Summary of Changes: DHHS Guidelines for Use of Antiretroviral Agents May 4, 2006

Hopkins HIV Report 2006 Jul; 18(4):10

John G. Bartlett, M.D.
Johns Hopkins

The following is a summary of changes contained in the May 4, 2006 edition of the “DHHS Guidelines for the Use of Antiviral Agents in HIV-infected Adults and Adolescents.”

1. Genotypic resistance testing is now recommended prior to initiation of antiretroviral therapy, and the results should influence the selection of the agents. An option is to obtain the resistance test earlier in the course of the infection for later use when treatment is to be started. The previous version of the guidelines recommended resistance testing only in patients who had been treated and had virologic failure. The change was prompted by three observations: First, there are reports that transmitted strains with resistant mutations persist for more prolonged periods than resistant strains that have evolved on non-suppressive therapy [Little SJ, et al. Conf Retroviruses Opportunistic Infect. 2004 Feb 8-11;11th: (abstract No. 36LB); Novak RM, et al. Clin Infect Dis. 2005 Feb 1;40(3):468-74]. For this reason, baseline testing in chronically infected persons may yield important information, although it is uncertain how long transmitted resistance persists. Second, some studies also show that patients with baseline resistance respond less well to initial treatment [Weinstock HS, et al. J Infect Dis. 2004 Jun 15;189(12):2174-80; Wensing Am, et al. J Infect Dis. 2005 Sep 15;192(6):958-66; Cane P, et al. BMJ. 2005 Dec 10;331(7529):1368; Saag MS, et al. JAMA. 2004 Jul 14;292(2):180-9; Gallant JE, N Engl J Med. 2006 Jan 19;354(3):251-60]. Further, recent studies indicate that up to 16% of treatment-naïve patients have resistance mutations. Finally, there are also studies showing that baseline testing is cost-effective [Sax PE, et al. Clin Infect Dis. 2005 Nov 1;41(9):1316-23]. This recommendation received a score of BIII meaning moderate priority (B) but no randomized controlled trials to support the recommendation (III).
2. The section on treatment interruption now states that treatment should be interrupted when it cannot be avoided, such as for surgery or serious adverse drug reactions. The prior document suggested that CD4-driven treatment interruption was an option, but recent clinical trials now indicate this strategy could be dangerous and needs more study. The Trivacan ANRS 1269 trial found that severe morbidity was significantly higher in the treatment interruption arm than in the continuous therapy arm at 24 months (17.6/100 patient-years vs. 6.7/100 patient-years; p=0.001) [Danel C, et al. Lancet. 2006 Jun 17;367(9527):1981-9]. The SMART trial, which was reviewed by Joel Gallant [HHR 2006;18(2):1], found that treatment interruption was associated with a statistically significant increase in HIV-related events, drug toxicities and deaths. Both trials used a study design that permitted drug discontinuation when the CD4 was >350/mm³ and re-initiation when the CD4 count was <250/mm³.
3. The section on hepatitis B co-infection has been rewritten to state that: a) lamivudine (3TC), tenofovir (TDF) and emtricitabine (FTC) have activity against hepatitis B virus (HBV), and discontinuation of these drugs may cause a HBV flare; b) HBV resistance is about 40% when 3TC is used as a single agent against HBV; c) immune reconstitution may be associated with an increase in hepatic transaminases; d) patients with immune reconstitution may have loss of HBV early antigen (HBeAg) that is associated with a hepatitis flare; and e) administration of PIs and NNRTIs are associated with high rates of transaminase elevations in coinfected patients. The cause of the transaminase elevation is unclear, since they may decrease with continued therapy. Nevertheless, the common recommendation is to stop the implicated drug when the increase in AST or ALT is >5-10 times the upper limit of normal. For management of HIV/HBV-co-infected persons:
4. • All should: a) be advised to avoid alcohol; b) be vaccinated against hepatitis A vaccine if non-immune; and c) be advised on methods to prevent HBV transmission.
   • The treatment regimen for HIV but not HBV should include a NRTI backbone of TDF/FTC or TDF/3TC (You have to treat HBV anyway unless you can avoid 3TC and FTC).
   • When the goal of therapy is either to treat HIV or both HIV and HBV, the treatment regimen should include TDF/FTC or TDF/3TC. Another option is entecavir alone for HBV).

2006-07-10
HHR-2006-07-04

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