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CROI Report: HIV-1 Drug Resistance Review
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Written by Andrew Zolopa, MD
Stanford University
TOPICS
- Inability of Standard Resistance Tests to Detect Low Level ("Minority") Resistance in Treatment Naïve & Experienced Patients
- New Drugs: Reyataz; TMC-114 for patients with resistance to protease inhibitors; Reverset: a new NRTI with in vitro activity against HIV with NRTI resistsnce
- Single Drug Interruption Strategy: nrti, nnrti, & PI interruption strategies
- Transmitted Drug Resistance May Persist
- Impact of Transmitted Drug Resistance on ARV
- Single Dose Nevirapine & drug resistance & its Negative Impact on Subsequent Treatment Response
- Select Triple Nucleoside/tide Regimens Have Led to High Viral Failure Rates (but Not All Triple Nuke Regimens) & HIV Drug Resistance
- K65R Mutation: its prevalence, mechanism of resistance, and mutational interactions
Introduction
The problem of drug resistance continues to challenge HIV providers and at this year's conference, we learned that in patients who experience virologic failure on antiretroviral (ARV) therapy have even more drug resistance than meets the eye from standard resistance test results. Attendees learned about the problem of so-called "minority variants" and their contribution to treatment failure. We also learned that drug resistant variants that are transmitted persist in some cases up to 3 years and maybe longer. We saw conflicting reports on the prevalence of transmitted resistance across countries and heard a discussion as to the potential causes of this global heterogeneity. The impact of transmitted resistance on response to ARV therapy was also the subject of a new study. We will review important results from Thailand on the resistance associated with single dose neviripine and the impact on subsequent treatment of the mother.
In this report we will review the virologic and resistance outcomes from several clinical trials of "all nucleoside/tide" ARV regimens that were presented at the conference with special attention to the prevalence, mechanism of resistance and mutational interactions of the K65R mutation. We will also review results of studies that explore the treatment strategy of removing one or more drugs from treatment regimens in patients with partial viral suppression, so-called "partial treatment interruption". And finally, we review a select few new drugs that either have unique resistance profiles and/or a potential role in treatment strategies of within class sequencing.
Minority Populations making a Big Impression: standard genotype resistance tests may not detect NNRTI resistance, but new ultrasensitive tests did in this study
Although resistance testing is now standard of care, the current technologies have shortcomings. Both phenotype and genotype tests are unable to detect "minority variants" which are HIV quazi-species that comprise less than 20-30% of the total HIV population circulating in the plasma of a patient. There are technologies that are more sensitive -- with a level of detection of minority variants down to <1% - however these technologies are not widely available and furthermore, it has remained unclear what the clinical impact of minority populations are on response to ARV therapy.
Mellors analyzed minority variants and the impact on treatment response using samples from the ACTG 398 trial. [abstract 39] Recall that the trial evaluated response to a "salvage regimen" that consisted of efavirenz, adefovir and various PI's in treatment experienced patients who had ongoing viremia (viral loads of >1000 copies) on their ARV regimen. Over half of the patients where naïve to NNRTI's while 44% were NNRTI experienced.
In the published results of the study, it was observed that patients who were NNRTI experienced did not respond to the treatment regimen as well as those who were NNRTI naive. Mellors showed that even in NNRTI-experienced patients with no NNRTI-related mutations detected at baseline by standard population-based sequencing did no better than those experienced patients with baseline mutations. This observation raised the possibility that there was NNRTI-associated resistance in the experienced patients that was simply not being detected by standard techniques. Using two different highly sensitive techniques to measure minority variants, the investigators found that many of the NNRTI-experienced patients with no detectable mutations by standard techniques indeed had NNRTI mutations at baseline detected by the more sensitive techniques. Furthermore, by phylogenetic mapping the investigators showed that in many cases these minority variants were the same mutations that emerged in the dominant population at treatment failure.
Note from Jules Levin: Mellors compared the frequency of minor NNRTI resistant variants among NNRTI naïve and experienced patients with negative standard genotypes for NNRTI mutations at baseline. He looked at 12 NNRTI-naïve and 11 NNRTI-experienced patients in study ACTG 398. Of the 12 naïve patients they were able to look at 9 of them, 9 had amplifiable samples. None of the 12 NNRTI-naïve study patients had detectable mutations by standard genotype testing. Using the sensitive test 2 patients had identifiable NNRTI resistance mutations: 1 patient had the K103N (this mutation was found in 1 of 41 genomes); a second patient had 2 mutations (100I + 225L) (these 2 mutations were present in 2 of 33 genomes, one in each). It appears that NNRTI resistance in naïve patients was at a low level, and clinical implications need further research. In the 11 NNRTI-experienced patients no mutations were detected by standard genotype; but in samples available for 10 patients, 6 patients had NNRTI mutations.
Hance and colleagues demonstrated that minority variants present at baseline in protease inhibitor experienced patients were selected for and emerged as the dominate variants at failure on a subsequent PI-containing regimen. [abstract 57] However, phylogenetic mapping revealed that the further out treatment failure occurred on the new regimen the less closely did the failure genotype map to the baseline sequence. It appears from this study that pre-existing minority variants are more likely to explain early virologic failures but there is also de novo resistance which develops while on a failing regimen and this mechanism of resistance becomes more common the longer the patient is on a failing ARV regimen.
Taken together these two studies clearly demonstrate that minority variants which can not be detected by standard resistance tests are responsible for treatment failure in at least some treatment experienced patients who go onto a new ARV regimen. These studies document that drug resistance in the setting of treatment failure is even more prevalent and complex than we have come to learn from using resistance testing in practice over that past several years.
To use the analogy that Mellors used in his presentation, we are only seeing the tip of the resistance iceberg with currently available resistance technologies. This of course is further bad news for patients trying to achieve virologic control after treatment failure and makes the need for new drugs that are not cross resistant to currently available agents ever more obvious.
However, being able to detect minority variants with more sensitive tests has not been shown to improve treatment choices for patients who are experiencing treatment failure compared to treatment choices that are based on standard resistance test results. The other point to emphasize here is the importance of a careful treatment history in accessing resistance test results. For example, in a patient who has had an NNRTI --containing regimen in the past and who was viremic during that exposure (even if only for a couple of weeks), it is likely they have NNRTI-associated resistance even if the current resistance tests does not detect any resistance.
Resistance Transmitted is anything but Transient: so far seen to last up to 3 years
It remained unclear, until recently, how long transmitted resistant variants would remain detectable in the plasma of newly infected individuals who were not on antiretroviral treatment. Little and colleagues presented 12 subjects that are part of the multi-center acute infection cohort - the characteristics of which have been previously published [abstract 36LB]. These 12 subjects were first enrolled into the cohort a median of 56 days after acute infection and were followed off ARV for a median of 255 days. All subjects were infected with HIV that had resistance to at least one class of antiretrovirals, 10 had NNRTI-related resistance, 5 had nRTI-related resistance (nukes) and 4 had PI-related resistance. The investigators monitored the time to mixture in which a wild-type virus variant was first detectable along with the resistant variant that was transmitted. The mean time to mixture was 375 days for NNRTI mutations, 362 days for nRTI mutations and no reversions were seen for the PI mutations. Even the M184V mutation which is thought to "disappear" relatively rapidly because of it's negative impact on viral fitness was actually seen to persist at least in one subject with a time to mixture of 327 days. Furthermore, there was only 1 patient who had a "complete reversion" to wild-type (that is no mixtures or mutations detected by standard genotyping techniques) and that occurred after 1019 days of follow up. These findings were supported by similar findings in study from the UK [abstract 684].
Resistance testing is now recommended in patients who are treatment naïve and have been infected in the past 1-2 years, this recent change in the guidelines is in part related to the data from Little and colleagues showing that resistance that is transmitted tends to persist in the plasma and is detectable by standard resistance testing methods. Even if the patient is not necessarily going to start antiretroviral therapy immediately, it is probably useful to obtain the genotype as part of the initial evaluation if the timing of infection falls with in this 1 to 2 year window and maybe longer.
Transmission of Drug Resistance: Is There a Global Trend and what are the Implications for Treatment?
There was a poster session [session 95, abstracts 676-685] devoted to the epidemiology of transmitted drug resistance from around the world. Taken as a whole, there was no overall dominant trend, of say increasing transmission of drug resistance worldwide. Rather, the results of the studies presented were quite heterogeneous and apparently conflicting. The prevalence of transmitted drug resistance varies by HIV subtype (usually lower levels in non-B clades), risk group (generally higher levels in MSM compared to heterosexuals), geographic location of infection (lower levels in countries or regions with less ARV available), and cluster outbreaks within "core" groups in a given country (eg IDU cluster in Switzerland). Given the wide variation in these factors world wide, it is not terribly surprising that there is not a dominate trend across the globe, particularly when one adds to these sources of variation - variation in definitions of drug resistance used in the various studies, convenience sampling and relatively small sample sizes.
What is the impact of transmitted resistance on response to initial treatment?
Previously published studies have indicated that transmitted resistance impacts response to first line ARV. In published studies by Little [NEJM 2001] and Grant [JAMA 2002], there was a slower rate of virologic response in those patients who had been infected with drug resistant viruses. In the CASCADE study, presented at this year's conference no such negative impact was observed. [abstract 685] Time to viral suppression was no different in the group who had transmitted drug resistance compared to the group with no resistance. Nor did the investigators find any impact on virologic response related to resistance to a particular class of ARV. However, the investigators caution that longer-term follow-up is required to determine the durability of response in patients with transmitted drug resistance.
Why did this study show no difference in response in those patients who had drug resistance while older studies did demonstrate a negative impact? In part this may reflect better treatment options available now compared those used in the earlier studies. In the CASCADE study, the over all response rate was quite impressive with 87% of subjects achieving viral loads of <500 copies within 3 months of initiating treatment. Use of potent boosted PI's and more convenient once a day regimens may have been better able to overcome transmitted resistance compared to older ARV regimens used in the earlier studies. Most transmitted resistance is limited to a single class -- and most commonly it is one or two mutations to the nucleoside reverse transcriptase inhibitors. It is likely, that potent regimens that contain boosted PI's and some of the newer nucleoside/tide RTI's will be able to over come this level of resistance and achieve good virologic suppression at least initially.
However, there may have been analytical differences between the studies that evaluated impact of transmitted resistance on initial treatment response that also help explain the differences in outcomes. In the CSCADE study, investigators state that there was no difference in time to viral suppression "after adjusting for individuals without a fully active HAART regimen". It would be of interest to know the response rates in the two groups (those with and without transmitted resistance) without statistical adjustment for number of active drugs. Furthermore, it is not clear how much access the treating physicians had to the resistance results in crafting an ARV regimen for the patients enrolled in the CASCADE cohort, but if the treating physicians had the resistance tests results in hand this would obviously influence the outcome of the study.
NNRTI Resistance after Single Dose Nevirapine: Negative Impact on Treatment Response
Perhaps one of the most important studies presented at this year's conference was a study from Thailand on the implications of single dose nevirapine used to prevent MTCT on subsequent treatment of the HIV-infected mother.[abstract 41LB] In this study, women who were exposed to SD-NVP (single-dose nevirapine) as part of the trial PHPT 2 were treated after delivery with a NNRTI-containing ARV regimen. Genotypic analysis from a plasma sample obtained 10 days postpartum, revealed NNRTI-related resistance in 18% of a random sample of women participating in this trial. 61 women had postpartum NVP plasma levels up to 24 days after delivery. 12 days postpartum 21% of women had the key NNRTI genotypic drug mutation, K103N.
Compared to a group of women who were not exposed to SD-NVP, the investigators found trends for decreased response rates at 3 and 6 months of ARV treatment in the women who had prior SD-NVP. Comparing response in the SD-NVP exposed women with detectable NNRTI-mutations to those who did not have detectable mutations after SD-NVP, the group with detectable mutations had poorer responses. Comparison of treatment response rates by the percent of subjects achieving viral loads of <50 copies at 6 months in the 3 groups (no SD-NVP, SD-NVP without mutations and SD-NVP with mutations), showed 75%, 53% and 34% had <50 copies/ml, respectively (p<0.01, trend). Thus, women exposed to single-dose nevirapine had lower response rates to NNRTI therapy. Another interesting observation from this study was that mothers who initiated treatment after a 6 month delay following SD-NVP exposure seemed to have better responses than those who initiated treatment earlier, although longer term follow up is required to substantiate this observation.
The obvious implication from this trial is the need to limit the development of NNRTI-resistance in women receiving ARV to prevent transmission of HIV to their newborns. Studies are now under way, looking at strategies which employ various combinations of ARV's to help decrease the substantial risk of NNRTI-resistance associated with SD- NVP. The study authors said "where or when HAART during pregnancy is not feasible or desirable, AZT-NVP regimen is the only regimen which matches the efficacy of HAART during pregnancy to prevent vertical transmission".
Note from Jules Levin: there were 3 studies presented in oral sessions at the conference on the use of single-dose nevirapine to prevent mother-to-child transmission. Martinson (abstract 38) reported on a study whose primary objective was to determine whether single dose NVP administered to both mother and infant leads to drug resistance, and secondarily to assess the effectiveness of the MTCT program. Nevirapine (NVP), given to mothers in labor and to neonates within 72 hours of delivery, is an effective, simple PMTCT regimen. The authors said the NVP regimen is operationally effective, transmission rate was 8.6% at weeks 4-10, but high level NVP resistance developed. 39% of women had NNRTI genotypic resistance: 21% had K103N mutation, 13% had K103N+Y181C, 5% had K103N+Y181C+G190A. 12% of infants had the K103N mutation and 30% of infants had the Y181C NNRTI mutation at 6 weeks after birth.
Lallemant reported on "A Randomized, Double-blind Trial Assessing the Efficacy of Single-dose Perinatal Nevirapine Added to a Standard Zidovudine Regimen for the Prevention of Mother-to-child Transmission of HIV-1 In Thailand" (abstract 40LB). The authors said that although zidovudine prophylaxis initiated at 28 weeks decreases in utero transmission of HIV to 1 to 2%, significant peripartum transmission still occurs. The hypothesis for the study is that without additional toxicity, logistical complications, or significant cost, perinatal NVP added to ZDV could further reduce intrapartum transmission. All study women received prophylaxis during the third trimester of pregnancy, and infants received 1 week of zidovudine and formula feeding. Mother-infant pairs were randomized into 3 groups: single nevirapine dose to the mother (200 mg) and infant (6 mg), Nevirapine-Nevirapine; Nevirapine-Placebo; and Placebo-Placebo. The study endpoint was virologically proven HIV infection of the infant. The study was primarily designed to test the superiority of NVP-NVP over PL-PL.
Transmission rates were 6.3% for PL-PL, 2.1% for NVP-PL, and 1.1% for NVP-NVP (ITT analysis: NVP-NVP vs PL-PL, p=0.00026). The transmission rate for NVP-PL was 2.8% vs 2.0% for NVP-NVP (ITT: non-inferior). 3.2% of mothers had skin rash within 10 days, and 15% had skin rash after 10 days. In a random sample of 90 women who received NVP intrapartum, and among women with detectable viral load at 12 days postpartum 20% of women had NVP genotypic resistance. The authors concluded: maternal and infant NVP+AZT prophylaxis decreases the risk of HIV perinatal transmission to levels comparable to HAART during pregnancy; NVP-NVP and NVP-PL were declared statistically equivalent, per protocol definition.
Resistance Associated with Certain "triple Nuc" ARV Therapy
Over the past year, we have seen several studies demonstrating relatively poor virologic responses associated with certain 'triple nuc" regimens. As a result, certain triple nucleoside/tide regimens are no longer recommended as regimens of first choice in most settings. However, Trizivir has not been shown to be associated with these poor responses; Trizivir is one pill taken twice daily and consists of abacavir (Ziagen), AZT, and 3TC in each pill. At the conference this year we heard additional reports of all nuc regimens and the resistance patterns seen with failure. We will focus on the resistance aspects of these studies.
Late last year, a "Dear Doctor" letter was widely circulated to practitioners regarding poor virologic responses in a small pilot study of once daily DDI, 3TC and TDF (tenofovir, a/k/a Viread). Jemsek presented the results of the study that was the basis of this letter. The open label uncontrolled study included 24 treatment naïve patients who received DDI EC 250 mg, TDF 300 mg and 3TC 300 mg all dose qday (once daily). [abstract 51] The study was terminated early given the poor responses seen. The average viral load change at 24 weeks was --0.49 log and apparently no patients achieved <50 copies/ml while on this combination. Of the 24 subjects enrolled, genotypes were available on 20, all had 184V or I mutations and 10 had the 65R mutation (7 of the 10 were present as mixtures with wildtype at codon 65). No NNRTI or PI mutations were detected. No PK data was available and adherence was not systematically evaluated.
The Tonus study was the third study evaluating the combination of ABC, 3TC and TDF as a once daily regimen for treatment naïve subjects. [abstract 52] This open label study was also terminated early like the previous studies given the reports of poor response. This study had the advantage over the prior two studies of this combination in that plasma and intracellular PK evaluation was performed to evaluate potential antagonistic drug-drug interactions that might have explained the poor responses observed. Virologic failure (never achieved <500 copies or a 0.7 log rebound) was observed in 12/36 subjects at week 24 - 8/12 failed to suppress and 4 rebounded. Failure was clearly associated with higher baseline viral loads, in fact all failures were seen in the group with baseline viral loads of >100,000.
In the 12 failures, 11 had genotypes available at failure and 9 had both K65R and M184V/I mutations detected. The other 2 had the 184V mutation only. In 10 subjects who did not meet failure criteria but had ongoing viremia, genotype revealed that 7/10 had 65R and 184V and 2 had the 184V alone. The PK analysis revealed adequate trough concentrations of all drugs in 32/37 subjects evaluated, 5 subjects had low Cmins for at least one drug in the regimen. In a subgroup of 14 subjects with intracellular tri/di phosphate levels evaluated all had detected levels but were not quantified.
Rick Elion presented interim results from an open label uncontrolled pilot study, COL 40263 another all nuc regimen. [abstract 53] In this case, unlike the other studies, the regimen used could be called a "quad nuc" regimen, consisting of Trizivir and TDF dosed q day (once daily). In this interim analysis, the investigators used the virologic failure criteria that were developed for another GSK sponsored study of ABC/3TC/TDF (ESS 30009). This endpoint termed early virologic non-response (EVNR) is defined as: <2 log decline and >50 copies by week 8 or >1 log rebound from nadir by week 8, in addition, failure was defined as >400 copies at week 24 or later. In the 123 subjects enrolled in the study, 88 had at least 8 weeks of evaluation and 54 had >24 weeks of evaluation. Over all, 24% met the EVNR definitions (17% in the group with baseline HIV RNA of <100,000 and 29% in those with >100,000 copies at baseline). On treatment analysis at 24 weeks, revealed 78% of subjects had viral loads of <400 copies and 67% were <50 copies. The investigators compared this response rate to that seen in ESS30009 and this cross study comparison favored the quad nuc regimen.
In terms of the resistance patterns seen in this study, genotypes were available on 8 subjects of 54 that experienced virologic failure after completing 24 weeks on study. Thymidine-analog mutations (TAM's) were present in 5 of the 8, 3 of these subjects had 184V in addition to the TAM's and only 1 subject had the K65R mutation.
The theme of higher failure rates with these particular triple nuc regimens continues with these studies but the response rates seen with the quad nuc regimen appears to be better. However, controlled trials are required to fully assess the efficacy of this treatment regimen. In terms of the resistance themes that emerge from these studies, it is clear that triple nuc regimens that contain 2 or more drugs that select for the 65R mutation show relatively high rates of that mutation at failure. The clinical implications of the K65R mutation on subsequent response to ARV therapy has not been fully explored but in the Tonus trial, good responses were achieved in patients who failed with the 65R. None-the-less there is concern since K65R is associated with reduced susceptibility on phenotype tests to all of the nucleosides/tides except for AZT (in which it causes hypersusceptibility) and possibly D4T. Since 65R makes viruses more susceptible to AZT, there is the suggestion that AZT-containing regimens may help prevent the emergence of 65R. Certainly there were fewer subjects with 65R at failure in the COL 40263 study compared triple nuc regimens of ABC/3TC/TDF or DDI/3TC/TDF. In the next section we will explore the prevalence of 65R, mechanisms of resistance and mutational interactions and the clinical implications of these observations.
K65R: Prevalence, Mechanism of Resistance and Mutational Interactions
In reviewing the VIRCO database, Parikh in collaboration with Bacheler showed that the prevalence of 65R is increasing although it still remains a relatively uncommon mutation in clinical samples sent for resistance testing (presumably from patients on failing ARV regimens). [abstract 54] The prevalence of 65R increased from 0.4% in 1998 to 3.6% in 2003. This trend may in fact be related to the increased use of nucleoside/tide analogs that select for this mutation (which includes ABC, DDI, DDC and TDF) and or the decreased use of drugs that might be antagonistic to it's development - namely AZT and possibly D4T.
Parikh went on to report that there is a strong negative correlation between the prevalence of TAM's and that of 65R in the VIRCO database. The investigators explored the potential molecular mechanisms that underlie this apparent antagonism. TAM's work by increasing the ability of the virus that possesses these mutations to remove nucleoside/tides that block reverse transcription through a process called pyrophosphorolysis. By more easily removing the analogs the virus is able to continue the process of reverse transcription and therefore, is "resistant' to the inhibitory effects of the drugs. The investigators showed that the presence of 65R reduced primer unblocking which resulted in a reduction in AZT resistance. Using two different clones with multiple TAM's (41L, 210W, 215Y and 67N,70R, 215F and 219Q) the investigators demonstrated that AZT resistance was reduced by 10 fold when the 65R mutation was added to the clone. Primer unblocking (pyrophosphorolyis) was reduced in these clones with TAM's and 65R. The investigators also demonstrated that TAM's reduced resistance mediated by 65R to ddC, ddI, ABC and TDF, although the mechanism of this antagonistic interaction was not defined.
In a second presentation examining the mechanisms of resistance of the 65R mutation, White and colleagues from Gilead described two important factors responsible for nucleoside/tide resistance. Mutants with 65R demonstrated decreased incorporation of ddI, TDF, ABC, d4T as well as AZT. This decrease in incorporation would be expected to result in resistance to these drugs. However, 65R, also was shown to decrease excision (pyrophosphorolysis) as was demonstrated in the study by Parikh et al. This would tend to decrease observed resistance seen with viruses that contained 65R (less excision equates to more inhibition, that is the inhibitor is better able to work -- therefore, less resistance, follow?). So when determining the impact of 65R on the resistance profile of a particular drug one needs to consider these two competing effects -- decreased incorporation, which increases resistance, and decreased primer unblocking or excision which should diminish resistance. In turns out for AZT, even though 65R decreases incorporation which should result in a virus that is resistant to AZT, the impact on decreasing excision of AZT is much greater and therefore the net effect is that viruses with 65R, tend to be hypersusceptible to AZT compared to wild-type viruses while for TDF, ddI and ABC the impact on incorporation outweighs the effect of decreased excision resulting in a virus that has reduced susceptibility to these drugs.
Why is it important for the practitioner to know K65R's mechanism of resistance? If we have an understanding the mechanism by which 65R causes resistance we will be better able to interpret the resistance resulting for patients in whom this mutation develops. Clinical questions that remain to be answered and will in part be informed by this knowledge include: How much virologic activity remains in the presence of 65R for drugs like TDF and ABC? Does the 65R associated hypersusceptibility of AZT have clinical implications? What impact does 65R have on the virologic activity of d4T?
K65R remains a relatively rare mutation as does the multi-nucleoside complex of Q151M. French investigators reported finding 24 clinical isolates with 65R out of a database that contained over 3,000 samples (prevalence 0.8%) but what was interesting is the investigators found that Q151M complex was associated with the 65R. [abstract 627] In the 33 samples in which a Q151M complex was found 9 also had the 65R mutation. It appeared that most of these cases where in TDF naïve patients. The evolution of these "double" mutants is unclear from the cross sectional survey of the database but it does raise the possibility of multi-nucleoside resistance pathways in which highly resistant viruses develop both 65R and Q151M. Further evaluation of other databases is required.
Strategies for Managing Patients with Multi-drug Resistant HIV: Can we use fewer drugs?
In the past year we have begun seeing reports evaluating the impact of stopping part of a patient's antiretroviral regimen who has MDR HIV and partial viral suppression. The idea is to reduce the burden of ARV in patients who are not able to achieve full viral suppression without subjecting the patient to the risks of a complete structured treatment interruption (STI). Some of the clinical questions that are being addressed in these studies include what kind of regimen is required and what is the minimum number of drugs required to maintain clinical stability in patients with partial viral suppression? Moreover, what role do PI's versus nRTI's play in maintaining partial suppression and CD4 stability?
In the COLATE study, investigators evaluated the impact of removing 3TC in patients with 184V. [abstract 549] Many practitioners maintain 3TC as part of salvage regimens even in patients with resistance to the drug. The main justification for keeping 3TC as part of salvage regimens is to maintain the 184V mutation which has been shown in vitro to diminish viral fitness. In this randomized controlled study, patients who were on failing ARV regimens with viral loads >1000 copies/ml (stratified by first regimen failure vs. subsequent failures) and who had evidence of the 184V mutation present were randomly assigned to a new ARV based on resistance testing with or without 3TC as part of the new regimen. There was no difference in virologic outcomes seen in the study and the study was stopped early by a data safety monitoring board who felt that continuing the study would lead to a null result (ie, no difference). In the 131 subjects enrolled, 41% were failing their first regimen and two thirds of the patients achieved <400 copies by week 48. In the group in which a follow up sequence could be obtained, those that received 3TC did maintain the 184V mutation while the 184V mutation became undetectable after 12-24 weeks in those who did not continue 3TC.
Although this study did not show any benefit to maintaining 3TC in patients with 184V, it does not prove that continued 3TC is ineffective in improving virologic response in patients unable to achieve complete suppression -- thru it's impact on viral fitness. The main limitation with this study is that the majority of subjects had very good virologic responses. Fitness impacts are not particularly relevant in patients who are able to achieve full suppression as was seen in this study. This study needs to be repeated in more treatment experienced patients who would be more likely to remain viremic while on a ARV regimen.
Maldarelli and colleagues from the NCI reported results on 6 patients who had ongoing viremia while on ARV and stopped 1 of their nucleosides (3 d4T, 1 ddI) or the NNRTI (2 stopped EFV). [abstract 623] All patients were on ARV regimens with stable viral loads >5,000 and CD4 counts >50. After close monitoring for 10 days, patient stopped one drug in their regimens while continuing the rest of the regimen. Over 14 days frequent sampling was performed. There were increases in viral load seen in all the patients who stopped a nRTI while those who stopped the NNRTI experienced no increase. Interestingly, in 2 subjects who stopped d4T had multiple TAM's at baseline and yet it appeared that d4T was still contributing to antiviral activity of the regimen. When d4T was reinstituted viral loads decreased promptly.
This study along with others reported at last year's meetings seem to indicate that nucleoside inhibitors continue to exert an antiviral effect in patients with partial viral suppression even though it appears from their resistance profile that these drugs should not have any activity. From these studies it is probably reasonable to continue at least one nRTI in most salvage regimens to attempt to take advantage of any residual antiviral effects this class may have in the setting of " pan-resistant" HIV. However, further study in larger cohorts and randomized controlled studies are required to better define the impact of nRTI's in the setting of salvage therapy and how best to optimize treatment for these patients.
Hunt and colleagues from UCSF reported on the immunological and virological impact of selectively stopping PI's ("partial treatment interruption or PTI") in patients with multi-drug resistant HIV and partial virologic suppression. [abstract 663] In this uncontrolled study, investigators stopped the PI in 17 patients with PI --resistance and partial viral suppression. They measured changes in CD8 activation, CD4 counts, viral load and resistance profile over time. CD4 counts declined at an average of 2 cells/ month of PI PTI and this rate of decline accelerated when there was loss of PI resistance. After adjusting for viral loads, the investigators found that CD8 activation markers increased and that there seemed to be an association with loss of PI resistance. Although the cause and effect relationships between viral load, PI resistance and CD8 activation are not clear from this study, the investigators suggest that CD8 activation as well as virologic factors determine the profile of change in CD4 counts and viral load during PI PTI's. Again randomized controlled studies are called for to better delineate the role of PI's in the setting of MDR-HIV in patients experiencing partial viral suppression.
Launay and colleagues from Paris, presented results from the "Vista study" (ANRS 109) in which investigators identified 26 patients with MDR HIV, who were viremic while on their ARV's and were put on "low dose" IDV/RTV with 3TC. The IDV doses were adjusted such that patients were to have Cmins of IDV that were calculated to be 50% of the patients IC50 (ie, a dose that would not expect to be fully suppressive). At 24 weeks viral loads increased by 0.22 log and CD4 counts dropped by 50 cells. The study was stopped early as a result of these findings. Although the CD4 declines were disappointing, the rate of decline was not statistical significantly different from the decline seen prior to entering the study. Furthermore, there was little evolution of resistance over the course of the study. This thoughtful approach to minimizing long term ARV toxicities while maintaining virologic and immunologic benefit by using a "minimal" ARV regimen deserves further study.
Drug Resistance, New Drugs and New Pathways: Reyataz & the 50L mutation; TMC-114; Reverset
Reyataz and the 50L Mutation
Given the prevalence of drug resistance and the problem of cross resistance, we continue to require new drugs with unique resistance profiles and new classes of antiretrovirals to treat many HIV infected patients in care today. The 50L mutation associated with ATV is unique to this PI and appears in vitro to not cause resistance to the other PI's. In fact, phenotypes with the 50L tend to be hypersusceptable to the other PI's in clinical isolates. Colonno and the group from BMS, reported on the resistance profile of patients failing ATV regimens from various BMS trials. [abstract 656] The investigators report that 50L is more commonly seen in PI-naïve patients who fail ATV as their first PI. In the 034 trial of PI-naive patients treated with unboosted ATV, 83% (5/6) who failed with PI resistance had the 50L mutation. In contrast, in PI-experienced patients treated with an ATV-containing regimen, the 50L mutation was seen less frequently. In the various trials of treatment-experienced patients, the 50L was observed in 0% to 35% of patients failing with new PI-resistance. In PI-experienced patients with preexisting PI resistance, the determinates for the development of 50L versus non-50L resistance pathway remain unclear -- nor is it clear what the PI sequencing implications are after failure with 50L versus a non-50L pathway.
TMC-114: new protease inhibitor for PI resistance
Investigators from Tibotec reported additional in vitro data TMC 114, a PI which demonstrates impressive in vitro activity against many PI-resistant isolates. [abstract 620] Using the Virco repository of clinical isolates, the investigators evaluated the phenotype fold change (FC) profile of TMC 114 in over 2200 samples that had at least some degree of resistance to at least one of the approved PI's (defined as IC50> 4 FC to at least one PI). The results remain encouraging from previous reports of similar data. The IC50's for TMC114 remained <4 FC for even the most highly resistant isolates. In isolates with phenotypic resistance to 6 out of 7 PI's the TMC114 FC remained <4 in nearly 80% and for isolates resistant to all 7 other PI's, TMC114 FC was less than 4 in over half the cases.
Once again TMC114 showed impressive short term virologic response in patients on failing PI regimens who had their PI switch to one of 3 different doses of TMC114, boosted with RTV (300mg/100mg BID, 600mg/100mg BID or 900mg/100mg q day) compared to a control group who remained on their failing PI. [abstract 533]. In this randomized phase 2a controlled study, 38 patients were enrolled and viral load response was monitored over 14 days. At day 14, viral load declines averaged 1.2 to 1.5 logs in the 3 TMC114 groups with maximal declines of up to 2.5 log seen. Interestingly, baseline susceptibility to TMC114 was not predictive of response. We look forward to the further development of this drug, particularly in patients with PI-resistance.
Reverset, new NRTI in early development
Reverset (RVT-202) is a novel cytidine nRTI analog (D-D4FC) with in vitro activity against HIV-1 strains that are resistant to AZT, 3TC, TDF and others. However, the multi-nucleoside resistance patterns (69insert and Q151M complex) appear in vitro to cause resistance to RVT-202. In vitro there is no mitochondrial toxicity noted and the compound has a long intracellular half life. Rob Murphy reported a phase I, monotherapy study in antiviral naïve subjects. [abstract 137]. In this dose ranging study, 30 subjects were randomized equally to one of three doses of RVT (50mg, 100mg or 200mg) versus placebo. Subjects were dosed for 10 days with 4 weeks of follow up. Viral loads declined in all treatment groups, with average declines of 1.2 to 1.7 logs by day 10. No statistically significant differences were seen between the study arms, although a trend favored the highest dose after day 10. The plasma half live was measured at 5.2 hours and no nRTI-associated resistance emerged during the course of the study. More patients receiving the RVT had "cold symptoms" compared to the placebo group but there were no other safety concerns. We anticipate clinical trials in patients with various patterns of nRTI-associated resistance.
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