Case #003:
Pharmacokinetically-enhanced PI Treatment Strategies in Patients with Low-level PI Resistance
(January 22, 2001)

Panel Clinician:
Richard Aranow, MD

Richard Aranow, MD
George W. Beatty, MD, MPH
Steven G. Deeks, MD
Betty J. Dong, Pharm.D
Amy V. Kindrick, MD
Jody Lawrence, MD
Michael L. Lim, Pharm.D (11/00-6/01)
John Stansell, MD (3/01-6/01)
Jason Tokumoto, MD
Paul Volberding, MD (11/00-3/01)

Disclaimer:
This information has been developed solely as an educational resource for health care professionals interested in HIV care and research. The information presented represents the views of the Panel members only and not necessarily those of the National HIV/AIDS Clinicians' Consultation Center's HIV Telephone Consultation Service (Warmline), the Positive Health Program at San Francisco General Hospital, or sponsoring organizations. Resistance testing can help identify whether certain drugs or classes of drugs might be ineffective, but cannot establish which drugs will be effective. Furthermore, test results can be inaccurate and interpretation of tests is not yet standardized. Because of the many factors involved in treatment decisions when resistant virus is present, the antiretroviral regimens and the therapeutic strategies discussed are not the only possible options and might be different from current Practice Guidelines. Other sources of information on resistance testing, such as clinical HIV websites, can be of help. Health care professionals should consult the HIV Telephone Consultation Service (Warmline) or HIV experts in their community before using any of the recommended therapeutic regimens or strategies in this document.

Consultation:
Consultation is available to California AIDS Drug Assistance Program providers through the California State Office of AIDS Voucher Program by calling the HRSA/ AIDS ETC National HIV Telephone Consultation Service (Warmline) at 1/800/933-3413. The HIV Resistance Testing Consultation Service is supported by a grant from the California State Office of AIDS through the Pacific AIDS Education and Training Center.

37 yo white man who first tested HIV positive in 1987. He is an intravenous drug user. He began using antiretrovirals in 1990 and his antiretroviral (ARV) drug history is as follows:

He is clinically well. He has been on Septra for PCP prophylaxis. There is no history of other antiretrovirals than those listed above. His adherence is believed to be good.

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This patient had not been heavily pretreated with antiretroviral therapy. Other than his initial course of AZT monotherapy, his only regimen has been stavudine (d4T), lamivudine (3TC), and indinavir (IDV). On this regimen, his viral load initially became undetectable for a few months but then remained at low but detectable levels for the past three years. His CD4 count also responded initially to the present regimen, rising to the mid 200’s and then falling to below 200. His CD4 is now approaching his pretreatment level.

This patient’s overall clinical course is not unusual. He has had a “smoldering” viral load with some CD4 response (although it unfortunately never became a robust response). Although his immune system and drug regimen were controlling the virus relatively well, mutations were accumulating during this time and his response to his regimen s appears to be weakening.

The genotype test results presented above are consistent with this antiretroviral history. The 184 mutation correlates with 3TC use and confers significant resistance to this drug. The other two nucleoside reverse transcriptase (NRT) mutations (41, 215) are consistent with both AZT and d4T use and probably confer moderate resistance to these thymidine analog drugs. As would be expected of somebody naïve to nonnucleoside reverse transcriptase inhibitors (NNRTI), there is no evidence of resistance to this class of drugs. Therefore, one expects the virus to be completely susceptible to the NNRTIs.

He has a number of important protease inhibitor (PI) mutations. Mutations at positions 90, 46 and 10 are know to be associated with clinical resistance to most of the currently available protease inhibitors. The virus also has several secondary mutations of uncertain significance. This resistance pattern is consistent with partial resistance to each of the currently available protease inhibitors. However, the level of resistance may be low enough that pharmacokinetically-enhanced PI treatment strategies may be effective.

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Goal of Therapy:
Since this patient has only had low level viral breakthrough on his first HAART regimen, durable viral suppression (e.g. undectable VL) is a reasonable goal.

There may be other treatment options available but the following recommendations were those addressed by the Panel. The majority of Panel members believed that the sole addition of ritonavir to this patient’s regimen may be the only change required to achieve an undetectable viral load. One Panel member felt strongly that follow-up option one with 2 NRTIs, 2 new PI’s and a NNRTI is the optimal initial regimen.

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