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(FCH/HIV, 22 April 2002)
Application for Inclusion of zidovudine and lamivudine
(included fixed-dose combinations)
on the WHO Model List of Essential Medicines
Both drugs are members 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-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 inhibitors (NRTIs) zidovudine (ZDV, AZT)
and lamivudine (3TC) are proposed for listing on the WHO Model List of Essential
Medicines. The drugs are generally used together to form a ‘nucleoside core’ to
which other drugs are added. The drugs are being proposed for listing jointly
because they are the most widely investigated, and most commonly used, dual
nucleoside regimen in contemporary multi-drug antiretroviral regimens. They are a
part of the three first-line treatments in the draft WHO Guidelines for use of antiretroviral drugs in resource-poor settings (ARV Guidelines). They are available as
a fixed drug combination from 7 manufacturers internationally.
The combination of ZDV and 3TC is recommended for treatment within an
appropriately monitored program, in combination with one or two other antiretroviral drugs, including nucleoside or non-nucleoside reverse transcriptase
inhibitors, or protease inhibitors. Antiretroviral therapy is recommended for HIVinfected children, adolescents and adults with symptomatic disease, and also for
asymptomatic patients with CD4+ cell counts at or below 200/mm 3.
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.
2
The literature search retrieved a large number of citations describing randomised
controlled trials involving ZDV + 3TC used as sole therapy, or in combination with
a range of other ARV agents. From these were selected 3 meta-analyses and 11
randomised controlled trials, which provided information on the performance of
ZDV/3TC compared with other dual nucleoside combinations which are
recommended as alternative regimens in the draft WHO ARV Guidelines.
This set of trials is informative, not only in providing unambiguous evidence of the
efficacy of ZDV+3TC as a dual nucleoside ‘core’ to combine with a range of other
ARVs, but also because the data establish the efficacy of alternative regimens
recommended in the draft WHO ARV Guidelines. In several comparisons
d4T+3TC and ddI+d4T were found to be at least as efficacious as ZDV+3TC and
as well tolerated (although qualitatively the nature of adverse reactions tended to
be different). In a large direct comparative study a fixed dose combination of
ZDV+3TC was found to have equivalent efficacy to concomitant use of the
individual drugs, and to lead to a higher level of adherence to treatment.
The data confirmed the efficacy of dual nucleoside regimens combined with
protease inhibitors, other nucleoside, and non-nucleoside reverse transcriptase
inhibitors, which appear to be as effective as the former, and in the case of
efavirenz, better tolerated.
1. Proposal for inclusion, change or deletion.
Zidovudine and lamivudine are 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. Currently zidovudine is
listed, but only for the indication of reducing the risk of mother to child
transmission of HIV infection.
Zidovudine and lamivudine are both nucleoside reverse transcriptase inhibitors.
The drugs are being proposed jointly because they are the most widely
investigated, and most commonly used, nucleoside ‘core’ in contemporary multidrug antiretroviral regimens. They are a part of the three first-line treatments in the
draft WHO guidelines for use of anti-retroviral drugs in resource-poor settings
(Table 1). They are available internationally individually, and in the form of several
fixed dose combination preparations. However, combinations of both drugs with
other nucleoside reverse transcriptase inhibitors (NRTIs) are possible. Because of
the risk of antagonism, leading to reduced efficacy, zidovudine (ZDV) should not
be used with stavudine (d4T) and lamivudine (3TC) should not be used with
didanosine (ddI).
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
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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: zidovudine, lamivudine and compounded
fixed-dose lamivudine + zidovudine
5. Listing Type Requested:
Listing of both drugs is requested on the Model List of Essential Medicines as
examples 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.
6. Information supporting the public health relevance of the submission:
Since the first clinical evidence of AIDS was reported over twenty years ago, an
estimated 25 million people have died as a result of HIV infection. Current
estimates suggest some 40 million persons worldwide are infected with HIV and
more than 90% of infected persons live in the developing world3. In 2001, 5 million
persons worldwide became infected with HIV, and 3 million others died from
HIV/AIDS-related causes.
In sub-Saharan Africa, the region most severely affected by HIV, 28.1 million
individuals are living with this infection. Eastern Europe — especially the Russian
Federation — continues to experience the fastest-growing epidemic in the world.
In 2001, there were an estimated 250 000 new infections in this region, bringing to
1 million the number of people living with HIV. In Asia and the Pacific, an
estimated 1 million people became infected in 2001; about 7.1 million people in
this region are now living with HIV/AIDS3. More than 1.8 million people in Latin
America and the Caribbean are living with HIV/AIDS, including the 190,000 adults
and children who became infected in 2001
In countries often already burdened by huge socio-economic challenges,
HIV/AIDS threatens human social welfare, developmental progress, and social
stability on an unprecedented scale. HIV/AIDS cripples the economic development
of entire countries, because it often strikes people during their most productive
working years. Of the 14,000 persons who became infected each day in 2001,
about 12,000 were aged 15 to 49 years3.
Left untreated, HIV infection results in a period of clinical latency that may last a
median of 3 to 10 years. Once symptomatic disease or AIDS develops, without
access to antiretroviral treatment, death results within an average of two years.
4
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 HIVrelated infections.

In Argentina a program similar to that of Brazil provides even greater coverage. A
special fund has been established to pay for antiretroviral drugs for those not
covered by social security (such as street vendors, small business people, the
unemployed, low-income pregnant women) 5.
Through the UNAIDS Drug Access Initiative Pilot Program, 6 treatment centres in
Abidjan, Côte d’Ivoire, offer antiretroviral therapy. Of the patients who received
therapy, 72% were heavily symptomatic upon initiation. Nonetheless, the overall
survival rate of was 93% at 6 months, 90% at 12 months, and 86% at 18 months.
When survival rates are re-calculated using a worst-case scenario in which
patients lost to follow-up are assumed to have died immediately after their last
clinic visit, 75% survived at 6 months, 64% at 12 months, and 55% at 18 months6.
The Senegal Initiative on Antiretroviral Therapy was launched in August 1998. A
partnership between the Senegalese government and the International
Therapeutic Solidarity Fund, it aims to have 7,000 patients on triple combination
therapy by the end of 2007. At the end of 2001, an estimated 550 adults and
children had received treatment. A prospective observational cohort study was
undertaken to assess the feasibility, effectiveness, adherence, toxicity and viral
resistance of antiretroviral therapy. The clinical and biological results of the study
were comparable to those seen in western cohorts, despite differences in HIV-1
subtype and an advanced disease stage when treatment was initiated. Fifty-eight
patients with advanced HIV disease demonstrated by CDC staging (16 patients in
CDC Stage B, 42 in CDC Stage C) and CD4+ cell count (median CD4+ cell count
= 108.5, IQR = 34 - 217) were given triple combination antiretroviral therapy (2
nucleoside analogues + 1 protease inhibitor). After 18 months of treatment,
participants gained a median of 180 CD4+ cells and showed a median drop in
plasma viral load of 2.8 log10 copies/ml. During the study period, there were 7
clinical AIDS-defining events with 6 deaths from HIV-related infections7. The
antiretroviral regimen was complex: indinavir, the protease inhibitor used in the
study, had to be taken in a fasting state every 8 hours, with maintenance of
hydration; didanosine (DDI), the nucleoside analogue given to 86% of participants,
is a buffered preparation which also had to be taken while fasting 1 to 2 hours
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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
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:
Zidovudine
Recommended Dosage: Adults and adolescents over the age of 12 years: 600 mg
daily, in two divided doses, in combination with other antiretroviral medications.
Children 6 weeks to 12 years of age: 160 mg/m2 every 8 hours (480 mg/m2/day to
a maximum of 200 mg every 8 hours).
Concomitant Antiretroviral Therapy: Zidovudine must be given in combination with
other antiretroviral medications.
Duration: Antiretroviral treatment is usually regarded as life-long.
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Guidelines: Guidelines The draft “WHO Antiretroviral Guidelines for Resource
Limited Settings”10 indicates zidovudine and lamivudine (in combination with one
or more additional other antiretroviral medicines) as 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.
Lamivudine
Recommended Dosage: Adults and adolescents at least 12 years old: 150 mg
twice daily. Children (3 months up to 16 years of age) 4 mg/kg twice daily (up to a
maximum of 150 mg twice a day).
Concomitant Antiretroviral Therapy: Lamivudine 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
Settings10 indicates zidovudine and lamivudine (in combination with one or more
additional other antiretroviral medicines) as 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.
Fixed dose combinations of ZDV and 3TC
Recommended Dosage: Adults and adolescents over the age of 12 years: 1 tablet
(containing 150 mg lamivudine and 300 mg zidovudine), taken twice daily. This
fixed-dose formulation is not suitable for children under 12 years of age.
Concomitant Antiretroviral Therapy: Fixed-dose lamivudine + zidovudine 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 indicates zidovudine and lamivudine (in combination with one or more
additional other antiretroviral medicines) as 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.
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8. Comparative effectiveness in clinical settings:
In compiling the evidence for this and related submissions for anti-retroviral drugs
we have created a common ‘stem’ in the form of information that is relevant to all
of the antiretroviral group. This is followed by information that is relevant to use of
this class of drug under the conditions described in this application, followed by
information which is specific to the individual agent under consideration.
Because of time constraints and the growing acceptance of the efficacy of highly
active anti-retroviral drug regimens in the last 5 years, we have relied in part on
secondary data sources – systematic reviews of randomised and non-randomised
studies conducted by the Cochrane Collaboration, or by independent groups who
have generally met standards that are considered appropriate to this type of work.
We have relied on individual trials where these provided data and insights not
available from systematic reviews.
Details of literature searches conducted
The principal data-bases maintained by the WHO that were searched were:
o The Cochrane Data-base of Systematic Reviews
o The ACP Journal Club reviews of published trials
o The data-base of reviews of abstracts of reviews of effectiveness (DARE)
o The Cochrane controlled trials register (CCTR)
o Medline
o Embase
o
o
AIDSLINE
CENTRAL
Search terms used were:
o
o
o
o
o
o
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: zidovudine (or AZT or ZDV) AND lamivudine (or
3TC),
Study selection:
o
o
o
Randomised comparative parallel-group controlled clinical trials
Compared ZDV in combination with 3TC with:
 Other dual nucleoside regimens (this part of the search was confined
to relevant published meta-analyses).
Examined the performance of ZDV and 3TC when included in combinations
comprising 3 or more drugs, involving concomitant use of another NRTI,
NNRTI or PI.
8
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 ZDV and
3TC as a ‘nucleoside core’. 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 unpublished data.
Categorisation of levels of evidence
The following rating scheme was used11:
 Level 1 – evidence from relevant high quality systematic reviews of
unbiased randomised comparative clinical trials
 Level 2 – evidence from at least one relevant unbiased randomised
comparative clinical trial.
 Level 3 – evidence from relevant controlled observational studies
Additional considerations for use in resource-poor settings





Co-morbidity
Simplicity (frequency of dosing, number of tablets)
Tolerability
Cost
Prior exposure to ARVs
General therapeutic issues: (common to the therapeutic category of antiretroviral drugs)
1. What is the validity of surrogate markers as predictors of morbidity and
mortality in patients with HIV/AIDS?
2. What evidence is there that triple (or quadruple) ARV therapy is superior to
single or dual therapy?
Class specific questions
3. Which combinations of drug classes have the best evidence in relation to
benefits and harms?
Agent-specific questions
4. What is the evidence for the efficacy and toxicity of anti-retroviral drug
combinations that include didanosine?
Results
1. What is the validity of surrogate markers as predictors of morbidity
and mortality in patients with HIV/AIDS? (Level 3 evidence)
Trials of anti-retroviral compounds have relied heavily on measuring the effects of
drugs on surrogate markers, usually CD4 cell counts and plasma HIV-1 RNA
levels. The validity of these markers depends on showing that they are correlated
with clinical outcomes, and that they should be able to capture the effects of
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outcomes12.
treatment on the major clinical
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 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,
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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.
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
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*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 lamivudine and zidovudine? (Level 1
and Level 2 evidence)
Zidovudine (ZDV or AZT) has been in clinical use for a number of years, initially as
mono-therapy, then in various dual treatment combinations and more recently as
part of multi-drug combinations involving a range of other antiretroviral drugs. Most
commonly ZDV has been used in combination with lamivudine (3TC), and this has
become the standard nucleoside ‘core’ combination treatment on which more
complex regimens are based.
Consistent with the wide experience of this combination of nucleoside RTIs, there
is a large literature base. Searching on the combination of ‘zidovudine’ (or ‘ZDV’
or ‘AZT’) and ‘lamivudine’ (or ‘3TC’) along with appropriate terms for ‘randomised
clinical trials’ yielded well over 200 citations. A full summary of this extensive
literature would be a demanding and time-consuming task, and to some degree is
academic, because many of the early studies (prior to 1997/98) generated data
that have been superseded, and are not particularly informative for contemporary
practice. So, the presentation of studies here is selective, directed by the
recommendations for ‘nucleoside cores’ in the draft WHO Guidelines (Table 1).
A brief consideration of dual and monotherapy comparisons is followed by a studyby-study consideration of the performance of ZDV/3TC in combination with other
anti-retroviral drugs.
Dual and monotherapy regimens
The meta-analysis of Staszewski et al (1997)21 summarized 4 randomised clinical
trials comprising data from 972 HIV-infected patients with baseline CD4 counts of
100-500*106/L. Subjects were randomised to treatment with ZDV/3TC or ZDV
monotherapy (3 trials) or ZDV+ddC (1 trial). In all, 118 patients progressed to new
AIDS clinical events and the risk was reduced significantly by ZDV/3TC therapy
(RR 0.51; 95% CI 0.37, 0.71) relative to control treatments (mainly ZDV
monotherapy).
In a draft (unpublished) Cochrane Review22 of three trials that compared
ZDV+3TC with ZDV monotherapy, the average reduction in HIV-1 RNA viral count
was 0.84 log10 copies/mm3. In a pooled analysis of 6 RCTs of ZDV+3TC (with
different comparators), including data from 1083 participants, Opravil et al (1998),
found that baseline HIV-RNA levels, and the duration of prior ZDV treatment both
negatively influenced the anti-viral efficacy of ZDV/3TC23.
12
The literature search yielded several studies that made direct comparisons of
ZDV/3TC with other established dual nucleoside regimens that are recommended
by WHO (d4T/3TC and ddI/d4T). Aboulker et al (1998) randomised subjects on a
range of different NRTIs to 3TC or placebo24. However the other regimens were
not determined at random. The study is significant in documenting the inferior
performance of a combination of ddI/3TC, which is not recommended by WHO.
McKinney et al (1998) found both ZDV/3TC and ZDV/ddI to be superior to ddI
alone25.
Comparisons of ZDV/3TC with more relevant dual nucleoside regimens are
summarised in Attachment 1. Kuritzkes et al 1999 (references are linked to the
Attachment) found ZDV/3TC to be equivalent in efficacy to d4T/3TC. Interestingly,
this study also found ddI/3TC to be effective, although it is generally viewed as a
sub-optimal combination. Molina et al 1999 (Attachment 1) found ZDV/3TC to be
effective in treatment-naïve individuals, although significantly less so than a
combination of ddI/d4T.
All of these studies documented fairly low rates of serious adverse reactions and
the regimens were well tolerated. While these studies of dual therapy are helpful
in establishing the efficacy and tolerability of DZV/3TC, they do not reflect
contemporary practice where dual nucleoside combinations are combined with a
3rd or 4th anti-retroviral drug.
Trials of multiple drug regimens that included ZDV/3TC
Foudraine et al 1998 (Attachment 1) compared ZDV/3TC (+IDV if HIV levels
remained elevated) with d4T/3TC (+IDV if HIV levels remained elevated) and
found no significant difference between the regimens, although there was a trend
in favour of the latter combination. Carr et al (2000) found no differences between
ZDV+3TC and ddI+d4T or d4T+3TC (both are alternative dual nucleoside
combination recommended in the draft WHO guidelines) when they were both
combined with IDV. However, this study found a smaller rate of ADRs leading to
cessation of treatment with d4T+3TC than with the alternatives. Eron et al found
that ZDV+3TC and ddI+d4T (when combined with IDV) had similar suppressive
effects on HIV RNA levels, although the rise in CD4 counts was higher with the
d4T+3TC regimen. A similar pattern was observed when the same nucleoside
combinations with IDV were compared by Squires et al. The overall rates of
severe ADRs were similar but Squires et al found a higher rate of nausea and
vomiting with ZDV+3TC and a higher rate of diarrhea and rash with d4T+3TC.
The study of Haas et al (2000) (Attachment 1) is significant for highlighting the
need to use IDV three times daily when combined with ZDV+3TC.
Staszewski et (1999) (Attachment 1) found that efavirenz (EFV) in combination
with ZDV+3TC was superior to IDV+ZDV+3TC. This finding is reflected in a
recently published meta-analysis (Torre et al 2001)26, which found that in 5
randomised trials combining 2 NRTIs with one non nucleoside reverse
transcriptase inhibitor (EFV or NVP), the rate of virological response was
somewhat higher than with 2 NRTIs combined with a protease inhibitor (pooled
13
Odds Ratio 1.6; 95% CI 1.1, 2.1), although no difference was seen in terms of
disease progression.
Staszewski et al (2001) (Attachment 1) also compared ZDV+3TC combined with
abacavir (ABC) and found this combination to have similar efficacy to
ZDV+3TC+IDV, although there was a trend favouring the IDV combination when
suppression of HIV levels below 50 copies/ml in subjects with high baseline levels
was considered. It should be noted that this was a sub-group analysis and the
statistical significance is borderline. Of note is the fact that this study employed a
ZDV/3TC fixed dose combination product. Finally, the study of Eron et al (2000)
has particular significance because it is a clinical equivalence (rather than a bioequivalence) comparison of a fixed combination preparation of ZDV/3TC with
concurrent use of the individual agents.
In conclusion, this set of trials is helpful, not only in establishing the efficacy and
tolerability of ZDV+3TC as an established dual nucleoside core to combine with
other ARVs, but also because the review helps establish the efficacy of alternative
regimens recommended in the draft WHO ARV Guidelines. In several
comparisons d4T+3TC and ddI+d4T were found to be at least as efficacious as
ZDV+3TC and at least as well tolerated, although qualitatively the nature of
adverse reactions tended to be different. This review has also confirmed the
efficacy of dual nucleoside regimens combined with protease inhibitors, and with
non-nucleoside reverse transcriptase inhibitors which appear to be at least as
effective as the former, and in the case of efavirenz, better tolerated.
9. Comparative evidence on safety (combination treatment with
zidovudine and lamivudine)
b. Adverse effects/reactions: headache, malaise and fatigue, nasal signs and
symptoms, cough, diarrhoea, nausea and vomiting, neuropathy, musculoskeletal
pain, insomnia and other sleep disorders, dizziness, fever or chills, abdominal
pain, depressive disorders, skin rashes, myalgia, abdominal cramps, arthralgia,
dyspepsia.
Laboratory abnormalities (Grade 3 or 4): neutropaenia, anaemia,
thrombocytopaenia; elevated amylase, ALT, AST, bilirubin.
Warnings:
Combinations of lamivudine + zidovudine should be used with caution in patients
who have bone marrow compromise evidenced by granulocyte count <1,000
cells/mm3 or haemoglobin <9.5 g/dL. Frequent blood counts are strongly
recommended in patients with advanced HIV disease who are treated with fixeddose lamivudine + zidovudine. For HIV-infected individuals and patients with
asymptomatic or early HIV disease, periodic blood counts are recommended.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported with the use of nucleoside analogues alone or in combination,
including lamivudine, zidovudine and other antiretrovirals. A majority of these
cases have been in women. Obesity and prolonged exposure to antiretroviral
14
nucleoside analogues may be risk factors. Particular caution should be
exercised when administering zidovudine 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 zidovudine 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).
Myopathy and myositis, with pathological changes similar to that produced by HIV
disease, have been associated with prolonged use of zidovudine, and therefore
may occur with therapy with fixed-dose lamivudine + zidovudine.
Changes in skin and nail pigmentation have been reported with the use of
zidovudine.
Precautions: Reduction of the dosages of lamivudine + zidovudine is
recommended for patients with impaired renal function. Patients with creatinine
clearance <50 mL/min should not receive fixed-dose lamivudine + zidovudine.
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:
Lamivudine: Lamivudine and zalcitabine may inhibit the intracellular
phosphorylation of one another. Therefore, use of fixed-dose lamivudine +
zidovudine in combination with zalcitabine is not recommended.
Zidovudine: Coadministration of ganciclovir, interferon-alpha, and other bone
marrow suppressive or cytotoxic agents may increase the haematologic toxicity of
zidovudine. Concomitant use of fixed-dose lamivudine + zidovudine with stavudine
should be avoided since an antagonistic relationship with zidovudine has been
demonstrated in vitro. In addition, concomitant use of zidovudine with doxorubicin
or ribavirin should be avoided because an antagonistic relationship has been
demonstrated in vitro.
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.]10
15
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
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 seven suppliers of fixed-dose lamivudine + zidovudine: Aurobindo (India)
annual cost of treatment $US 270, Cipla (India) $US 285, Hetero (India) $US 288,
FarManguinh (Brazil) $US 351, GPO (Thailand) $US 475, Ranbaxy (India) $US
548, and Glaxo SmithKline (UK) $US 730. By comparison, lamivudine costs range
from $US 91 – 248; zidovudine costs range from $US 193 to 584; stavudine from
$US 44 to $US 137; and didanosine from $US 190 – 891.
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
16
Attachment 1 : Results of trials
involving ZDV and 3TC as a dual
nucleoside combination therapy
(Pages 17 – 20)
17
Attachment 1(cont): Results of ZDV/3TC Trials (2-drug comparisons)
Kuritzkes
et al
199927
Molina et
al 199928
Study details
RCT: Open
ddI
or
d4T
then (factorial)Blind
ddI/3TC
or
d4T/3TC
v
ZDV+3TC (2 arms)
N=299; treatment-naïve
RCT: Open
ddI+d4T
or
ZDV+3TC
or
ddI+d4T followed by
ZDV+3TC
N=151; treatment naïve
Change in HIV-RNA levels at 24 weeks
ZDV+3TC
d4T/3TC
ZDV+3TC
ddI/3TC
- 1.28 log10
-1.23 log10
-1.20 log10
-1.16 log10
pNS
Toxicity (grade 3 or worse)
ZDV+3TC (pooled
data – 2 arms)
24/108 (22%)
Comparators (pooled)
48/184 (26%)
pNS
Note this
combination
seems to have
been effective
Adverse events
Change in HIV-RNA levels at 24 weeks
ddI+d4T
ZDV+3TC
ddI+d4T then
ZDV+3TC
ddI+d4T
N 51
-2.26 log10
p<0.001
+124
p=0.02
-1.26 log10
-1.58 log10
Change in CD4 counts
+62
+118
Neuropthy 1
Hb<6.5
0
Cessation
Due to ADR 1
51
ddI+d4T then
ZDV+3TC
49
0
1
2
0
2
0
ZDV+3TC
18
Attachment 1 (cont): Results of ZDV/3TC Trials (3-drug comparisons)
Foudraine
et al 199829
Carr et al
200030
Eron et al.
200031
RCT:Open
ZDV/3TC
Or
d4T/3TC
N=47; ARV naïve
IDV added at 12/52 if HIV
RNA >500 copies/ml
RCT: Open
ZDV+3TC+IDV
Or
DdI+d4T+IDV
Or
D4T+3TC+IDV
N=109 treatment naïve
RCT: Open
ddI+d4T+IDV
or
ZDV+3TC+IDV
Plasma HIV-1 RNA at 24 weeks
ZDV/3TC (+IDV)
d4T/3TC (+IDV)
-1.65 log10
-1.95 log10 pNS
HIV-1 RNA <500 copies/ml
15/20 (75%)
18/19 (95%) pNS
Change in HIV-RNA levels
ddI+d4T+IDV
ZDV+3TC+IDV
-2.42 log10
-2.94 log10
p NS
d4T+3TC+IDV
-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
N=205
<3/52 treatment with ARV
PI-naïve
Squires et
al 200032
RCT: Open
ZDV+3TC+IDV
Or
d4T+3TC+IDV
ADRs not mentioned in abstract
ADRs leading to cessation of treatment
ddI+d4T+
d4T+3TC+
ZDV+3TC+
IDV
41%
IDV
34%
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.
41% (p>0.20)
35%
Increase in CD4 counts at 48 weeks
+150
(p=0.001)
+106
ZDV+3TC+IDV
d4T+3TC+IDV
HIV RNA <500 copies/ml at weeks 40-48
54%
62% (p NS)
Median time-weighted average change in CD4 counts
110
142 (p=0.033)
Serious ADRs not different between study
arms; however, nausea and vomiting
commoner with ZDV-containing treatment and
diarrhea and rash commoner with d4Tcontaining treatment
19
Haas et al.
200033
Cohen
Stuart et
al 199934
RCT: Open
ZDV+3TC + IDV (TDS)
Or
ZDV +3TC+IDV (BD)
N=433 but stopped after
interim analysis
RCT: Open
ZDV+3TC+SQV(SGC)
Or
ZDV+3TC+IDV
N=70; ARV-naïve
Eron JJ et
al 200035
RCT: Open
ZDV+3TC+PI
Or
Fixed dose combination
(FDC)
of ZDV/3TC (same dose)+PI
N=223 – all had used
ZDV/3TC+PI for >10 weeks
Staszewsk
i et al.
199936
RCT: Open
ZDV+3TC+EFV
Or
ZDV+3TC+IDV
Or
EFV+IDV
N=450; naïve to PI, NNRTI
or 3TC
ZDV+3TC + IDV (TDS)
ZDV +3TC+IDV (BD)
HIV-RNA levels <400 copies/ml at 24 weeks
(87 subjects)
91%
64%
p<0.01
ZDV+3TC+SQV(SGC)
ZDV+3TC+IDV
HIV-RNA levels <50 copies/ml at 24 weeks
74.3%
71.4%
No mention of ADRs in abstract
(Text suggests that CD4 advantage to SQV
disappears after 24 weeks)
No ADR data in abstract
p=0.73
Change in CD4 count
+162
+89
p=0.01
Success (avoiding increase of 0.5 log10 increase in HIVRNA)
ZDV/3TC+PI
(FDC) ZDV/3TC+PI
92.9%
96.4%
pNS
Adherence (missed doses at weeks 8 and 16)
Overall Adverse Events
ZDV/3TC+PI
19%
(FDC) ZDV/3TC+PI
21%
p NS
ZDV/3TC+PI
(FDC) ZDV/3TC+PI
FDC superior at both times:
p=0.007 @ 8/52; p=0.046 @ 16/52
ZDV+3TC+EFV
ZDV+3TC+IDV
HIV-RNA levels <50 copies/ml at 48 weeks
70%
p<0.001
48%
ZDV+3TC+EFV
ZDV+3TC+IDV
Discontinuation because of ADRs
27%
p=0.005
43%
20
Staszewski
et al. 200137
RCT: Blind
(FDC) ZDV+3TC+ABC
Or
(FDC) ZDV+3TC+IDV
N=562 ARV-naïve
(FDC) ZDV+3TC+ABC
(FDC) ZDV+3TC+IDV
HIV-RNA levels <400 copies/ml at 48 weeks
133/262 (51%)
136/265 (51%)
HIV-RNA levels <50 copies/ml at 48 weeks
(Baseline HIV RNA levels >100K)
30/96 (31%)
45/100 (45%)
95% CI for difference
(-27%, 0%)
No difference in
treatment-limiting
ADRs but 1 death
from hypersensitivity
with ABC
21
Attachment 2: comparisons of nucleoside reverse transcriptase inhibitors
(based on a review of product information)
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.
Advantages
*potent, durable antiretroviral activity when
combined with a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor
Disadvantages
* 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
zidovudine
$193 (Cipla, 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;
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;
Fixed dose
zidovudine/lamivudine
preparations
Cost of originator brand
$730/year (GSK).
Details as for
zidovudine and
lamivudine (see above)
Details as for
zidovudine and
lamivudine (see above)
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
Cost of equivalent
generic products: $270
(Aurobindo) to $548
(Ranbaxy)
23
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;
24
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