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(FCH/HIV, 22 April 2002)
Application for Inclusion of didanosine 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 worldwide 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 nucleoside reverse transcriptase inhibitor (NRTI) drug didanosine is proposed
for listing on the WHO Model List of Essential Medicines. The drug is generally used
along with another NRTI to form a ‘nucleoside core’ to which other drugs are added.
Didanosine in combination with stavudine (d4T) is recommended as an alternative
nucleoside core to zidovudine and lamivudine (3TC) in the (Draft) WHO guidelines
for use of ARV drugs in resource poor settings. Core combinations with other NRTIs
are possible (with the possible exception of lamivudine). The combination of ddI and
d4T is recommended for treatment within an appropriately monitored program in
combination with one or two other anti-retroviral drugs, including nucleoside or nonnucleoside reverse transcriptase inhibitors, or protease inhibitors. 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.
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. Sixteen randomised trials involving ddI were
retrieved, of which 5 included ddI/d4T as part of a 3-drug combination. In direct
comparisons of dual nucleoside regimens that are considered effective, ddI/d4T was
found (variously) to be equivalent or superior, and as well tolerated, as ZDV/3TC.
When ddI/d4T was trialed as part of a 3-drug combination it was found, in
combination with IDV, to be equivalent to, or superior to ZDV/3TC/IDV and
equivalent to d4T/3TC/IDV. Generally the combination is fairly well tolerated.
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Pancreatitis appears a commoner complication with ddI/d4T than with ZDV/3TC,
which is more inclined to cause anemia.
In conclusion, the data reviewed here support the use of ddI and d4T, in
combination, as a nucleoside ‘core’, a basis for 3 or 4-drug regimens comprising
other NRTIs, NNRTIs, or PIs. Didanosine is available from 6 manufacturers at prices
ranging from $US 190-891 for a year’s treatment. At present there are no fixed dose
combination product available that contain didanosine.
1. Proposal for inclusion, change or deletion of a drug.
Didanosine 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. Didanosine (ddI) should be viewed as an example
of the class of nucleoside analogue reverse transcriptase inhibitors (NRTI). The drug
is generally used along with another NRTI to form a ‘nucleoside core’ to which other
drugs, for instance protease inhibitors (PIs), non-nucleoside reverse transcriptase
inhibitors (NNRTIs) or another NRTI are added. Most commonly ddI is combined
with stavudine (d4T), but other combinations with alternative nucleoside analogues
are possible, and may be preferred when local factors such as availability, price and
formulation (as fixed drug combinations) are taken into account. These latter factors
may change quite rapidly depending on production developments and market forces.
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/mm 3, 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 provided
4. International Nonproprietary Name: didanosine
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
members of this class of drugs may serve as alternatives, depending on quality,
price and local availability.
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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 world 3. In 2001, 5 million persons
worldwide became infected with HIV, and 3 million others died from HIV/AIDSrelated 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 pervasive antiretroviral therapy. In the USA, the
introduction of triple combination antiretroviral therapy in 1996 lead 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 lowincome 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 antiretrovirals for those not covered by
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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, 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
5
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: Didanosine must be taken on an empty stomach, at least 30
minutes before or 2 hours after eating.
Adults: dosage is based on body weight is as follows:
Tablets:
400 mg once daily or 200 mg twice daily for patients  60 Kg.
250 mg once daily or 125 mg twice daily for patients < 60 Kg.
Powder:
250 mg twice daily for patients  60 Kg.
167 mg twice daily for patients < 60 Kg.
Enteric-coated, delayed-release tablets:
400 mg once daily for patients  60 Kg.
250 mg once daily for patients < 60 Kg.
Paediatrics: The recommended dose of didanosine in paediatric patients is 120
mg/m2 twice daily. There are no data on once-daily dosing of didanosine in
paediatric patients. Enteric-coated delayed-release didanosine has not been studied
in paediatric patients.
Concomitant Antiretroviral Therapy: Didanosine must be given in combination with
other antiretroviral medications.
Duration: Antiretroviral treatment is usually regarded as life-long.
Guidelines: The draft “WHO Antiretroviral Guidelines for Resource Limited
Settings”10 recommends didanosine (in combination with two other antiretroviral
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medicines) as part of a second-line regimen for the treatment of HIV/AIDS (see
Table 1).
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 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 the main 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
Search terms used were:
o
o
o
o
o
o
Anti-retroviral or antiretroviral
Nucleoside reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
Individual drug names: zidovudine, stavudine (d4T), lamivudine (3TC),
abacavir, nelfinavir, lopinavir, indinavir, ritonavir, efavirenz, nevirapine.
Note: this list covers the drugs listed under first and second-line ARV
regimens recommended in the draft WHO guidelines (see Table 1).
Randomised Clinical trials (exploded)
Note: The literature search used here, although comprehensive, is not complete.
In particular, trials presented at conferences, and available only as published
conference proceedings, were not included and no attempt was made to retrieve
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unpublished data. The results should be viewed as a fairly representative listing
of trials that are readily available through Medline and Embase searching.
Study selection:
o
o
o
o
Randomised comparative parallel-group controlled clinical trials
Compared ddI in combination with d4T with:
 Other dual nucleoside regimens
 Single drug regimens
Examined the performance of ddI with another NRTI in a dual-drug nucleoside
core, if this was likely to provide insights not available from other studies
Examined the performance of ddI and d4T when included in combinations
comprising 3 or more drugs, usually an additional protease inhibitor or a nonnucleoside reverse transcriptase inhibitor.
Note: The examination of 2-drug combinations does not imply any endorsement
of such regimens as effective treatments; these data are included here to help
establish the efficacy and safety of the combination of ddI and d4T as a
‘nucleoside core’.
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?
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Agent-specific questions
4. What is the evidence for the efficacy and toxicity of anti-retroviral drug
combinations that include didanosine?
Note: in addressing this question studies were selected in which didanosine had
been used in at least one arm in a combination that involved 1 or more additional
anti-retroviral drugs from the NRTI, NNRTI or PI classes. We have included data
from 2-drug studies, because these help establish the legitimacy of using ddIcontaining combinations as a ‘nucleoside core’ – a basis for a 3 or 4-drug
combination (see Table 1).
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 clinically. 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. 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 a wealth of clinical experience suggesting that multiple drugs with different
modes of action are necessary to achieve sustained viral suppression (induction).
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Such combination treatments are standard recommendations in clinical practice
guidelines. 15,16,17 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 Review18. 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
DDC19. 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.
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
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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 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 didanosine? (Level 2 evidence)
Sixteen randomised trials were retrieved by the literature search, of which 5 included
ddI/d4T as part of a 3-drug combination. The remainder comprised a variety of
comparisons of different 2-nucleoside RTI combinations, comparisons with individual
NRTIs, dose response studies and comparisons of once and twice daily dosing with
ddI. (The references are linked to the tables in Attachment 1)
Three studies (Kuritzkes et al 1999, Ruxrungtham et al 2000, Havlir et al 2000)
compared ddI monotherapy with a variety of 2-NRTI combinations. All studies
showed some efficacy of ddI monotherapy, but it was invariably less effective than
when compared with ddI-containing dual combinations, or combinations of 2 other
NRTIs. Kline et al 1999 found ddI+d4T to be superior to d4T alone in children.
Significantly these studies concluded that certain NRTI combinations did not display
the expected additive anti-retroviral actions, and investigators recommended
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specifically that ddI/3TC and d4T/ZDV may be less effective combinations. These
studies supported the use of ddI/d4T, ZDV/3TC and ddI/ZDV nucleoside
combinations as being superior to monotherapy with ddI.
Although it did not include a ddI/d4T arm, the large Delta (1996) trial has been
included in this review (Attachment 1) because it studied serious clinical outcomes
and showed that a combination of ddI and ZDV was superior to ZDV alone, and
probably superior to a combination of ddC and ZDV in delaying death or the onset of
AIDS clinical end-points.
In direct comparisons of dual nucleoside regimens that are considered effective,
ddI/d4T was found to be superior to ZDV/3TC by Molina et al (1999), equivalent to
ddI/ZDV by Angarano et al (1997), and equivalent to ddI/ZDV and ddC/ZDV by
Garcia et al (1999). The previously mentioned Delta trial (1996) found that the rate of
death and progression to AIDS clinical endpoints was less frequent with ddI/ZDV
than with ZDV/ddC.
The remaining trials that studied mono or dual therapy combinations established the
relevance of the currently recommended doses of ddi/d4T (Pollard et al 1999) and
the apparent efficacy and safety of single daily dosing of ddI (Monno et al 1999,
Mobley et al.1999).
When ddI/d4T was trialed as part of a 3-drug combination it was found, in
combination with IDV, to be equivalent to ZDV/3TC/IDV and d4T/3TC/IDV (Carr et al
2000). Eron et al (2000) found ddI/d4T/IDV to be superior to ZDV/3TC/IDV. As was
found with studies of the dual nucleoside regimen, ddI was equally effective given
once or twice daily in combination with a protease inhibitor or a non-nucleoside RTI –
NVP (Kazatchkine et al 2000, Garcia et al 2000).
In conclusion, the data reviewed here support the use of ddI and d4T, in
combination, as a nucleoside ‘core’, a basis for 3 or 4-drug regimens comprising
other NRTIs, NNRTIs, or PIs. On the basis of these data it appears that the
combination of ddI/d4T is equally effective to the widely used combination of
ZDV/3TC, with similar tolerability, albeit a different ADR profile (see below and
Attachment 2). The data also support the use of ZDV/3TC and ddI/ZDV and possibly
d4T/3TC. However, the data indicate a possible disadvantage for combinations of
ddI/3TC and d4T/ZDV.
9. Comparative evidence on safety (See attachment 1 for results from
clinical trials of didanosine):
b. Adverse effects/reactions: diarrhoea, peripheral neuropathy, abdominal pain,
rash/pruritus, pancreatitis.
Laboratory abnormalities (Grade 3 or 4): elevated amylase, AST, ALT, alkaline
phosphatase, uric acid.
Warnings:
12
Didanosine must not be used as a single agent to treat HIV or added on as a sole
agent to a failing regimen.
Patients with phenylketonuria: didanosine tablets contain 36.5 mg of phenylalanine.
Fatal and nonfatal pancreatitis have occurred during therapy when didanosine was
part of a combination regimen that included stavudine, with or without hydroxyurea,
in both treatment-naive and treatment-experienced patients, regardless of the
degree of immunosuppression. Didanosine should be suspended in patients with
signs or symptoms of pancreatitis and discontinued in patients with confirmed
pancreatitis. Patients treated with didanosine and stavudine (with or without
hydroxyurea) and any other agents that are toxic to the pancreas, may be at
increased risk for pancreatitis.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have
been reported with the use of nucleoside analogues alone or in combination,
including didanosine and other antiretroviral drugs. A majority of these cases have
been in women. Obesity and prolonged exposure to nucleoside analogues may be
risk factors. Fatal lactic acidosis has been reported in pregnant women who received
the combination of didanosine and stavudine with other antiretroviral agents. The
combination of didanosine and stavudine should be used with caution during
pregnancy and is recommended only if the potential benefit clearly outweighs the
potential risk.
Particular caution should be exercised when administering didanosine to any patient
with known risk factors for liver disease; however, cases of lactic acidosis have also
been reported in patients with no known risk factors. Generalized fatigue, digestive
symptoms (nausea, vomiting, abdominal pain, and sudden unexplained weight loss);
respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms (including
motor weakness) might be indicative of lactic acidosis development. Treatment with
didanosine 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). Patients treated with this combination should be closely monitored for
signs of liver toxicity Retinal changes and optic neuritis have been reported in
patients taking didanosine.
Precautions:
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or
feet, has been reported in patients receiving didanosine therapy. Peripheral
neuropathy has occurred more frequently in patients with advanced HIV disease, in
patients with a history of neuropathy, or in patients being treated with neurotoxic
drug therapy, including stavudine.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat
enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement,
13
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.
In patients with severely impaired renal function, dosage reduction is recommended.
Didanosine has been associated with asymptomatic hyperuricaemia; treatment
suspension may be necessary if clinical measures aimed at reducing uric acid levels
fail.
Drug Interactions:
Drugs that should not be coadministered with didanosine: allopurinol, ganciclovir,
methadone, alcohol.
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.]11
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.] 11
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
six suppliers of didanosine: Aurobindo (India) $US 190 annual cost of treatment,
Bristol Myers Squibb (US) $US 310, Far Manguinh (Brazil) $US 477, Hetero (India)
$US 555, Cipla (India) $US 584, and GPO (Thailand) $US 891. By comparison,
zidovudine costs range from $US 193 to 584; lamivudine from $US 91 to 248; and
stavudine from $US 44 to 137.
14
11. Summary of regulatory status of the medicine (in country of origin and
preferably in other countries as well): TBA
12. Availability of pharmacopoeial standards: TBA
15
Attachment 1 results of Didanosine
studies
Pages 16-20
16
Attachment 1: Results of Didanosine Trials (2-drug comparisons)
Benefits
ddI+ZDV
Author
Study details
ddC+ZDV
ADRs leading to cessation of trial treatment
ddI+ZDV ddC+ZDV ZDV alone
Death or progression to AIDS endpoints at
30 months
DELTA
study
group
199620
RCT: Blind
ddI+ZDV
or
ddC+ZDV
or
ZDV monotherapy
N=3207 Majority had no
previous ARV use
Hazard Ratio with
ddI+ZDV
v
ZDV alone
0.67(95% CI 0.56, 0.80)
Angarano
199721
RCT:
Blind ddI +d
d4T
or
ddI +ZDV
N= 38; Treatment-naïve
Viral load reduced by
71% . No breakdown by
treatment group
Pollard et
al. 199922
RCT:
Blind
ddI +d
d4T
in 5 different doses
N=86; Treatment-naïve
Trend to greater
response in 3 higher
dose groups than in 2
lower dose groups
Kline et
al. 199923
RCT:
Blind
ddI +d
d4T
or
d4T monotherapy
N=108 children (mean age 5y);
Results from subset previously
treated with ZDV monotherapy
Hazard Ratio with
ddC +ZDV
v
ZDV alone
0.79(95% CI 0.66, 0.94)
N
1080
Total events
346
Pancreatitis
9
Elevated amylase
10
Elevated ALT/AST 14
Peripheral neuropath 12
Anemia
5
Neutropenia
5
1072
290
3
5
17
63
13
8
1055
297
2
4
14
25
11
14
HIV-1 RNA viral load at 8 weeks
Full manuscript not
retrieved
No further details available
Toxicity
HIV-1 RNA viral load at 28 weeks
2/86 patients developed
peripheral neuropathy
Change in HIV-RNA levels at 48 weeks
ddI +d
d4T
-0.51 log10
stats not reported
NB only 8% suppressed
HIV-RNA levels below
200 copies/ml with dual
therapy
d4T alone
-0.17 log10
Withdrawals and toxicity
89% of subjects completed 48 weeks treatment.
Described as ‘well tolerated’
Full paper could not be retrieved
17
Attachment 1(cont): Results of Didanosine Trials (2-drug comparisons)
Kuritzkes
et al
199924
Study details
RCT: Open
ddI
or
d4T
then (factorial)Blind
ddI alone
or
ddI+3TC
or
ZDV+3TC
Note presentation of results
limited to ddI and d4T arms
N=299; treatment-naïve
Change in HIV-RNA levels at 24 weeks
ddI alone
ddI + 3TC
d4T alone
d4T+3TC
- 0.68 log10
-0.82 log10
-0.49 log10
-1.03 to
p>0.22 v ddI
alone
p=0.001v d4T
alone
Toxicity (grade 3 or worse)
ddI + 3TC
D4T + 3TC
14/55 (25%)
13/57 (23%)
14/292 (4.8%)
permanently
discontinued study
medication because of
severe toxicity – no
breakdown by study
group
Change in HIV-RNA levels at 12 weeks
Monno et
al. 199925
Molina et
al 199926
RCT: Open
ddI (OD)+d4T
or
ddI (BD)+d4T
N=84; Treatment naïve
RCT: Open
ddI+d4T
or
ZDV+3TC
or
ddI+d4T followed by
ZDV+3TC
N=151
Treatment naïve
ddI (OD)+d4T
ddI (BD) +d4T
-1.18 log10
-0.88 log10
Adverse events
Both regimens were reported as ‘safe and well
tolerated’. Full manuscript not available.
p NS for main comparison
Change in HIV-RNA levels at 24 weeks
ddI+d4T
ZDV+3TC
ddI+d4T then
ZDV+3TC
Adverse events
ddI+d4T
N 51
-2.26 log10
-1.26 log10
-1.58 log10
p<0.001
HIV-RNA levels< 50 copies/ml at 24 weeks
47%
4%
9%
p<0.001
Change in CD4 counts
+124
+62
+118
p=0.02
Neuropthy 1
Hb<6.5
0
Cessation
Due to ADR 1
ZDV+3TC
51
ddI+d4T then
ZDV+3TC
49
0
1
2
0
2
0
18
Attachment 1(cont): Results of Didanosine Trials (2-drug comparisons)
Mobley et
al 199927
Garcia et
al 199928
Ruxrungtham et al
200029
(Thai
patients)
RCT:Blind
ddI(OD) +d4T
or
ddI(BD) +d4T
N=87
Treatment naïve
RCT: ?Open
ddI+d4T
or
ddI+ZDV
or
ZDV+ddC
or
d4T+3TC+RTV
or
no treatment
N=161 treatment naïve
(asymptomatic) early disease
Change in HIV RNA levels at 12 weeks
ddI(OD) +d4T
ddI(BD) +d4T
ddI(OD) +d4T
ddI(BD) +d4T
-1.83 log10
-1.80 log 10
2 (5%)
No difference noted for
any individual ADR
4 (9%)
HIV-RNA <400 copies/ml at 12 weeks
18/44 (41%)
17/43 (40%)
Change in HIV RNA levels 52 weeks
ddI+d4T
ddI+ZDV
ZDV+dd
C
d4T+3TC+
RTV
-1.84
-1.72
-1.65 log10
-2.3 log10
log10
log10
p<0.001
HIV-RNA below 200 copies/ml at 1 year
6/11 (18%) 9/32 (28%) 7/29 (24%) 30/33 (91%)
p=0.001 3v2
drug
regimens
HIV-RNA <500 copies/ml at 24 weeks
Pooled results for high and low dose ddI+d4T
1 (3%)
6 (19%)
3 (9%)
10 (30%)
p=0.02
Adverse
effects on
lipids
seen with
3 drug
Open
ddI+ZDV
ZDV+ddC
Adverse Events: any Grade3 or 4
d4T+3TC+RTV
ddI+d4T
RCT:
ddI+d4T (high or low doses of
each)
or
ddI alone
N=78
ARV-naïve
Adverse Events: any Grade3 or 4
ddI+d4T
ddI alone
49/63 (78%)
3/15 (20%)
p<0.001
HIV-RNA <50 copies/ml at 24 weeks
8/63 (13%)
p=0.31
logistic modelling : possible
benefit of ‘high dose’ ddI but
not d4T
1/15 (7%)
Adverse effects
Diarrhea more common with with high dose
ddI (RR2.56, p=0.09); nausea commoner with
high dose d4T (RR3.70, p=0.07)
19
Havlir et
al 200030
RCT: Partially Blind: (ZDV
placebo)
ddI+ZDV
or
d4T+ZDV
or
ddI alone
or
d4T alone
N= 144; >12/52 previous ZDV
monotherapy
Adverse Events
Change in HIV RNA levels at 16 weeks
ddI+ZDV
d4T+ZDV
ddI alone
d4T alone
-0.56 log10
p=0.02 for
ddI v d4T
comparisons
PNS for
higher CD4
count (data
not shown)
-0.14 log10
-0.39 log10
-0.14 log10
Signs and symptoms of peripheral neuropathy
seen in 6 receiving d4T, 2 subjects on
ZDV+d4T, 5 subjects on ddI+ZDV
Attachment 1(cont): Results of Didanosine Trials (3-drug comparisons)
Villalba et al
199731
Carr et al
200032
Eron et al.
200033
RCT: open
ddI+d4T+IDV
or
3TC+d4T+IDV
N=54; ZDV for >6/52
RCT: open
ddI+d4T+IDV
or
ZDV+3TC+IDV
Or
d4T+3TC+IDV
N= 109 treatment-naive
RCT: open
ddI+d4T+IDV
or
ZDV+3TC+IDV
N=205
<3/52 treatment with ARV
PI-naïve
HIV-RNA <50 copies/ml at 1 months
ddI+d4T+IDV
3TC+d4T+IDV
8/11 (73%)
35/43 (81%)
Change in HIV-RNA levels
ddI+d4T+IDV
ZDV+3TC+IDV
d4T+3TC+IDV
2,42 log10
-2.94 log10
p NS
-2.47 log10
HIV-1 RNA levels <500 copies/ml at 40-48weeks
ddI+d4T+IDV
ZDV+3TC+IDV
54/102 (53%) (p=0.068)
42/103 (41%)
HIV_1 RNA levels <50 copies/ml at 48 weeks
41% (p>0.20)
35%
Increase in CD4 counts at 48 weeks
+150
(p=0.001)
+106
Adverse Effects
No details of ADRs – Note very unbalanced
nature of the trial
ADRs leading to cessation of treatment
ddI+d4T+
IDV
41%
ZDV+3TC+
IDV
34%
D4T+3TC+
IDV
18%
p=0.06 for
differences
Overall rates of serious adverse reactions
similar in each group (8% in each group)
1 patient on ddI/d4T group had lactic acidosis
and 1 had pancreatitis; 1 patient on ZDV/3TC
group had severe anemia.
20
Attachment 1(cont): Results of Didanosine Trials (3 or 4 -drug comparisons)
Kazatchkine
et al 200034
Garcia et al
200035
RCT: open
ddI (OD) +d4T (or ZDV)
+/-PI
or
ddI (BD) +d4T (or ZDV)
+/-PI
N=121 on stable ddIcontaining regimen
RCT: open
ddI(OD)+d4T+NVP(OD)
or
ddI(BD)+d4T+NVP(BD)
N= 94; ARV-naïve
Change in HIV RNA levels at 24 weeks
ddI (OD) +d4T (or ZDV)
+/-PI
+0.31 log10
ddI (BD) +d4T (or ZDV)
+/-PI
+0.17 log10
Adverse Effects
No difference between the groups in rates of
either mild or severe ADRs.
p NS
Change in HIV RNA levels at 52 weeks
ddI(OD)+d4T+NVP(OD)
-1.84 log10
p NS
ddI(BD)+d4T+NVP(BD)
-1.78 log10
HIV_1 RNA levels <200 copies/ml at 48 weeks
73%
p NS
68%
Severe adverse reactions
Rates of discontinuation because of adverse
events were nearly identical in the two groups
21
Attachment 2 Comparisons of characteristics of nucleoside reverse
transcriptase inhibitors
Two nucleoside analogue reverse transcriptase inhibitors (NRTIs) invariably 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.
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
* resistance profile of
recommended dual NRTIs
allows for 2nd line combination
Non-proprietary name
Cost p.a. US $
Advantages
Disadvantages
* 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;
* fixed dose
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;
Latest price offers
reported by MSF Feb
26th 2002
zidovudine
$193 (Cipla, India) to
$584 (GlaxoSmith
Kline, UK)
22
lamivudine
$91 (Aurobindo, India)
to $248 (Ranbaxy,
India)
*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
$190 (Aurobindo, India)
to $891 (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
$44 (Cipla, 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;
23
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