Case 2
Volume 1 Number 2
July 2009
Clinical Cases in Resistance is an ongoing series of patient profiles that illustrate key practice points for clinicians on the use and interpretation of resistance tests in the overall care of HIV-infected patients.
Dr. Rafael E. Campo is Professor of Clinical Medicine in the Division of Infectious Diseases at the University of Miami School of Medicine in Miami, Florida. Dr. Campo's current work focuses on therapy for HIV infection, resistance to antiretroviral agents, and salvage therapies for treatment experienced patients. Dr. Campo is a paid consultant for Virco Lab, Inc.
A 29-year-old immigrant worker who stopped HAART for 4 months, returns to the clinic after recently restarting therapy
Medical History
The patient was diagnosed with HIV in 2006 when he presented to care with central nervous system (CNS) toxoplasmosis in his native country in South America.
Treatment History
Treatment for the CNS toxoplasmosis was initiated using a combination of pyrimethamine and sulfadiazine. A few months later, the patient initiated antiretroviral therapy (efavirenz + zidovudine/lamivudine). It is not known what the CD4 cell count and HIV RNA level were at that time. Over the next 2 years the patient improved clinically as noted by his weight gain and lack of symptoms related to CNS toxoplasmosis. At that time, treatment with pyrimethamine and sulfadiazine was stopped. The physician told the patient that his immune system was looking better and that his virus was "detectable but low level." In early 2008, the patient illegally immigrated to the United States to work as a migrant worker.
Treatment History in the United States
While in the United States, the patient was unable to continue antiretroviral therapy because of lack of access to medication. In July 2008, approximately 4 months after entering the country, the patient presents to the clinic in good health, but expressed a desire to restart antiretroviral therapy. When questioned, the patient was unable to recall his previous HIV RNA levels and CD4 cell counts or whether a resistance test had been performed while in South America. In addition, the medical records from the patient's native country were not available.
Virologic and immunologic assays revealed an HIV RNA level and CD4 cell count of 385,000 copies/mL and 220 cells/mm3. A genotype was ordered and the results showed the presence of 215 C/D (see Practice Points 1 and 2). Given these results and the limited information on the patient’s initial care in South America, it was decided to restart the original regimen of efavirenz + zidovudine/lamivudine. The rationale for using this regimen was 1) no new drugs would be put at risk, and 2) under the same selective pressure, there was a high probability that any archived resistance mutations would emerge.
Current Evaluation
The patient returned to the clinic 4 weeks after restating antiretroviral therapy following a 4 month period of being off therapy. His HIV RNA level and CD4 cell count were 412,000 copies/mL and 201 cells/mm3, respectively. A virco®TYPE HIV-1 was ordered. CLICK here to see the results
The virco®TYPE HIV-1 report showed selection of numerous nucleoside (41L, 74I, 184V, 215Y, 219E) and non-nucleoside (101E, 181C, 190S) resistance-associated mutations with limited NRTI and no NNRTI antiretroviral activity (see Practice Points 3, 4, and 5). Based on these results, the newly prescribed regimen comprised darunavir + ritonavir + raltegravir + tenofovir DF. After 6 months, the regimen was well tolerated and his HIV RNA level was <50 copies/mL and CD4 cell count was 435 cells/mm3.
Practice Points
1. Resistance testing optimally should be done before initiating antiretroviral therapy. However, resistance-associated mutations are unlikely to be detected if there is no selective pressure, unless they constitute a significant percentage (~20%) of the circulating variants of HIV-1. 1
2. The presence of 215C/D revertants are indicative of prior resistance to thymidine analogs that has partially reverted back to susceptibility. 2
3. The selective pressure associated with the re-initiation of antiretroviral therapy after a long period of time of being off-therapy can flush out archived resistance mutations
4. The prolonged failure of an NNRTI-containing regimen will lead to the selection of a large number of NNRTI and NRTI resistance-associated mutations. This has been well described in developing countries where there is limited access to periodic HIV RNA testing and antiretroviral resistance assays, and many patients receive NNRTI-based regimens as their first HAART. 3
5. The selection of 3 or more NNRTI mutations associated with etravirine resistance leads to high level resistance to etravirine. 4
Not an actual patient. This case study is for educational purposes only and does not constitute professional medical advice. It should not be relied upon for making patient treatment decisions.
References
1. Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3, 2008; 1-139. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
2. Violin M, Cozzi-Lepri A, Velleca R, et al. Risk of failure in patients with 215 HIV-1 revertants starting their first thymidine analog-containing highly active antiretroviral therapy. AIDS. 2004;18:227-235.
3. Hosseinipour H, van Oosterhout JJ, Weigel R, et al. Resistance profile of patients failing first line ART in Malawi when using clinical and immunologic monitoring. Program and abstracts of the 17th International AIDS Conference; August 3-8, 2008; Mexico City, Mexico. Abstract TuAB0105.
4. Haubrich R, Cahn P, Grinsztejn B, et al. DUET-1: week 48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of etravirine (ETR; TMC125) versus placebo in 612 treatment-experienced HIV-1-infected patients. Program and abstracts of the 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, Massachusetts. Abstract 790.