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1
(FCH/HIV, 22 April 2002)
Application for Inclusion of efavirenz
on the WHO Model List of Essential Medicines
The drugs is a member of the therapeutic class of HIV-1 nonnucleoside reverse transcriptase inhibitors
Summary of Proposal
Since the first clinical evidence of AIDS was reported over twenty years ago, an
estimated 25 million people have died as a result of HIV infection. Current
estimates suggest that around 40 million persons world-wide are infected with HIV
and more than 90% of infected persons live in the developing world. Growing
experience of the provision of anti-retroviral therapy in resource-poor settings (eg.
Brazil, Côte d’Ivoire, Senegal, Haiti, India) indicates that treatment can be
provided in an effective and safe manner. The delivery of anti-retroviral treatment
in low-income countries has been aided by the development of fixed drug
combinations and substantial reductions in the prices of certain products.
The non-nucleoside reverse transcriptase inhibitor efavirenz is proposed for listing
on the WHO Model List of Essential Medicine. Other members of this class of
drugs may serve as alternatives, depending on quality, price and local availability.
It should be noted that HIV-2 reverse transcriptase is not inhibited by nonnucleosides reverse transcriptase inhibitors.
A search of several data-bases, including the Cochrane Library, Medline and
Embase, retrieved systematic reviews and articles supporting the use of HIV-1
RNA levels and CD4 cell counts as valid surrogate measures for changes in the
rates of clinical outcomes during treatment of HIV-infected subjects. The literature
search also provided evidence that combinations of 3 or 4 anti-retroviral drugs are
superior to dual or single drug therapy. The latter are no longer regarded as
satisfactory treatment, because of low efficacy rates and the development of
resistance.
Extensive library searches compiled by the Cochrane Review Group for HIV/AIDS
resulted in the retrieval of a total of 15 good quality randomised clinical trials.
As initial therapy (6 trials), efavirenz in combination with two nucleoside reverse
transcriptase inhibitors (in five trials zidovudine and lamivudine), was superior to
two nucleoside reverse transcriptase inhibitors alone. Efavirenz-containing
regimens were equal or superior to protease inhibitor-containing regimens in
achieving long-term viral suppression, and efavirenz-containing regimens that
lacked nucleoside reverse transcriptase inhibitors were inferior to those that
contained them.
As salvage therapy in failing regimens, efavirenz has been examined in 5 trials.
These studies showed that efavirenz was an effective drug for non-nucleoside
2
reverse transcriptase-naïve patients who were failing nucleoside reverse
transcriptase inhibitor regimens, and efavirenz plus protease inhibitors (either
nelfinavir or indinavir) was superior to efavirenz or to a single protease inhibitor.
Efavirenz has also been tested (4 trials) as an alternative to protease inhibitors in
patients who are susceptible to the lipodystrophy syndrome induced by these
drugs (switch therapy). The three trials for which data are available showed that
efavirenz was comparable to, or superior to, continuing existing protease inhibitors
in maintaining viral suppression; that efavirenz was comparable to nevirapine and
abacavir in maintaining viral suppression; and that efavirenz was more likely than
nevirapine or abacavir to be associated with hypercholesterolemia and
hypertriglyceridemia.
Overall efavirenz was quite well tolerated. Although certain side effects were
common (for instance rash, CNS effects, including dizziness, impaired
concentration, dreaming), the rates of discontinuation because of toxicity were
equivalent to, or lower than, those seen with combination therapy that included
protease inhibitors.
Efavirenz can be administered as once daily treatment. It is presently not
available as a fixed dose combination with other antiretroviral agents. The costs
of a year’s treatment vary from $US485 (Aurobindo) $US500 (Merck) to $US1040
Hetero).
1. Proposal for inclusion, change or deletion.
Efavirenz is proposed for inclusion on the WHO Model List of Essential
Medicines, as part of a multi-drug antiretroviral regimen for the treatment of HIV1/AIDS within an appropriately monitored program. Antiretroviral therapy is
recommended for HIV-infected children, adolescents, and adults with symptomatic
disease, and also for asymptomatic patients with CD4+ cell counts at or below
200/mm3. Where CD4+ cell testing is unavailable, clinicians can use the presence
of a total lymphocyte count below 1200/mm3, but only in symptomatic patients.1,2
2. Name of the focal point in WHO submitting the application:
HIV/AIDS Department at WHO; the person responsible is Dr Dr Bernhard
Schwartländer, Director of Evidence and Policy.
3. Name of the organization(s) consulted and/or supporting the application:
Supporting letters may be submitted – please contact Dr Robin Gray (WHO/EDM)
at [email protected]
4. International Nonproprietary Name: efavirenz
5. Listing Type Requested:
3
Listing is requested on the Model List of Essential Medicines as an example of the
therapeutic class of HIV-1 non-nucleoside reverse transcriptase inhibitors. Other
members of this class of drugs may serve as alternatives, depending on quality,
price and local availability. HIV-2 reverse transcriptase is not inhibited by nonnucleosides reverse transcriptase inhibitors.
6. Information supporting the public health relevance of the submission:
Since the first clinical evidence of AIDS was reported over twenty years ago, an
estimated 25 million people have died as a result of HIV infection. Current
estimates suggest some 40 million persons worldwide are infected with HIV and
more than 90% of infected persons live in the developing world3. In 2001, 5 million
persons worldwide became infected with HIV, and 3 million others died from
HIV/AIDS-related causes.
In sub-Saharan Africa, the region most severely affected by HIV, 28.1 million
individuals are living with this infection. Eastern Europe — especially the Russian
Federation — continues to experience the fastest-growing epidemic in the world.
In 2001, there were an estimated 250 000 new infections in this region, bringing to
1 million the number of people living with HIV. In Asia and the Pacific, an
estimated 1 million people became infected in 2001; about 7.1 million people in
this region are now living with HIV/AIDS3. More than 1.8 million people in Latin
America and the Caribbean are living with HIV/AIDS, including the 190,000 adults
and children who became infected in 2001
In countries often already burdened by huge socio-economic challenges,
HIV/AIDS threatens human social welfare, developmental progress, and social
stability on an unprecedented scale. HIV/AIDS cripples the economic development
of entire countries, because it often strikes people during their most productive
working years. Of the 14,000 persons who became infected each day in 2001,
about 12,000 were aged 15 to 49 years3.
Left untreated, HIV infection results in a period of clinical latency that may last a
median of 3 to 10 years. Once symptomatic disease or AIDS develops, without
access to antiretroviral treatment, death results within an average of two years.
In high-income countries, an estimated 1.5 million people live with HIV, many of
them productively, thanks to antiretroviral therapy. In the USA, the introduction of
triple combination antiretroviral therapy in 1996 led to a decline of 42% in deaths
attributable to HIV/AIDS in 1996-973.
The feasibility efficacy and adherence with antiretroviral therapy has been
demonstrated in a number of national and smaller pilot programs in middle- and
low-income countries.
In Brazil, the policy of universal access to antiretroviral drugs has reduced the
number of AIDS-related deaths by nearly 50% and cut the incidence of
opportunistic infections by 60 - 80%4. Between 1997 and 2000, Brazil saved
4
approximately US $677 million in averted hospitalisations and treatment of HIVrelated infections.

In Argentina a program similar to that of Brazil provides even greater coverage. A
special fund has been established to pay for antiretroviral drugs for those not
covered by social security (such as street vendors, small business people, the
unemployed, low-income pregnant women) 5.
Through the UNAIDS Drug Access Initiative Pilot Program, 6 treatment centres in
Abidjan, Côte d’Ivoire, offer antiretroviral therapy. Of the patients who received
therapy, 72% were heavily symptomatic upon initiation. Nonetheless, the overall
survival rate of was 93% at 6 months, 90% at 12 months, and 86% at 18 months.
When survival rates are re-calculated using a worst-case scenario in which
patients lost to follow-up are assumed to have died immediately after their last
clinic visit, 75% survived at 6 months, 64% at 12 months, and 55% at 18 months6.
The Senegal Initiative on Antiretroviral Therapy was launched in August 1998. A
partnership between the Senegalese government and the International
Therapeutic Solidarity Fund, it aims to have 7,000 patients on triple combination
therapy by the end of 2007. At the end of 2001, an estimated 550 adults and
children had received treatment. A prospective observational cohort study was
undertaken to assess the feasibility, effectiveness, adherence, toxicity and viral
resistance of antiretroviral therapy. The clinical and biological results of the study
were comparable to those seen in western cohorts, despite differences in HIV-1
subtype and an advanced disease stage when treatment was initiated. Fifty-eight
patients with advanced HIV disease demonstrated by CDC staging (16 patients in
CDC Stage B, 42 in CDC Stage C) and CD4+ cell count (median CD4+ cell count
= 108.5, IQR = 34 - 217) were given triple combination antiretroviral therapy (2
nucleoside analogues + 1 protease inhibitor). After 18 months of treatment,
participants gained a median of 180 CD4+ cells and showed a median drop in
plasma viral load of 2.8 log10 copies/ml. During the study period, there were 7
clinical AIDS-defining events with 6 deaths from HIV-related infections7. The
antiretroviral regimen was complex: indinavir, the protease inhibitor used in the
study, had to be taken in a fasting state every 8 hours, with maintenance of
hydration; didanosine (DDI), the nucleoside analogue given to 86% of participants,
is a buffered preparation which also had to be taken while fasting 1 to 2 hours
after any other medication. Despite the complexity of the regimen, 80% of patients
(IQR 72-87%) showed adherence 80% at 18 months.
In Cange, a Haitian village, the non-profit organization Partners in Health has
introduced antiretroviral therapy to a small number of seriously ill AIDS patients,
based on their Directly-Observed Therapy (DOT) programme for multiple-drug
resistant tuberculosis. This DOT programme has been successful, with 90% of all
registered TB cases in the Cange catchment area considered cured, compared
with just 26% in other regions of Haiti. Sixty-five patients were selected to receive
triple combination antiretroviral therapy on the basis of clinical indicators of severe
HIV disease (e.g. wasting, recurrent opportunistic infections, severe neurological
complications, etc.). Shortly after initiating treatment, most patients showed clinical
improvement. To counter critics and test the effectiveness of the programme,
5
blood samples were sent to Boston for viral-load analysis. The results showed
that 83% of patients on triple therapy had unquantifiable viral load measures. For
the most part, side effects have been minimal and easily managed and there are
support groups to encourage adherence.8
At HIV clinics in Pune and Ahmedabad, India, a recent study demonstrated the
benefit of triple combination antiretroviral therapy (nevirapine + 2 nucleoside
analogue RTs) in 347 patients with advanced HIV disease. At 12 months, 64.6%
of the study participants experienced an increase of more than 20% in CD4+ cell
counts. Twenty-three secondary clinic events during the study were reported,
including 6 deaths (4 TB-related, 1 cryptococcal meningitis, 1 non-Hodgkin’s
lymphoma) — an AIDS-associated mortality rate of 5.7% at six months. This
program was also significant for the fact that it relied on generic drugs supplied by
Indian pharmaceutical manufacturers.9
Thus, in addition to the large amount of clinical data from high-income countries,
there is a small but growing body of clinical evidence to support the use of ARVs
in developing countries. Significant price reductions have also been achieved in
many developing countries and new funding and delivery mechanisms are being
developed to expand their availability. These factors warrant the addition of this
class of drugs to the Model List of Essential Drugs (with appropriate consideration
of their use in resource-limited settings).
7. Treatment details:
Dosage: Adults: 600 mg efavirenz once daily, in combination with a protease
inhibitor and/or nucleoside analogue reverse transcriptase inhibitors. Efavirenz
may be taken with or without food; however, a high fat meal may increase the
absorption of efavirenz and should be avoided. In order to improve the tolerability
of nervous system side effects, bedtime dosing is recommended during the first
two to four weeks of therapy and in patients who continue to experience these
symptoms.
Paediatric patients: Efavirenz should be taken on an empty stomach, once daily,
preferably at bedtime. Doses for paediatric patients 3 years of age or older and
weighing between 10 and 40 Kg are as follows:
10 to < 15 Kg = 200 mg
15 to < 20 Kg = 250 mg
20 to < 25 Kg = 300 mg
25 to <32.5 Kg = 350 mg
32.5 to <40 Kg = 400 mg
40 Kg or more = 600 mg
Concomitant Antiretroviral Therapy: efavirenz must be given in combination with
other antiretroviral medications.
Duration: Antiretroviral treatment is usually regarded as life-long.
6
Guidelines: The draft “WHO Antiretroviral Guidelines for Resource Limited
Settings”10 indicates efavirenz (in combination with two nucleoside analogue
reverse transcriptase inhibitors) is recommended as a first-line regimen for the
treatment of HIV/AIDS.
Special Requirements: Adequate resources for monitoring and specialist oversight
are a pre-requisite for the introduction of this class of drugs.
8. Comparative effectiveness in clinical settings:
In compiling the evidence for this and related submissions for anti-retroviral drugs
we have created a common ‘stem’ in the form of information that is relevant to all
of the antiretroviral group. This is followed by information that is relevant to use of
this class of drug under the conditions described in this application, followed by
information which is specific to the individual agent under consideration.
Because of time constraints and the growing acceptance of the efficacy of highly
active anti-retroviral drug regimens in the last 5 years, we have relied in part on
secondary data sources – systematic reviews of randomised and non-randomised
studies conducted by the Cochrane Collaboration, or by independent groups who
have generally met standards that are considered appropriate to this type of work.
We have relied on individual trials where these provided data and insights not
available from systematic reviews.
Details of literature searches conducted
The principal data-bases maintained by the WHO that were searched were:
o The Cochrane Data-base of Systematic Reviews
o The ACP Journal Club reviews of published trials
o The data-base of reviews of abstracts of reviews of effectiveness (DARE)
o The Cochrane controlled trials register (CCTR)
o Medline
o Embase
o
o
AIDSLINE
CENTRAL
Search terms used were:
o
o
o
o
o
o
o
Anti-retroviral or antiretroviral
Nucleoside reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
Randomised clinical trial (exploded and as text word)
Individual drug names: efavirenz
Study selection:
o
Randomised comparative parallel-group controlled clinical trials
7
o
Examined the performance of efavirenz when included in combinations
comprising 3 or more drugs, involving concomitant use of NRTIs, other
NNRTIs or PIs.
Categorisation of levels of evidence
The following rating scheme was used11:
 Level 1 – evidence from relevant high quality systematic reviews of
unbiased randomised comparative clinical trials
 Level 2 – evidence from at least one relevant unbiased randomised
comparative clinical trial.
 Level 3 – evidence from relevant controlled observational studies
Additional considerations for use in resource-poor settings





Co-morbidity
Simplicity (frequency of dosing, number of tablets)
Tolerability
Cost
Prior exposure to ARVs
General therapeutic issues: (common to the therapeutic category of antiretroviral drugs)
1. What is the validity of surrogate markers as predictors of morbidity and
mortality in patients with HIV/AIDS?
2. What evidence is there that triple (or quadruple) ARV therapy is superior to
single or dual therapy?
Class specific questions
3. Which combinations of drug classes have the best evidence in relation to
benefits and harms?
Agent-specific questions
4. What is the evidence for the efficacy and toxicity of anti-retroviral drug
combinations that include didanosine?
Results
1. What is the validity of surrogate markers as predictors of morbidity
and mortality in patients with HIV/AIDS? (Level 3 evidence)
Trials of anti-retroviral compounds have relied heavily on measuring the effects of
drugs on surrogate markers, usually CD4 cell counts and plasma HIV-1 RNA
levels. The validity of these markers depends on showing that they are correlated
with clinical outcomes, and that they should be able to capture the effects of
treatment on the major clinical outcomes12. Both of these markers may be viewed
as being on the ‘causal pathway’ between viral infection and disease outcomes,
but more directly in the case of viral measures. The viral end-point has come to be
8
regarded as superior to a measure as a prognostic marker, although results have
not been entirely consistent. A meta-analysis of trials of 2 NRTIs (plus NNRTI or
PI), which included 36 treatment arms, found that baseline CD4 counts were
significantly correlated with virologic suppression at 6 and 12 months, whereas a
similar correlation was not found with baseline viral load and subsequent viral
suppression13. The authors concluded that baseline CD4 cell count was a better
predictor of drug induced viral suppression than baseline viral load. In the other
meta-analysis of surrogate measures uncovered by the literature search, Hill et al
reviewed results from 15 randomised trials that used surrogate markers and also
included measures of disease progression14. This review included data from
15038 patients, of whom 3532 patients progressed to clinical outcomes. The
analyses documented that there were significant correlations between the relative
hazards for clinical progression and changes in both HIV-1 RNA levels and CD4
cell counts. The authors concluded that these markers, together, were useful in
monitoring treatment responses. However the data also indicate the value of
using CD4 cell counts alone. Another meta-analysis has quantified the
relationship between changes in surrogate measures and development of AIDS or
death. In an analysis based on 16 randomised trials of NRTIs, Babiker et al.
estimated that the average hazard reduction was 51% (95% CI 41, 59%) for each
reduction in HIV RNA levels of 1*log10, and 20% (95% CI 17, 24%) for each
increase of 33% in CD4 cell count15. These studies are supported by a wealth of
observational data from developed countries, showing that the use of highly active
anti-retroviral therapy, tested on the basis of surrogate markers in many trials, has
profoundly influenced the outcomes for patients with HIV infection.
2. What evidence is there that triple (or quadruple) ARV therapy is
superior to single or dual therapy? (Level 1 evidence)
There is extensive clinical experience suggesting that multiple drugs with different
modes of action are necessary to achieve sustained viral suppression (induction).
Such combination treatments are standard recommendations in clinical practice
guidelines. 16,17,18 There is insufficient space and time to present all of the relevant
studies documenting the success of multi-drug induction therapy to the Expert
Panel. However, a smaller number of trials have documented the value of various
maintenance regimens introduced after successful induction therapy and these
studies are relevant. Four trials that compared 3 or 4 drug maintenance regimens
with 2 drug regimens were included in a Cochrane Review19. Use of a two-drug
maintenance regimen was associated with an odds ratio for virologic failure (loss
of HIV suppression) of 5.55 (95% CI 3.14, 9.80). These results complement an
earlier systematic review, which synthesised data from 6 trials that compared the
results of zidovudine monotherapy with treatment combinations comprising ZDV
with DDI or DDC20. Although mainly of historical interest now, the review studies
clinical outcomes and showed that the addition of DDI to ZDV resulted in a
reduced odds of disease progression and death (OR 0.74, 95% CI 0.67, 0.82) and
(0.72, 95% CI 0.64, 0.82) respectively. The addition of DDC gave similar results:
disease progression, 0.86 (95% CI 0.78, 0.94); and death, 0.87 (95% CI 0.77,
0.98). After 3 years the rates of mortality were ZDV 59%, ZDV+DDC 63% and
ZDV+DDI 68%. The reviewers concluded that the combination of ZDV and DDI
was probably superior to ZDV plus DDC.
9
The most recent review of the importance of multiple drugs in treatment of
HIV/AIDS was recently published in the BMJ21. These investigators pooled data
from 54 randomised clinical trials. The odds ratio for disease progression with 3
drugs compared with 2 drugs was 0.62 (95% CI 0.50, 0.78), but data were
considered inadequate to determine if a general advantage was achieved by
addition of a fourth drug.
3. Which combinations of drug classes have the best evidence in
relation to benefits and harms? (Level 2 evidence)
Unfortunately this is a question that is not yet addressed in published systematic
reviews. Enquiries directed to the AIDS/HIV review group in the Cochrane
Collaboration revealed that relevant reviews are underway but results are not yet
available. Some of the data from the limited number of trials comparing different
combinations of 3 or more anti-retroviral drugs will be reviewed in relation to the
individual drugs (see below). However there are broad questions about which
combinations should be used as first line treatment, and in what sequence should
they be employed. The clinical practice guidelines mentioned earlier address some
of these issues and point out that choice is determined not only by direct evidence
of comparative clinical efficacy, but also by tolerability and toxicity, presence of comorbidity, concern about the development of viral resistance, and more pragmatic
considerations such as pill burden and adherence to therapy. With recognition that
none of the available regimens eradicates the virus, but suppression is desirable,
HIV infection has come to be regarded as a chronic disease, which requires longterm (albeit sometimes intermittent) drug therapy. An additional consideration is a
wish to ‘preserve’ more active anti-retroviral regimens for later in the course of
therapy. This has led to recommendations to conserve PI-containing regimens,
using those based on combinations of NRTIs and NNRTIs early in therapy. These
considerations are reflected in the advice contained in the draft WHO Antiretroviral
Guidelines for Resource Limited Settings. The summary of regimens
recommended in this document is reproduced as Table 1
10
Table 1. Recommended First-Line Antiretroviral
Regimens in Adults
Regimen
ZDV/3TC plus
EFV* or NVP*
ZDV/3TC/ABC*
ZDV/3TC** plus
RTV enhanced
PI or NFV
Pregnancy
Considerations
- Substitute NVP
for EFV in
pregnant women
or women for
whom effective
contraception
cannot be
assured
- ABC safety
data limited
- LPV/r safety
data limited
- NFV: most
supportive
safety data
Major Toxicities
- ZDV-related anemia
- EFV-associated CNS
symptoms
- Possible teratogenicity
of EFV
- NVP-associated
hepatotoxicity and severe
rash
- ZDV-related anemia
- ABC hypersensitivity
- ZDV-related anemia
- NFV-associated
diarrhea
- IDV-related
nephrolithiasis
- PI-related metabolic
side effects
*ZDV/3TC is listed as the initial recommendation for dual NsRTI component based on efficacy,
toxicity, clinical experience and availability of fixed dose formulation. Other dual NsRTI
components can be substituted including d4T/3TC, d4T/ddI and ZDV/ddI depending upon countryspecific preferences. ZDV/d4T should never be used together because of proven antagonism.
** RTV-PI includes IDV/r, LPV/r, and SQV/r.
4. What is the evidence for the efficacy and toxicity of anti-retroviral
drug combinations that include efavirenz? (Level 2 evidence)
Efavirenz has been the subject of multiple trials that comprise three different uses
of the drug: (1) as initial therapy, (2) as salvage therapy for patients who are
failing initial regimens and (3) as “switch” therapy for patients who are being
successfully treated with protease inhibitors but who have protease inhibitorrelated lipodystrophy.
Efavirenz as initial therapy
For initial therapy, efavirenz has been examined in six well conducted randomized
controlled trials (see Table 2 for brief summaries; for fuller details of trials see
Attachment 1. References are linked to Tables 2-4).
The trials retrieved by the literature search established that efavirenz, in
combination with two nucleoside reverse transcriptase inhibitors (in five trials
zidovudine and lamivudine), was superior to two nucleoside reverse transcriptase
inhibitors alone; that efavirenz-containing regimens were equal or superior to
protease inhibitor-containing regimens in achieving long-term viral suppression;
and that efavirenz-containing regimens that lacked nucleoside reverse
transcriptase inhibitors were inferior to those that contained them.
11
Table 2. Trials of efavirenz-containing antiretroviral regimens as initial
therapy.
Trial
ACTG
388
Authors
Fischl 200222
N
517
Regimen
ZDV+3TC and
1. EFV+IDV
2. NFV+IDV
3. IDV
ZDV+3TC and
1. EFV 200 mg
2. EFV 400 mg
3. EFV 600 mg
4. Placebo
Summary of Findings
EFV+IDV superior in achieving smaller
proportion of virologic failures at 2.1
years (p=0.04). Grade 3 or 4 toxicities
equivalent among arms.
All three doses superior to placebo. No
difference among three EFV doses. No
difference in adverse effects among four
arms.
DMP
266005
Gallant 199823
Haas 199824
Hicks 199825
Labriola 199826
Manion et al
199927
MoralesRamirez 199828
Staszewski
199829
Staszewski
199930
Tashima 199931
137
450
1. EFV+ZDV+
3TC
2. EFV+IDV
3. IDV+ZDV+
3TC
Levy 200132
1266
DPC
083201
Ruiz 200233
134
Merck
067
Isaacs 199834
71
1. EFV+ZDV+
3TC
2. EFV+IDV
3. IDV+ZDV+
3TC
ZDV+3TC and
1. DPC 083 50
mg qd
2. DPC 083
100 mg qd
3. DPC 083
200 mg qd
4. EFV
1. IDV 1.2 gm
bid + EFV
300 mg bid
2. IDV 1 gm tid
+ EFV 600
mg qd
EFV+ZDV+3TC superior to other two
regimens in achieving viral suppression
by two tests at 48 weeks. Both EFVcontaining regimens had lower rates of
discontinuation for adverse events than
IDV+ZDV+3TC. EFV-containing
regimens had higher incidence of
dizziness, impaired concentration,
insomnia and abnormal dreaming.
EFV+ZDV+3TC superior to other
regimens in achieving viral suppression
at 2 years (80% v. 60% v. 65%).
DPC006
DMP
266006
No difference in viral suppression at 24
weeks among four arms. No differences
in premature discontinuation. Dizziness
was more common with EFV than with
DPC 083 (a new third-generation nonnucleoside reverse transcriptase
inhibitor)
Twice per day and thrice per day dosing
regimens comparable.
Presumably patients also received
NRTIs, but no information in abstract.
Also not clear if this study was for initial
therapy or for NRTI failure.
3TC, lamivudine; EFV, efavirenz; IDV, indinavir; NFV, nelfinavir; NRTI, non-nucleoside
reverse transcriptase inhibitor; ZDV, zidovudine
Efavirenz-containing initial antiretroviral therapy regimens are additionally the
subject of several ongoing trials (ACTG A5095, AIEDRP AI-02-01 [in acute HIV
infection], AIEDRP AI-07-001, CPCRA 058, FDA 229R [Hoffman LaRoche], FDA
229S [Roche Laboratories], FDA 259H [Agouron Pharmaceuticals], FDA 302C
[Bristol-Meyers Squibb], FDA 308B [Glaxo SmithKline], Initio [MRC]). These trials
12
largely focus on protease inhibitor-sparing initial regimens (e.g., ACTG A5095
[zidovudine + lamivudine + abacavir and/or efavirenz] or AIEDRP AI-07-001
[stavudine + didanosine and indinavir/low-dose ritonavir or efavirenz]). The Initio
trial goes a step beyond these and tests a three-arm induction/maintenance
regimen with induction therapy with didanosine + stavudine + efavirenz and/or
nelfinavir followed by maintenance therapy with Trizivir (a fixed combination of
zidovudine, lamivudine and abacavir) + nelfinavir or efavirenz or saquinavir/lowdose ritonavir (Babiker 2001)35.
Efavirenz as salvage therapy
Efavirenz has been examined in five well conducted randomized controlled trials
as salvage therapy for failing regimens (see Table 3). In all five of these studies
the regimens that had failed contained nucleoside reverse transcriptase inhibitors
only, and most typically these were dual therapy. These studies showed that
efavirenz was an effective drug for non-nucleoside reverse transcriptase-naïve
patients who were failing nucleoside reverse transcriptase inhibitor regimens and
that efavirenz plus protease inhibitors (either nelfinavir or indinavir) were superior
to efavirenz or to a single protease inhibitor. Additionally, a meta-analysis of the
three DMP 266 salvage trials showed that efavirenz could provide prolonged viral
suppression in patients with HIV RNA levels of over 100,000 copies/ml. However,
since dual therapy is no longer a recommended option (only triple nucleoside
reverse transcriptase inhibitor therapy with abacavir as the third drug is currently
recommended), these studies may not be the best evidence for whether or not
efavirenz is an effective salvage drug. This is because failure is due to viral
resistance mutation, and without participants having been exposed to protease
inhibitors in their initial regimens the efficacy of efavirenz-containing regimens for
salvage therapy cannot be directly examined in these studies. Use of efavirenz for
treatment of patients who have failed protease inhibitor-containing initial regimens
has, however, been the subject of multiple uncontrolled studies and is also the
subject of current ongoing randomized controlled trials (e.g., CPCRA 057, FDA
245F).
13
Table 3. Trials of efavirenz as component of salvage therapy for
patients failing NRTI-containing regimens.
Trials
Author
N
ACTG
364
Albrecht 199836
Albrecht 199937
Albrecht 200038
Winters 199939
196
1 or 2 new
NRTS and
1. NFV
2. EFV
3. NFV+ EFV
ACTG
368
Squires 199940
Squires 200041
123
1. IDV 1 gm tid
+ EFV 600
mg qd
2. IDV 1.2 gm
bid + EFV
300 mg bid
NRTIs
DMP
266003
Cohort
IV
DMP
266004
Havlir 1998a42
Kahn 199843
Riddler 1998a44
Riddler 1998b45
Riddler 200046
Mayers 199847
101
1. EFV+IDV
2. IDV
(arm 2 added
d4T+EFV at
week 12)
ZDV+3TC and
1. EFV 400 mg
2. EFV 600 mg
3. Placebo
NRTIs
DMP
266020
Fessel 199848
Haas 199849
Havlir 1998b50
Manion et al
199926
Haas 200151
327
≤2 NRTIs and
1. EFV + IDV
2. Placebo +
IDV
NRTIs
93
Regimen
Failed
regimen
NRTIs
NRTIs
Findings
NFV+EFV superior to NFV
alone and to EFV alone in
achieving viral suppression
at 40-48 weeks. EFV alone
superior to NFV alone. No
difference in grade 3 or 4
events.
Trend toward IDV tid + EFV
qd achieving superior viral
suppression compared to
IDV bid + EFV bid. This
study had two other arms
examining these regimens ±
ABC.
EFV+IDV achieved superior
viral suppression compared
to IDV (with EFV+d4T added
later).
Both EFV-containing
regimens achieved superior
viral suppression at 16
weeks. 600 mg regimen
achieved higher proportion
of viral suppression than 400
mg regimen.
EFV+IDV superior to IDV
alone in achieving viral
suppression by ultrasensitive
assay (HIV RNA <50
copies/ml) at 24 weeks.
Discontinuation
due
to
adverse events higher in
EFV regimen.
3TC, lamivudine; ABC, abacavir; d4T, stavudine; EFV, efavirenz (also known as DMP 266); IDV,
indinavir; NFV, nelfinavir; NRTI, nucleoside reverse transcriptase inhibitor; ZDV, zidovudine.
Efavirenz as “switch” therapy from protease inhibitors
Switching from protease inhibitors to efavirenz in patients with virologic
suppression has been examined in four randomized controlled trials (Table 4).
Because patients on protease inhibitor therapy are susceptible to disorders of lipid
metabolism (the lipodystrophy syndrome), there is interest in switching from
protease inhibitors to drug classes, such as the non-nucleoside reverse
transcriptase inhibitors, that are believed to have a lower incidence of this
disorder. The three trials for which data are available (see table 4) showed that
efavirenz was comparable to or superior to continuing existing protease inhibitors
14
in maintaining viral suppression; that efavirenz was comparable to nevirapine
and abacavir in maintaining viral suppression; and that efavirenz was more likely
than nevirapine or abacavir to be associated with hypercholesterolemia and
hypertriglyceridemia. Protease inhibitor switching is also the subject of three
ongoing trials (e.g., ACTG A5039, ACTG A5103, DMP 266-027); DMP 266-027
was reported in an abstract at the International Conference on AIDS in 2000, but
tabular results were not available.
Table 4. Trials of efavirenz as switch therapy for patients with viral
suppression on nucleoside reverse transcriptase inhibitor- and protease
inhibitor- containing regimens.
Trials
Author
N
Regimen
Prior
regimen
DMP
049
Becker 200152
346
NRTIs and
1. EFV
2. Continue
existing PIs
NRTIs,
PIs
SWAT
CH
Negredo
2001A53
Negredo 200254
77
Existing NRTIs
and
1. NVP
2. EFV
3. Continue
existing PI(s)
NRTIs,
PIs
Martinez 200255
460
Existing NRTIs
and
1. NVP
2. EFV
3. ABC
NRTIs,
PIs
Katalma 200056
165
Existing NRTIs
and
1. EFV
2. Continue
existing PI(s)
NRTIs,
PIs
DMP
266027
Findings
EFV maintained superior
viral suppression at 24
weeks, EFV associated with
fewer missed doses. No
difference in premature
discontinuation of study.
All three arms maintained
comparable viral suppression
at 12 months. NVP
associated with lowest total
cholesterol and triglyceride
levels. Discontinuation due
to adverse events similar.
All three arms maintained
comparable viral
suppression.
Hypercholesterolemia and
discontinuation due to
adverse events significantly
lower in ABC arm.
No results available
ABC, abacavir; d4T, EFV, efavirenz (also known as DMP 266); NRTI, nucleoside reverse
transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor.
9. Comparative evidence on safety of efavirenz
b. Adverse effects/reactions: nausea, rash, dizziness, impaired concentration,
vomiting, insomnia, headache, diarrhoea, abnormal dreams, somnolence, pruritus,
depression, anorexia, nervousness, dyspepsia.
Laboratory abnormalities (Grade 3 or 4) include neutropenia; elevated bilirubin,
AST, ALT, GGT, amylase, glucose, CPK. Increases in total cholesterol of 10 - 20
15
% have been observed in some uninfected volunteers receiving efavirenz.
Increases in non-fasting total cholesterol and HDL of approximately 20 % and 25
%, respectively, were observed in patients treated with efavirenz + zidovudine +
lamivudine and of approximately 40 % and 35 %, in patients treated with efavirenz
+ indinavir. The effects of efavirenz on triglycerides and LDL were not wellcharacterised. The clinical significance of these findings is unknown.
Warnings:
Efavirenz must not be used as a single agent to treat HIV or added on as a sole
agent to a failing regimen. Significant central nervous system birth defects
(anencephaly, anophthalmia, cleft palate) were observed in 3 of 20 infants born to
pregnant monkeys who received efavirenz during early pregnancy at doses
resulting in plasma concentrations comparable to those seen with human
therapeutic exposure (CDC, Nightingale). There have been two case reports of
myelomeningocele in human infants born to women who was receiving efavirenz
at the time of conception and during the first trimester (DeSanti, Fundaro).Thus,
the use of efavirenz should be avoided in women who may become pregnant.
Women of childbearing potential should undergo pregnancy testing prior to
initiation of antiretroviral therapy.
Special populations:
Because of the extensive cytochrome P450-mediated metabolism of efavirenz and
limited clinical experience in patients with chronic liver disease, caution must be
exercised in administering efavirenz to patients with mild-to-moderate liver
disease. Patients should be monitored carefully for dose-related adverse events,
especially nervous system symptoms. Laboratory tests should be performed to
evaluate their liver disease at periodic intervals. In patients with known or
suspected history of Hepatitis B or C infection and in patients treated with other
medications associated with liver toxicity, monitoring of liver enzymes is
recommended. In patients with persistent elevations of serum transaminases to
greater than 5 times the upper limit of the normal range, the benefit of continued
therapy with efavirenz needs to be weighed against the unknown risks of
significant liver toxicity.
Convulsions have been observed rarely in patients receiving efavirenz, generally
in the presence of known medical history of seizures. Patients who are receiving
concomitant anticonvulsant medications primarily metabolised by the liver, such as
phenytoin and phenobarbital, may require periodic monitoring of plasma levels.
Caution must be taken in any patient with a history of seizures.
Precautions:
Nervous system symptoms: There have been reports of delusions and
inappropriate behaviour in patients receiving efavirenz. Severe acute depression
(including suicidal ideation/attempts) have also been reported in both efavirenztreated and control-treated patients. Fifty-two per cent of patients receiving
efavirenz reported CNS system and psychiatric symptoms. These symptoms
included, but were not limited to, dizziness, impaired concentration, somnolence,
abnormal dreams, and insomnia. In controlled trials, these symptoms were severe
in 2.6 % of patients receiving 600 mg efavirenz daily and in 1.4 % of patients
16
receiving control regimens.
Rash: Mild-to-moderate rash has been reported in clinical studies with efavirenz
and usually resolves with continued therapy. Appropriate antihistamines and/or
corticosteroids may improve the tolerability and hasten the resolution of rash.
Severe rash associated with blistering, moist desquamation or ulceration has been
reported in less than 1 % of patients treated with efavirenz. The incidence of
erythema multiforme or Stevens-Johnson Syndrome was approximately 0.1 %.
Efavirenz must be discontinued in patients developing severe rash associated with
blistering, desquamation, mucosal involvement or fever. If therapy with efavirenz is
discontinued, consideration should also be given to interrupting therapy with other
antiretroviral agents to avoid development of resistant virus.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast
enlargement, and “cushingoid appearance” have been observed in patients
receiving antiretroviral therapy. The mechanism and long-term consequences of
these events are currently unknown. A causal relationship has not been
established.
Drug Interactions:
Efavirenz has been shown in vivo to induce CYP3A4 (cytochrome P450 3A4).
Other compounds that are substrates of CYP 3A4 may have decreased plasma
concentrations when coadministered with efavirenz. In vitro studies have
demonstrated that efavirenz inhibits 2C9, 2C19, and 3A4 isozymes in the range of
observed efavirenz plasma concentrations. Coadministration of efavirenz with
drugs primarily metabolised by these isozymes may result in altered plasma
concentrations of the coadministered drug. Therefore, appropriate dose
adjustments may be necessary for these drugs.
Drugs that should not be coadministered with efavirenz: astemizole, terfenadine,
midazolam, triazolam, cisapride, ergot derivatives.
Drugs which require a dose increase when coadministered with efavirenz: When
coadministered with efavirenz, indinavir doses must be increased from 800 mg to
1000 mg every 8 hours. Coadministration of methadone with efavirenz resulted in
decreased plasma levels of methadone and signs of opiate withdrawal.
Methadone dose was increased by a mean of 22% to alleviate withdrawal
symptoms. When coadministered with efavirenz, the daily dose of rifabutin must
be increased by 50 per cent.
Other potentially clinically significant drug interactions with efavirenz: warfarin,
saquinavir, ritonavir, clarithromycin, rifampin, ethinyl estradiol. Concomitant use of
efavirenz and St. John's wort (Hypericum perforatum) or St. John's wort-containing
products is not recommended. There is a potential for additive CNS system effects
when efavirenz is used concomitantly with alcohol or psychoactive drugs.
c) Variation in safety due to health systems and patient factors:
17
Antiretroviral therapy cannot be successfully introduced in a healthcare system
vacuum. However, facilities and personnel infrastructure can be expanded in
parallel with the implementation of antiretroviral agent delivery programmes.
Health care provider and patient education, an essential health care package, and
the ability to do at least limited clinical and laboratory monitoring are all necessary
to try to insure programmatic success. [WHO Draft Antiretroviral Guidelines for
Resource Limited Settings, p. 2.]
It is well established that the introduction of any antimicrobial therapy for an
infectious disease is association with the induction and spread of drugs resistance
as an inevitable consequence. Although an obvious concern, this is not a reason
to delay introduction of large-scale antiretroviral therapy programmes. Rather,
education of providers and patients, attention to drug adherence, monitoring the
population for drug resistance, and institution of strategies to try to limit drug
resistance are the components of an appropriate response. It is possible that the
risk of the spread of resistant viral strains in the population may be balanced by
the potential for the reduction of HIV transmission by the introduction of
antiretroviral therapy. [WHO Draft Antiretroviral Guidelines for Resource Limited
Settings, p. 15.]
10. Summary of available data on comparative cost and cost-effectiveness
within the pharmacological class or therapeutic group:
Cost of therapy
The most recent list of price offers (dated February 25th 2002 ) compiled by MSF
lists four suppliers of efavirenz: Aurobindo (India) $US 485 annual cost of
treatment, Merck (US) $US 500, Cipla (India) $US 668, and Hetero (India) $US
1040. By comparison, nevirapine (an alternative NNRTI) costs range from $US
150 to 438.
11. Summary of regulatory status of the medicine (in country of origin and
preferably in other countries as well): TBA
12. Availability of pharmacopoieal standards: TBA
18
Attachment 1: results of efavirenz
studies
Pages 18-24
19
Attachment 1: Results of efavirenz (EFV) trials
1. Efavirenz as a component of initial antiretroviral regimens
AUTHOR
Fischl 2002
ACTG 388
Gallant et al
1998
Haas et al
1998
Hicks et al
1998
Labriola et
al 1998
Manion et al
1999
DMP 266005
Isaacs R et
al 1998
Merck 067
METHODS
PATIENTS
DETAILS
No or limited
prior ART
CD4≤200 and
HIV RNA
≥80,000
N=517
Asymptomatic
or mildly
symptomatic;
no prior ART
exposure
N=137
PI and NNRTI
naïve
CD4≥100, HIV
RNA ≥10,000
N = 71
RCT:Open
ZDV+3TC
Blind
1. EFV+IDV
2. NFV+IDV
3. IDV
RCT:
Open
ZDV 300 mg
bid + 3TC
150 mg bid
Blind
5. EFV 200
mg qd
6. EFV 400
mg qd
7. EFV 600
mg qd
8. Placebo
RCT:
Open
4. IDV 1.2
gm bid +
EFV 300
mg bid
5. IDV 1gm
tid + EFV
600 mg qd
BENEFITS
Efavirenz regimen
Comparator
regimen
Virologic failure (mean follow up 2.1 years)
EFV+IDV 23% (p=0.04 NFV+IDV 46%
c/w other 2 arms)
(p=0.006 c/w/ other 2
arms)
IDV 31%
HIV-1 RNA plasma levels < 400 copies/ml
At W16:
EFV 200 mg 96%
Placebo 48%
EFV 400 mg 85%
EFV 600 mg 88%
At W24:
EFV 200 mg 96%
EFV 400 mg 91%
EFV 600 mg 100%
TOLERABILITY AND ADVERSE EFFECTS
Efavirenz regimen
Comparator
regimen
Grade 3 or 4 signs and symptoms
EFV+IDV 24% (NS)
NFV+IDV 28%
IDV 21%
Grade 3 or 4 laboratory abnormalities
EFV+IDV 34% (NS)
NFV+IDV 36%
IDV 34%
Nausea and/or headache and/or fatigue
EFV 200 mg 67% EFV
Placebo 73%
400 mg 82%; EFV 600
mg 74%.
Placebo 65%
HIV RNA <400 copies/ml at 16 weeks
bid 86%
tid 75%
At W12:
bid 79%
tid 58%
At W8:
bid 58%
tid 39%
Study drugs were generally well tolerated; two
patients in the BID group and one in the TID group
required discontinuation of study medications
attributed to drug toxicity
20
Efavirenz as a component of initial antiretroviral regimens (continued)
MoralesRamirez et
al 1998,
Staszewski
et al 1998,
Manion et al
1999,
Staszewski
et al 1999*,
Tashima et
al 1999
DMP 266006
Asymptomatic
or mildly
symptomatic;
PI, NNRTI,
and 3TC naïve
(only 15% had
prior NRTI
therapy)
CD4>50
HIV
RNA>10,000
N= 450
RCT:
Open
4. EFV 600
mg qd +
ZDV 300
mg bid +
3TC 150
mg bid
5. EFV 600
mg qd +
IDV 1 gm
q8h
6. IDV 800
mg q8h +
ZDV 300
mg bid +
3TC 150
mg bid
HIV RNA <400 copies/ml at 48 weeks (ITT)
EFV+ZDV+3TC 70%
IDV+ZDV+3TC 48%
(p<0.05 c/w
IDV+ZDV+3TC or
EFV+IND)
EFV+IND 53%
HIV RNA <50 copies/ml at 48 weeks (ITT)
EFV+ZDV+3TC 64%
IDV+ZDV+3TC 47%
(p<.05 c/w
IDV+ZDV+3TC or
EFV+IND)
EFV+IND 43%
Discontinuation because of any reason
EFV+ZDV+3TC 27%
IDV+ZDV+3TC 43%
(p=0.005).
Discontinuation because of adverse event
EFV+ZDV+3TC 6%
IDV+ZDV+3TC 20%
(p=0.001 c/w either
EFV+IND 6%
EFV-containing
regimen)
Rash
EFV+ZDV+3TC 34%
EFV+IND 34%
IND+ZDV+3TC 18%
CNS symptoms (dizziness, impaired concentration,
insomnia, abnormal dreaming)
EFV+ZDV+3TC 58%
IDV+ZDV+3TC 26%
EFV+IND 53%
(p<0.001)
21
2. Efavirenz as a component of salvage therapy
AUTHOR
Albrecht et
al 1998
Albrecht et
al 1999
Albrecht et
al 2000*
Winters et al
1999
ACTG 364
METHODS
PATIENTS
DETAILS
NRTI
exposure in
prior ACTG
trials (ACTG
175; rollover
studies ACTG
302/303) and
who remained
on same
treatment at
entry
HIV RNA ≥500
N=196
RCT:
Open
1 or 2 new
NRTIs
(ddI+d4T,
3TC+d4T, or
ddI+3TC)
Blind
1. NFV 750
mg tid
2. EFV 600
mg qd
3. NFV +
EFV
BENEFITS
Efavirenz regimen
Comparator
regimen
Plasma HIV RNA at 16 weeks
<400 copies/ml:
NFV+EFV 81% (p=0.03 NFV 64%
c/w NFV)
EFV 69%
<50 copies/ml:
NFV+EFV 67%
(p=0.001 c/w NFV)
NFV 39%
EFV 62% (p=0.01 c/w
NFV)
HIV RNA at 40-48 weeks
<400 copies/ml:
NFV+EFV 74%
(p=0.001 c/w NFV)
NFV 35%
EFV 60% (p-0.004 c/w
NFV)
NFV 22%
<50 copies/ml:
NFV+EFV 67%
(p=0.008 c/w EFV,
p=0.001 c/w NFV)
EFV 44% (p=0.008 c/w
NFV)
TOLERABILITY AND ADVERSE EFFECTS
Efavirenz regimen
Comparator
regimen
“There was no significant difference among the
three treatment groups with respect to time to the
development of the first grade 3 (severe) or grade
4 (life-threatening) signs or symptoms, which
occurred in a total of 36 patients (18%) – 12 in the
NFV group, 10 in the EFV group and 14 in the
NFV+EFV group (p>0.3 for all pairwise
comparisons). The most frequent grade 3 or 4
signs or symptoms reported were aches, pain, or
discomfort (in 13 patients [7%]) and diarrhea or
loose stools (in 7 patients [4%]). A grade 3 or 4
rash developed in only three patients (2%). Grade
2 (moderate) peripheral neuropathy developed in
six patients (3%).” (Albrecht, 2001)
22
Efavirenz as a component of salvage therapy (continued)
Squires et al
1999*
Squires et al
2000
ACTG 368
NRTIexperienced
but PI, NNRTInaive pts with
CD4 cell <250
with ≥2
months ZDV
(or d4T) + 3TC
(rollover of
ACTG 320)
All pts
randomized to
ABC v.
placebo
N=283
Pts with
CD4>50
rerandomized
to IDV tid +
EFV + ABC v.
IND bid + ABC
N=123
RCT:
For pts with
CD4≤50:
1. ABC 300
mg bid
2. Placebo
For pts with
CD4 50-249:
1. IDV 1 gm
tid + EFV
600 mg
qd + ABC
300 mg
bid
2. IDV 1.2
gm bid +
EFV 300
mg bid +
ABC 300
mg bid
3. IDV 1 gm
tid + EFV
600 mg
qd
4. IDV 1.2
gm bid +
EFV 300
mg bid
HIV RNA level ≥500 copies/ml at 16 weeks
(virologic failure)
IDV tid + EFV qd 21%
IDV bid + EFV bid 28%
(p=0.22)
At W32:
IDV tid + EFV qd 33%
(p=0.07)
IDV bid + EFV bid 48%
IDV bid + EFV bid 47%
At W48:
IDV tid + EFV qd 37%
(p=0.17)
23
Efavirenz as a component of salvage therapy (continued)
Havlir et al
1998
Kahn et al
1998*
Riddler et al
1998a
Riddler et al
1998b
Riddler et al
1998c
Riddler et al
2000
DMP 266-003,
Cohort IV
Mayers et al
1998
DMP 266-004
Asymptomatic
or mildly
symptomatic
NRTI
experienced
(71%)
N=101
NNRTI and PI
naïve, ZDV +
3TC
treatment for
≥ 8 weeks,
HIV RNA
≥2,500
copies/ml,
CD4 > 50
N=93
RCT:
Blind
1. EFV 200 mg qd
+ IDV
800/1000mg tid
2. IDV 800/1000
mg tid (Arm 2
added d4T +
EFV at W12)
Both arms
increased EFV to
600 mg qd at W36
RCT:
Blind
1. EFV 400 mg +
ZDV + 3TC
2. EFV 600 mg +
ZDV + 3TC
3. ZDV + 3TC +
placebo
HIV RNA <400 copies/ml at 72 weeks
EFV + IDV 73%
IDV + (EFV+d4T) 57%
(p=0.037)
At W60:
EFV + IDV 91%
“The most frequently reported treatment-related
adverse events among all patients receiving EFV
(n=93) were diarrhea and nausea (Riddler 2000).”
IDV + (EFV+d4T) 79%
IDV + (EFV+d4T) 68%
At W48:
EFV + IDV 89%
Mean increase in CD4 cells/ml at 120
weeks
EFV+IDV 374.8
IDV + (EFV+d4T) 266.3
± 36.1
± 36.1
Decrease in HIV RNA (in log 10) copies/ml,
CD4 cells/mm3 at 16 weeks
ZDV + 3TC + EFV (400
ZDV + 3TC +
mg) 0.65 ± 0.75 (p≤0.05
placebo 0.05
c/w placebo)
±0.11
ZDV + 3TC + EFV (600
mg) 0.49 ± 0.15 (p≤0.05
c/w placebo)
Increase in CD4 cells/ml
ZDV + 3TC + EFV (400
ZDV + 3TC +
mg) 50.34 ± 14.37
EFV placebo
(p=0.05 c/w placebo)
9.48 ± 17.35
ZDV + 3TC + EFV (600
mg) 43.19 ± 24.8 (NS)
“Some patients in all treatment groups described
potentially drug-related adverse events, most of
which were mild to moderate in intensity. Overall,
EFV did not alter the general tolerability or safety
of the combination of ZDV + 3TC.”
24
Efavirenz as a component of salvage therapy (continued)
Fessel et al
1998
Haas et al
1998
Manion et al
1999
Haas et al
2001*
DMP 266020
NRTI
experienced
≥8 weeks, no
prior PI or
NNRTI
HIV-1 RNA
≥10,000
copies/ml;
CD4 >50
cells/mm3;
N=327
Manfredi &
Chiodo
2001
Manion et al
1999
≥12 months of
NRTI
monotherapy
and ≥15
months of
IDV- or RTVcontaining
HAART
N=59
HIV RNA
≥100,000
RCT
Blind
≤2 NRTIs plus
4. IDV 800 mg tid
+ EFV placebo or
5. EFV 600 mg qd
+ IDV 1000 mg
tid
NRTI-experienced
patients not on
NRTIs at entry
began 1 or 2 NRTls
on Day 1.
HIV RNA <400 copies/ml at 24 weeks (ITT, non-completers counted
as treatment failures)
EFV 60% (p=0.114)
Placebo 51%
HIV RNA <50 copies/ml at 24 weeks (ITT)
EFV 49% (p=0.031)
Placebo 38%
Further details not
available at time of
writing
Reanalysis of DMP
266-003, DMP 266005, DMP 266-020
Trial
DMP
266-
HIV RNA<400 copies/ml (%)
HIV RNA <50 copies/ml (%)
Wk
OBS LOCF NC=F
Wk
003
84
84
70
65
60
76
74
70
005
48
91
77
60
16
67
53
53
020
36
77
66
50
24
74
54
54
OBS LOCF NC=F
Discontinuation because
of adverse events
EFV 11.5% Placebo
5.3%
(p=0.043)
25
3. Efavirenz as a component of switch therapy
Katalma
2000
DMP 266027
PI and NRTI
experienced
pts with HIV
RNA <50
N=165
Negredo et
al 2001a
Negredo et
al 2001b
Negredo et
al 2002*
SWATCH
Martinez et
al 2002
On PI(s) ≥12
months,
NNRTI naïve
CD4>300
HIV RNA<80
N=77
Treated with
PI plus 2
NRTIs
HIV RNA
<200 for ≥6
months
N=460
RCT:
Open
5. EFV 600
mg +
continue
existing
NRTIs
6. Continue
existing
PI(s) +
NRTIs
RCT:
Open
Existing
NRTIs plus
4. NVP
5. EFV
6. Continue
existing
PI(s)
RCT
Existing
NRTIs plus
1. NVP
2. EFV
3. ABC
HIV RNA ≥50 copies/ml
No data available
HIV RNA <80 copies/ml
NVP 96%
EFV 92%
PI(s) 92%
Total cholesterol (mg/dl) at 12 months
EFV 218±52
Discontinuation because of adverse events
EFV 12%
NVP 8%
PI(s) 8%
NVP 199±38 (p<0.03)
PI(s) 229±42
Triglyceride level (mg/dl)
EFV 218±214
NVP 160±94 (p<0.01)
PI(s) 229±158
HIV RNA <200 copies/ml at 12 months (ITT)
EFV 74% (p=0.7)
NVP 78%
ABC 77%
Mean increase in CD4 cells/ml
EFV 51
NVP 41
ABC 51
Key: 3TC, lamivudine; ABC, abacavir; ACTG, NIH AIDS Clinical Trials Group; ART, antiretroviral therapy; bid, twice a day (i.e., q12h); c/w, compared with; d4T,
stavudine; DMP 266, efavirenz (code in early developmental trials); EFV, efavirenz; HAART, highly active antiretroviral therapy (≥3 drugs from ≥2 different
classes); IDV, indinavir; ITT, intention to treat analysis; LOCF, last observation carried forward analysis; NC=F, non-completer equals failure (i.e., intention to
treat) analysis; NFV, nelfinavir; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NVP, nevirapine; OBS,
“on treatment” analysis; PI, protease inhibitor; RCT, randomized controlled trial; tid, three times per day (i.e., q8h); ZDV, zidovudine
26
Attachment 2 Characteristics of non-nucleoside reverse transcriptase
inhibitor-based regimens:
Advantages
Disadvantages
*potent, durable antiretroviral activity
*HIV-2 reverse transcriptase is not inhibited by
NNRTIs.
* improvement in surrogate markers established;
longer-term clinical data appears to confirm benefit
* efavirenz shown to be teratogenic;
* use of NNRTIs spares protease inhibitor class
* low genetic barrier to resistance
nevirapine shown to be hepatoxic
Non-proprietary name
Cost p.a. US $
Advantages
Disadvantages
nevirapine
$150 (Aurobindo, India)
to $438 (Boehringer
Ingelheim, Germany)
*1 tablet taken twice
daily;
* can be taken with or
without food;
* generally welltolerated;
*penetrates blood/brain
barrier;
* can be used in
pregnancy;
*requires step-up
dosing;
*potentially lifethreatening hepatic
events and skin
reactions;
*high level resistance to
nevirapine occurs after
only one specific gene
mutation in HIV.
Resistance to
nevirapine confers
cross-resistance to
other nNRTI drugs,
including efavirenz. ;
* multiple potential drug
interactions;
* cannot be used with
rifampin;
* not active against
Group O subtypes;
27
efavirenz
$485 (Aurobindo, India)
to $1040 (Hetero, India)
*once-daily dosing;
* can be taken with or
without food;
* penetrates the bloodbrain barrier;
*high level resistance to
efavirenz occurs after
only one specific gene
mutation in HIV.
Resistance to efavirenz
confers crossresistance to other
nNRTI drugs, including
nevirapine;
*mild-to-moderate brain
and psychiatric side
effects occur in about
half of patients taking
efavirenz;
*teratogenic: must not
be used in pregnancy;
* multiple potential
drug interactions;
* cannot be used with
rifampin;
* not active against
Group O subtypes;
28
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