Clinical Cases in HIV Resistance

Volume 1 Number 3
November 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 49-year-old African American male, with a history of IDU, unexpectedly presents to the clinic with viremia and declining CD4 cell count after being lost to follow-up for 2.5 years.

Medical History

The patient was diagnosed with HIV in late 1999 and had a history of IDU dating back to 1990. Overall, the patient was in good health. For approximately 6 months after diagnosis, the patient remained asymptomatic except for minor weight loss and intermittent diarrhea.

Treatment History

In June 2000, the patient initiated antiretroviral therapy with a regimen of efavirenz + zidovudine/lamivudine. As was standard practice at the time, no genotype was preformed prior to initiating therapy. The patient's baseline HIV RNA level and CD4 cell count were 385,000 copies/mL and 22 cells/mm ³ , respectively.

Over the next 5 years, the patient remained off of intravenous drugs. During this time he was employed and reported good adherence to the HAART regimen, maintained HIV RNA levels <50 copies/mL for approximately 90% of the time, and had no major complaints of adverse events. By December 2005, the CD4 cell count had climbed to 575 cells/mm ³ .

However, a month later the patient lost his job due to a relapse in intravenous drug use. From January to May 2006, the patient continued to attend his regularly scheduled clinic visits. Adherence to his HAART regimen began to decline, and by the March 2006 visit his HIV RNA level became detectable (280 copies/mL; CD4 560 cells/mm ³ ). At the May 2006 follow-up visit, a genotype was ordered after noting that the HIV RNA level had risen to 2550 copies/mL (CD4 570 cells/mm ³ ). The genotype revealed the 184V mutation; however, this information could not be conveyed to the patient because he missed the next couple of clinic visits.

In September 2006, the patient unexpectedly appeared at the clinic. Taking note of the genotype results, the physician-in-attendance recommended that the patient stop his HAART regimen and return in 1 week so that his regular physician could start the patient on a new HAART regimen. The patient failed to show up 1-week later and was lost to follow-up for the next 2.5 years.

Current Evaluation

In early 2009 the patient appeared at the clinic and noted that he had recently completed a 2-month drug rehabilitation program and had been "clean" since. In addition, the patient reported he had continued to take efavirenz + zidovudine/lamivudine "plus some other HIV drugs" that he had obtained from acquaintances during the 2.5 years he was lost to follow-up because he "knew how important it was to be compliant with medicine."

The HIV RNA level and CD4 cell count were 108,520 copies/mL and 281 cells/mm ³ , respectively. A virco ^® TYPE HIV-1 was ordered please click here to see a copy of the report.

The genotype showed the 184V mutation, which confers resistance to lamivudine and emtricitabine. The virco ^® TYPE HIV-1 report also showed several of the classic nucleoside analog mutations (NAMs) (67N, 70R, 215F, and 219E) although there was some susceptibility remaining for zidovudine, didanosine, stavudine, abacavir, and tenofovir DF. The presence of 184V is known to re-sensitize the virus to some NRTIs; however, there was a mixture of 184V and 184 wild-type (184wt/V) and the virco ^® TYPE assumed a worst case scenario when calculating the fold change and discounted the re-sensitizing effects of 184V on zidovudine, stavudine, and tenofovir DF. On the other hand, the presence of 103N, 219E, and 329L had a re-sensitizing effect on zidovudine, stavudine, didanosine, abacavir, and tenofovir DF resulting in a reduced response call for these drugs even with the presence of 4 NAMs. The presence of the 103N mutation confers phenotypic resistance to the first generation NNRTIs efavirenz and nevirapine although it does not impact susceptibility to etravirine; however, the presence of other NNRTI mutations such as L100I (and, to a lesser extent, 214F and 219E) explained the reduced susceptibility to etravirine. The patient had never been prescribed protease inhibitors but the report noted several mutations associated with PI resistance. It was felt he may have taken PIs as part of the "other HIV drugs" he acknowledged with this selective pressure leading to partial PI resistance. However, there was still full susceptibility to lopinavir/r, tipranavir/r, and darunavir/r.

Based on these results, the newly prescribed regimen consisted of darunavir/r + emtricitabine/tenofovir DF + raltegravir. This regimen was chosen because the virus was fully susceptible to darunavir and raltegravir. Also, emtricitabine would enable the 184V mutation to persist and continue to make the virus at least partially susceptible to tenofovir DF. The new regimen was well tolerated and after 4 weeks the HIV RNA level was <50 copies/mL and the CD4 cell count climbed to 392 cells/mm ³ . The patient continues with the drug rehabilitation program.

Practice Points

1. Failure of an efavirenz + zidovudine/lamivudine regimen frequently leads to the selection of resistance to several, if not all, all components of the regimen. The longer the failing regimen is continued, the greater the accumulation of resistance mutations. ¹
2. The103N mutation does not lead to resistance to etravirine; several different NNRTI mutations need to be present for a loss of susceptibility to etravirine to occur. ^2,3
3. Use of at least 2 and preferably 3 fully active agents in a regimen is associated with a high level of virologic and immunologic success. ^4,5

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. Deeks SG. International perspectives on antiretroviral resistance. Nonnucleoside reverse transcriptase inhibitor resistance. J Acquir Immune Defic Syndr. 2001;26(suppl 1):S25-S33.
2. 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.
3. Johnson M, Campbell T, Clotet B, et al. DUET-2: week 48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 591 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 791.
4. 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 Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
5. Hammer SM, Eron JJ Jr, Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA. 2008;300:555-570.