This month’s Research Focus, “Trends in HIV Care, Part 1,” is a summary of a roundtable discussion with 4 health care providers from the AIDS Community Health Center (ACHC) in Rochester, NY.
This month’s Research Focus, “Trends in HIV Care, Part 1,” is a summary of a roundtable discussion with 4 health care providers from the AIDS Community Health Center (ACHC) in Rochester, NY. The ACHC is a not-for-profit HIV medical clinic that provides specialty and primary care for persons with HIV/AIDS. Three current topics of interest to HIV care providers are presented and discussed using the evidence available to date with an eye toward the future of HIV care. The topics presented are expanded uses of new antiretroviral classes, a contemporary approach to anal dysplasia, and reimbursement for new and emerging diagnostic technologies. Although evidence supporting our understanding of these topics to date is discussed, be advised that the discussions also include off-label uses for some antiretroviral agents and diagnostic technologies.
EXPANDED USES OF NEW ANTIRETROVIRAL CLASSES
When to start therapy and what to use are pivotal issues in HIV care. In the most recent US treatment guidelines from the Department of Health and Human Services (DHHS) and from the International AIDS Society–USA (IAS-USA), the pendulum swing toward earlier treatment is particularly notable.1,2 These guidelines now state that the decision to initiate therapy before the CD4+ cell count decreases to less than 350/µL should be individualized, based on the presence of comorbidities (eg, active hepatitis B or C, cardiovascular disease, and HIV-associated nephropathy) and a patient’s readiness for treatment. The association between uncontrolled viral replication and the increased risk of morbidity and mortality at all CD4 levels is given as additional evidence to support earlier treatment.2,3 For first-line therapy, both guidelines continue to recommend the traditional approach using 2 NRTIs in combination with either an NNRTI or a protease inhibitor (PI).1,2
Still, the DHHS and IAS-USA guidelines are not always in agreement on treatment issues. Rather than confuse the picture, their differences offer several viable options for HIV providers and play an important role in providing a framework for HIV treatment. Because individualized therapy is critical to treatment planning, providers’ clinical experience and judgment are important drivers of treatment decisions in the end. For example, the IAS-USA guidelines recommend the integrase inhibitor raltegravir as first-line therapy “in highly selected circumstances.”2 While the IAS-USA does not give examples of these special circumstances, these best situations are likely to be defined over time as more clinical experience is gained with raltegravir. At the outset, these newer and well-tolerated agents appear that they can not only be part of a lifetime regimen but can also increase our therapeutic options for treatment-naive and -experienced patients.
Currently, the newly available agents maraviroc, an entry inhibitor (specifically a CCR5 coreceptor inhibitor), and raltegravir are labeled for use in treatment-experienced patients whose infections are known to be resistant to other antiretroviral agents.4 In the short term, the novel mechanisms of action of maraviroc and raltegravir, when combined with optimized background regimens, provide additional opportunities for complete viral suppression in treatment-experienced patients.
Clinical experience with maraviroc and raltegravir that adds to the existing safety and efficacy data will likely lead to their positioning as first-line regimens,5 similar to our clinical experience with other newly introduced antiretrovirals. Novel regimens should be at least as good as the time-honored ones with which we have experience.5 In an editorial, Hirschel and Calmy5 note that an efavirenz-based regimen is “hard to beat” because of its durability, potency, and convenience. They suggest that maraviroc and raltegravir have the potential to evolve to first-line agents because of their pharmacokinetics and initially favorable safety profiles. A summary of the status of these agents as part of first-line therapy is shown in Table 1.
Recent reports of raltegravir’s efficacy and safety in 2 clinical trials in treatment-naive patients at 48 and 96 weeks, respectively, have helped establish the groundwork for this drug’s first-line use.6,7 In both trials, raltegravir was compared with efavirenz, when used in a regimen with an NRTI backbone of tenofovir/emtricitabine. The 48-week data from the STARTMRK trial showed that the raltegravir-based regimen outperformed the efavirenz-based regimen, with fewer CNS adverse events and a shorter time to virological response.6 There were no clinical differences in virological outcomes (ie, proportion of patients achieving an HIV RNA level below 50 copies/mL), and the raltegravir-based regimen was deemed noninferior to the efavirenz-based regimen.
Maraviroc has appeal as a first-line agent because of its inhibition of the CCR5 (R5) coreceptor site for viral entry into CD4 cells. For reasons that are not clearly understood, most cases of primary and early HIV-1 infection occur with the CCR5-tropic strain of virus,8 making maraviroc an attractive, theoretical option in treatment-naive patients. In the original MERIT study analysis, when maraviroc was compared with an efavirenz-based regimen, it failed to meet noninferiority criteria.9 However, in a reanalysis of the 48-week data using a more sensitive tropism assay, the two regimens performed equally well, and maraviroc met the criteria for noninferiority.10 The results of this reanalysis help reinforce the importance of defining the optimum timing and sequencing for using maraviroc, since the risk of developing X4 coreceptor tropism increases with the duration of HIV infection.8,11,12
Although first-line use is still an unlabeled indication for both agents, incorporating either into first-line regimens will require a rethinking of the traditional treatment paradigm recommended in the current guidelines. An important part of this evolution in our thinking is the treatment strategy of class-sparing regimens. Some examples of other class-sparing options under investigation include raltegravir plus the lopinavir/ritonavir boosted PI coformulation13 and raltegravir with the abacavir/lamivudine NRTI backbone.14
Over the long term, newer agents may provide an opportunity to reevaluate the concept of salvage therapy. As contemporary agents are introduced, their improved tolerance and convenience help reinforce the contribution of treatment adherence to achieve and maintain viral load suppression. Looking to the future, we should consider whether the concept of salvage therapy, as we know it today, might become obsolete with the use of these newer antiretrovirals.
Eventually, these newer agents may play an important role as part of a preventive regimen for occupational HIV exposure. If the tropism status and resistance data of the source patient are up-to-date and readily available, the use of maraviroc as a preventive agent is particularly appealing because of its mechanism of action.15 It has also been suggested that raltegravir can be part of an “expanded regimen” for postexposure prophylaxis when the source patient is known to have high-level resistance to other agents.16
Still, advancing therapy with newer agents requires some caution while clinical trials data emerge and as we use these agents outside of a clinical trial setting. Additional data are needed to address the initial concerns regarding the risk of serious adverse events and the emergence of drug resistance. For example, early reports of cancer associated with the integrase inhibitor class in treatment-experienced patients still need clarification.17,18 The latest data from the STARTMRK trial (ie, 48-week data) do not show a significant difference in the incidence of malignancies in treatment-naive patients on the raltegravir-based regimen compared with those on the efavirenz-based regimen.6 Concerns regarding raltegravir’s low genetic barrier to resistance have emerged from the drug’s use as salvage therapy in patients with triple-class resistance.19,20 The primary integrase inhibitor mutations that developed have conferred resistance to both raltegravir and the investigational integrase inhibitor elvitegravir.20 While we await additional data on drug resistance with this class, the preliminary data reinforce the importance of optimizing the patient’s background regimen.
Similarly, some reports have suggested a paradoxical immune response to maraviroc because of its potential impact on immune surveillance, which may increase the risk of certain infections and malignancies. To date, this represents a theoretical concern that has not been borne out in clinical trials.17,18
A CONTEMPORARY APPROACH TO ANAL DYSPLASIA
While there are still many unknowns about the human papillomavirus (HPV), the link between HPV and cancer is becoming increasingly clear.21 We know that HPV interferes with host defense mechanisms that regulate squamous cell production that results in condylomata. We also know that oncogenic and nononcogenic HPV strains can and do exist in a single person and that HIV-infected persons are more commonly infected with the oncogenic strains.21
Although genital warts have been recognized as a sexually transmitted disease since ancient times, the current epidemic of HPV-related cancers has its roots in the 1960s and 1970s during the so-called sexual revolution. This epidemic is similar to that seen with hepatitis C, where the clinical manifestations of infection may take more than 20 years to develop.22 In the case of infection with HPV, the slow growth of the virus attracts little immune system response, resulting in dysplasia and, eventually, cancer.
The numbers, as we know them, tell only part of the story. Estimates are that there will be more than 5000 cases of anal cancer in the United States in 2008, with about 680 deaths.23 While this estimated number of deaths is relatively small, it represents only the “tip of the iceberg.”24 The real problem lurks below the surface: it is believed that there is a substantial number of asymptomatic persons infected with HPV who are unaware they are infected, in large part because they have not been screened-a situation similar to that with HIV infection and hepatitis C. Because so many people have now been infected with HPV for 2 or more decades, the potential for an “explosive epidemic” is looming.
In addition, the estimated 680 deaths annually do not account for all of the morbidity associated with HPV infection. The overall morbidity and cost of anal fulgurations or extensive salvage procedures, such as abdominoperineal resections for recurrent anal cancer after radiation therapy and chemotherapy, has not been reported.
The incidence of anal squamous intraepithelial lesions in a single year was found to be 12% in a population of HIV-infected men and women.25 In addition, the incidence of anal cancer is 2% per year in the United States.23 Of the entire US population, 75% have evidence of HPV infection, making it the most prevalent sexually transmitted infection and an incurable one24: while we can treat dysplasia, we cannot eradicate HPV infection in someone whose immune system cannot clear the virus on its own.
The prevention story is unsettling. Condoms do not prevent HPV transmission because the virus is transmitted from the skin of one person to the skin of another. Condoms obviously cover only limited amounts of skin, leaving the thighs, buttocks, and scrotum of sexual partners unprotected. While anal receptive sex is the most efficient way to transmit HPV to the squamous cells of the anal canal, skin cells that become infected can then infect adjacent skin cells, which, over time, can result in infections of the perianal skin and the anal canal.26 A piece of this puzzle for women is the so-called field effect. In women whose initial HPV infection is in the vagina, secretions can transport the virus to the anal canal because of the proximity of the two orifices. In other words, penetrative sex is not necessary to develop anal HPV infection for men or women.
While HPV infection has the attention of an increasing number of health care providers, there is still no consistent approach to dealing with the problem. Certainly, an HPV vaccine will have an impact over the long term as vaccination programs are implemented. An HPV vaccine for men will likely be as important as it is for women.
HPV infection also has the attention of health care organizations and payers, but the approach has been uneven in terms of clinical practice and reimbursement. For example, the problem of anal HPV infection is not limited to persons also infected with HIV. All women, whether HIV infected or not, and HIV-negative men who have sex with men are candidates for HPV infection. Of note, most of the women who have been screened for and found to have cervical dysplasia since the 1950s have not been HIV-infected.
Evidence is accumulating to support anal dysplasia screening with anal Papanicolaou testing and diagnosis with high-resolution anoscopy, a 20-minute office procedure that involves the examination of the anal mucosa with a magnifying colposcope, a procedure similar to cervical colposcopy, which allows for directed biopsies.27 The basis for what we know about anal dysplasia screening today, and the need to intervene before dysplasia becomes invasive cancer, comes from our understanding of the value that cervical cancer screening has demonstrated in saving the lives of thousands of women.
Cervical cancer screening and treatment procedures have required modification for their use for the anal canal because of the anatomical differences. The anal Papanicolaou test is performed as a 10-second sampling of cells with a swab or brush and without visualization. Because the anus is not smooth like the cervix, the sampling swab or brush may not sample cells from every anal crypt and fold. The anal Papanicolaou test may underrepresent
the degree of dysplasia within the anal canal, so any abnormality on an anal Papanicolaou report should be followed up with high-resolution anoscopy. Biopsies samples taken from microscopic abnormalities are sent for pathological evaluation, and it is the results of this evaluation that are diagnostic and that direct treatment. Low-grade dysplasia, ie, anal intraepithelial neoplasia (AIN) 1, can be monitored every 6 months, while biopsy-proven high-grade dysplasia (AIN 2 or 3) and carcinoma in situ must be removed to prevent the development of invasive squamocellular carcinoma of the anus.
The only, readily available therapies for the removal of precancerous lesions of the anal canal before they become invasive have been surgical excision and fulguration. These procedures are commonly associated with more rapid return of condylomata because instrumentation seems to carry the virus into additional anal tissue. Surgical procedures also result in weeks to months of postoperative pain and anal dysfunction.
The emerging, noninvasive treatment of choice is infrared photocoagulation ablation, which allows “spot” treatment of biopsy-proven high-grade dysplasia. Infrared photocoagulation ablation is also accomplished during a 20-minute office procedure, after infiltration of a local anesthetic. Most patients do not require narcotic analgesics and may return to work the same day. Recurrences following treatment occur because all of the cells of the circumferential anal canal will eventually become infected with HPV. Some groups of cells have likely been infected before others, so precancerous lesions develop over an unpredictable time course, making long-term, routine monitoring both necessary and lifesaving.
A limiting factor in many HIV treatment settings is availability of providers with experience in high-resolution anoscopy and noninvasive treatment procedures. More clinical settings that offer these services for HIV-infected and non–HIV-infected populations alike will be needed as we move toward a more consistent approach to screening for and treating anal dysplasia. (A list of current providers of high-resolution anoscopy is available at www.analcancerinfo.ucsf.edu.)
Looking ahead of the curve, it makes sense, for now, to screen for anal dysplasia because the data we have suggest that screening is the right thing to do. Several organizations have set forth guidelines regarding the screening for and diagnosis of anal dysplasia.28-30 A summary of these recommendations is shown in Table 2.
One day, anal dysplasia and its attendant complications may be a problem of the past if HPV vaccine protection is extended to future generations of men and women. An interim analysis of a study evaluating the use of a quadrivalent HPV6/11/16/18 vaccine in adolescent boys and men has shown that after 30 months of follow-up, the frequency of new penile lesions and persistent HPV infection was 90% less in the vaccine group than in the placebo group, paving the way for expanding the vaccine’s use to men and boys.31
Finally, we will need to be prepared to make clinical decisions as new data on the currently available HPV vaccine become available. Since vaccination must occur before exposure to HPV, the timing of our decisions is critical to take advantage of the opportunities afforded by having a vaccine. At a minimum, that opportunity includes the ability to protect young people from a life-threatening virus. It is hoped that we will have that same opportunity one day with our ability to prevent HIV infection.
NEW AND EMERGING DIAGNOSTIC TECHNOLOGIES: REIMBURSEMENT ISSUES
New diagnostic tests are often FDA-approved and available faster than our ability to incorporate them into clinical practice.32 Barriers to incorporating new technologies into medical practice include the following:
• The necessary uptake time for health care providers to become familiar with new technologies and their use.
• Their availability from diagnostic laboratories.
• Consensus regarding their value.
• Uneven reimbursement.
The history of viral load testing provides a good example. The FDA approved the first-generation viral load test in 1996.33 In our own experience, reimbursement did not follow the introduction of this test into clinical use. Our third-party payers asked for 2 criteria to support the use of viral load testing: one, the evidence to support its value and, two, an algorithm to outline its use.
We developed a 1-page outline indicating that stable patients would have a maximum of 4 tests reimbursed per year. Unstable patients with treatment failure or undergoing a regimen change would have the test done at the provider’s discretion, with the reason noted in the medical record for auditing purposes. Fortunately, this was in the era before the extensive use of prior authorizations, and we were able to avoid delays in test ordering, with more timely delivery of care.
Over time, as viral load testing evolved to a standard of care and the cost of the test decreased, the algorithm became unnecessary and was largely forgotten.
Newer diagnostic technologies for HIV care and primary care will need to be evaluated and incorporated into our practice. In the end, these new technologies support an approach to personalized medicine that keeps us on the cutting edge and avoids the expense of prescribing drugs that will lead to adverse events or may be ineffective.
The use of the HLA-B*5701 test to assess risk of abacavir hypersensitivity reaction is a good example of a diagnostic test that helps avoid adverse events. In this case, a negative test result has been shown to have a 100% negative predictive value for abacavir hypersensitivity, allowing the drug to be used more safely.34 For the most part, this test has been adopted as standard of care before abacavir use.1 Also in this test’s favor is that it is a genetic test that needs to be performed only once on a given patient and it is moderately priced (cost range $50 to $150 per test). Still, some providers may encounter uneven reimbursement for HLA-B*5701 testing and will need to dialogue with some laboratory providers and third-party payers to ensure access to the test for their patients.
The cytochrome P-450 (CYP450) genotyping test can be helpful in the selection of antidepressant drugs. While not all antidepressant drugs are metabolized by the CYP450 pathway, those that are included in current test kits are amitriptyline (Elavil), clomipramine (Anafranil), desipramine (Norpramin), imipramine (Tofranil), and paroxetine (Paxil). This test has gained more acceptance among mental health professionals. However, HIV care providers often prescribe antidepressants for patients and might find this technology useful in drug selection. In brief, this genotyping test classifies patients into 1 of 4 phenotypes based on the rate of CYP450 metabolism (normal, intermediate, slow, and ultrarapid).35,36 Slow metabolizers are likely to accumulate higher than expected drug levels, which results in an adverse event or drug intolerance. Ultrarapid metabolizers represent patients who will metabolize the drug in question too quickly and will have a delayed or absent therapeutic response.28
There are several FDA-approved assays available through many commercial laboratories (AmpliChip, Roche Diagnostics; CodeLink Human P450, GE Healthcare; Drug Met Genotyping Test, Jurilab, Ltd; Tag-It Mutation Detection Kit, Tm Bioscience Corporation). Currently, the price of these tests, about $1000 depending on the assay and laboratory, has put them out of reach in many clinical settings. As a first step, we are working with our third-party payers on a reimbursement strategy that will allow us to use these tests in patients in whom antidepressant medication has failed in the past. The approach will likely use a prior authorization strategy with review by the health plans’ medical utilization management staff. Open access to CYP450 testing is not an option at this point, but the prior authorization approach makes the test available on a limited basis while a best practice model for its use and interpretation is developed.
In addition to its application to psychotropic drugs, CYP450 testing has relevance to antiretroviral use. Efavirenz, for example, is metabolized by the CYP2B6 enzyme. While availability of CYP450 testing for efavirenz is still in its early stages and not yet commercially available, research-based testing has been used to guide efavirenz therapy and dose adjustments. Japanese investigators have used a genotyping test for CYP2B6 to identify mutations associated with the slow metabolism of efavirenz, which results in elevated efavirenz levels and an increased risk of efavirenz-related CNS toxicity.37 The prevalence of mutations in 456 patients was 18%, and all patients with mutations at alleles *6 and *26 had plasma efavirenz levels that were roughly 3 or more times above normal. Dose adjustments from 800 mg/d to 400 or 200 mg/d resulted in improvement in CNS symptoms in a subset of 10 of 14 patients, all of whom maintained viral load suppression. The investigators concluded that genotype-based dose reduction is feasible and can reduce efavirenz-associated CNS symptoms.
Finally, the role of CCR5 tropism as a predictor of response to the CCR5 coreceptor inhibitor maraviroc has been established.17,18 Currently, there are 2 FDA-approved assays for use as diagnostic tests (Trofile, Monogram Biosciences, Inc; SensiTrop, Pathway Diagnostics Corporation). The availability of the HIV tropism test has reignited the discussion of HIV-1 tropism as a prognostic marker for CD4+ cell depletion and HIV disease progression to AIDS.12 While a cause-and-effect relationship between tropism and disease progression has not been established, providers need to follow the emerging data that might reposition these tests beyond their current use in selecting maraviroc as a therapeutic option. The use of such a diagnostic test as a predictor of disease progression is currently off-label.
In this current era of HIV treatment, providers will still need to work with laboratories and third-party payers to facilitate access to and reimbursement of newer diagnostic technologies. Our experience suggests that this can be a time-consuming process, especially when dealing with reimbursement issues. In the end, optimizing outcomes for our patients depends on adequate reimbursement.
No potential conflict of interest relevant to this article was reported by the authors. Dr Valenti moderated the roundtable on which this article is based and prepared the first draft of the manuscript from the transcript of the discussions. Each coauthor prepared and presented his or her individual discussions and contributed to and edited the final draft of the manuscript.
References1. 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. www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed November 17, 2008.
2. Hammer S, Eron JJ, Reiss P, et al; International AIDS Society–USA. Antiretroviral treatment of adult HIV infection. 2008 recommendations of the International AIDS Society–USA panel. JAMA. 2008;300:555-570.
3. Strategies for Management of Antiretroviral Therapy (SMART) Study Group; Lundgren JD, Babiker A, El-Sadr W, et al. Inferior clinical outcome of the CD4+ cell count–guided antiretroviral treatment interruption strategy in the SMART study: role of CD4+ cell counts and HIV RNA levels during follow-up. J Infect Dis. 2008;197:1145-1155.
4. United States Food and Drug Administration. Drugs used in the treatment of HIV infection. www.fda.gov/oashi/aids/virals.html. Accessed September 20, 2008.
5. Hirschel B, Calmy A. Initial treatment for HIV infection-an embarrassment of riches. N Engl J Med. 2008;358:2170-2172.
6. Lennox J, Dejesus E, Lazzarin A, et al. STARTMRK, a phase III study of the safety & efficacy of raltegravir-based vs efavirenz-based combination therapy in treatment-naive HIV-infected patients. 48th International Conference on Antimicrobial Agents and Chemotherapy; October 25-28, 2008; Washington, DC. Abstract H-896a.
7. Markowitz M, Nguyen BY, Gotuzzo E, et al. Sustained antiretroviral efficacy of raltegravir as part of combination ART in treatment-naive HIV-1 infected patients: 96-week data. 17th International AIDS Conference; August 3, 2008; Mexico City. Abstract TUAB0102. www.aids2008.org/Pag/PSession.aspx?s=256. Accessed September 20, 2008.
8. Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med. 1998;339:33-39.
9. Heera J, Saag M, Ive P, et al. Virological correlates associated with treatment failure at week 48 in the phase 3 study of maraviroc in treatment-naive patients. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston. Abstract 40LB. www.retroconference.org:8888/2008/Abstracts/33388.htm. Accessed September 20, 2008.
10. Saag M, Heera J, Goodrich J, et al. Reanalysis of the MERIT study with the enhanced Trofile assay. 48th International Conference on Antimicrobial Agents and Chemotherapy; October 25-28, 2008; Washington, DC. Abstract H-1232a.
11. Shepherd JC, Jacobson LP, Qiao W, et al. Emergence and persistence of CXCR4-tropic HIV-1 in a population of men from the multicenter AIDS cohort study. J Infect Dis. 2008;198:1104–1112.
12. Burger H, Hoover D. HIV-1 tropism, disease progression, and clinical management. J Infect Dis. 2008;198:1095-1097.
13. National Institutes of Health. Raltegravir + lopinavir/ritonavir or emtricitabine/tenofovir for HIV treatment naive subjects. http://clinicaltrials.gov/
ct2/show/NCT00654147?term=Raltegravir+OR+Isentress[TREATMENT]+AND+HIV+[CONDITION]&rank=3. Accessed November 17, 2008.
14. National Institutes of Health. Pilot study with Isentress (raltegravir) and Epzicom (abacavir/lamivudine) in treatment naive HIV-infected subjects (SHIELD).http://clinicaltrials.gov/ct2/show/NCT00740064?term=Raltegravir+OR+Isentress[TREATMENT]+AND+HIV+[CONDITION]&rank=5. Accessed November 17, 2008.
15. MÃ©chai F, Quertainmont Y, Sahali S, et al. Post-exposure prophylaxis with a maraviroc-containing regimen after occupational exposure to a multi-resistant HIV-infected source person. J Med Virol. 2008;80:9-10.
16. Siegel MO, Kan V, Benator DA. Raltegravir for postexposure prophylaxis following occupational exposure to HIV. AIDS. 2008;22:2552-2553.
17. Gulick RM, Lalezari J, Goodrich J, et al; MOTIVATE Study Teams. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008;359:1429-1441.
18. FÃ¤tkenheuer G, Nelson M, Lazzarin A, et al; MOTIVATE 1 and MOTIVATE 2 Study Teams. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med. 2008;359:1442-1455.
19. Charpentier C, Karmochkine M, Laureillard D, et al. Drug resistance profiles of HIV integrase gene in patients failing raltegravir-salvage therapy. 6th European HIV Drug Resistance Workshop; March 26-28, 2008; Budapest. Abstract 48.
20. McColl DJ, Fransen S, Gupta S. Resistance and cross-resistance to first generation integrase inhibitors: insights from a phase II study of elvitegravir (GS-9137). Antiviral Ther. 2007;12:S11. Abstract 9.
21. Patel P, Hanson D, Sullivan P, et al; Adult and Adolescent Spectrum of Disease Project and HIV Outpatient Study Investigators. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med. 2008;148:728-736.
22. Seeff L. Natural history of chronic hepatitis C. Hepatology. 2002;36(5 suppl 1):S35-S46.
23. National Institutes of Health, National Cancer Institute. Surveillance, Epidemiology and End Results: Anal Cancer. http://seer.cancer.gov/statfacts/ html/anus.html. Accessed September 20, 2008
24. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med. 1997;102:3-8.
25. Conley L, Bush T, Darragh T, et al. Incidence and predictors of anal squamous intraepithelial lesions in the SUN study after 1 year of follow-up. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston. Poster 1022.
26. Chiao E, Giordano T, Palefsky J. Screening HIV-infected individuals for anal cancer precursor lesions: a systematic review. Clin Infect Dis. 2006;43:223-233.
27. Wexler A, Berson A, Goldstone S, et al. Invasive anal squamous-cell carcinoma in the HIV-positive patient: outcome in the era of highly active antiretroviral therapy. Dis Colon Rectum. 2008;51:73-81.
28. New York State Department of Health AIDS Institute. Human papillomavirus. http://hivguidelines.org/GuideLine.aspx?guideLineID=102. Accessed September 20, 2008.
29. Centers for Disease Control and Prevention; Workowski KA, Berman SM. HPV infection and genital warts. Sexually transmitted diseases treatment guidelines 2006. MMWR. 2006;55(RR-11):62-67. www.fascrs.org/patients/conditions/anal_cancer. Accessed September 20, 2008.
30. American Society of Colon & Rectal Surgeons. Anal cancer. http://www.fascrs.org/patients/conditions/anal_cancer.
31. Palefsky J, Giuliano A; Male Quadrivalent HPV Vaccine Efficacy Trial Study Group. Efficacy of the quadrivalent HPV vaccine against HPV 6/11/16/18-related genital infection in young men. 2008 European Research Organization on Genital Infection and Neoplasia (EUROGIN) International Multidisciplinary Conference; November 12-15, 2008; Nice, France. Abstract TC2-11. www.eurogin.com/ 2008/EUROGIN2008_LastMinuteAbstracts.pdf. Accessed November 18, 2008.
32. Valenti WM. Companion diagnostic tests in HIV medicine: the road to personalized medicine. AIDS Reader. 2007;17:546-549.
33. United States Food and Drug Administration. FDA HIV/AIDS Time Line-A Chronology of Significant Events. www.fda.gov/oashi/AIDS/miles.html. Accessed September 20, 2008.
34. Mallal S, Phillips E, Carosi G, et al; PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358:568-579.
35. de Leon J, Armstrong SC, Cozza KL. Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics. 2006;47:75-85.
36. de Leon J, Susce MT, Pan RM, et al. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry. 2005;66:15-27.
37. Gatanaga H, Hayashida T, Tsuchiya K, et al. Successful efavirenz dose reduction in HIV type 1–infected individuals with cytochrome P450 2B6 *6 and *26. Clin Infect Dis. 2007;45:1230-1237.