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Case Studies in Multidrug-Resistant HIV Infection

April 2007

Case 1

D.T. is a 43 year-old male inmate diagnosed with HIV infection in 1994 who has a history of AIDS (by CD4 cell count), distal peripheral neuropathy, hypertriglyceridemia and major depression. He presents for a routine infectious diseases clinic appointment two months after being incarcerated with a complaint of extreme fatigue. He recently had routine laboratories performed and these were normal except for a platelet count of 118 thousand. His hepatitis B surface antibody is positive but his hepatitis C antibody is negative. He is serving a four-year prison sentence.

He has a history of less than perfect adherence in years past, partially due to depression and lack of ability to tolerate medications. His nadir (lowest ever) CD4 cell count was 60/mm3 in August of 2002. At his last visit six weeks prior his HIV RNA PCR (viral load) was 17,000 copies/mL and the CD4 cell count was 726/mm3 (25%). Four months prior outside records indicate his viral load was 1,200 copies/mL.

His current medications included lopinavir/ritonavir, saquinavir, lamivudine, gemfibrozil, fish oil and fluoxetine.

His past antiretroviral history includes treatment with each of the following: zidovudine, zalcitabine, didianosine, lamivudine, tenofovir, stavudine, abacavir, efavirenz, indinavir and amprenavir.

A genotype was obtained on his current medication and revealed the following mutations:

NRTI: 67N, 184V, (other mutations detected: K219S)
PI mutations: 10I, 24I, 33F, 46L, 54V, 63P, 71V, 82A, 84V

Prior genotypes outside of prison reveal:

NRTI: 41L, 67N, 210W, 215Y, 184V
NNRTI: 103N, 181C
PI: 10I, 24I, 33F, 46L, 54V, 71V, 82A, 84V

Question: Taking into consideration the genotype results, medication history and past issues with adherence, what would be your next antiretroviral regimen?

Discussion: This patient has an extensive past antiretroviral experience. In addition, he has had mental health and substance abuse problems that have negatively impacted his ability to adhere to his HIV therapies. Since his incarceration he has been seen by mental health and is responding well to his antidepressant. After a 40-minute discussion regarding his commitment to HIV therapy during which he pledged to be adherent to HIV and mental health care it was decided to craft a new regimen of darunavir boosted with ritonavir, and fixed dose emtricitabine/tenofovir and zidovudine were selected.

Darunavir was selected despite the presence of a few mutations associated with reduced susceptibility to this protease inhibitor including the 33F and 84V mutations. Data from the darunavir package insert suggest that as many as 40% of treatment experienced patients with two major mutations associated with reduced darunavir susceptibility can achieve reductions in viral load below 50 copies/mL at 24 weeks. The patient harbors virus that is resistant to all the non-nucleoside reverse transcriptase inhibitors (NNRTI) and even though these mutations are not evident on his latest genotype resistance test, they persist and will reemerge if NNRTIs are used. Therefore, no currently approved NNRTIs will work against his virus. He also has developed a number of damaging mutations conferring resistance to drugs in the nucleoside reverse transcriptase inhibitor (NRTI) class. It is possible that his virus does retain some susceptibility to tenofovir, so this drug is being added to his regimen. In addition, there are some data to suggest that maintenance of the 184V mutation associated with lamivudine and emtricitabine resistance leads to reduced pathogenicity of HIV and that continuation of these drugs may inhibit the "fitness" of the virus. Lastly, other data indicate that HIV has difficulty maintaining resistance mutations to both zidovudine and tenofovir. The use of zidovudine in this case is somewhat novel and does not provide an antiretroviral effect -- as the genotype reveals that the detected virus is resistant to this NRTI -- rather, it is an attempt to protect against tenofovir resistance.

The clinician and patient also discussed the addition of enfuvirtide, an injected fusion inhibitor. This agent would be expected to provide additional antiretroviral activity and work well with his new combination of medications. However, the patient was opposed to twice-daily injections at this point and preferred to reserve this drug in case of suboptimal response to his new regimen or for a subsequent regimen.

Prior to receipt of his medications, the patient was counseled regarding potential toxicities of the drugs. He was encouraged to give the medications a chance and told that his body would most likely adjust should he have early problems such as gastrointestinal discomfort.

After approximately 3 weeks, the patient underwent laboratory testing. The viral had decreased by 2 log10 to 936 copies/mL and the patient was tolerating the medications. He reported 100% adherence with the new regimen and this was supported by nursing records as his medications were administered under direct observation. He reports less fatigue, despite addition of zidovudine. Routine laboratory results were unremarkable. Six weeks after initiating his regimen the viral load was less than 50 copies/mL and the CD4 cell count was 810/mm3. A fasting lipid panel revealed a triglyceride level of 165 mg/dL, LDL cholesterol of 102 mg/dL, and cholesterol of 44 mg/dL on gemfibrozil and fish oil capsules. A return clinic visit at three months after therapy initiation is scheduled to document continued viral suppression, to assess for adverse effects and adherence and provide continued adherence counseling and encouragement.

Case 2

B.D. is a 45 year-old woman with AIDS (CD4 nadir = 21/mm3), genital herpes simplex and history of venous stasis disease. She was diagnosed with HIV in 1994 and has been treated with a variety of antiretrovirals as listed below. Early in her treatment she suffered from intolerance to most of her HIV medications and often was non-adherent. However, over the years she has been able to tolerate her HIV therapy and has become adherent despite treatment with challenging antiretroviral regimens. Her current medications (since about 12/03) are lopinavir/ritonavir, lamivudine/zidovudine and tenofovir.

Three months ago her CD4 cell count was 184/mm3 and her viral load was 38,000 copies/mL. A genoptype resistance test was performed and revealed an extensive number of resistance mutations in each of the three classes of antiretrovirals tested (see 101). A repeat viral load is drawn and reveals a viral load of 29,000 copies/mL but no significant change in her CD4 cell count.

Her past antiretroviral history includes treatment with each of the following agents: Stavudine, didanosine, efavirenz, indinavir, nelfinavir, saquinavir and amprenavir.

Question: What would be her best next step in treating her HIV infection?

Discussion: First, the patient should be placed on appropriate prophylaxis for pneumocystis jiroveci pneumonia (formerly, pneumocystis carinii) then attention can turn to her antiretroviral options. Unfortunately, she now has multi-drug resistant HIV and few of the currently available antiretrovirals would be predicted to suppress the replication of her virus. The many resistance mutations her HIV has developed are likely a consequence of her inability to adhere to her medications, especially when she was prescribed early HIV agents that were more difficult to take than current therapies. Further, her initial therapy consisted of monotherapy with zidovudine and then a series of dual NRTIs with the subsequent addition of protease inhibitors. These sequential rounds of suboptimal therapy also contributed to the development of drug resistance.

Like the patient in Case 1, this patient has mutations in the reverse transcriptase region of her virus's genome that render all current NNTRIs essentially useless. Her NRTI options are almost equally as bleak, although tenofovir may still retain some modicum of activity. Likewise, she has few protease inhibitor choices remaining. Her genotype detects mutations to darunavir and tipranavir; however, unlike the case for current NNRTIs resistance to these protease inhibitors, is reduced with the accumulation of mutations such that it may require development of four, five or more major mutations to leave the virus impervious to the antiretroviral activity of these agents. Therefore, with just two or three such mutations, some activity of the protease inhibitor agents can be expected. Additionally, she is naïve to enfuvirtide and she is willing to receive twice daily subcutaneous injections, if necessary.

While we have the option of enfuvirtide we do not have a critical mass of agents to add to this drug to provide a regimen that could be expected to reduce her viral load to undetectable levels and keep it there. Either darunavir or tipranavir can be useful but the resistance present may truncate their antiretroviral effect. The addition of at least one other new agent anticipated to be active against this virus would increase confidence in her "salvage" regimen.

Based on the data presented at CROI 2007, we could expect the integrase inhibitor raltegravir, to be effective against this patient's virus (see main article). Participants in the Benchmrk studies were, like our patient, resistant to or experienced with drugs in all three original classes of antiretrovirals. In these studies those patients who received raltegravir and either darunavir or enfuvirtide (and were naïve to these two agents) had the best outcomes. Among those who took all three agents, 98% achieved viral loads less than 50 copies/mL at 16 weeks.

TMC-125 would be another agent that may provide some antiretroviral activity. The activity of TMC-125 is diminished as NNRTI mutations accumulate, therefore, if she harbors additional mutations -- acquired during her treatment with efavirenz but not sufficiently present now to be detected -- this drug may be less useful.

Therefore, it is decided to maintain her current therapy with the plan to start raltegravir, darunavir/ritonavir, enfuvirtide and tenofovir/emtricitabine once the integrase inhibitor becomes available, anticipated to be within the next six months. The risks of maintaining the current regimen including the cultivation of additional resistance mutations versus discontinuing her regimen and experiencing an even greater rise in viremia and attendant reduction in CD4 cell count are explained to the patient. She voices understanding of the considerations and opts to continue on her present therapy until the raltegravir becomes available and the new combination can be started.

Nichole Kiziah, Pharm.D., is with the North Carolina Department of Corrections. She has nothing to disclose.

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This article was provided by Infectious Diseases in Corrections Report. It is a part of the publication Infectious Diseases in Corrections Report.