Management of Treatment-Naïve Patients

Hopkins HIV Report 2007 Mar; 19(2):1-3, 12

Joel E. Gallant, M.D., M.P.H.
Johns Hopkins

For the first time, the mid-winter CROI meeting was held in a “warm” city— Los Angeles. LA didn’t turn out to be very warm by southern California standards, but at least it wasn’t Boston or Chicago. Most of the big news from CROI pertained to new drugs for treatment-experienced patients, including raltegravir and maraviroc (see New Data on Treatment-Experienced Patients and Drug Resistance on p 4). However, some studies were presented that had relevance to initial therapy.

Rilpivirine vs. Efavirenz

Rilpivirine (TMC278), another second generation non-nucleoside reverse transcriptase inhibitor (NNRTI) from Tibotec, has the advantages of a long half- life and high potency at low doses, making it a logical candidate for initial therapy and for eventual coformulation. Study TMC278-C204, presented by Anton Pozniak, was a phase IIB study in which 600 treatment-naïve patients were randomized to receive one of 3 doses (25, 75, or 150 mg daily) of rilpivirine or efavirenz (EFV) plus either zidovudine/lamivudine (AZT/3TC) or tenofovir/emtricitabine (TDF/FTC) [Abstract LB144]. At 48 weeks, there was no difference among arms in the proportion of patients with viral loads below 50 c/mL, with approximately 80% of participants achieving that goal using an intention to treat (ITT), non-completer=failure analysis. Notably, there were more central nervous system (CNS) side effects, rash, and hyperlipidemia in the EFV arm. Since the study was not blinded, the difference in CNS side effects, which are both suggestible and subjective, may be hard to evaluate. However, the rash and lipid effects are more objective. Rilpivirine could represent the first real threat to the dominance of EFV as the cornerstone of first-line therapy.

Viral Dynamics in ACTG 5142

The results of ACTG 5142 were first presented at the International AIDS Conference in Toronto last year [Riddler S, et al. Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. ThLB0204]. In that study the combination of EFV plus 2 nucleoside analog reverse transcriptase inhibitors (NRTIs) was virologically superior to the combination of lopinavir/ritonavir (LPV/r) plus 2 NRTIs. However, there was a significantly greater CD4 response in LPV/r-treated patients, and the resistance consequences of failure with EFV were greater than with LPV/r.

In Los Angeles, we heard a presentation on viral dynamics in this study that may at least partially explain the superior virologic outcome with EFV [Haubrich R, et al. Conf Retrovir Opportunistic Infect 2007 Feb 25-28;14: (abstract no. 137)]. Phase I viral decay was assessed in a substudy of 5142, with viral load measurement at 2, 7, 10, and 14 days. Phase I decay was found to be fastest in EFV-treated patients, and was highly correlated with day 7 viral load reduction, which had been measured in the overall study population. Therefore, the investigators looked further at 7-day viral load decline in all patients. They found that it was significantly greater among EFV- treated subjects, and that a greater 7-day viral load decline was associated with a lower risk of virologic failure at 24, 48, and 96 weeks. Some have argued that the superior response with EFV observed in ACTG 5142 was due to greater tolerability or convenience; however, the current study suggests that differences in potency may have played a role.

Another presentation from 5142 looked at metabolic complications and lipoatrophy [Haubrich R, et al. Conf Retrovir Opportunistic Infect 2007 Feb 25-28;14: (abstract no. 38)] and will be discussed in greater detail in the May 2007 issue. Not surprisingly, lipoatrophy occurred most frequently in stavudine (d4T)-treated patients, was intermediate in those taking AZT, and was no different among TDF- treated patients than in those on the NRTI- sparing arm of LPV/r plus EFV. What surprised most of us in the audience was that loss of limb fat, as defined by DEXA, was significantly more common among EFV recipients than among those taking LPV/r, and that the lipid benefits of EFV were confined to triglycerides. This study will probably have little effect on clinical practice, since the move away from thymidine analogs has diminished concerns about emerging lipoatrophy. Nevertheless, the difference between EFV and LPV/r was unexpected and must be explained. Lipoatrophy is clearly not a direct side effect of EFV, since it was not observed in those taking EFV plus LPV/r without NRTIs. It’s also not a simple EFV vs. PI difference, since lipoatrophy was less common with EFV than with nelfinavir in ACTG 384. There is presumably an interaction between EFV and NRTIs that increases the risk of fat loss, but this interaction has not yet been defined.

Once vs. Twice Daily LPV/r: ACTG 5073

Data were presented from ACTG 5073, a study comparing once- vs. twice-daily LPV/r (soft-gel formulation), combined with FTC plus either TDF or extended release d4T [Mildvan D, et al. Conf Retrovir Opportunistic Infect 2007 Feb 25-28;14: (abstract no. 138)]. A subset of those randomized to the once-daily arm received directly observed therapy (DOT) for the first 24 weeks. There was no difference in the primary endpoint: time to virologic failure at 48 weeks, either between once and twice daily LPV/r or for self-administered therapy vs. DOT. However, in a subset analysis, patients with baseline viral loads above 100,000 c/mL were more likely to fail with once daily therapy than with twice daily therapy. This is consistent with pharmacokinetic data, which has shown lower and more variable LPV trough concentrations with once daily administration. However, it is not consistent with the Abbott 418 study, in which no difference in efficacy was observed across all viral load strata.

Current labeling supports the use of once daily LPV/r for PI-naïve patients, in whom lower LPV trough levels are presumably still high enough to suppress fully susceptible virus. However, the DHHS guidelines list once-daily LPV/r as an alternative regimen. It’s worth noting that most of the data on once-daily LPV/r come from studies in which the older soft-gel capsule formulation was used. Once-daily use of the new tablet formulation is easier because of lower pill burden and better tolerability.

DAUFIN: Once vs. Twice Daily Nevirapine

The DAUFIN study compared two regimens in treatment-naïve patients: twice daily AZT/3TC plus nevirapine (NVP) vs. once daily TDF, 3TC , and NVP [Rey D, et al. Conf Retroviruses Opportunistic Infect 2007 Feb 25-28;14: (Abstract 503)]. The intention was to enroll 250 subjects, but the study was stopped after enrollment of only 71 participants because of unexpectedly high rates of virologic failure (25%) and resistance, including NNRTI mutations, K65R, and M184V, in the once-daily arm. There was also a high rate of discontinuation in the AZT/3TC arm, mostly due to adverse events. The reason for the failure of the once-daily regimen isn’t known. Since there was no arm in which AZT/3TC was combined with once-daily NVP and no arm combining TDF plus 3TC with twice-daily NVP, we can’t say whether the failure was due to once-daily administration of NVP, the combination of NVP with TDF and 3TC, or both. However, NVP concentrations were adequate in the once-daily arm, making it unlikely that these findings can be explained on a purely pharmacokinetic basis. Failure was more common among patients with high baseline viral loads and/or low baseline CD4 counts. This study emphasizes the importance of using well tested regimens, and avoiding regimens that should work but that have not been formally studied.

Studies of Didanosine for Initial Therapy

The GESIDA 3903 study compared AZT/3TC plus EFV with didanosine (ddI), 3TC, and EFV in 369 treatment-naïve patients at 45 sites [Berenguer J, et al. Conf Retroviruses Opportunistic Infect 2007 Feb 25-28;14: (Abstract 504)]. In a preliminary 24-week analysis, there was no difference in the proportion of patients with viral loads below 50 c/mL by ITT analysis (71% in ddI-treated patients vs. 66% in AZT-treated patients, p=0.16). Similarly, there was no difference in virologic response by on- treatment analysis. Patients in the ddI arm had a mean CD4 increase of 128 cells/mm³, compared to 110 in the AZT arm. There was significantly more drop-out due to hematologic toxicity in the AZT arm.

The combination of ddI, EFV, and either 3TC or FTC has not been widely used, but it has demonstrated efficacy in a number of uncontrolled trials or trials in which it was compared against non-standard regimens. In this trial, preliminary results suggest advantages over the standard regimen of AZT/3TC plus EFV. However, AZT has been replaced for first-line therapy by TDF and abacavir (ABC), which are better tolerated and less toxic. Given its potential to cause pancreatitis and neuropathy, it is unlikely that ddI will ever be used for first- line therapy in the developed world. However, generic versions are available, and there are arguments, both from toxicity and resistance standpoints, supporting its use as an alternative to thymidine analogs in resource-limited settings.

The Tshepo study, conducted in Botswana, randomized 650 treatment-naïve patients to one of six initial regimens [Bussmann H, et al. Conf Retroviruses Opportunistic Infect 2007 Feb 25-28;14: (Abstract 507)]. NRTI backbones included AZT/3TC, d4T/3TC, and AZT/ddI. In addition, patients were randomized to receive either EFV or NVP. At two years, an impressive 95.5% of patients taking AZT/3TC or d4T/3TC still had viral loads below 400 c/mL. However, failure with resistance was observed in 11% of those on AZT/ddI compared with only 2% on the two other NRTI backbones (p=0.002), and this arm was prematurely terminated based on the recommendation of the Data Safety and Monitoring Board. Common resistance mutations included thymidine analog mutations, especially at codons 67, 70, and 215. Mortality was low in this study, but treatment-modifying toxicity was common, occurring in 18% of participants. Frequent toxicities included anemia, lipodystrophy, severe skin rashes, and lactic acidosis. The Tshepo study also compared DOT with standard of care, and found no significant difference in outcome, presumably because of the high rates of adherence and low rates of virologic failure in the overall study population.

This study demonstrates the fact that HAART can be highly effective and durable in resource-limited settings, but also points out that drug toxicity is common, an important concern in countries with few options for treatment modification. It also emphasizes the point made by so many other studies: that NRTI-containing initial regimens should include either 3TC or FTC.

Observational Studies Supporting Efavirenz for First-Line Therapy

An analysis of the Veterans Administration database looked at choice of first-line antiretroviral regimen in over 6000 patients [Braithwaite S, et al. Conf Retroviruses Opportunistic Infect 2007 Feb 25-28;14: (Abstract 520)]. Overall adherence was poor in this predominately black, male veteran population, with only 63% of prescriptions being filled as prescribed. However, adherence was better among EFV-treated patients, and those on EFV were more likely to have undetectable viral loads after 1 year. The virologic superiority of EFV was less apparent when it was compared against newer ritonavirboosted PIs (LPV/r and ritonavir-boosted atazanavir or fosamprenavir). In the ART Cohort Collaborative, an analysis of over 20,000 patients in 16 cohorts found that 6month viremia was lower with EFV than with all other third agents (combined with AZT/3TC), although this did not translate into a significant difference in clinical outcomes [Mugavero M, et al. Conf Retroviruses Opportunistic Infect 2007 Feb 25-28;14: (Abstract 527)].

These cohort studies support the results of ACTG 5142 and other studies that have demonstrated the superiority of EFV-based regimens. However, there is a strong potential for selection bias in observational cohort studies. EFV has often been viewed, perhaps for good reason, as the preferred agent, but one that should be given only to patients most likely to be adherent. As a result of this “cherry picking,” EFV may do better in cohort studies because it’s given to those who would have done well on any regimen. Were patients treated with EFV in the VA study more likely to fill their prescriptions because they were taking EFV, or were they prescribed EFV because they were more likely to fill their prescriptions? It’s impossible to tease these issues out in these cohort studies, though both factors could have played a role in the ultimate outcome.

Conclusions

From a treatment standpoint, the 2007 CROI will be remembered primarily for the BENCHMRK and MOTIVATE trials (see New Data on Treatment-Experienced Patients and Drug Resistance on p 4), which foretell the dawn of a new era in which most HIV- infected patients who are adherent to therapy will be able to achieve virologic suppression despite extensive resistance. The data on initial therapy was less earth-shattering, but still important.

The next important conference will be the International AIDS Society conference, to be held in Sydney in July. Next year’s CROI will be back in chilly Boston, February 3-7, 2008.

2007-01-10
HHR-2007-03-01

Copyright © 2007 - The Johns Hopkins University AIDS Service, Division of Infectious Diseases. Permission to use and reproduce portions of this newsletter is hereby granted provided that author and publication are fully credited and both copyright and permission notice appear with reprinted material. Inquiries may be directed to Sharon McAvinue, Managing Editor. Website: Johns Hopkins AIDS Service.

Organizations providing financial support do not participate in the editorial process or otherwise influence editorial decisions. The information presented in The Hopkins HIV Report represents the standards of care of the Johns Hopkins AIDS Service. Every effort is made to ensure the timeliness and accuracy of information presented in this newsletter, but standards of care change rapidly; therefore, the authors, editors, and publisher will not in any way be held liable for the timeliness of information or for errors, omissions, or inaccuracies in this publication. Readers should review carefully the product information contained in manufacturers’ package inserts for any drug mentioned in this publication; mention of products does not constitute endorsement.

AEGiS is a 501(c)3, not-for-profit, tax-exempt, educational corporation. AEGiS is made possible through unrestricted funding from Boehringer Ingelheim, Bridgestone/Firestone Charitable Trust, Bristol-Myers Squibb Company, Elton John AIDS Foundation, Gill Foundation, the National Library of Medicine, Quest Diagnostics, Roche and Trimeris, and donations from users like you.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1980,2008. AEGiS. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS, or the party credited as the provider of the content.