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As of October 2003, there were 20 approved antiretroviral agents, belonging to four classes, with which to design combination regimens containing at least three drugs. These four classes include the nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), nonnucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), and fusion inhibitors (FI).

Summary of Recommended Regimens. Since the introduction in 1995 of PI and potent combination antiretroviral therapy (previously referred to as “highly active antiretroviral therapy” or “HAART”), a substantial body of clinical data has been amassed to guide the selection of initial therapy for the previously untreated patient. To date, most clinical experience with use of combination therapy in treatment-naïve individuals has been based on three different types of combination regimens, namely: NNRTI-based (1NNRTI + 2 NRTI), PI-based (1-2 PI + 2 NRTI), and triple NRTI-based regimens. Recommendations are,
accordingly, organized by these categories.

NNRTI–Based Regimens (1-NNRTI + 2NRTIs)

NNRTI-based regimens are commonly prescribed as initial therapy for treatment-naïve patients. In general, these regimens have the advantage of lower pill
burden as compared to most of the PI-based regimens. Use of NNRTI-based regimens as initial therapy can preserve the PIs for later use, reducing or delaying patient exposure to some of the adverse effects more commonly associated with PIs. The major disadvantage of currently available NNRTIs is their low genetic barrier for development of resistance. These agents only require a single mutation to confer resistance, and cross resistance often develops across the entire class. As a result, patients who fail this initial regimen may lose the utility of other NNRTIs and/or may transmit NNRTI-resistant virus to others.

Preferred NNRTI-Based Regimens:
♦ Efavirenz + (zidovudine or tenofovir) + (lamivudine or emtricitabine) (except during first trimester of pregnancy or in women with high pregnancy potential)

Alternative NNRTI-Based Regimens:
♦ Efavirenz + (didanosine or abacavir or stavudine) + (lamivudine or emtricitabine) (except during pregnancy, particularly the first trimester, or in women
with high pregnancy potential)

 or
♦ Nevirapine-based regimens may be used as an alternative in adult females with CD4 + T cell counts <250 cells/mm3 and adult males with CD4 + T cell counts <400 cells/mm3 .

The following NNRTIs are not recommended as initial therapy:
• Delavirdine – because of inferior antiretroviral potency and three times daily dosing (DII)
• Nevirapine for adult females with CD4 + T cell counts >250 cells/mm3 and adult males with CD4 + T cell counts >400 cells/mm3 unless the benefit clearly outweighs the risk
* Women with high pregnancy potential are those who are trying to conceive or who are not using effective and consistent contraception.

PI-Based Regimens (1 or 2 PIs + 2 NRTIs)

PI-based regimens (1or 2 PIs + 2 NRTIs) revolutionized the treatment of HIV infection, leading to sustained viral suppression, improved immunologic
function, and prolonged patient survival. Since their inception in the mid-1990s, much has been learned about their efficacy as well as some short term and
long term adverse effects. To date, nine PIs have been approved for use in the United States. Each agent has its own unique characteristics based on its clinical efficacy, adverse effect profile, and pharmacokinetic properties.In selecting a PI-based regimen for a treatment-naïve patient, factors such as dosing frequency, food and fluid requirements, pill burden, drug interaction potential, baseline hepatic function, and toxicity profile should be taken into consideration. A number of metabolic abnormalities, including dyslipidemia, fat maldistribution, and insulin resistance, have been associated with PI use. The eight PIs differ in their propensity to cause these metabolic complications. At this time, the extent to which these complications may result in adverse long term consequences, such as increased cardiac events in chronically-infected patients, is unknown.

Preferred PI-based regimens • Lopinavir/ritonavir + zidovudine + (lamivudine or emtricitabine) as preferred PI-based regimens.
Alternative PI-based regimens may include:
• Atazanavir*, fosamprenavir, ritonavirboosted** fosamprenavir), ritonavir-boosted ** indinavir), nelfinavir, or ritonavirboosted** saquinavir  – all used in
combination with (zidovudine or stavudine or tenofovir* or abacavir or didanosine) + (lamivudine or emtricitabine)
• Lopinavir/ritonavir + (abacavir or stavudine or tenofovir or didanosine) + (lamivudine or emtricitabine)


PIs not recommended as initial therapy):
• Unboosted indinavir – because of inconvenient three times daily dosing and need to take on an empty stomach or a light meal
• Ritonavir as sole PI – because of high incidence of gastrointestinal intolerance
• Unboosted saquinavir (hard gel or soft gel capsule) – because of poor oral bioavailability, three times daily dosing, and high pill burden
• Ritonavir-boosted tipranavir – because of lack of clinical trial data in treatment-naïve patients
* ritonavir 100mg per day is recommended when tenofovir is used with atazanavir.
** ritonavir at daily doses of 100-400mg used as a pharmacokinetic-booster

From:

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents - May 4, 2006 - Developed by the panel on Clinical
Practices for Treatment of HIV Infection convened by the Department of Health and Human Services (DHHS) and the Henry J.
Kaiser Family Foundation It is emphasized that concepts relevant to HIV management evolve rapidly. The Panel has a mechanism to update recommendations on a regular basis, and the most recent information is available on the AIDSinfo Web site (http://AIDSinfo.nih.gov).
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents May 4, 2006 Developed by the DHHS Panel on
Antiretroviral Guidelines for Adults and Adolescents - A Working Group of the Office of AIDS Research

June 2006