January 2008

Top 10 HIV/AIDS Stories of 2007

Kimberly Woodhull, PharmD, LT USPHS

1. New DHHS HIV Treatment Guidelines

On Dec 1, 2007, the Department of Health and Human Services released an update of Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents. The major changes made in the revision include:

1. Two new resistance tests to be used prior to initiation of Abacavir and/or the new class of CCR5 antagonists
2. HLA B5701 test for hypersensitivity to Abacavir
3. Viral tropism test for utility or failure of a CCR5 antagonist
4. Genotyping for all treatment naive patients entering into care regardless of whether ART will be initiated or not.  This addresses the fact that transmitted resistant viruses can be detected by genotyping a couple of years after infection.  If the patient chooses not to start medication therapy right away, the resistant pattern could be helpful in determining an effective therapy at the time the person does decide to start medication.
5. Initiation of therapy. Recommended for all patients with a history of an AIDS defining illness and for those with a CD4 <350.  Prior, medication was offered to those with a CD4 between 200 and 350, all pregnant women, patients with HIV associated nephropathy, and a co-infection with hepatitis B.  Treatment options for Hep B/HIV co-infection are listed on page 47.  There is an excellent risk versus benefit table on page 58 that could be used for patient information.
6. Nelfinavir. Due to the recent discovery of EMS in nelfinavir and its potential teratogenic activity, nelfinavir is not recommended in women who are or have the potential to become pregnant.
7. New classes of drugs: integrase inhibitors (raltegravir) and of the new entry inhibitors/CCR5 antagonist drug (maraviroc) are scattered throughout the text and tables.  They include the new NNRTI, etravirine which is available in expanded access programs.
8. An excellent discussion of immunologic failure in patients that respond virologically with VL<75 without a CD4 response to therapy can be found on page 34.

DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 Infected adults and adolescents. Rockville, MD: Department of Health and Human Services, December 1, 2007. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

2. New Treatment Options

Treatment options were expanded in 2007. Two new drugs and classes were approved by the FDA. First was maraviroc (Selzentry®), a CCR5 antagonist, indicated in combination with other antiretroviral agents for treatment-experienced adult HIV-infected patients. However, maraviroc was not recommended in patients who had a dual/mixed tropic or CXR4-tropic virus; therefore, a tropism assay was recommended prior starting maraviroc. The dose also depended on other concomitant medications. Second was raltegravir (Isentress®), an integrase inhibitor, indicated in combination with other antiretroviral agents for the treatment of HIV-infection. This should be used in treatment-experienced adult patients with resistance or intolerance to at least one drug in each oral antiretroviral class. The dose being 400mg twice daily with or without food.

Also in 2007, etravirine, a second generation non-nucleoside reverse transcriptase inhibitor underwent review for approval dosed at 200mg twice daily. It was shown to be effective even in patients who were resistant to other NNRTIs, such as Sustiva®. Etravirine is suspected to receive approval in early 2008.

Aside from the two new drugs approved in 2007 by the FDA, a dose of 1400mg of fosamprenavir (Lexiva®) for protease inhibitor (PI) naïve patients along with 100mg of ritonavir in adult patients who had not previously taken a PI were also approved. Information about fosamprenavir can be found on the product label.

Isentress (raltegravir) Full Prescribing Information. Merck & Co., Inc. Accessed October 2007.

FDA - Pfizer Inc, Maraviroc Tablets NDA 22-128, Antiviral Drugs Advisory Committee (AVDAC) Briefing Document, April 24, 2007. Available at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4283b1-01-Pfizer.pdf.

Lazzarin A, Campbell T, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomized, double-blind, placebo-controlled trial. Lancet 2007:370-39-48.

Wohl D, T Lancaster, DeJesus E., et al. Determination of body composition changes by total body dual-energy x-ray absorptiometry after 48 weeks of treatment with once-daily fosamprenavir (FPV) boosted with two different doses of ritonavir(r) plus abacavir (ABC)/lamivudine (3TC): COL100758. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention. July 22-25, 2007. Sydney, Australia. Abstract (poster) TUPEB080.

3. Entecavir use in Hepatitis B Virus/HIV Co-Infected Patients

Entecavir has been widely used for the treatment of Hepatitis B (HBV). In patients with HBV/HIV co-infection it has activity against HIV replication and selection for M184V mutations. This mutation causes resistance to entecavir and lamivudine/emtricitabine. Therefore, the Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents – December 1, 2007, advises that entecavir not be used for the treatment of HBV infection in HBV/HIV co-infected patients without a fully suppressive antiretroviral regimen.

DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 Infected adults and adolescents. Rockville, MD: Department of Health and Human Services, December 1, 2007. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.

McMahon MA, Jilek BL, Brennan TP, et al. The HBV drug entecavir -- effects on HIV-1 replication and resistance. N Engl J Med 2007;356:2614-2621.

4. Which is better Prezista/Norvir® or Kaletra®?

In this 48-week efficacy and safety study comparing darunavir/ritonavir (Prezista/Norvir®) to lopinavir/ritonavir (Kaletra®), there was an estimated 10 to 11% difference in decreasing viral load to <400 and <50 copies/ml, respectively, with Prezista/Norvir® being superior. The median change from baseline in CD4 cell count was similar between the two groups. In the lopinavir/ritonavir group, 11% of patients discontinued treatment due to virological failure, compared with 1% in the darunavir/ritonavir group. The authors concluded that Prezista/Norvir ® is non-inferior to Kaletra® in treatment experienced patients.

Madruga JV , Berger D, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomized controlled phase III trial. The Lancet 370 (9581): 49-58. July 7, 2007.

5. Circumcision and Homosexual Men

Male circumcision has been associated with a lower risk for HIV infection in international observational studies in three randomized, controlled clinical trials of heterosexual men. However, little is known about the association between circumcision and HIV risk in homosexual men. According to a study of more than 1400 homosexual men presented at the 17 th Meeting of the International Society for Sexually Transmitted Diseases Research, circumcision status may have little effect on whether men who have sex with men go on to develop HIV. The study found no relationship between circumcision and HIV seroconversion. Another study presented at the National HIV Prevention Conference in 2007 confirmed these results. In a study among U.S. Black and Hispanic men who have sex with men, male circumcision did not offer any level of protection against HIV. Based on these findings, recommendations for circumcision in homosexual men cannot be made at this time as a protective measure against HIV seroconversion.

Darves, Bonnie. Circumcision Not Protective Against HIV Seroconversion in Homosexual Men. Article available at: http://www.medscape.com/viewarticle/560823

Male Circumcision Does Not Offer Protection Against HIV Among U.S. Black, Hispanic MSM, Study Says. December 5, 2007. Available at: http://www.kaisernetwork.org/ daily_reports/rep_index.cfm?hint=5&DR_ID=49239

6. Treating Herpes May Lower Risk of HIV Spread

Treating genital herpes may have positive outcome on patients with HIV. A study reported that among women dually infected with HIV-1 and herpes simplex virus (HSV)-2 or genital herpes, treatment with valacyclovir reduces HIV viral load levels in blood and in genital secretions. Decreased viral load may reduce HIV transmission. More studies need to be conducted to determine the impact on HIV control.

Nagot N, Ouédraogo A, Foulongne V, et al. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N Engl J Med 2007;356:790-799.

7. Prescreening for Abacavir Hypersensitivity Recommended

Abacavir hypersensitivity testing was discussed back in the August ARV Corner article. Since then, genetic testing is now available and recommended by the DHHS treatment guidelines to be performed prior to initiating abacavir therapy. By screening for HLA-B*5701, the provider can determine if a patient is predisposed to have the hypersensitivity reaction caused by abacavir. If a patient tests positive for HLA-B*5701, abacavir containing regimens should not be prescribed and abacavir should be added to the patient’s medication allergy profile.

DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 Infected adults and adolescents. Rockville, MD: Department of Health and Human Services, December 1, 2007. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.

8. Nelfinavir and Pregnancy

Ethyl methanesulfate ( EMS), a potential Class 2B human carcinogen, was found in European nelfinavir (Viracept®) manufactured by Roche and the product was recalled.  Pfizer producers of U.S. nelfinavir and EMS levels were reportedly lower but of unknown significance.  They were not recalling the drug, just giving pediatric and pregnancy guidelines at this time. Due to the recent discovery of EMS in nelfinavir and its potential teratogenic activity, the new DHHS guidelines state that nelfinavir is not recommended in women who are or have the potential to become pregnant. The Antiretroviral Pregnancy Registry reports no increase in birth defects in women taking nelfinavir. If no other choice of antiretroviral therapy is available, the benefit of continuing nelfinavir outweighs the risk of stopping the drug.  If other options are available, medication should be switched.  Insufficient studies to date are poor in determining whether EMS crosses the placenta or is found in breast milk.

D HHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 Infected adults and adolescents. Rockville, MD: Department of Health and Human Services, December 1, 2007. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf

9. QuantiFERON® for tuberculosis screening in HIV patients

The QuantiFERON®-TB Gold test (QFT-G) is a whole-blood test for use as an aid in diagnosing Mycobacterium tuberculosis infection, including latent tuberculosis infection and tuberculosis disease. QFT-G was approved in 2005 but there was limited data for use in immunocompromised patients. A study of 701 HIV-infected patients who had QFT-G screen for tuberculosis was conducted over 6 months. The study concluded that QFT-G test is highly sensitive and may reveal sub- or preclinical TB even in moderately immunocompromised HIV patients. However, more data is needed before QFT –G test can be universally recommended as a screening tool for tuberculosis in HIV-infected patients.

Aichelburg MC, et al. Correlation of clinical data with reactivity in the interferon-g release assay for tuberculosis antigens in HIV-infected patients. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract MOPEB021. Available at: http://www.ias2007.org/pag/Abstracts.aspx?SID=153&AID=2261

10. Renal function and Tenofovir (Viread®)

Tenofovir (TDF) has been shown to cause effects on renal function. This study looked at renal function in HIV-infected patients after 2 years of tenofovir treatment. Changes in creatinine clearance (CrCL) were compared between groups receiving TDF and non-TDF regimens at 6, 12, and 24 months. There was a greater decrease in CrCL in the TDF group compared to the non-TDF group at all time periods. At 24 months, CrCL decreases by ≥ 30 ml/min was 23.2% on TDF-based regimens versus 9.7% on a non-TDF regimen. Therefore, the TDF-containing regimen was associated with a greater decrease in CrCL at 2 years compared to the non-TDF regimens. As a result, tenofovir may not be the best option for patients with baseline abnormal renal function. However in patients with normal baseline renal function, tenofovir is a great antiretroviral that can be used with close monitoring.

Javanbakht M, Khanlou H, Chien C, et al. Renal function changes at two years in HIV-infected patients treated with tenofovir-DF. In: Program and abstracts of the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract MOPEB064. Available at: http://www.iasociety.org/Default.aspx?pageId=11&abstractId=200702676

Editor:

CDR Scott Giberson
Principal Consultant

HIV/AIDS Program

Indian Health Service
301-443-2449 (office)
Scott.giberson@ihs.gov

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