Case Summary
This case is continued from a previous case. See Part I here.
The Clinician Consultation Center received a call from a new infectious diseases provider in Texas about a 50 year-old patient who was newly referred to her for care. The patient was diagnosed with HIV in 1990, and has been on multiple antiretroviral therapy (ART) regimens since then. His current regimen consists of abacavir, co-formulated lamivudine/zidovudine, and twice daily ritonavir-boosted darunavir (8 pills/day)—he has been on this for approximately one and a half years. Although he remembers being on multiple combinations in the past, he cannot recall specific names or other details.

The patient has not had persistent viral suppression on his current ART regimen: most recent CD4 is 300 cells/mm3 and viral load is 540 copies/mL. His genotype shows clinically-significant resistance mutations in both the NRTI and NNRTI classes: namely M184V, K101P, K103N, V179I. Adherence has been a concern in the past but the patient is now enrolled in intensive case management services and will receive directly observed therapy.

The patient is concerned about the number of pills he takes overall and would like to know if his ART regimen can be simplified, ideally to a one-pill-daily combination. The calling provider is unsure of the best clinical approach when making a decision regarding regimen simplification, and wants to know what options are available to the patient.

CCC Consultant Response
It is important to first recognize that the patient is experiencing treatment failure on his current ART combination: the DHHS guidelines define virologic failure as the inability to achieve or maintain suppression of viral replication to an HIV RNA level < 200 copies/mL5. Even though the patient’s main concern is simplicity, a potent and effective combination still needs to be identified.

In order to construct an appropriate regimen for this patient, his resistance testing results should be examined closely. The M184V mutation causes high-level resistance to lamivudine and emtricitabine and low-level resistance to didanosine and abacavir; it also increases susceptibility to tenofovir, zidovudine, and stavudine. However, presence of M184V is not necessarily a contraindication to continued treatment with lamivudine or emtricitabine. It has been shown that M184V decreases viral fitness and may lead to clinically significant reductions in viral load (up to 0.6-0.7 log)6-7. Therefore, it may be prudent to include tenofovir/emtricitabine in his next regimen and monitor renal function closely: tenofovir use has been associated with decreases in creatinine clearance and in this patient with co-morbid diabetes and hypertension, he may be at higher risk for developing renal disease.

The NNRTI-related mutations K101P, K103N, and V179I collectively produce high-level resistance to etravirine (2.5 + 0 + 1.5 = 4 on the Tibotec etravirine weighted genotypic susceptibility score) and high-level resistance to the other NNRTIs.

Because the patient has no significant PI-associated mutations and no history of integrase inhibitor use, boosted PIs and integrase inhibitors will likely be active agents here.
It is unlikely that a one-pill-daily regimen will sufficiently include [the recommended minimum] two fully active agents for this patient. However, there are some options which may decrease his overall pill burden:

a. Continue twice-daily ritonavir-boosted darunavir. Stop abacavir and lamivudine/zidovudine, and start tenofovir/emtricitabine once daily. This should result in two fully active agents (darunavir and tenofovir), with a possible additional benefit of decreased viral fitness by maintaining the M184V mutation. It will require 5 pills/day.

b. Continue twice-daily ritonavir-boosted darunavira. Stop abacavir and lamivudine/zidovudine, and start co-formulated abacavir/lamivudine/dolutegravir once daily. This should result in two fully active agents (darunavir and dolutegravir) and possibly partial activity from a third (abacavir). Again, there may be the possible additional benefit of decreased viral fitness by maintaining the M184V mutation. This regimen requires 5 pills/day.

c. Continue twice-daily ritonavir-boosted darunavira. Stop abacavir and lamivudine/zidovudine, and start tenofovir/emtricitabine once daily. Additionally, start raltegravir 400mg twice a day. This should result in three fully active agents (darunavir, raltegravir, and tenofovir) with the possible benefit of decreased viral fitness as above. It will require 7 pills/day.

The CCC consultant advised the treating clinician that the best approach would be to inform the patient that none of the currently-available single tablet regimens (STR) are likely to fully control his HIV, given the resistance mutations present. The risk of choosing to start a STR would include not having enough fully active agents present– this could then potentially lead to new mutations, virologic failure, and possible clinical progression. Any benefit in decreased pill burden with STRs in this scenario is likely outweighed by the aforementioned risks. However, the patient does have options which, although not STR’s, involve combinations with significantly decreased pill burden. The key differences between the new options involve varying side effect and drug interaction profiles, dosing schedules, and number of fully active agents. The CCC consultant advised the treating clinician to review each option with the patient, discussing risks and benefits, and ultimately share the decision-making process with the patient.

* Once-daily darunavir (boosted with either ritonavir or cobicistat) is NOT recommended for co-administration with phenobarbital.

References
1. Practice Parameter: A guideline for discontinuing antiepileptic drugs in seizure-free patients — Summary Statement
2. Stopping Antiepileptic Drugs: When and Why?
3. University of Liverpool HIV drug interaction website
4. Toronto General Hospital – University Health Network
5. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services.
6. Deeks SG, Hoh R, Neilands TB, Liegler T, et al. Interruption of Treatment with Individual Therapeutic Drug Classes in Adults with Multidrug-resistant HIV-1 Infection. J Infect Dis. 2007 Feb 1; 195(3): 387-91.
7. Turner D, Brenner B, Wainberg M. Multiple Effects of the M184V Resistance Mutation in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1. Clin Diagn Lab Immunol. 2003 Nov; 10(6): 979-981.

Because CCC consultations are based on information provided by the caller or clinician accessing the online consultation center, without the benefit of a direct evaluation or examination of the patient, consultations are intended to be used as a guide. They do not constitute medical advice and are not to serve as a substitute for medical judgment. This Case of the Month includes consultation based on the most up-to-date evidence at the time of its publication. To learn about current recommendations, please call one of our clinical consultation lines.