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Gender, Race, and Antiretroviral Therapy: An Expert Interview at ICAAC 2006 With Princy Kumar, MD


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Editor's Note:
The topic of pharmacogenomics is gaining more attention among researchers involved in drug development and clinical research. Advances in this field hold promise in terms of tailoring diagnostics or drug treatments based on genetic characteristics of individual patients. In HIV medicine, investigators with expertise in this area are currently exploring critical issues such as response rates, adverse effects, and pharmacodynamics among subpopulations of HIV-infected persons. A deeper understanding of these genetic nuances is important, as the epidemiology of the HIV pandemic has become more complex and diversified over time, with women and people of color increasingly represented among the HIV-infected population. Princy N. Kumar, MD, examined these issues in one study that enrolled a high percentage of HIV-infected women and people of color. Dr. Kumar, Professor, Departments of Medicine and Microbiology, Georgetown University School of Medicine, Washington, DC; Chief, Infectious Diseases, Georgetown University Hospital, Washington, DC,spoke with Scott Williams, Editorial Director of Medscape HIV/AIDS, about the highlights of this important issue at the 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) held September 27-30, 2006, in San Francisco, California.

Medscape: Dr. Kumar, we are going to talk for a few minutes today about gender, race, and HIV therapy, so it seems appropriate to first provide some context. Since the initial cases of AIDS were first recognized 25 years ago, the virus has spread considerably beyond the demographic groups originally associated with HIV and AIDS. How has the epidemiology in the United States changed over the past quarter century, particularly in regard to new infections in people of color and women?

Dr. Kumar: The [US Centers for Disease Control and Prevention] CDC recently published some very interesting data[1] that, in many ways, reinforced what we are seeing in clinical practice. They reported that approximately 1.2 million cases of HIV/AIDS had been reported to the CDC by the end of 2004; the proportion of cases for women was about 15% overall; and from 2001 to 2004, it was up to 27%. In 2004, estimated HIV/AIDS case rates for blacks (76.3 per 100,000 population) and Hispanics (29.5 per 100,000) were 8.5 and 3.3 times higher, respectively, than rates for whites (9.0 per 100,000). So, overall, that is just looking at HIV/AIDS rates by race. When they looked at rates for males or females, they saw very disturbing numbers. The rate of AIDS among black women is 4 times that among Hispanic women and more than 20 times that among white women. Black and Hispanic women represent more than 80% of diagnosed cases among US women. Those were the sort of numbers we were seeing in practice, but that is the first time we saw them published from the CDC.

The next numbers were not in this issue, but the CDC published other data in their Sexually Transmitted Disease journal.[2] That publication brought up other issues that I as a clinician found particularly interesting, and that was where in the United States the epidemic is moving. They gave the numbers about the epidemic moving to the Southern states and more to rural areas. If you look at the latest data, 39% of all HIV-infected individuals live in the South, and 20% of all HIV-infected individuals live in nonurban areas. Why is that important? Because those women tend to be poorer, they tend to be less educated, and they tend to be taken care of by providers who care for fewer HIV-infected patients. The numbers also showed that they are less likely to be on even standard prophylaxis, and less likely to get even standard antiretroviral regimens.

All of this shows the evolving epidemiology of HIV/AIDS and how it is clearly moving into women and people of color. For me, the greatest take-home point when I looked at this is that 80% of all cases of AIDS in women are in people of color. It is really a very important issue.

Medscape: Let's move to some of the clinical concerns around HIV therapy in terms of gender and race. Pharmacogenomics has been a topic of increasing interest among some HIV researchers and clinicians in recent times. Given that, in broad terms, what are some of the areas in the treatment of HIV infection in which gender and race might affect clinical outcomes?

Dr. Kumar: A lot of work is going into understanding pharmacogenomics because it may explain differences where treatment response or side effects are seen based on gender or race. Some of the more recent studies have raised awareness of differences in pharmacogenomics for practicing clinicians.

I think the single most important study to date in pharmacogenomics was ACTG 5095 [substudy ACTG 5097s],[3] and that was really looking at the levels of efavirenz and neuropsychological testing and seeing whether there was a difference in the levels and in neuropsychological testing.

The best way to understand the data is as follows: efavirenz is metabolized by the CYP2B6 enzyme system, there are different CYP2B6 genotypes among different racial groups, and the differences of interest are single nucleotide polymorphisms at codon 516. There are 3 different genotypes: (1) G/G, (2) G/T, and (3) T/T. And why is that important? Because if you have the T/T, you are much less able to clear your efavirenz, and if you don't clear your efavirenz, what is going to happen is you are going to get much higher drug levels. Higher levels may be associated with greater central nervous system (CNS) toxicity.

So how does that all fit into recent findings, especially with regard to race? Twenty percent of African-Americans have the T/T genotype at position 516 vs just 3% of whites. And so, that makes us think that African-Americans who have the T/T genotype at position 516 are likely to clear the efavirenz more slowly and more likely to have higher levels. That does not mean that efavirenz should not be used in African-Americans. Eighty percent of African-Americans don't have this genotype, but it really raises the level of consciousness in our mind if an African-American patient comes to you with CNS side effects, that there may be a rationale for why those side effects developed, or were more severe. This study is one of the single most important studies from a practical standpoint, in terms of race and drug metabolism.

Medscape: There are certainly other issues that are related to this topic. One of them has been the hypersensitivity reaction associated with abacavir. These are obviously a matter of serious concern, but predicting such reactions would make it possible to select other antiretroviral drugs for patients who are at risk, or using this drug with more confidence in persons at less risk. There has been some progress in this regard with respect to the identification of one HLA haplotype that is preferentially associated with these reactions. At this meeting, we saw more data with one group of investigators exploring a screening test, and another looking at the rate of hypersensitivity reactions in black persons compared with persons with HIV of other races. What did these investigators from these 2 studies find?

Dr. Kumar: The issue of abacavir hypersensitivity is of practical importance because abacavir hypersensitivity, if not diagnosed, is quite serious, and more importantly, if patients are rechallenged, has led to fatalities. So there has been a lot of interest among practitioners to see whether we can predict who will have the abacavir hypersensitivity.

At this conference, there were 2 important datasets that were presented that addressed this question. First, Dr. Denise Sutherland-Phillips from GlaxoSmithKline presented data about abacavir hypersensitivity in African-American patients. Overall, if you look at the package insert, abacavir hypersensitivity is reported in about 5% to 8% of the general population. If you look at published results,[4] and if you look at African-Americans vs whites, we have seen a lower incidence of abacavir hypersensitivity in African-Americans, and that has been observed in my clinical practice as well.

What Dr. Denise Sutherland-Phillips presented at this meeting[5] was a look at the 5 larger studies that GlaxoSmithKline did between the years of 2000 and 2005 -- five of the larger studies using abacavir in the backbone regimen, and compared the abacavir hypersensitivity in African-Americans vs the overall population. Together, the 5 studies had about 2800 patients enrolled, so it is a huge dataset. In the overall population, the risk of hypersensitivity was 6.6%. In African-Americans, it was 3.6% -- about half of what has been seen in the general population.

She then went on to give a biological reason why this is lower in African-Americans. And as you may know, several years ago now, Simon Mallal,[6] from Australia, published the seminal study showing the association between the haplotype HLA-B*5701 and abacavir hypersensitivity. Dr. Sutherland-Phillips then showed the prevalence of this specific haplotype around the world. In the United States among whites, it is about 8.0%, 2.0% among Hispanics, and 2.5% among African-Americans. She postulated that African-Americans are less likely to have this haplotype, and probably have less chance of having abacavir hypersensitivity than whites. But she was very careful -- no test substitutes for good clinical judgment, and she took particular pains to point that out. This is something to begin thinking about, something to start incorporating into clinical trials, not something we should go home today and use. It is not a test you can just write an order for. It is done mainly in the research labs, and it is an expensive test.

Medscape: In another study at ICAAC, Currier and coworkers[7] evaluated sex-related differences in toxicity and response to antiretroviral therapy in 3 pivotal trials of the protease inhibitor fosamprenavir. This was with or without ritonavir boosting. Did the investigators find any overall differences in efficacy between men and women?

Dr. Kumar: What Dr. Currier did was look at the 3 big clinical trials of fosamprenavir. The trials were: (1) the NEAT study, (2) the SOLO study, and (3) the CONTEXT study. The SOLO study looked at fosamprenavir given once a day with boosted ritonavir and compared it with nelfinavir. The NEAT study was fosamprenavir unboosted twice a day compared with nelfinavir. The SOLO and the NEAT were in treatment-naive patients. And in the CONTEXT study, they initially started with 3 arms: (1) fosamprenavir once-daily, (2) fosamprenavir twice daily, and (3) lopinavir/ritonavir. CONTEXT was in treatment-experienced patients.

And what Currier and her colleagues did was combine the whole dataset and looked at it, and that came up to 1239 patients. The question was whether there was a difference in efficacy and a difference in toxicity between men and women, especially because 25% of the patient population was female. There were no apparent sex differences in response to treatment (ie, viral load less than 400 copies/mL) at weeks 24 and 48. Men were more likely to have elevations in transaminases, triglycerides, and cholesterol than were women, but overall, no major differences in safety between men and women were noted.

At the same session, there was another study by Anne Collier and her colleagues from the University of Washington that looked at darunavir (TMC114). Again, they went back and looked at the whole dataset that Tibotec had. They used data from the POWER 1, 2, and 3 studies, and that was over 900 patients. They looked at whether there an effect of race, gender, and age, and again found that there were no differences where efficacy or side effects were concerned based on age, gender, or race. This really ties into a number of other datasets that are coming. If you get good therapies, and if you have access to care, then gender and race do not make a difference.

Medscape: Data from the PREPARE study were presented at this meeting and seemed to indicate the possibility of different baseline resistance mutations based on a subject's race. What did they find, and were there any lessons to be applied to clinical management of people with HIV?

Dr. Kumar: The study that you are referring to was done by Ross and colleagues[8] at GlaxoSmithKline. They looked at the dataset of all the trials that they have of treatment-naive patients to pick up baseline resistance mutations. As you know, it is a very relevant topic because we have seen an increase in resistance mutations in treatment-naive patient populations. First, they asked: "What is the prevalence of primary resistance mutations over time?", and second, "Are there differences based on race, regions of the United States, and viral load, among others?" What they were able to show is that the NNRTI mutations have clearly increased from 2001 to 2005, and that is consistent with almost every other published study -- that the incidence of NNRTI mutations is increasing. There was less resistance in the Western parts of the United States than in the rest of the United States. And the third thing that was important is that there was less resistance among the PI mutations and the NNRTI mutations for blacks when compared with whites.

The study investigators have once again made us aware about the increase in NNRTI mutations. In their poster, they also discussed what to do if you cannot get a baseline genotype test. The DHHS recommendations are to get a baseline genotype before initiating therapy, but there are clearly clinics that are not able to get a baseline resistance test because of cost issues. If you cannot get a baseline resistance test, then you may want to rethink whether an NNRTI should be your choice as first-line antiretroviral therapy. That is the way I interpreted their conclusion.

Medscape: Turning to a recently published study that you authored, the ESS4002 study[9] analyzed race and gender. Could you tell us about some of the key elements of the study design, important take-home points, and how the information might affect clinical management of HIV disease?

Dr. Kumar: I like to refer to this study as a women's study because, although it was just a small, 274-patient study, it enrolled a high proportion of women. It was a phase 4 study. And what we wanted to look at was the effect of different regimens on the lipid profile -- did the different regimens have different lipid profiles, and what was the effect of race and gender on the lipid profile?

The 3 arms of the study were:

  1. Twice-daily regimens of fixed-dose combination abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg triple nucleoside tablet (TZV);
  2. Fixed-dose combination lamivudine 150 mg/zidovudine 300 mg (CBV) + nelfinavir (NFV); and
  3. Stavudine (d4T) + lamivudine (3TC) + NFV.

As you remember, the study was done about 4 to 5 years ago, but 50% of the patients who entered the study were women, 40% were black, and 37% were Hispanic, so that is why we were able to collect a lot of information about race and gender. We did fasting lipids at multiple time points over this 96-week study, and what we were able to show is that TZV had the best lipid profile compared with the other 2 arms. At week 96, LDL-cholesterol was significantly lower in TZV group than in the other 2 treatment groups among both women and men, and this measure was lower in the TZV group than in the d4T/3TC/NFV group among both Hispanics and black patients. Although triglycerides increased in all 3 groups, they changed the least in women and Hispanic patients receiving TZV.

Medscape: Thank you so much for sharing your insight with us today. It is much appreciated, and I am sure lots of people will find it useful.

Dr. Kumar: Thank you very much.

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