Another revision of the DHHS "Guidelines for the Use of Antiretroviral Agents in HIV- 1-Infected Adults and Adolescents" was published, in draft form for public comment, on November 10, 2003. This represents a new style for the Guideline Panel, intended to address relevant issues in a more timely fashion and to permit "audience participation". This reflects the velocity of changes that take place in this field, which was forced, in part, by the introduction of 4 new antiretroviral agents in 2003. The decision to invite public comment is based, to a large extent, on the substantial precedent with other guidelines. The following is a summary of the more recent changes accompanied by a comment:

Regimens for Treatment-Naïve Patients

A distinction is now made between "preferred" and "alternative" regimens. The preferred are: (1) efavirenz/lamivudine/(zidovudine or tenofovir or stavudine), or (2) lopinavir/ritonavir/lamivudine /(zidovudine or stavudine). The alternative regimens consist of eleven other combinations, including abacavir/lamivudine/(zidovudine or stavudine). The preferred regimens are selected based on clinical trial data that suggests "…optimal efficacy and durability with acceptable tolerability and ease of use."

Comment: It needs to be emphasized that the alternative regimens may be preferred in some patients. With regard to the classification, to my knowledge, this and the WHO guidelines are the only guidelines that make specific recommendations rather than the generic "PI or boosted PI combined with two nucleosides." The rationale for this specificity is, at least in part, the data from multiple clinical trials that make generic recommendations less useful, given variation among regimens in efficacy, toxicity, convenience, or potential for drug interactions. Thus, the emphasis is on the specific regimens that have been used in clinical trials with demonstrated efficacy and durability.

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New Drugs

The new drugs approved in 2003 are enfuvirtide, atazanavir, emtricitabine and fosamprenavir. Emtricitabine and atazanavir are included as components of alternative regimens, and enfuvirtide is discussed in terms of salvage therapy.

Comment: It should be noted that atazanavir is recommended without ritonavir boosting, in large part reflecting the fact that studies in treatment-naïve patients were completed with unboosted atazanavir. Fosamprenavir was approved very recently and is, therefore, not mentioned in this version of the guidelines.

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Triple NRTI Regimens to Avoid

The combinations of tenofovir + lamivudine + either abacavir or didanosine are now listed as combinations to avoid.

Comment: This admonition is based on the therapeutic trial showing virologic failure in 49% of patients given TDF/ABC/3TC compared to 5% in those given EFV/ABC/3TC [Gallant JE, et al. ICAAC, Sept, 2003, Abstract H-1722a].

Similarly, there was a 91% failure rate in another trial with TDF/ddI/3TC ["Dear Health Care Professional Letter" from Gilead Sciences, Inc., 10/14/03].

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Preferred Dual NRTI Combinations With a PI or NNRTI

The preferred combination is 3TC/(AZT or d4T) and the combination of tenofovir/3TC is also included when combined with efavirenz. Alternatives with efavirinz are lamivudine + tenofovir. Emtricitabine (FTC) is listed as an alternative to lamivudine and the combination of ddI and 3TC or FTC is also classified as an alternative dual-NRTI regimen in combination with efavirenz or nevirapine.

Comment: Lamivudine + either AZT or d4T are recommended in virtually all of the preferred and alternative regimens based on the fact that they have shown "durable virologic potency for over five years" when combined with other agents. Nevertheless, the provider is warned that commonly noted side effects include bone marrow suppression with AZT, and prolonged use of d4T has been associated with high rates of lipoatrophy, peripheral neuropathy and/or lactic acidosis. The combination of tenofovir + 3TC is recommended with efavirenz based on data from the Gilead 903 trial.The combination of d4T and ddI is not generally recommended due to high rates of peripheral neuropathy, pancreatitis and hyperlactatemia. Other dual nucleoside combinations in the "not recommended" category are ddC + either d4T or ddI (additive for peripheral neuropathy) and AZT/d4T (pharmacologic antagonism). Hydroxyurea is simply not recommended. FTC is listed as an alternative to 3TC rather than a preferred agent because of its recent approval with less long-term data. The combination of ABC/3TC is not currently mentioned in the guidelines, although there are increasing data supporting its use.

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Drug Interactions

Following are the most significant changes:

• Atorvastatin: The recommendation for use in combination with all PIs, including atazanavir, is to use the lowest starting dose (10 mg qd) and monitor carefully.
• Vardenafil: Data are available showing increased levels with indinavir (16 fold increase in vardenafil AUC) and ritonavir (49 fold increase) but are not available for other PIs. The recommendation with all PIs is to start with 2.5 mg and do not exceed that dose for 24 hours, or for 72 hours when given with ritonavir.
• Atazanavir: The major concerns are use of this drug with tenofovir or efavirenz because of reduction in atazanavir levels. The recommendation is to avoid concomitant use unless ATV is combined with ritonavir (300 mg ATV/100 mg RTV qd); other drug interactions with ATV include buffered ddI (take two hours before or one hour after buffered ddI or use ddI-EC); clarithromycin due to 94% increase in clarithromycin AUC with possible QTc prolongation (reduce clarithromycin dose by 50% or use alternative agent); other drugs that may increase QTc (use with caution or avoid); rifabutin dose is 150 mg qod or 3 times/week; drugs to avoid with concomitant use include proton pump inhibitors, bepridil, rifampin, simvastatin, lovastatin, and indinavir.
• Voriconazole: There are no data for interactions with any PI or NNRTI, but the concern is a "potential for bi-directional inhibition, monitor for toxicities and/or voriconazole effectiveness".

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PI Combinations

New additions are: (1) indinavir in the 400 mg bid regimen with ritonavir (100-400 mg bid) is accompanied by a caution for renal toxicity; (2) amprenavir/Kaletra in combination should be APV 600-750 mg bid + LPV/r standard or 533/133 mg (4 tabs) bid; (3) Atazanavir with ritonavir should be 300/100 mg qd.

It should be noted that the above summary hits the highlights. There are many other changes that are not included because they are considered less important. It is emphasized that this is a "draft document" with invited comments that may prompt changes prior to the official version. This mechanism for public comment is now expected with each revision.

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