Choosing Optimal Antiretroviral Therapies in 2008

One fun thing to do at an International AIDS Conference-aside from the social aspects and the presentations, protests, and theatre found in the Global Village-is to match your wisdom and art in the selection of antiretroviral drug regimens to that of a large audience of HIV-treating physicians and expert panel members. In this sense, the 17th International AIDS Conference, held this year in Mexico City, did not disappoint. One session, led by Drs Pedro Cahn and Carlos del Rio, involved highly interactive, case-based questions that covered key issues and controversies in the initiation of antiretroviral treatment and managing treatment failure.^1,2 The audience first heard a clinical case, then they were asked to decide whether initiation of treatment was warranted, and finally, they were asked to choose from among a series of possible regimens. Participants pressed an electronic touch pad, which tallied responses and presented them visually. This afforded opportunities for lively discussions among the expert panelists. Three of these cases are summarized here.

Case 1. This case involved an asymptomatic HIV-positive young man with an HIV RNA level of 600 copies/mL, a CD4⁺ cell count of 750/µL, and a wild-type viral genotype. Also, he was coinfected with hepatitis B virus (HBV), with an HBV DNA level of 16 million copies/mL. Although there was no majority opinion among the audience as to what treatment to start, a sizable minority (43%) agreed with the panel experts that tenofovir, emtricitabine, and efavirenz-a combination regimen capable of controlling both viruses-was necessary. This is in agreement with recent International AIDS Society treatment guidelines, in which earlier antiretroviral therapy was recommended for those with active HBV or hepatitis C virus coinfection.³

Some audience members chose a regimen that substituted atazanavir for efavirenz. The expert panel pointed out that the possibility of developing an immune reconstitution inflammatory syndrome with atazanavir would be enhanced.

For those wishing to delay antiretroviral treatment, the audience was reminded that to treat this patient's hepatitis B with entecavir was ill-advised; entecavir also has anti-HIV activity and, used as monotherapy, might therefore lead to rapid selection for HIV-resistant variants.⁴ A better choice would be telbivudine, recently shown to have a greater HBV suppressive effect than lamivudine in both hepatitis B e antigen (HBeAg)-positive and -negative persons⁵ in the absence of an anti-HIV effect.

Case 2. This case involved a 55-year-old African American woman with a CD4⁺ cell count of 530/µL, an HIV RNA level of 226,000 copies/mL, and a wild-type genotype. Her initial evaluation revealed 3+ proteinuria and a serum creatinine level of 1.3 mg/dL. An abdominal ultrasonogram showed a bilateral increase in kidney size with no obstruction. Her creatinine clearance was low, at 41 mL/min. Most (80%) of the audience felt that initiation of antiretroviral therapy was warranted, consistent with new treatment guidelines addressing HIV-associated nephropathy.³ Although there could have been other reasons for this patient's nephropathy, her normal blood pressure and blood glucose level led panelists to decline recommendations of a renal biopsy. Her bilateral kidney enlargement remained unexplained.

Most audience members avoided tenofovir-containing regimens, given this drug's known potential for renal toxicity.⁶ They were about equally divided in their preference for starting treatment with a boosted protease inhibitor (PI) regimen or an efavirenz-based regimen.

Case 3. This case involved a 48-year-old asymp­tomatic man with a CD4⁺ cell count of 460/µL, an HIV RNA level of 87,000 copies/mL, and a wild-type virus. He smoked 5 cigarettes per day, had a serum glucose level of 112 mg/dL, a serum creatinine level of 1.6 mg/dL, a normal creatinine clearance, and 1+ proteinuria. With elevated lipid levels, his calculated Framingham risk score placed him at moderate risk for a cardiovascular event: 16.6% risk of any event and 11.9% risk of a myo­cardial infarction at 10 years.

Possibly because of his relatively high CD4 count, only 53% of the audience felt that antiretroviral therapy should be started. In terms of regimen choice, 33% selected a regimen of tenofovir, emtricitabine, and efavirenz and 19% chose zidovudine, lamivudine, and efavirenz. Few selected a ritonavir-boosted PI. The panel of experts noted the risk of hyperlipidemia in HIV-infected persons with significant, underlying, classic cardiovascular disease risks, which may be exacerbated by exposure to PIs.

Given his elevated creatinine level, close monitoring of renal status was suggested if a tenofovir-containing regimen was to be used. Indeed, a creatinine clearance greater than 60 mL/min is required in most clinical trials of tenofovir-based regimens.⁶ Tenofovir-associated neph­rotoxicity has been defined as a drop in creatinine clearance of 25 mL/min or greater or a decrease in the glo­merular filtration rate greater than 50%.⁵ Concomitant use of an NNRTI with tenofovir, which was the regimen chosen by most audience members in this case, can decrease the risk of renal toxicity.⁶

Subsequent case discussions focused on the use of newer antiretroviral drugs. The genetic barrier to drug resistance for many antiretrovirals is quite low, requiring only a single point mutation to confer substantial loss of activity.⁷ Recently published results from the Merck-sponsored BENCHMRK-1 and -2 studies ("Blocking Integrase in Treatment-Experienced Patients with a Novel Compound against HIV, MeRcK" studies) show that combining the integrase inhibitor raltegravir with an optimized background regimen potently suppresses pan–drug-resistant HIV.⁸ This has led to suggestions that the newest antiretroviral agents should be evaluated in clinical trials with treatment-naive HIV-positive persons.

However, raltegravir also suffers from a low genetic barrier to drug resistance.⁷ In addition, although pleas have been made to evaluate these agents in resource-limited settings for both adults and children,⁷ the monetary costs of such strategies are staggering. As Dr Anthony Fauci stated in Mexico City, commenting on current antiretroviral treatment practices, "It is extremely improbable that we will have the structure and financial ability to take on all the people who require [antiretroviral therapy] and then treat them for life."⁹ The cost of universal treatment access-the aspirational goal of the G8 member nations for 2010 as set forth in the "Toyako Framework for Action"-has been estimated at $42.2 billion for 2010 and $54.0 billion for 2015, compared with the $8.1 billion spent on HIV/AIDS in the developing world last year.⁹

References:

References1. Eron J, Reiss P, Carr A, et al. Initial antiretroviral therapy: current considerations for treatment-naive patients. 17th International AIDS Conference; August 3-8, 2008; Mexico City. Abstract MOSS0201.
2. Walmsley S, del Rio C, Hammer S, et al. Strategies for antiretroviral failure: managing early, late, and complicated failure. 17th International AIDS Conference; August 3-8, 2008; Mexico City. Abstract MOSS0202.
3. Hammer SM, Eron JJ Jr, Reiss P, et al; the International AIDS Society-USA. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA. 2008;300:555-570.
4. Pessoa MG, Gazzard B, Huang AK, et al. Efficacy and safety of entecavir for chronic HBV in HIV/HBV coinfected patients receiving lamivudine as part of antiretroviral therapy. AIDS. 2008;22:1779-1787.
5. Lai CL, Gane E, Liaw YF, et al; Globe Study Group. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med. 2007;357:2576-2588.
6. Castellano C, Williams W, Kepler TB, et al. Clinical predictors of tenofovir-associated nephrotoxicity in HIV-1-infected patients. 17th International AIDS Conference; August 3-8, 2008; Mexico City. Abstract WEAB0104.
7. Havlir DV. HIV integrase inhibitors-out of the pipeline and into the clinic. N Engl J Med. 2008;359:416-418.
8. Steigbigel RT, Cooper DA, Kumar PN, et al BENCHMRK Study Teams. Ral­tegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359:339-354.
9. Ingham R. War on AIDS: money nightmare seems set to return. Agence France Presse. August 8, 2008.