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Initiating Antiretroviral Therapy in a Treatment-naïve Patient—When and What to Use?
disadvantages of a treatment that he/she will probably need to take
Table 1: Antiretrovirals Approved in the US and Europe,
throughout life, or at least for many years.
December 2007
What to Start With?
Nucleoside analogs Protease inhibitors
The decision of which regimen to use is complex and will depend on the
Zidovudine (AZT) Saquinavir (SQV)
Didanosine (ddI) Indinavir (IDV)
available data and recommendations, plus a combination of drug and
Lamivudine (3TC) Nelfinavir (NFV)
patient characteristics. When choosing the best option, efficacy, tolerability,
Stavudine (d4T) Lopinavir/rtv (LPV/r)*
and pill burden should be taken into account, as well as data on primary
Abacavir (ABC) Atazanavir (ATV)
resistance. The patient-related factors to consider include previous diseases
AZT/3TC* Fosamprenavir (FPV)
(e.g. psychiatric disturbances, chronic hepatitis, renal disease), cardio-
AZT/3TC/ABC* Tipranavir (TPV)
vascular risk factors, adherence issues (e.g. work schedule, timing of meals), ABC/3TC* Darunavir (DRV)
and psychological factors (e.g. risk that others will become aware of HIV Ritonavir (rtv)**
status if medications need to be refrigerated, tendency for depression).
Nucleotide analogs Entry inhibitors
Tenofovir (TDF) Enfuvirtide (ENF,T-20, fusion inhib.)
Even though more than 20 antiretroviral compounds are now approved for
TDF/FTC* Enfuvirtide (ENF,T-20, fusion inhib.)
use in the US and Europe and a few more will soon come onto the market
Maraviroc (MAR, CCR5 antag.)
Non-nucleoside reverse
(see Table 2), only two treatment strategies are recommended to date:
3–5
a
transcriptase inhibitors Integrase inhibitors
backbone of two nucleoside analogs (NAs) plus a non-nucleoside reverse
Nevirapine (NVP) Raltegravir (RAL)
transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r).
Efavirenz (EFV)
Delavirdine (DLV)
§
Non-nucleoside Reverse Transcriptase
Etravirine (TMC125)
#
Inhibitor-based Regimens
* Fixed-dose combinations. ** Used as a booster for all protease inhibitors, except NFV. # Available in Europe
There are two approved NNRTIs—efavirenz and nevirapine
18,19
—both with
through expanded access. § Not available in Europe. Inhib = inhibitor. Antag = antagonist.
extensive experience, including some data suggesting good antiretroviral
activity in severely immunosuppressed patients.
20,21
The only direct head-to- 1,400/100mg, respectively.
29,30
However, it should be borne in mind that at
head randomized comparison of these drugs in naïve patients was the large least two studies have suggested a lower efficacy of once-daily lopinavir/r in
2NN trial,
22
in which similar efficacy (viral load <50 copies/ml) between arms patients with baseline viral loads >5 log compared with in those with
was observed but non-inferiority of nevirapine could not be demonstrated. baseline loads <5 log.
24,30
In addition, there are now some data on
In addition, a greater frequency of hepatotoxicity, mainly with the not-yet- saquinavir/r once daily (2,000/100mg and 1,600/100mg),
31
although these
approved once-daily dose, and two related deaths were documented in the doses have not yet been approved. A disadvantage of lopinavir/r compared
nevirapine arm. These findings, together with a recent recommendation
23
with other compounds concerns its lipid profile, mainly regarding
warning against use of nevirapine in men with >400 CD4 cells/µl and triglycerides.
24,27
However, taking into account that many other factors are
women with >250 CD4 cells/µl, have influenced some guidelines and led to involved in cardiovascular risk,
32
the clinical relevance of this difference is
recommendations to use nevirapine as an alternative for patients who uncertain. Atazanavir seems to have the best profile but, when boosted
cannot take efavirenz. In other guidelines, both drugs are still with ritonavir, the lipid changes are not as favorable.
33
recommended,
17
based on the extended use of nevirapine in the last decade.
Non-nucleoside Reverse Transcriptase Inhibitors versus
Ritonavir-boosted Protease Inhibitor-based Regimens Ritonavir-boosted Protease Inhibitors
Several PI/rs are now available: lopinavir, atazanavir, fosamprenavir, Both strategies have their benefits, but the efficacy shown by NNRTI
saquinavir, darunavir, and tipranavir. The last two compounds have been regimens, their long-term tolerability, their favorable lipid profile (mainly
approved for pre-treated patients, although large clinical trials have also with nevirapine), and their low pill burden
34,35
compared with most PI/rs have
been conducted in naïve patients. In fact, non-inferiority and a favorable influenced the use of NNRTIs as first-line therapy in most patients. The main
safety profile were observed at 48 weeks comparing darunavir/r with advantage of PI/rs is their higher genetic barrier to resistance
36
and some
lopinavir/r in naïve patients.
24
evidence of immune reconstitution. ACTG5142
37
compared head-to-head
lopinavir/r versus efavirenz in naïve patients. The efavirenz arm was
Efficacy seems to be similar for all of the four PI/rs used in the naïve associated with a better virological outcome and the lopinavir/r arm with a
population. Lopinavir/r showed durable virological and immunological greater CD4 response and a lower rate of resistance mutations. Of note,
responses in a clinical trial with a follow-up of seven years.
25
In shorter a metabolic substudy
38
showed that efavirenz was associated with a higher
studies, fosamprenavir/r
26
and saquinavir/r
27
were non-inferior to lopinavir/r rate of lipoatrophy; however, an arbitrary definition of limb fat loss was
at 48 weeks. Although atazanavir/r has not yet been approved in Europe for used (>20%) and the clinical relevance of this cut-off is not well defined.
39
naïve patients, it is being used in this scenario by many physicians because
of its convenient dosing schedule and favorable lipid profile: it is the only Nucleoside Analog-based Regimens
PI/r initially approved for once-daily dosage.
28
Indeed, the factors that may Use of three NAs, specifically zidovudine/lamivudine/abacavir,
40
has proved to
defer PI/r use are the convenience and tolerability of the drug. Lopinavir/r be less potent than an efavirenz-based regimen and is considered an
and fosamprenavir/r have been approved by the US Food and Drug alternative for patients who cannot use the first-line regimens. In addition,
Administration (FDA) for once-daily dosage at 800/200mg and other triple NA combinations, such as tenofovir/lamivudine plus didanosine or
US INFECTIOUS DISEASE 11
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