Important note: Information in this article was accurate in March 2004. The state of the art may have changed since the publication date. 
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Groundbreaking new clinical trial results were few and far between at the 11th CROI. However, there were several trials worth highlighting related to the management of treatment-experienced patients and a great deal of new data and insights on antiretroviral resistance mechanisms.
Boosted Atazanavir vs Lopinavir in Treatment-Experienced Patients: 48-Week
Follow-up 48-week data from the BMS-045 trial were presented by Edwin DeJesus in a poster session [Abstract 547]. This trial randomized 358 subjects who had failed at least two HAART regimens and were PI-, NNRTI-, and NRTI-experienced to receive 1) atazanavir (ATV) / ritonavir (RTV) (300/100 mg qd); 2) lopinavir/ritonavir (LPV/r, 3 tablets bid); or 3) ATV (400 mg) / saquinavir (SQV) (400/1200 mg qd) each in combination with an NRTI backbone. Twenty-four-week data from this study garnered considerable attention at last year’s IAS conference in Paris [Bardo et al., Abstract 118 2nd IAS, Paris, 2003], as ATV/RTV performed as well as LPV/r in this experienced study population, results that have been upheld by 48-week data presented at CROI. In an intent-to-treat analysis, 56% and 38% of patients randomized to the ATV/RTV arm achieved a VL <400 c/mL and <50 c/mL, respectively, compared to 58% and 46% of those in the LPV/r arm (differences not statistically significant). The efficacy of the ATV/SQV arm was inferior, as it was at 24 weeks. Increases in total cholesterol and triglycerides were significantly higher in the LPV/r group than the ATV/RTV arm, and more patients in the LPV/r arm were treated with lipid-lowering drugs (19% vs 12%, P<0.05).
It should be noted that the participants in this trial were not highly treatment-experienced, and these results should not be extrapolated to true “salvage” situations. Extrapolation to PI-naïve patients may be appropriate, however. The results of BMS 045 will undoubtedly increase enthusiasm for the use of ATV, and especially RTV-boosted ATV, as a first-line PI.
You Don’t Need Suspenders if You’re Already Wearing a Belt
Scott Hammer presented results from the ACTG 372A study, showing that intensification with abacavir (ABC) provided no benefit in patients whose viral loads were already suppressed a on 3-drug HAART regimen [Abstract 56]. A total of 229 AZT-experienced participants who had achieved VL <500 c/mL in the parent study with indinavir (IDV) and 3TC plus either AZT or d4T were randomized to add ABC 300 mg bid or placebo. Over a median follow-up of 4.4 years, the composite endpoint of virologic failure or treatment discontinuation was reached by 53% in the ABC group and 55% assigned to placebo. In secondary analyses, there were also no significant differences between the groups in rates of virologic failure alone, episodes of intermittent viremia >50 c/mL (blips), or low-level viremia measured using an ultrasensitive viral load assay with a limit of detection of 6 c/mL. It should be noted, however, that intensifying successful regimens is not often done, whereas there is some support for intensification strategies in patients with persistent low level viremia on HAART [Katlama C, et al. AIDS. 2000 May 5;14(7):781-9 and Schooley RT, et al. AIDS. 2002 Jun 14;16(9):1257-63].
Several rationales have been proposed over the years for continuing 3TC in the regimens of patients with known or suspected 3TC-resistance. The M184V reverse transcriptase mutation decreases viral fitness and antagonizes the development of thymidine analogue mutations (TAMs), K65R, and Q151M. Moreover 3TC is almost universally well tolerated, has a low pill burden, and does not appear to contribute to mitochondrial toxicity. The COLATE trial addressed the question of whether continuing 3TC after 3TC failure is beneficial [Abstract 549]. One hundred thirty-one subjects who had a VL >1,000 c/mL on a 3TC-containing regimen (91% had M184V at study enrollment) were randomized to either continue or discontinue 3TC in an open-label format. Subjects’ clinicians chose a regimen consisting of at least 3 drugs prior to randomization; the mean number of drugs, excluding 3TC, remained similar in the two arms over 48-weeks of follow-up. There were no differences in the average change in viral load (-1.4 log10 c/mL with 3TC vs -1.5 log10 c/mL with no 3TC) or in viral load <50 c/mL at week 48 (52% with 3TC and 44% with no 3TC). The authors concluded that the trial showed no evidence that continuing 3TC in the setting of known or suspected 3TC resistance provides benefit.
Notably, some drugs (like ABC and ddI) can maintain M184V, and the lack of difference between the study arms might be explained if M184V, and its purported beneficial effects, were maintained in the group not receiving 3TC. However, this did not appear to have occurred to a great extent: M184V was detected in over 80% of participants who experienced virologic failure in the 3TC arm during follow-up, while less than 20% of those failing therapy in the non-3TC-containing arm had a detectable M184V mutation during the last 6 months of the trial.
Two caveats about this trial should be noted. First, a potential benefit of main-taining M184V with 3TC is thwarting the development of some of the more troubling nucleoside resistance mutations. While this issue will be further explored in the COLATE trial, analysis of mutations other than M184V that emerged during the study had not been completed as of the presentation at CROI. Second, the relative benefit of M184V on viral fitness may be most evident in true salvage situations. The participants in COLATE were not heavily pretreated; nearly 70% achieved a VL <400 c/mL at week 48, and approximately 50% achieved a VL <50. These rates of viral suppression are similar to those seen in ART-naïve trials and may have obscured a modest benefit of M184V on viral fitness.
K65R: Balancing the Effects of Mixed Mechanisms
| Table: HIV Mechanisms of Resistance to NRTI | ||
| Resistance Mechanisms | ||
| NRTI-Associated Resistance Mutations |
Blocked Incorporation of NRTI into RNA Transcripts |
Excision of NRTI After Incorporation |
| TAMS (41, 67, 70, 210, 215, 219) |
-- | ↑↑ |
| M184V | ↑↑ (3TC); ↑ (Others) | ↓ |
| K65R | ↑↑ | ↓ |
The K65R mutation is a recent upstart in the world of NRTI resistance because of the use of thymidine analog-sparing regimens, and, most notably, the spectacular failures of triple nucleoside HAART regimens that do not contain AZT or d4T (see Gallant JE, “Antiretroviral Therapy: The Naïve Patient”, p 1). Considerable attention was focused on the K65R mutation and its mechanisms of action at this year’s CROI. In a symposium, Lisa Demeter [Abstract 162] provided an overview of mechanisms of resistance to NRTIs, and U. Parikh [Abstract 54] and K.L. White [Abstract 55] presented oral abstracts focusing on the interactions between K65R and other NRTI-associated resistance mutations.
Thymidine analog mutations (TAMs) cause resistance to NRTIs by increasing the ability of HIV’s reverse transcriptase enzyme to excise these agents from transcripts after they have been incorporated, with T215Y being the most efficient (Table, above right). As these mutations accumulate, the result is broad resistance to all NRTIs. In contrast, the M184V mutation potently blocks incorporation of 3TC into growing RNA transcripts, producing complete resistance to this drug (Table, above right). However, M184V also has a detrimental effect (from the point of view of the virus, that is) on the ability of HIV to excise previously incorporated NRTI. M184V also blocks incorporation of other NRTIs, but much less efficiently than it blocks incorporation of 3TC (ABC, ddI >> AZT, d4T, TDF). Thus, in the cases of ABC and ddI, the aggregate effect of M184V’s counteracting influence on incorporation and excision is to produce detectable but clinically insignificant loss of susceptibility to these agents. Conversely, in the case of AZT, d4T, and TDF, the aggregate effect of M184V is to antagonize HIV’s primary mechanism of resistance to these agents: NRTI excision.
There is a similar trade-off for K65R. In combination, K65R and M184V cause complete resistance to 3TC and substantial loss of susceptibility to ddI and ABC. Interestingly, although TDF plays an important role in selecting the K65R, the net effect of the K65R/M184V combin-ation on TDF is much less pronounced, because the decreased incorporation of TDF and the antagonized excision balance out. The interplay between these two primary NRTI resistance mechanisms was used to explain the nearly universal failure of triple NRTI regimens containing TDF, 3TC plus either ABC or ddI [Demeter LM, et al. Abstract 162]. Emergence of the K65R/M184V combination produces high-level resistance to 3TC, ABC, and ddI, effectively leaving TDF monotherapy. In cell cultures HIV susceptibility to AZT is increased by K65R, and this has been borne out in clinical experience, where K65R is a rare mutation in AZT-containing regimens [White KL, et al. Abstract 55]. Additionally, from a clinical perspective, triple NRTI regimens that contain AZT (or d4T), while not as effective as PI or NNRI-based regimens, are not afflicted by the Achilles heel of non-thymidine-containing triple NRTI regimens (see Gallant JE, “Antiretroviral Therapy: The Naïve Patient”, p 1).
In deep salvage situations, the ability to achieve virologic suppression probably hinges on the ability to overcome existing PI resistance with serum drug concen-tration. R. Bertz presented preliminary results from the ABT 049 study, in which 33 heavily experienced patients were randomized to receive LPV/r (Kaletra) 667/167 mg (5 capsules) bid or LPV/r 400/300 mg (3 capsules) bid plus RTV 200 mg bid both in combination with 2-3 NRTIs selected by participants’ clinicians [Abstract 134]. LPV trough levels were similar in the two arms and 60% to 70% higher than those historically seen with regular LPV/r dosing. Viral suppression was similar in the two arms, but there was a trend toward better tolerability in the arm containing 5 LPV/r capsules than in the arm with extra RTV. In a multivariate analysis both the LPV inhibitory quotient (IQ, defined as the LPV trough divided by the protein-binding adjusted IC50 for the subject’s particular HIV isolate) and the number of active NRTIs in the regimen were strongly associated with the log10 decline in viral load on therapy as well as the likelihood of achieving a VL <400 c/mL.
Of course toxicity is the other side of the double-edged sword when attempting to increase drug concentrations. For example, IDV concentrations have been correlated with nephrolithiasis and cutaneous toxicity. Similarly, Barrios reported that higher ATV plasma concentrations were significantly associated with the degree of hyperbili-rubinemia [Abstract 606]. Additionally, considerable attention was focused on efavirenz (EFV) pharmacogenomics, race, and central nervous system side effects. In substudies of ACTG 5095, the trial comparing EFV/AZT/3TC/ABC, EFV/AZT/3TC, and AZT/3TC/ABC (the latter arm discon-tinued due to high failure rate), EFV clearance and central nervous system side effects were found to be strongly associated with a CYP2B6 polymorphism (the ctyo-chrome P450 enzyme most directly involved with EFV metabolism) an allelic variant that is more common in blacks than whites [Haas D, et al. Abstract 133]. These differences may explain the significantly lower EFV clearance (and significantly higher drug concentrations) in blacks and Hispanics than in non-Hispanic whites in the ACTG 5095 sub-study [Ribudo H, et al. Abstract 132].
Forty-eight-week data from BMS 045 continued to show similar virologic efficacy of ATV/RTV and LPV/r in treatment experienced patients, with better lipid parameters in the former group. This suggests that boosting drug concentrations well above the viral IC50, reasonable dosing and pill burdens, and tolerability are the main factors currently driving the overall effectiveness of PI-based regimens. Adding ABC to IDV-based regimens was not associated with any durability benefit in patients with suppressed viral loads, and continuing 3TC in the presence of M184V was not associated with benefit in minimally to moderately antiretroviral-experienced patients initiating a salvage regimen. Finally, additional basic science and clinical research has shed light on the K65R resistance mutation and how its effects on NRTI incorporation and excision lead to different net effects for different drugs, particularly in combination with M184V.
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