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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