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(22 April 2002)
Application for Inclusion of abacavir on
WHO Model List of Essential Medicines
Drug is a member of the therapeutic class of HIV nucleoside analogue
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-limited 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 nucleoside reverse transcriptase inhibitor abacavir 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.
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 7 randomised controlled trials of abacavir (ABC) and 5
uncontrolled single arm studies that provided insights into the efficacy and safety of this
drug for different indications.
As initial therapy in antiretroviral-naïve subjects (3 trials), abacavir (ABC) in combination
with two nucleoside reverse transcriptase inhibitors (zidovudine and lamivudine), was
superior to two nucleoside reverse transcriptase inhibitors alone. Abacavir-containing
regimens appeared equivalent to protease inhibitor-containing regimens in achieving viral
suppression (with the possible exception of subjects with high baseline viral loads), and
there was some evidence of better adherence to treatment than with the PI -containing
regimens.
One trial studied the addition of ABC (or placebo) in patients receiving dual and triple-drug
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regimens with detectable viral loads (above 400c/mL) (intensification therapy). Overall,
patients receiving abacavir were significantly more likely than those on placebo to have a
viral load (VL)<400c/mL at 48 weeks. However, only 13% of patients in the ABC arm had
VL<50c/mL (vs. 0% of patients in the placebo arm).
Abacavir has also been tested (3 trials) as an alternative to protease inhibitors
(replacement therapy) in patients who were receiving stable combined drug therapy. All
three trials showed high rates of continued viral suppression in patients randomized to
abacavir-based regimens.
Overall abacavir was quite well tolerated. Overall rates of adverse reactions were similar
to, or less than, what was seen with Pi-containing regimens and adherence rates were
similar or higher. However hypersensitivity reactions with ABC were observed in several
trials with reported rates between 2% and 10%.
Abacavir can be administered as twice daily treatment. It is presently available as a fixed
dose combination with ZDV and 3TC from one manufacturer (GSK - TrziverTM) at an
annual treatment cost of $US 2409. The costs of a year’s treatment with ABC alone varies
from $US 1387 (GSK) to $US 2628 (Hetero).
1. Summary statement of the proposal for inclusion, change or deletion.
Abacavir is proposed for inclusion on the WHO Model List of Essential Medicines, as part
of a multi-drug antiretroviral regimen for the treatment of HIV/AIDS within an appropriately
monitored program. Abacavir should be viewed as an example of the class of nucleoside
analogue reverse transcriptase inhibitors. Other examples of this group may sometimes be
preferred when local factors such as availability and price are taken into account.
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: abacavir sulfate
5. Listing Type Requested:
Listing is requested on the Model List of Essential Medicines as an example of the
therapeutic class of HIV nucleoside analogue reverse transcriptase inhibitors. Other
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members of this class of drugs may serve as alternatives, depending on quality, price and
local availability.
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/AIDS 3. 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 years 3.
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 approximately US $677 million in averted
hospitalisations and treatment of HIV-related 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.
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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. Sixtyfive 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, 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
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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:
Recommended Dosage: Adults: 300 mg twice daily, in combination with at least two other
antiretroviral drugs. There are no food restrictions.
Children and adolescents 3 months to 16 years of age: 8 mg/Kg twice daily, to a maximum
of 300 mg twice daily, in combination with at least two other antiretroviral drugs.
Formulations: Abacavir 300mg tablets; Abavacir 300mg + Zidovudine 300mg +
Lamivudine 150mg fixed dose combination tablets (“Trizivir”TM).
Concomitant Antiretroviral Therapy: Abacavir must be given in combination with other
antiretroviral medications.
Duration: Antiretroviral treatment is usually regarded as life-long with the exceptions of
post-exposure prophylaxis and for the prophylaxis of infants of HIV-infected mothers.
Guidelines: The draft “WHO Antiretroviral Guidelines for Resource Limited Settings”10
indicates abacavir (in combination with two other antiretroviral medicines) is a preferred
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. Familiarity with the diagnosis of and
response to Abacavir hypersensitivity reaction is of particular importance.
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
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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
o
AIDSLINE
AIDSTRALS
AIDSDRUG
Search terms included:
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: eg abacavir (ABC)
Study selection:
o
o
Randomised comparative parallel-group controlled clinical trials
Examined the performance of abacavir 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)
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 Tolerability


Cost
Prior exposure to ARVs
General therapeutic issues: (common to the therapeutic category of anti-retroviral
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 abacavir?
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 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
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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.
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,
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presence of co-morbidity, 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 long-term (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.
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
diarrhoea
- 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 country-specific 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 abacavir? (Level 2 evidence)
Abacavir is a fairly well-studied and widely used NRTI. It is the most potent single NRTI
currently available, reducing HIV viral load (VL) by 1-5-2.0 logs when studied as
monotherapy. Abacavir requires a minimal pill burden (one pill BID); the combination of
abacavir with zidovudine and lamivudine can be given as a single tablet BID. Abacavir is
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associated with a rare but potentially lethal toxicity, however: 3-5% of patients treated with
abacavir in clinical studies have developed a severe hypersensitivity reaction, including
fever, rash, malaise, nausea, vomiting, abdominal pain, and cough/dyspnea, that resolves
with immediate discontinuation of the drug, but proves rapidly fatal with each successive
dose. Once abacavir is stopped due to suspicion of this reaction, it should never be
restarted.
Most trials of abacavir have used the 300mg BID dosage in combination with at least two
additional antiretroviral agents. This formulation has been studied in several different
clinical settings: (1) as initial therapy; (2) as substitute for a protease inhibitor in simplifying
an antiretroviral regimen that is successfully suppressing viral replication; (3) as
intensification of a failing antiretroviral regimen; and (4) as part of rescue therapy in
patients with viral rebound after numerous antiretroviral regimens.
The antiretroviral efficacy of Abacavir in combination therapy has been studied in three
randomized controlled trials involving treatment-naïve subjects (Spreen, 199922;
Staszewski 200123; Jordan 200224). These trials are summarised in Attachment 1.
Spreen randomized treatment-naïve patients to triple-NRTI therapy with ABC+ZDV+3TC
vs. dual NRTI therapy with ZDV+3TC for 48 weeks, with the option adding open label ABC
or other agents to failing regimens at 16 weeks. At week 16, 75% of pts in the ABC arm
had undetectable viral loads vs. 35% in the dual-NRTI arm (p<0.001); 74% of pts in the
ABC arm maintained suppression at week 48.
To compare the potency of ABC-based triple NRTI therapy to that of PI-based therapy,
Staszewski randomized 562 treatment-naïve patients to ABC+ IDV-placebo or IDV+ABCplacebo for 48 weeks. All patients also received open label Combivir (AZT+3TC). When
antiretroviral efficacy was analyzed, regardless of baseline patient viral load, ABC+2NRTI
was equivalent to IDV+2NRTI: 51% of each group had HIV VL<400 copies/mL at 48
weeks. A slightly higher proportion of patients randomized to indinavir vs abacavir had
VL<50 c/mL (46% vs. 40%). Most notably, however, was the finding that patients with a
baseline VL>100,000 copies/mL were less likely to have a VL<50c/mL at 48 weeks if
randomized to Abacavir (31%) than if randomized to indinavir (45%). There was little
difference in prevalence of clinical side effects, lab abnormalities, discontinuations, or
study withdrawals between the abacavir-based and indinavir-based arms. Jordan
conducted a randomized trial of open label ABC vs. IDV, each with ZDV+3TC, to study
viral efficacy and adherence in 329 treatment-naïve patients (see Attachment 1). This
study found a greater probability of 95% adherence with ABC vs. IDV (72% vs. 45%,
p=0.001), as well as a dose response relationship between adherence and probability of
VL<400c/mL at 48 weeks.
In an intensification study, Katlama et al (2001)25 randomized 185 patients with detectable
viral loads (above 400c/mL) on dual and triple-drug regimens to abacavir vs. placebo plus
their stable background therapy for 48 weeks. Overall, patients receiving abacavir were
significantly more likely than those on placebo to have a VL<400c/mL at 48 weeks (25%
vs. 5% p,<0.001). However only 13% of patients in the Abacavir arm had VL<50c/mL (vs.
0% of patients in the placebo arm). Here, too, the magnitude of baseline VL played a role:
in the Abacavir arm, 41% of patients with a baseline VL<5000c/mL had a VL<400c/mL at
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week 48, vs. 9% of patients with a baseline VL>5000c/mL. Taken together, these three
trials suggest that triple NRTI-therapy with ABC is (a) superior to dual-NRTI therapy in
ART-naïve patients; (b) possibly equivalent to PI-based triple drug therapy in ART-naïve
patients with moderate baseline VL; and (c) only modestly successful in intensifying a
failing regimen.
There are three open-label, randomized trials of abacavir as replacement for protease
inhibitors in stable, suppressive triple-drug regimens (Clumeck, 200126; Katlama-TRIZAL,
200127; Martinez, 200228) (see Attachment 1). All three trials showed high rates of
continued viral suppression in patients randomized to abacavir-based regimens; the study
by Martinez showed the efficacy of abacavir to equal that of the non-nucleoside reversetranscriptase inhibitors efavirenz and nevirapine, when used to simplify successful, PIbased combination therapy.
Three single-arm, retrospective studies (Khanna, 200029; Moyle, 200030; Tenorio, 200031)
(see Table 1) examined the use of abacavir in treating patients with extensive antiretroviral
experience and viral rebound on their current regimen (rescue therapy). The studies by
Khanna and Tenorio showed disappointingly modest rates of viral suppression in highly
antiretroviral-experienced patients. Moyle, by contrast, studied NNRTI-naïve patients
failing PI-based regimens; 58% of those who received rescue therapy including efavirenz
and abacavir demonstrated VL<500c/mL at 24 weeks, with a mean rise in CD4 count of 97
cells. In a prospective, open label, single arm study of ABC+ZDV+3TC given to PI-naïve,
patients experiencing viral rebound on dual-NRTI therapy, Henry et al32 demonstrated
moderately successful viral suppression at 48 weeks, with higher likelihood of failure
among patients with a higher VL at study entry.
Finally, two additional, open-label, single-arm, prospective studies examined novel uses of
abacavir (see Attachments 1). Kirkland33 found a high rate of viral suppression among
incarcerated, ART-naïve patients treated with ABC+ZDV+3TC given as two pills BID in
directly-observed therapy (DOT). Chapuis34 treated 41 ART-naïve patients early in
infection (antibody-positive with mean CD4 count 756/mm3 and mean VL 28,000c/mL ) for
72 weeks with a two-drug, NRTI+PI regimen consisting of abacavir + amprenavir, and
found 70% of patients to have a VL<50c/mL at 72 weeks.
9. Comparative evidence on safety (See attachment 1 for results from clinical
trials of abacavir):
b. Adverse effects/reactions: Adults: nausea, malaise and/or fatigue, vomiting, diarrhoea,
anorexia, insomnia and other sleep disorders, fever and/or chills, headache, severe
sensitivity reactions (see below).
Laboratory abnormalities (Grade 3 or 4): anaemia, neutropaenia; elevated liver function
tests, and CPK elevations; elevations of blood glucose; elevated triglyceride elevations.
Paediatric: nausea and vomiting, fever, headache, diarrhoea, rashes, anorexia.
Laboratory abnormalities (Grade 3 or 4): anaemia, neutropenia; elevations in liver function
tests, creatine kinase.
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Warnings:
Abacavir must not be used as a single agent to treat HIV or added on as a sole agent to a
failing regimen.
Fatal hypersensitivity reactions have been associated with therapy with abacavir. Patients
developing signs or symptoms of hypersensitivity (which include fever; skin rash; fatigue;
gastrointestinal symptoms such as nausea, vomiting, diarrhoea, or abdominal pain; and
respiratory symptoms such as pharyngitis, dyspnoea, or cough) should discontinue
abacavir as soon as a hypersensitivity reaction is suspected. To avoid a delay in diagnosis
and minimize the risk of a life-threatening hypersensitivity reaction, abacavir should be
permanently discontinued if hypersensitivity cannot be ruled out, even when other
diagnoses are possible (e.g., acute onset respiratory diseases, gastroenteritis, or reactions
to other medications). Abacavir must not be restarted following a hypersensitivity reaction
because more severe symptoms will recur within hours and may include life-threatening
hypotension and death. Severe or fatal hypersensitivity reactions can occur within hours
after reintroduction of abacavir in patients who have no identified history or unrecognised
symptoms of hypersensitivity to abacavir therapy.
In clinical studies, approximately 5% of adult and paediatric patients receiving abacavir
developed a hypersensitivity reaction. This reaction is characterized by the appearance of
symptoms indicating multi-organ/body system involvement. Symptoms usually appear
within the first 6 weeks of treatment with abacavir, although these reactions may occur at
any time during therapy. Frequently observed signs and symptoms include fever; skin
rash; fatigue; and gastrointestinal symptoms such as nausea, vomiting, diarrhoea, or
abdominal pain. Other signs and symptoms include malaise, lethargy, myalgia, myolysis,
arthralgia, oedema, pharyngitis, cough, dyspnoea, headache, and paraesthesia. Some
patients who experienced a hypersensitivity reaction were initially thought to have acute
onset or worsening respiratory disease. The diagnosis of hypersensitivity reaction should
be carefully considered for patients presenting with symptoms of acute onset respiratory
diseases, even if alternative respiratory diagnoses (pneumonia, bronchitis, pharyngitis, or
flu-like illness) are possible. Physical findings include lymphadenopathy, mucous
membrane lesions (conjunctivitis and mouth ulcerations), and rash. The rash usually
appears maculopapular or urticarial but may be variable in appearance. Hypersensitivity
reactions have occurred without rash.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been
reported with the use of nucleoside analogues alone or in combination, including abacavir
and other antiretrovirals. A majority of these cases have been in women. Obesity and
prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Particular
caution should be exercised when administering abacavir to any patient with known risk
factors for liver disease; however, cases have also been reported in patients with no
known risk factors. Treatment with abacavir should be suspended in any patient who
develops clinical or laboratory findings suggestive of lactic acidosis or pronounced
hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of
marked transaminase elevations).
Precautions:
13
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:
An increased methadone dose may be required in a small number of patients receiving
abacavir.
c) Variation in safety due to health systems and patient factors:
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 compiled by MSF lists two suppliers of abacavir:
GlaxoSmithKline (UK) annual cost of treatment $US 1387 and Hetero (India), $US 2628.
By comparison, zidovudine costs range from $US 180 (Ranbaxy) to $US 584 (GSK),
lamivudine from $US 91 to 248; stavudine from $US 44 to $US 137; and didanosine from
$US 190 to 891. However, it may be more appropriate to compare the price of abacavir
with other drugs that are combined with dual nucleoside therapy, for instance nevirapine
($US 166 – 438), nelfinavir ($US 1380 – 3139) and efavirenz ($US 438 – 1040).
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
14
Attachment 1: Results of the trials of abacavir
Pages 14 - 19
15
ATTACHMENT 1 RESULTS OF CLINICAL TRIALS OF ABACAVIR
AUTHOR
METHODS
STUDY DETAILS
Staszewski et
al. 200123
CNAAB3005
RCT of safety, equivalence
Open: combivir (ZDV+3TC) +
Blind:
IDV/placebo Q8h
or
ABC/placebo BID
N= 562 ARV-naïve; HIV
VL>10,000c/mL; CD4>100/mm3.
Equivalence= 95% CI between
–12% and +12%
‘Abacavir*
Regimen
BENEFITS
Comparator
Regimen
% all pts w/HIV VL<400 copies/mL at 48
weeks:
51%
--Similar rise in CD4
count between groups.
--No difference in time to
viral rebound regardless
of baseline VL.
% all pts w/HIV VL<50 copies/mL at 48
weeks:
40%
46%
95% CI (-15% ,+2%)
51%
95%CI (-9%,
+8%)
% of pts with baseline HIV VL>100,000
c/mL and HIV VL<50 c/mL at 48 weeks:
31%
45%
95% CI (-27% , 0%)
TOLERABILITY AND ADVERSE EFEFCTS
‘Abacavir*
Comparator
Regimen
Regimen
No difference in most prevalent side effects (nausea,
vomiting, malaise, headache), except for renal side
effects: <1% for ABC group, 5% for IDV group
Severe lab abnormalities:
--ABC+ZDV+3TC: 16%
--IDV+ZDV+3TC: 19%
Discontinued study drug::
--ABC+ZDV+3TC: 17%
--IDV+ZDV+3TC: 22%
Deaths:
--ABC+ZDV+3TC: 3 (1 hypersensitivity, 2 MI)
--IDV+ZDV+3TC: 1 (heroin/cocaine overdose)
Drop-outs:
--ABC+ZDV+3TC: 99 (41 w/adverse events)
--IDV+ZDV+3TC: 96 (50 w/adverse events)
16
Staszewski et
al. 199835
CNAB2002
2 phase dose ranging study:
Randomized, double-blind:
ABC 100mg, 300mg, or 600mg
BID to 24 weeks,
then
Open-label: ABC 300mg+ZDV
300mg+3TC 150mg BID to 48
weeks.
N=60 ARV-naïve patients;
VL>30,000 c/mL; CD4
>100/mm3.
NB: based on interim analysis
showing less ABC potency at
100mg, at four weeks, pts
randomized to ABC 100mg BID
were offered open-label ABC at
higher doses; by 24 weeks, only
3 pts remained on 100mg dose.
Katlama et al.
200125
CNA3002
RCT
Of open-label stable background
therapy (SBG) + blinded
ABC vs. Placebo x 48 weeks..
N= 185 pts on >12 weeks SBG
with HIV VL 400-50,000c/mL;
CD4 >100/mm3
Most common SBG:
ZVD/3TC (36%)
2NRTI + PI or NNRTI (21%)
% of pts on ABC+ZDV+3TC with HIV
VL<400 c/mL at 48 weeks (pooled from --Withdrawals due to adverse events during
randomized phase: 4 (1 MI; 1 rhabdo; 2
all ABC doses)
65%
No comparison arm
% of pts on ABC+ZDV+3TC with HIV
VL<50 c/mL at 48 weeks (pooled from
all ABC doses)
43%
No comparison arm
--At four weeks, decrease in log10 VL among
pts receiving 300mg or 600mg ABC (-1.55
and -1.61 respectively), were significantly
greater than that achieved by 100mg ABC,
but not significantly different from each other.
--Differences between 300mg and 600mg
doses of ABC remained insignificant at 24
weeks.
--CD4+ cell counts increased a median of
118/mm3 over 48 weeks (range 62-186
cells).
% Pts with HIV VL<400c/mL at 48
weeks
25% (p<0.001)
5%
% Pts with HIV VL<50c/mL at 48 weeks
13%
0%
hypersensitivity).
--Grade 3-4 lab abnormalities during randomized
phase: 6.
--Withdrawals during open-label phase: 2
(nausea/vomiting and depression/skin rash).
--Similar nature/frequency of adverse events in all
dose groups; trend towards increased nausea and
malaise
with increased dose.
13 pts quit study due to
12 pts quit study due to
AE
AE
12% switch to open-label 37% switch to open
by 48 weeks
label by 48 weeks
52% complete 48 weeks 15% complete 48
as randomized
weeks as randomized
Overall 25% of participants prematurely discontinue
study.
17
d4T/3TC (19%)
ZDV/ddI (10%)
--41% of pts on SBG+ABC with baseline
VL<5000c/mL had VL<400 at 48 weeks vs.
9% of pts on SBG+ABC with BL
VL>5000c/mL.
--CD4 cells increased a median of 102/mm3
in pts on SBG+ABC vs. 57 in pts on SBG
alone.
18
Author
Spreen et al.
199922
CNAA3003
Clumeck et al.
200126
CNA30017
Study details
RCT: Double blind
ABC+ZDV+3TC vs.
ZDV+3TC x 16 weeks; option
to add open label ABC at 16
weeks, or to unblind, add other
ART if VL>400 confirmed.
Followed to 48 weeks.
N= 173 ART-naïve.
Open label, randomized trial
of continued (2NRTI+PI) vs.
2NRTI+ ABC replacing PI
N= 211 pts with HIV
VL<50c/mL since starting
stable ART consisting of
NRTI+PI >6 months prior to
entry.
Abacavir regimen
Comparator regimen
% pts with HIV VL<400c/mL at 16 weeks:
Tolerability and adverse events
Trial reported in abstract form; no adverse event data.
75% (p<0.001)
35%
74% remain <400c/mL
at 48 weeks.
--No significant difference in median CD4 rise over 48
weeks between pts who received ABC and those who
did not (150 and 152 /mm3 respectively).
Treatment Failure (HIV VL>400c/mL or
premature discontinuation of therapy) over 48
weeks
12% (p<0.03)
failure due to AE: 8
virologic failure: 4
other failure: 0
23%
failure due to AE: 14
virologic failure: 2
other failure: 8
--No significant difference in grade 3-4 lab abnormalities.
--2% incidence of hypersensitivity in ABC group
--Pts in ABC arm experienced significantly higher
incidence of nausea, malaise, fatigue.
19
Khanna et al.
200029
(Swiss HIV
Cohort Study)
Single arm retrospective
study
of heavily pre-treated patients
switched to salvage therapy
with ABC+NNRTI+1 or 2 new
PIs.
N= 23 pts on HAART
(2NRTI+PI), w/o exposure to
ABC or NNRTI, with HIV
VL>1000c/mL, and hx of
median 4 drug changes since
starting ART.
--At six months, 2
patients (9%) had HIV
VL<500c.mL, and 10 pts
(43%) had decrease in
HIV VL>0.5 log10.
--Seven pts increased
CD4 count >30% above
baseline.
--Of 20 pts analyzed, 18
harbored multiple PR and
RT resistance mutations.
No comparator arm.
Eight pts dropped out of study (35%)
-Five pts quit study due to adverse events (4 rash, 1
neuropathy)
--Three pts quit due to non-response, including one with
clinical progression (KS, CMV retinitis).
20
Author
Study Details
Benefits
Abacavir Regimen
Kirkland et al.
200233
(NZTA4007)
Moyle et al.
200030
(from CNA3008
study)
Open-label clinical trial
(Single arm) of
ZDV+3TC+ABC, given as 2
pills BID, as DOT for 24
weeks.
N= 108 incarcerated, ARTnaïve pts with VL>400c/mL
and CD4>50/mm3.
Retrospective
analysis of pts experiencing
virologic failure on PI-based
regimen, switched to salvage
therapy including ABC+(EFV
or NVP)+2, 3, or 4 additional
drugs.
N= 31 pts naïve to NNRTI and
ABC, with detectable HIV VL
and CD4<100/mm3 with a
history of ART with at least 2
NRTI and PI.
Comparator Regimen
% of pts with HIV VL<400 c/mL at 24 weeks:
85%
68% (missing=failure)
No comparator group.
% of pts with HIV VL<50 c/mL at 24 weeks:
75%
No comparator group.
62% (missing=failures)
--Pts w/BL VL<100,000 c/mL were more likely to reach
undetectability at 24 weeks.
--Median CD4 increase 111/mm3 at 24 weeks
% of Pts with HIV
VL<500c/mL at 24
weeks:
--ABC+EFV: 58%
--ABC+NVP:11%
Mean change in CD4 at
24 weeks:
--ABC+EFV: +97.4
--ABC+NVP:+25.7
No comparator arm.
--90% received 2 additional drugs; baseline
characteristics similar between pts receiving EFV vs
NVP; virologic response unrelated to BL CD4, VL, #
drugs received, or sensitivity of virus to drugs received.
Tolerability/Adverse Effects
Abacavir Regimen
Comparator Regimen
18 pts withdrew:
--6 LTFU
--4 virologic failure
--4 adverse events (2 hypersensitivity)
--2 withdrew consent
--2 other
--No difference in adverse events in EFV vs NVP group.
--No ABC hypersensitivity reactions.
--Five deaths, due to HIV progression
21
Henry et al
200132
(TARGET)
Open label prospective
Single arm 48 week trial of
ABC+ZDV+3TC given as 2
pills BID to NRTIexperienced,PI-naïve pts with
virologic failure.
N=87 pts w/HIV
VL<50,000c/mL; CD4>50/mm3
not currently receiving ZDV.
Most common Baseline ART:
3TC+d4T (61%); d4T+ddI
(19%)
Tenorio et al.
200031
Retrospective analysis
of salvage regimens including
both ABC+EFV (grouped into a
single arm) in heavily ARTexperienced clinic pts.
N= 37 pts identified; only the
29 who remained on meds for
>4 weeks analyzed.
Mean CD4 115/mL; VL 5.14
log10 c/mL;Mean # prior
regimens 5; mean # new drugs
started 3.
Abacavir Regimen
Comparator Regimen
% of pts with undetectable HIV VL at 48 weeks:
<400c/mL:
--82% (ITT=observed)
--52% (ITT M=F)
--Median change inCD4
at 48weeks: +66/mm3
No comparator regimen.
--pts with virologic failure
had higher baseline HIV
VL than those who
maintained suppression.
--M184V mutation at BL
not associated with
virologic outcome; TAMs
at BL more common in pts
w/ virologic failure.
Outcomes at one year:
No comparator regimen
<50c/mL:
--56% (ITT=observed)
--36% (ITT M=F)
--2 pts w/ HIV VL<50
c/mL
--11 pts (38%) had
sustained virologic
response (not specified)
at one year; associated
w/ fewer prior regimens,
greater initial drop in
viremia.
--13 pts (45%) had
increased CD4 count at
one year (median
+60/mm3).
Abacavir Regimen
Comparator Regimen
--15% rate of withdrawal from study (nausea, malaise,
fatigue, vomiting most common)
--3.4% with ABC hypersensitivity.
--Clinical failure in 20 pts
(69%).
--9 pts w/ clinical
progression of disease
(non-responders).
--3 deaths due to disease.
--31 pts w/ adverse rxns
--8 pts (22%) discontinued
at least one drug.
--one ABC
hypersensitivity.
No comparator regimen
22
Chapuis et al.
200034
(CNAB2006)
Virologic efficacy at 72 weeks:
Nonrandomized, open label,
observational, prospective
trial
Of ABC+AMP for 72 weeks in
ART-naive pts.
N= 41 pts with VL>5000c/mL;
CD4 >400/mm3.
At baseline, mean CD4
756/mm3; mean HIV VL 4.45
log10 c/mL.
Author:
Martinez et al.
200228
Study Details:
Randomized open label
Regimen simplification trial of
pts with suppressed VL on
PI+2NRTI randomized to
replace PI with ABC, NVP or
EFV for 12 months.
N= 460 pts with HIV
VL<200c/mL for >6 months on
ART consisting of at least one
PI+2NRTI..
--% pts w/ HIV VL < 50
c/mL: 70%
No comparator regimen
--% pts w/ HIV VL < 5
c/mL: 39%.
--Mean change in CD4
count: +240/mm3
Benefits:
Abacavir Regimen
Comparator Regimen
% of Pts with HIV VL<200c/mL at 12 months:
ABC+2NRTI: 77%
(p=0.7 for main
comparison)
NVP+2NRTI: 78%
EFV+2NRTI: 74%
Mean change in CD4
count at 12 months:
+51/mm3.
Mean change in CD4
count at 12 months:
+41/mm3 (NVP); +51/mm3
(EFV).
7 pts (17%) withdrew
prematurely:
--4 w/ protocol defined
adverse events (2 rash; 1
chemical pancreatitis; 2
ABC hypersensitivity).
--3 voluntarily
--2 LTFU @ 72 wks.
--no clinical lipodystrophy
Tolerability/Adverse Events:
Abacavir Regimen
Comparator Regimen
% of pts who discontinued due to AEs:
ABC+2NRTI: 6%
(p=0.009 for main
comparison)
NVP+2NRTI: 16%
EFV+2NRTI: 17%
23
Jordan et al.
200224
(CNA3014)
Author:
Katlama et al.
200127
(TRIZAL)
Randomized open label viral
efficacy and adherence trial
Of ABC+ZDV/3TC vs.
IND+ZDV/3TC in ART-naive
pts for 48 weeks.
N329 ART-Naïve Pts.
Study Details:
Randomized, open label trial
Of Trizivir (combined
ABC+ZDV+3TC) vs. continued
HAART for 48 weeks.
209 pts with HIV VL<50 c/mL
on HAART and no hx of prior
virologic failure.
Most common prestudy
regimen: PI+2NRTI (63%).
Abstract does not provide
CD4, VL data from before pretrial ART was started.
Efficacy and adherence at 48 weeks:
Pts reporting difficulty taking regimen:
pts w/ 95% adherence
with HIV VL<400c/mL:
86%.
pts w/ 95% adherence
with HIV VL<400c/mL:
77%.
9%
(p<0.001 for comparison)
Pts w/95% adherence:
72%
(P.001 for comparison).
Pts
w/95%
adherence:
45%
Benefits:
Abacavir Regimen
Comparator Regimen
Pts with treatment failure (defined as 2
consecutive HIV VL>400c/mL or premature
discontinuation of randomized therapy) at 24
weeks:
20%
36%
17%
Tolerability/Adverse Events:
Abacavir Regimen
Comparator Regimen
--Adverse events were most likely reason for treatment
discontinuation in both arms.
--10% incidence of ABC hypersensitivity in Trizivir arm.
--Pts report Trizivir easier to take than continued HAART
(p<0.0001).
24
Attachment 2 Characteristics of nucleoside reverse transcriptase inhibitors
Two nucleoside analogue reverse transcriptase inhibitors (NRTIs) usually form the “backbone” of all currently
recommended antiretroviral regimens. NRTIs were the first class of antiretroviral drugs to be introduced; consequently the
most extensive clinical experience is recorded about these drugs. Presently ABC is usually ‘added on’ to the nucleoside
core.
Advantages
Disadvantages
*potent, durable antiretroviral activity when
combined with a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor
* adverse events associated with long-term
antiretroviral use, but a causal relationship has
yet to be established
* clinical benefit established, confirming validity of
surrogate marker improvement
* hypersensitivity reactions are severe and
sometimes fatal
* resistance profile of recommended dual NRTIs
allows for 2nd line combination
Non-proprietary name
Cost p.a. US $
Advantages
Disadvantages
zidovudine
$180 (Ranbaxy, India)
to $584 (GlaxoSmith
Kline, UK)
* penetrates blood/brain
barrier;
* resistance profile
allows for 2nd and
possibly 3rd line NRTI
combination;
* twice-daily dosing;
* can be taken with or
without food;
* compounded
formulations with
lamivudine; lamivudine
and abacavir; and
lamivudine and
nevirapine available;
* few drug interactions;
* can be administered
with rifampin
*anaemia;
*high level resistance to
zidovudine usually
confers resistance to
abacavir;
25
lamivudine
$66 (Aurobindo, India)
to $234 (Glaxo
SmithKline, UK)
*very well tolerated;
*twice-daily dosing and
long half-life means
potential for once-daily
dosing;
* can be taken with or
without food;
*active against hepatitis
B virus;
* resistance profile
allows for 2nd and
possibly 3rd line NRTI
combination;
* compounded
formulations with
zidovudine; zidovudine
and abacavir;
zidovudine and
nevirapine available;
* no significant drug
interactions;
* can be administered
with rifampin
*single mutation at
codon 184 of reverse
transcriptase can confer
high-level resistance;
didanosine
$197 (Aurobindo, India)
to $650 (GPO,
Thailand)
*twice-daily dosing but
long half-life allows for
once daily dosing;
* delayed-release,
enteric-coated
formulation available;
* can be administered
with rifampin;
* few drug interactions;
* buffered formulation
must taken on an empty
stomach;
* peripheral neuropathy;
* fatal and nonfatal
pancreatitis have
occurred during therapy
when didanosine was
part of a combination
regimen that included
stavudine
stavudine
$31 (Aurobindo, India)
to $137 (FarManguinh,
Brazil)
* well-tolerated;
* twice daily dosing;
* can be administered
with rifampin;
* few drug interactions;
* peripheral neuropathy;
* fatal and nonfatal
pancreatitis have
occurred during therapy
when didanosine was
part of a combination
regimen that included
stavudine
abacavir
$1387 (Glaxo
SmithKline, UK) to
$2628 (Hetero, India)
* twice-daily dosing;
*compounded
formulation with
zidovudine and
lamivudine available;
* penetrates blood/brain
barrier;
*can be used with
rifampin;
*no significant drug
interactions;
* serious, potentially
fatal hypersensitivity
reaction reported in 5%
of clinical trials
subjects;
26
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Convention and Trade Center, Seattle, February 24th-28th 2002. Available at www.retroconference.org
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approach’. WHO 2002.
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777-784
13
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Antiretroviral Therapy. Journal of Aquired Immune Deficiency Syndrome 2001; 28: 313-319
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Gallant, JE. Strategies for Long-term Success in the Treatment of HIV Infection. JAMA 2000; 283: 1329-1334
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