations are to avoid the proton pump inhibitors (PPIs) and to separate histamine-2 blockers (H2Bs) by 12 hours from ATV dosing.5 One should be quite cautious in interpreting drug levels because of major patient intervariability. In fact, the data from Guiard-Schmid and colleagues attest to high interpatient variability, where the range was 203 to 1976 ng/mL for the ATV/ritonavir combined with PPI group and 65 to 1944 ng/mL for the non-PPI group, allowing some patients to have inadequate levels. We are surprised by these findings, because the PPI group has slightly better levels than non-PPI group. It would be helpful to know the lower levels of sensitivity and the coefficient of variation for their assays. Furthermore, the median levels obtained by Guiard-Schmid et al (551 ng/mL in the PPI group vs. 469 ng/mL in the non-PPI group) may be adequate for naive patients but would be inadequate in patients with antiretroviral experience. Recent studies have shown that higher ATV concentration trough (Ctrough) levels (ie, 774-850 ng/mL) were more likely to reduce viral load (VL) in experienced patients.6-8 We are starting to understand the relation between drug levels and antiviral activity of the agents better, but many questions are still unanswered. One interesting issue is the intracellular levels of these agents and their relation to other drugs, particularly ritonavir, and viral suppression. We have seen patients in our cohort with undetectable serum levels of ATV and <50 HIV RNA copies/mL. There are also other reports showing lack of failure in these types of patients.9 Our group is currently in the process of investigating the intracellular levels and their relation to viral suppression. Until this information is available, it would be wise to follow the current recommendation on avoiding PPIs and separating H2Bs with ATV. Homayoun Khanlou, MD* Stan Louie, PharmD† Charles Farthing, MD* *AIDS Healthcare Foundation Sherman Oaks, CA and †University of Southern California, Los Angeles, Los Angeles, CA

To the Editor: Many patients with multidrug-resistant HIV have limited options for salvage antiretroviral therapy. Until new and more potent agents are available, physicians often must design new regimens with current available antiretroviral agents to control HIV viremia and maintain CD4 counts. The use of dual-boosted protease inhibitor (PI)-containing regimens is one option that may offer several benefits.1 Pharmacokinetic enhancement of 2 different PIs with low-dose ritonavir may result in a higher genetic barrier to resistance and possibly in synergistic activity against HIV. The combination of atazanavir, fosamprenavir, and minidose ritonavir may meet these criteria. Given that fosamprenavir is an inducer of CYP-3A4 metabolism, potential dose alterations and longer follow-up may be warranted. We examined the trough concentrations (Ctrough) of atazanavir and fosamprenavir in treatment-experienced patients receiving atazanavir + fosamprenavir + ritonavir who have been intolerant to or have failed lopinavir/ritonavir for a duration of 24 weeks and followed their CD4 and HIV RNA levels. Seventeen patients were selected. Nine patients were given a combination of atazanavir 150/fosamprenavir 700/ritonavir 100 mg twice daily, and 5 patients atazanavir 200/fosamprenavir 700/ritonavir 100 mg twice daily. Three patients did not tolerate ritonavir and were switched to atazanavir 400/fosamprenavir 700 mg twice daily. The Ctroughs were analyzed using a centralized laboratory with validated techniques (Consolidated Laboratory Services, Van Nuys, CA). The minimum Ctrough of atazanavir and amprenavir were defined, respectively, as 0.27 μg/mL and 0.28 μg/mL. None of the patients were receiving concomitant nonnucleoside reverse transcriptase inhibitors. Nine of 14 patients on boosted regimens (3 on atazanavir 200 mg) were receiving tenofovir 300 mg and emtricitabine 200 mg once daily as part of a nucleoside reverse transcriptase inhibitor backbone, and 2 patients were on fixed-dose zidovudine/lamivudine/abacavir twice daily and 1 was on abacavir + lamivudine twice daily. Two patients were on dual-boosted PIs only (1 with history of lactic acidosis and the other with severe lipoatrophy). The other 3 patients on nonboosted combinations were on abacavir and lamivudine twice daily. All regimens produced atazanavir and amprenavir Ctrough well above the minimum acceptable concentrations (Figs. 1 and 2). At 24 weeks, the 3 regimens did improve CD4− cell count (average: +151 vs. +134 vs. +95 cells/mm3) and reduce HIV RNA (average: −2.6 vs. −2.11 vs. −3.7 log10, respectively). Overall, at week 24, 10 of 17 patients (60%) achieved HIV RNA levels <400 copies/mL and 4 of 17 (24%) had <50 copies/mL. Interestingly, 2 patients with a very high level of resistance in the protease gene (one with 9 significant mutations including V82A and L90M, and another with 12 significant mutations including I84V and L90M) responded to <50 copies/mL. At 24 weeks, the average total cholesterol levels were 195 vs. 237 vs. 177 mg/dL and triglycerides 210 vs. 196 vs. 177 mg/dL, respectively. One patient on 150 mg/700 mg/100 mg developed grade 3 hyperlipidemia at week 8 and stopped ritonavir with improvement. Four patients did receive concomitant statins.FIGURE 1: Mean atazanavir levels in 3 different regimens.FIGURE 2: Mean amprenavir levels in 3 different regimens.Overall clinical tolerance was excellent, particularly vis-à-vis the digestive system. However, the occurrence of hyperlipidemia constitutes a limiting factor. In addition, the numbers on a nonritonavir regimen were too small to draw any conclusion, but the lower Ctroughs are of concern. Among different PIs, it appears that combination of atazanavir and fosamprenavir with low-dose ritonavir could offer a great pharmacokinetic advantage, allowing concentrations above the relevant IC50 (50% inhibitory concentration) to be achieved safely. This is of importance in the clinical setting, particularly in the presence of multidrug-resistant HIV infection with an increase in the Cmin:IC50 ratio. Previous studies have shown that higher atazanavir Ctrough levels (ie, 0.774-0.850 μg/mL) were more likely to reduce viral load in experienced patients.2,3 However, in the absence of ritonavir inhibition, the Ctrough of atazanavir was low, requiring administration of an extra dose of atazanavir (400 mg twice daily). The use of therapeutic drug monitoring did allow for adjustment of dosing in patients in whom ritonavir was not used because of patients' preference, intolerability, or history of severe hyperlipidemia. In these patients, although the Ctrough may have been acceptable for wild-type virus, a dose increase was thought to be necessary. Another implication of these findings is the importance of therapeutic drug monitoring in the treatment of HIV-infected patients, particularly in those with advanced-stage disease in whom the use of numerous drugs and thus many interactions are expected. In conclusion, these results appear to indicate that a combination of atazanavir 150 or 200 mg twice daily and fosamprenavir 700 mg twice daily with low-dose ritonavir may offer adequate Ctrough values for both drugs and may be a viable option for some treatment-experienced patients. Further larger studies evaluating the pharmacokinetics, the effect on P-glycoprotein, and plasma-protein-binding, the virologic efficacy, and the synergism of this combination are perhaps warranted. Homayoun Khanlou, MD Laveeza Bhatti, MD, PhD Charles Farthing, MD AIDS Healthcare Foundation Los Angeles, CA

OBJECTIVE:To evaluate the efficacy of a program designed to improve adherence to antiretroviral therapy among patients with poor adherence.METHODS:A randomized intervention trial was conducted among 90 HIV-positive patients experiencing treatment failure as a result of noncompliance with their medication regimen. Eligible participants were randomly assigned to an adherence case management intervention with monetary reinforcement (CM) or to a standard of care group (SC). The CM participants met regularly with a treatment advocate for individualized adherence support. Efficacy was measured in terms of reductions in viral load and improvements in immune function at weeks 12, 24, and 48.RESULTS:After 48 weeks, 55% (n=26) of those in the CM achieved at least a 1-log10 drop in viral load as compared to 28% (n=12) in the SC group (P=.0089). Furthermore, the mean CD4 count was 209 cells/mm3 for the CM group as compared to 150 cells/mm3 in the SC group (P=.0333). Based on logistic regression analysis, being in the CM was an independent predictor of reduction in viral load (odds ratio=2.49; P=.0514).CONCLUSION:The individualized adherence intervention is feasible and effective in reducing viral load and improving immune function.

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BACKGROUND Improved treatment options are needed for patients infected with multidrug-resistant human immunodeficiency virus type 1 (HIV-1). The nonpeptidic protease inhibitor tipranavir has demonstrated antiviral activity against many protease inhibitor-resistant HIV-1 isolates. The Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST-1) trial is an ongoing, open-label study comparing the efficacy and safety of ritonavir-boosted tipranavir (TPV/r) with an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI/r) in treatment-experienced, HIV-1-infected patients. METHODS Six hundred twenty antiretroviral-experienced patients were treated at 125 sites in North America and Australia. Before randomization, all patients underwent genotypic resistance testing, which investigators used to select a CPI/r and an optimized background regimen. Patients were randomized to receive TPV/r or CPI/r and were stratified on the basis of preselected protease inhibitor and enfuvirtide use. Treatment response was defined as a confirmed reduction in the HIV-1 load of > or = 1 log10 less than the baseline level without treatment change at week 24. RESULTS Mean baseline HIV-1 loads and CD4+ cell counts were 4.74 log10 copies/mL and 164 cells/mm3, respectively. At week 24, a total of 41.5% of patients in the TPV/r arm and 22.3% in the CPI/r arm had a > or = 1-log10 reduction in the HIV-1 load (intent-to-treat population; P<.0001). Mean increases in the CD4+ cell count of 54 and 24 cells/mm3 occurred in the TPV/r and CPI/r groups, respectively. Adverse events were slightly more common in the TPV/r group and included diarrhea, nausea, and vomiting. Elevations in alanine and aspartate aminotransferase levels and in cholesterol/triglyceride levels were more frequent in the TPV/r group. CONCLUSIONS TPV/r demonstrated superior antiviral activity, compared with investigator-selected, ritonavir-boosted protease inhibitors, at week 24 in treatment-experienced patients with multidrug-resistant HIV-1 infection.

Previous investigational data using abacavir (ABC), lamuvidine (3TC), and zidovudine has suggested the possibility of triple nucleoside analogue reverse transcriptase inhibitors (NRTI) therapy as an option in the treatment of HIV infection. We performed a pilot study to assess the potency of once daily ABC+ 3TC+ tenofovir (TDF) in the treatment of HIV-infected naive patients. CD4 and HIV-viral load (VL) were followed monthly. Patients were considered to be nonresponder/failing if there was no reduction in VL by >/= 2 log(10) by week 8 and/or a rebound in VL after initial suppression. Resistance testing was then obtained. Nineteen patients naive to antiretroviral therapy (3 women and 16 men) were enrolled, of whom, 2 did not return (withdrew from study at week 2). Median VL and CD4 count at baseline were 147,167 copies per milliliter (5.16 log(10); [range, 7650->750,000]) and 277 cells/mm(3) (range, 59-598). Eight patients had VL > 100000 at baseline. Of 17 patients eligible for follow-up, 5 (27%) were responders (virologic success). Twelve patients (63%) were considered nonresponders and/or with virologic failure. The study was prematurely interrupted because of a high rate of treatment failure. Resistance testing available for 11 nonresponders (58%) showed: 2 patients with wild-type, 5 patients with M184V (reducing susceptibility to 3TC and ABC), 4 patients with M184V+K65R (K65R is responsible for reducing susceptibility to ABC, 3TC and TDF), and none with K65R alone. In conclusion, the combination of ABC, 3TC and TDF cannot be recommended for the initial regimen in HIV treatment-naive patients.

The goal of this study was to optimize the hydroxyurea dosage in HIV-infected patients, and to minimize the toxicity and maximize the antiviral efficacy of the hydroxyurea-didanosine combination. In a randomized, open-label study (RIGHT 702, a multicenter trial performed in private and institutional practices), three daily doses (600 microg, 800-900 microg, and 1200 microg) of hydroxyurea were administered in combination with didanosine and stavudine to 115 chronically HIV-infected patients, one-third antiretroviral drug naive, with viremia between 5000 and 200,000 copies/ml regardless of CD4+ cell count. The primary efficacy end point was the proportion of patients with plasma HIV-1 RNA levels below 400 copies/ml after 24 weeks of therapy. In the RIGHT 702 intent-to-treat population the lowest (600 mg) dose of hydroxyurea was better tolerated, associated with fewer adverse events, and more potent by all efficacy parameters, including the primary end point (76 versus 60% patients with viremia<400 copies/ml at week 24 for the 600-mg and 800- to 900-mg dose groups, respectively; p=0.027), the mean area under the curve (60.3 versus 65.8; p=0.016), and the mean log10 decrease (-1.95 versus -0.77; p=0.001). Patients receiving 600 mg of hydroxyurea daily also had the highest CD4+ cell count, CD4+/CD8+ cell ratio, and lowest CD8+ cell count and percentage (p=0.035). The RIGHT 702 trial provides an explanation for the increased toxicity and decreased efficacy of hydroxyurea when it was used at high dosage (1200 mg daily). At the optimal dosage of 600 mg daily, hydroxyurea, in combination with didanosine, deserves reevaluation for the long-term management of HIV/AIDS worldwide, because of its excellent resistance profile, durability, and affordability.

Coformulated zidovudine/lamivudine/abacavir fixed-dose (ZDV/3TC/ABC-FDC; Trizivir, GlaxoSmithKline) has been widely used because of its convenience, tolerability, and simplicity. It also offers the possibility of reserving both the protease inhibitor and nonnucleotide reverse transcriptase inhibitor classes (NNRTIs). Based on the ACTG 5095 trial, this combination was found to be less effective than 2 efavirenz-based regimens at all viral load strata.1 As a result, it has been recommended to intensify such regimens. We chose to intensify with tenofovir in a number of cases, and we now report our results with this strategy. An analysis of patients taking Trizivir, 1 pill twice a day with HIV viral load of <1000 copies/mL but >50, who had tenofovir 300 mg once daily added to their regimen for intensification was performed retrospectively. Fifteen patients (12 male) were identified. Patients were receiving current Trizivir twice a day prior to adding tenofovir for an average of 10 months. The combination of Trizivir plus tenofovir was well tolerated and no patients discontinued the treatment due to an adverse event. Table 1 and Figure 1 summarize the findings.TABLE 1: Baseline and Follow-up DataFIGURE 1: Percentage of patients with undetectable HIV-RNA (light gray: <400; dark gray: <50 copies/mL).At week 24, 11 of 15 (73%) of the patients had achieved HIV RNA <50 copies/mL, compared with 2 of 15 (13%) at baseline, with a mean log10 decline of 1.33 in HIV RNA and a mean increase in CD4 of 66 cells/mm3. To our knowledge, this is the first study to look at intensification of Trizivir with tenofovir. Our results showed that adding tenofovir to Trizivir in patients with HIV RNA <1000 copies/mL can result in further decreases in viral load through 24 weeks. When Trizivir and tenofovir are started simultaneously, successful responses have been observed in treatment-experienced patients2 and in patients who are antiretroviral naive.3,4 In one study (COL40263), Trizivir and tenofovir were administered together in antiretroviral-naive patients as a once-daily regimen, with 76% of subjects experiencing an early virologic response after 8 weeks.3 Virologic nonresponse was observed only in 8 of 54 subjects (15%) at 24 weeks of follow-up. In another recent study, the combination of Trizivir with tenofovir was found comparable to the regimen of ZDV/3TC (Combivir) and efavirenz in initial therapy for treatment-naive HIV-infected persons.4 By intent-to-treat (ITT) analysis, 68% of patients on the quad-NRTI arm achieved HIV RNA levels of <50 copies/mL at 48 weeks, which was similar to the 67% result observed in patients receiving Combivir with efavirenz. Lastly, the combination of Trizivir with tenofovir has been used successfully in subjects with early virologic failure on a regimen of either ZDV or stavudine (d4T) given with 3TC and either a protease inhibitor or an NNRTI.5 In this study, after 24 weeks of therapy, on ITT analysis, 65% of patients achieved HIV RNA of <50 copies/mL (80% of patients when an as-treated analysis was used). The combination of Trizivir plus tenofovir as quad-NRTI therapy would have the potential to preserve future treatment options with other drug classes. Previous studies have indicated that ZDV may play a role in inhibiting the emergence of K65R.6 A recent analysis of HIV-1 isolates in the Virco database pointed out to a bidirectional antagonism between the K65R mutant and thymidine analogue mutations.7 Therefore, the presence of ZDV (a thymidine analogue) may preselect for thymidine analogue mutations and delay the emergence of K65R. Preliminary results from virologic failures in patients taking Trizivir plus tenofovir have supported this hypothesis as more patients developed thymidine analogue mutations than K65R.3 However, this strategy is not without risks, leading perhaps to a broad NRTI cross-resistance. In summary, this small data set suggests that intensifying therapy for patients in whom an initial regimen of Trizivir fails, with a viral load still <1000 copies/mL, using tenofovir is perhaps a reasonable therapeutic strategy. This approach offers the potential for improved potency while reserving other classes for future use. Before such a strategy can be recommended, however, its benefits and risks need to be evaluated in larger clinical trials. Homayoun Khanlou, MD* Bill Guyer, PharmD† Charles Farthing, MD* *AIDS Healthcare Foundation LosAngels, CA, and †Gilead Sciences Foster City, CA