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1
(FCH/HIV, 22 April 2002)
Application for Inclusion of nelfinavir mesylate on
The WHO Model List of Essential Medicines
Drug is a member of the therapeutic class of HIV protease 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. In 2001, 5 million persons
worldwide became infected with HIV, and 3 million others died from HIV/AIDSrelated causes. 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 antiretroviral 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 protease inhibitor drug nelfinavir is proposed for listing on the WHO Model List
of Essential Medicines. Nelfinavir is recommended as a first line therapy in
combination with zidovudine and lamivudine in the (Draft) WHO guidelines for use of
ARV drugs in resource poor settings. It should be used within an appropriately
monitored program in combination with two or more other anti-retroviral drugs,
including nucleoside or non-nucleoside reverse transcriptase inhibitors, or another
protease inhibitor. 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.
Twelve randomised controlled clinical trials of nelfinavir were recovered by the
search. In total these trials evaluated 21 treatment arms, of which 11 included
nelfinavir as part of triple therapy; 9 arms included nelfinavir in combination with 2
nucleoside reverse transcriptase inhibitors. In these trials nelfinavir-containing
combinations displayed similar efficacy to other protease inhibitor-containing
combinations, with some evidence of superior tolerability. The most common
adverse effect was diarrhea.
2
Currently, nelfinavir can be sourced from only two manufacturers internationally.
Nelfinavir is not available in fixed dose combinations and at current prices is
substantially more expensive than other protease inhibitors.
1. Proposal for inclusion, change or deletion of a drug.
Nelfinavir 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. Nelfinavir should be viewed as an example of the
class of protease inhibitors. Other examples of this group may sometimes be
preferred when local factors such as availability and price are taken into account.
Current practice is to combine protease inhibitors with two or more other drugs,
typically nucleaoside reverse transcriptase inhibitors (NRTIs) or non-nucleoside
reverse transcriptase inhibitors (NNRTIs).
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: nelfinavir mesylate
5. Listing Type Requested:
Listing is requested on the Model List of Essential Medicines as an example of the
therapeutic class of HIV protease 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 world 3. In 2001, 5 million persons
worldwide became infected with HIV, and 3 million others died from HIV/AIDSrelated causes.
3
In sub-Saharan Africa, the region most severely affected by HIV, 28.1 million
individuals are living with this infection. Eastern Europe — especially the Russian
Federation — continues to experience the fastest-growing epidemic in the world. In
2001, there were an estimated 250 000 new infections in this region, bringing to 1
million the number of people living with HIV. In Asia and the Pacific, an estimated 1
million people became infected in 2001; about 7.1 million people in this region are
now living with HIV/AIDS. 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 20013.
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%. Between 1997 and 2000, Brazil saved approximately US
$677 million in averted hospitalisations and treatment of HIV-related infections4.
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
social security (such as street vendors, small business people, the unemployed, lowincome 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
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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
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, and
the evidence from randomised clinical trial (reviewed below), there is a small but
growing body of clinical evidence to support the use of ARVs in developing
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countries. Significant price reductions have also been achieved in many developing
countries and new funding and delivery mechanisms are being developed to expand
their availability.
These factors warrant the addition of this class of drugs to the Model List of Essential
Drugs (with appropriate consideration of their use in resource-limited settings).
7. Treatment details:
Recommended Dosage: Adults and adolescents: 1250 mg (5 x 250 mg tablets) twice
daily. An alternative regimen is 750mg three times daily, which has been trialed
quite extensively.
Nelfinavir should be taken with food as the maximum plasma concentrations and
area under the plasma concentration-time curve (AUC) were 2- to 3-fold higher
under fed conditions compared to fasting.
Concomitant Antiretroviral Therapy: Nelfinavir 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 nelfinavir (in combination with two nucleoside analogue reverse
transcriptase inhibitors) 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.
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 that 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.
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Details of literature searches conducted
The principal data-bases maintained by the WHO that were searched were:
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The Cochrane Data-base of Systematic Reviews
The ACP Journal Club reviews of published trials
The data-base of reviews of abstracts of reviews of effectiveness (DARE)
The Cochrane controlled trials register (CCTR)
Medline
Embase
Search terms used were:
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Anti-retroviral or antiretroviral
Nucleoside reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
Trial and Clinical Trial (including exploded terms)
Individual drug names: zidovudine, stavudine (d4T), lamivudine (3TC), abacavir,
nelfinavir, lopinavir, indinavir, ritonavir, efavirenz, nevirapine.
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
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
Randomised comparative parallel-group controlled clinical trials
Compared NFV in combination with one or more NRTIs, NNRTIs, or other PIs
against:
o Non PI-containing drug combinations
o PI-containing drug combinations
o Combinations of NFV with 2 NRTIs were of particular interest as these
are regimens recommended in the WHO draft guidelines (Table 1).
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 combinations of 3 or 4-regimes that
include a PI.
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.
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 Level 3 – evidence from relevant controlled observational studies
Additional considerations for use in resource-poor settings
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Simplicity (frequency of dosing, number of tablets)
Tolerability
Cost
Co-morbidity
Prior exposure to ARVs
General therapeutic issues: (common to the therapeutic category of anti-retroviral
drugs)
1. What is the validity of surrogate markers as predictors of morbidity and
mortality in patients with HIV/AIDS?
2. What evidence is there that triple (or quadruple) ARV therapy is superior to
single or dual therapy?
Class specific questions
3. Which combinations of drug classes have the best evidence in relation to
benefits and harms?
Agent-specific questions
4. What is the evidence for the efficacy and toxicity of anti-retroviral drug
combinations that include nelfinavir?
Note: in addressing this question studies were selected in which nelfinavir had
been used in at least one arm in a combination that involved 2 or more
additional anti-retroviral drugs from the NRTI, NNRTI or PI classes.
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
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progression14.
disease
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).
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 co-
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morbidity, concern about the development of viral resistance, and more pragmatic
considerations such as pill burden and adherence to therapy. With recognition that
none of the available regimens eradicates the virus, but suppression is desirable,
HIV infection has come to be regarded as a chronic disease which requires 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 Settings10. 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
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 nelfinavir? (Level 2 evidence)
The results of trials that included nelfinavir-containing regimens retrieved by the
literature search are summarized in Attachment 1(references are linked to the Table
of results).
10
Despite access to the results of 12 trials involving this recently introduced
protease inhibitor, the total number of patients assessed in these studies is modest.
The trials themselves are heterogeneous in terms of the drug combinations,
comparator regimens and the response variables used – usually viral load
suppression to between <50 and <400 copies/ml. This variation precludes any
meaningful data pooling.
There were 21 NFV-containing arms in the 12 trials (Attachment 1). A total of 11
treatment arms included NFV as part of triple therapy; 9 arms included NFV in
combination with 2NRTIs, one of the most common treatment combinations in
contemporary practice. The remaining study arms included almost all possible
permutations of NFV with a NRTI, a NNRTI and other PIs.
Arguably the arms that included NFV in combination with 2NRTIs are most relevant
to this submission and they are highlighted below. As the trials are recent, the great
majority of patients had been previously treated, sometimes extensively, with ARVs.
The majority of trials were unblinded.
When NFV was combined with 2, virological responses varied from 22% to 67%,
with a very small study documenting viral responses of 55% with a BD regimen. One
study (Saag et al 2001) studies responses to different doses of NFV: 750 mg v 500
mg TDS. Although overall results using the standard assay found a non-significant
trend in favour of the higher dose, its advantage became apparent when an ultrasensitive assay was performed and when survival analysis was conducted on
response data (p=0.0007 for difference between 750mg and 500mg dose groups).
Four studies studies involved patients who had been lightly treated in the past. The
studies of Saag et al (2001) and Gartland et al (2001) involved patients who were
ARV-naïve, and HIV-RNA responses of <400 copies/ml of 50-67% at 24-28 weeks
were seen. These trials are relevant because the majority of patients in developing
countries, at least initially, are likely to be receiving their first course of anti-retroviral
treatment. In their trial Wiznia et al found similar rates of response in PI-naïve
subjects (viral counts <400/ml) to a combination of NFV +2NRTIs (44%) as to a
combination of NFV, NVP and STV (50%) and RTV, NVP and STV (46%). Using a
more demanding standard (<50 copies/ml) Moyle et al found similar responses in PInaïve subjects with NFV and 2 NRTIs (38%) as with SQV and 2 NRTIs (42%). In
both these studies somewhat higher rates of response were seen with 4 drug
regimens.
It is possible to draw some general conclusions from this literature. Nelfinavir exhibits
similar anti-viral activity to other members of the protease inhibitor class. However
there is modest evidence from the trials to support claims of better tolerability. Smith
et al 2001 (see Attachment 1) found a lower rate of discontinuation because of
intolerance or toxicity with in combination with saquinavir and stavudine than when
ritonavir was combined with these two other drugs. Roca et al 2000 found lower
rates of discontinuation (for toxicity or for any reason) in combination with
lamivudine and stavudine than with indinavir combined with these two other drugs.
Roca also found a higher rate of a combined endpoint of ‘adequate adherence’ to
therapy with the nelfinavir combination than with the indinavir combination.
11
A qualitative overview of the differing characteristics of drugs in the protease inhibitor
class is provided in Attachment 2. This has been prepared from the approved
product information for the various drugs, and generally bears out the conclusion of
reasonable tolerability.
9. Comparative evidence on safety (See attachment 1 for results from
clinical trials of nelfinavir):
Adverse effects/reactions: The most common adverse effect is mild to moderate
diarrhea, reported by up to 32% of participants in clinical trials of nelfinavir. Other
adverse effects include nausea, flatulence, asthenia, rash, abdominal pain.
Laboratory abnormalities (Grade 3 or 4) include neutropenia, lymphocytopenia,
anaemia; elevated AST, ALT, creatine kinase, and triglycerides.
Warnings:
Patients with phenylketonuria: nelfinavir Oral Powder contains 11.2 mg
phenylalanine per gram of powder.
Diabetes: New onset diabetes mellitus, exacerbation of pre-existing diabetes
mellitus and hyperglycemia have been reported during post-marketing surveillance in
HIV-infected patients receiving protease inhibitor therapy. Some patients required
either initiation or dose adjustments of insulin or oral hypoglycaemic agents for
treatment of these events. In some cases diabetic ketoacidosis has occurred. In
those patients who discontinued protease inhibitor therapy, hyperglycemia persisted
in some cases. Because these events have been reported voluntarily during clinical
practice, estimates of frequency cannot be made and a causal relationship between
protease inhibitor therapy and these events has not been established.
Precautions:
General: Nelfinavir is principally metabolized by the liver. Therefore, caution should
be exercised when administering this drug to patients with hepatic impairment.
Hemophilia: There have been reports of increased bleeding, including spontaneous
skin haematomas and hemarthrosis, in patients with hemophilia type A and B treated
with protease inhibitors. In some patients, additional factor VIII was given. In more
than half of the reported cases, treatment with protease inhibitors was continued or
reintroduced. A causal relationship has not been established.
Redistribution/accumulation of body fat: Redistribution/accumulation of body fat
including central obesity, dorsocervical fat enlargement, peripheral wasting, breast
enlargement, and “cushingoid appearance” have been observed in patients receiving
protease inhibitors. The mechanism and long-term consequences of these events
are currently unknown. A causal relationship has not been established.
Drug Interactions:
12
Nelfinavir is an inhibitor of CYP3A (cytochrome P450 3A). Coadministration of
nelfinavir and drugs primarily metabolized by CYP3A may result in increased plasma
concentrations of the other drug that could increase or prolong both its therapeutic
and adverse effects. Nelfinavir is metabolized in part by CYP3A. Coadministration of
nelfinavir and drugs that induce CYP3A may decrease nelfinavir plasma
concentrations and reduce its therapeutic effect. Coadministration of nelfinavir and
drugs that inhibit CYP3A may increase nelfinavir plasma concentrations
Drugs that should not be coadministered with nelfinavir: amiodarone, quinidine,
astemizole, terfenadine, ergot derivatives, rifampin, midazolam, triazolam, cisapride.
Drugs which require a dose reduction when coadministered with nelfinavir: A dose
reduction of rifabutin to half the standard dose is necessary when nelfinavir and
rifabutin are co-administered.
Other potentially clinically significant drug interactions with nelfinavir:
carbamazepine, phenobarbital, phenytoin, and indinavir may increase nelfinavir
plasma concentrations; ritonavir may decrease nelfinavir plasma levels. Plasma
concentrations of the oral contraceptives ethinyl estradiol and norethindrone may be
decreased by nelfinavir.
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 success11. [WHO Draft Antiretroviral Guidelines for Resource Limited
Settings, p. 2.]
It is well established that the introduction of any antimicrobial therapy for an
infectious disease is association with the induction and spread of drugs resistance as
an inevitable consequence. Although an obvious concern, this is not a reason to
delay introduction of large-scale antiretroviral therapy programmes. Rather,
education of providers and patients, attention to drug adherence, monitoring the
population for drug resistance, and institution of strategies to try to limit drug
resistance are the components of an appropriate response. It is possible that the risk
of the spread of resistant viral strains in the population may be balanced by the
potential for the reduction of HIV transmission by the introduction of antiretroviral
therapy. [WHO Draft Antiretroviral Guidelines for Resource Limited Settings, p. 15.]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 – see attachment 1)
compiled by MSF lists two suppliers of nelfinavir, Roche (US) annual cost of
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treatment $US2585 (incl 15% rebate in kind) and Aurobindo (India) $US2924. By
comparison, indinavir costs range from $US 600-986, and ritonavir from $US 6503504, saquinavir $US 814 (100% rebate in kind), and amprenavir $US 3176.
11. Summary of regulatory status of the medicine (in country of origin and
preferably in other countries as well): TBA
12. Availability of pharmacopoieal standards: TBA
14
Attachment 1 results of nelfinavir
studies
Pages 15-18
15
Eron
200120
Saag
200121
Chavanet
200122
Gartland
200123
RCT:Open
NFV(TDS)+ APV
or
IDV+APV
or
SQV-SGC+APV
or
APV alone followed by
APV+3TC+ZDV
N= 34; PI-naïve
RCT: Blind
NFV 750TDS + ZDV+3TC
Or
NFV 500TDS + ZDV+3TC
N=297 ARV-naïve
Or
ZDV+3TC
RCT: Open
NFV+SQV+Nuc recycled
Or
SQV+RTV+Nuc recycled
N=31 with multiple failures of
HAART
RCT: Blind
NFV (TDS)+ZDV+3TC
Or
ZDV+3TC
N=105 ARV-naïve
Change in HIV-1 RNA copies/ml at 48 weeks
NFV+APV
IDV+APV
SQV+APV
-1.7 log10
no stats
-3.4 log10
-2.7 log10
Change in CD4 Count (cells)
+274
+119
no stats
Adverse events
Diarrhea 55%, nausea 39& - no breakdown by group
3 grade 3 /4 events – 2 severe hypertryglyceridemia (IDV
and SQV), severe oral lesions (APV/3TC/ZDV).
+96
HIV-RNA <400 copies/ml at week 24
NFV 750TDS
+ ZDV+3TC
67%
NFV 500TDS +
ZDV+3TC
50%
ZDV+3TC
7%
Diarrhea in 20% of 750mg recipients v 1% of 500mg
recipients; only 2 subjecs discontinued therapy as a result
(p<0.001 for efficacy comparison)
HIV-RNA <50 copies/ml at week 24
55%
30%
4%
HIV-RNA <50 copies/ml at week 48
61%
37%
Stabilisation or decrease of > 0.5 log10 at 24 weeks
NFV+SQV+Nuc
SQV+RTV+Nuc
8/15
10/17
pNS
Difference in reduction in HIV RNA at 28 weeks
NFV (TDS)+ZDV+3TC
ZDV+3TC
-1.01 (95% -0.79, -1.23)
HIV RNA <400 copies/ml at 28 weeks
13/26 (50%)
9/52 (17%)
Increase in CD4 counts
101.5 cells/ml
47.0 cells/ml
(p=0.004 for efficacy comparison)
5 participants developed elevated ALT or diarrhea; no
breakdown by treatment group
ADR : Nausea
NFV (TDS)+ZDV+3TC
17%
ADR:Diarrhea
45%
ZDV+3TC
40%
14%
Note the late addition of NFV to dual nucleoside therapy
resulted in similar benefits to those seen in the randomised
portion of the study
16
Albrecht
200124
RCT:
Open 2NRTI+ blind NFV
(TDS)
or EFV
or NFV (TDS) +EFV
N= 195; Prev use of HAART
JensenFangel
200125
RCT:
Open NVP+N
NFV (BD) +2NRTI
or
NFV (BD)+2NRTI
N= 56; Prev ‘heavily’ treated
Smith
200126
RCT:
Open/blind
(abstract only)
NVF (TDS) +SQV(SG)+STV or
RTV+SQV(SG)+STV or
DLV+SQV(SG)+STV
N=73; Prev treated with
NRTI+/- PI
Gulick
200027
RCT:
Open/partially blind
NFV(TDS)+SQV(SG)+DLV
and/or ADE*
or
RTV+SQV(SG)+DLV
and/or ADE*
*Factorial trial (4 arms).
NFVvRTV: open comparison
N=277 NNRTI-naïve;
Prev treated with PI
HIV-RNA <500 copies/ml at weeks 40/48
NFV+EFV+2NRTI
EFV+2NRTI 60%
74%
NFV+2NRTI 35%
p=0.03 for main
No differences in CD4
comparison;
count rises between the
groups
HIV-RNA <200 copies/ml at week 36
NVP+NFV+2NRTI
NFV+2NRTI 22%
52%
No differences in CD4
p=0.047 for main
count rises between the
comparison;
groups
Change in plasma viral loads at week 24
NFV+SQV+STV
RTV+SQV++STV
-.26 log(10)
-0.71 log(10)
p NS for main
DLV+SQV+STV
comparison;
-0.29 log(10)
No differences in CD 4
count rises between the
groups
HIV-RNA <500 copies/ml at week 16
NFV regimens pooled
RTV regimens pooled
33%
28%
(95% CI 24%, 41%)
(95% CI 20%, 36%)
p NS for main
No differences in CD 4
comparison;
count rises between the
NFV and RTV groups
Grade 3 or 4 ADRs – no diffce between groups
Grade 3 or 4 lab abnormalities – no diffce between
groups
Permanent dropouts
NFV+EFV+2NRTI
EFV+2NRTI 11%
11%
NFZ+2NRTI 29%
Withdrawals due to ADRs at 24 weeks
8 withdrew from 4No patient was withdrawn
drug NVP- containing
because of ADRs from the
combination (5 rash 3
3-drug regimen
diarrhea). No w/d
because of liver tox.
Discontinuation for intolerance or toxicity
NFV+SQV+STV 15%
RTV+SQV++STV 35%
DLV+SQV+STV 5%
Withdrawals and toxicity
NFV regimens pooled
RTV regimens pooled W/D
W/D by week 16:
by week 16: 8/136 (5.9%)
8/139 (5.8%)
Grade 3 or greater
reactions not different
between NFV and RTV
groups (p=0.35)
17
Study details
Wiznia
200028
RCT:
Open
NFV (TDS) +d4T+3TC+NVP
or
NFV (TDS) +d4T+NVP
Or
NFV (BD or TDS) +d4T+3TC
or
RTV+d4T+NVP
N=181 children <17years
prev treated with NRTI
24 week follow up
Viral markers
ARV-experienced, PI-naïve
HIV-RNA <400 copies/ml at week 16
NFV(TDS)
+d4T+3TC
+NVP
N=41
NFV (TDS)
+d4T+NVP
NFV (TDS)
+d4T+3TC
RTV+d4T+
NVP
N=44
N=50
N=41
61%
50%
44%
46%
HIV-RNA <50 copies/ml at 48 weeks
Moyle
200029
Roca
200030
RCT:
Open
NFV (TDS) +SQV(SG)+2NRTI
or
NFV(TDS) +2NRTI
or
NFV(TDS) + SQV (SG)
or
SQV(SG) + 2 NRTI
N=157; PI-naïve
RCT:
Open
NFV(TDS)+STV+LMV
or
IDV+ STV+LMV
N=112 All ARV-experienced
Withdrawals and toxicity
Rashes in 27% of NEV recipients
Regimens equivalent
NFV+d4T+3TC+NVP had highest retention rate (61%),
followed by NFV+d4T+3TC (46%). Retention rate of
64% in a small parallel open study where NFV was
administered BD:
Adverse events
NFV + 2
NRTI
N=26
SQV(SG)+
2NRTI
N=26
NFV+SQV
+2NRTI
N=51
NFV+SQV
63%
61%
65%
47&
N=54
HIV-RNA <200 copies/ml at 24 weeks
Nelfinavir regimen
Comparator regimen
18/37 (49%)
15/33 (45%)
p NS for comparison
Adequate adherence to therapy#
33/47 (70%)
20/42 (48%)
ADRs described as ‘mild’ in all groups – mainly GI; no
difference according to regimens. Only 4/157
‘reportable’ ADRs. Diarrhea commoner in NFVcontaining regimens
Side effects leading to cessation of therapy
Nelfinavir regimen
Comparator regimen
7/55 (12%)
19/55 (34%)
Discontinuation for any reason
21/55 (38%)
33/55 (60%)
18
Reijers
199831
RCT:
Open
NFV(TDS)+STV+LAM+SQV
(continued induction)
or
NFV+STV
or
NFV+SQV
(maintenance regimens)
N=31
ARV-naïve; all had achieved HIV
RNA levels <50 copies/ml
Undetectable HIV-1 RNA at 36 weeks after
induction treatment
Nelfinavir regimen
Comparator regimen
1/11 (9%)
9/14 (64%) of pooled
maintenance arms
Adverse events (only reported for induction
phase)
33/43 subjects suffered from diarrhea. One patient
discontinued therapy as a result
10/43 had liver enzyme rises; 3 required
discontinuation of treatment
*Frequently there was more than one NFV-containing regimen tested in the trial. Because the
is always used in combination the most intensive NFV-containing regimen was designated
the intervention group
# adherence to therapy was defined as keeping all appointments, reported taking more than 80% of treatment and
HIV-RNA >1.5 log10 below pre-treatment level.
NFV nelfinavir; RTV ritonavir; ADE adefovir; APV amprenavir; IND indinavir; SQV saquinavir; LAM (3 TC)
lamivudine; ZDV zidovudine; DEL delavirdine; STV stavudine; EFV efavirenz; NVP nevirapine;;
19
Attachment 2 – Characteristics of protease inhibitors
Overview of protease inhibitor-based regimens including two nucleoside
analogue reverse transcriptase inhibitors:
Advantages
Disadvantages
*potent, durable antiretroviral
activity
* adherence difficult with original TID dosing
regimens; addition of ritonavir can reduce dosing to
BID or QD.
* clinical benefit established,
confirming validity of
surrogate marker
improvement
* adverse events associated with long-term
antiretroviral use, but a causal relationship has yet
to be established
Characteristics of individual drugs
Non-proprietary
name
Cost p.a. US $
Advantages
Disadvantages
Nelfinavir
$2585 including 15%
rebate in kind (Roche
USA) to $2924
(Aurobindo, India)
* well-tolerated;
* resistance profile may
allow 2nd line PI
regimen;
* twice-daily dosing;
* active against Group
O subtypes;
*mild to moderate
diarrhea in ca 30% of
patients;
*high level resistance
usually confers crossresistance with other
protease inhibitors;
* high pill burden (10
tablets daily
* cannot be used with
rifampin:
20
Indinavir
$600 (Merck, US) to
$985 (Hetero, India)
* active against Group
O subtypes;
*only PI to penetrate
blood/brain barrier;
* dosing regimen every
8 hours, empty stomach
or with fat-free, very low
protein snack;
*extra hydration, at
least 2 litres, required
daily;
*nephrolithiasis
reported in 9 - 43% of
users;
* moderate pill burden
(6 capsules daily);
* cannot be used with
rifampin;
* multiple potential drug
interactions
*high level resistance
usually confers crossresistance with other
protease inhibitors
Indinavir +
ritonavir
cost variable,
depending on dose
*combination reduces
cost;
* allows for twice-daily
dosing;
* can be taken with
food;
* reduces hydration
requirement;
* active against GroupO
subtypes
*optimal dosing not
established;
*limited clinical data on
combination available;
* nephrolithiasis
incidence may be
increased;
* cannot be used with
rifampin;
* multiple potential drug
interactions;
Saquinavir softgel capsule
$814 (including 100%
rebate in kind) Roche
USA
*well-tolerated;
* twice daily dosing;
*active against Group O
subtypes;
* mild to moderate
diarrhea in ca 20% of
patients;
*high pill burden (16
capsules daily);
*soft-gel capsules must
be stored in
refridgerator in warm
climates; 3 month shelflife at room temperature
(25C or lower);
*cannot be used with
rifampin;
*high level resistance
usually confers crossresistance with other
protease inhibitors
*low level resistance to
saquinavir-sgc with only
one gene mutation will
often allow successful
switching to another
protease inhibitor
combination therapy
21
Saquinavir softgel capsule +
ritonavir
N/A
*combination reduces
cost;
* allows twice-daily
dosing (400 mg SQVsgc + 100 mg RTV);
* allows once daily
dosing (1600 mg SQVsgc + 100 mg RTV);
*optimal once-daily
dose not established;
*limited clinical data on
once-daily dosing;
*soft-gel capsules must
be stored in
refridgerator in warm
climates; 3 month shelflife at room temperature
(25C or lower);
*cannot be used with
rifampin;
Ritonavir
$650 (Abbott US) to
$3504 (Hetero, India)
*twice-daily dosing;
*active against group
O subtypes
*adverse events
mostly GI-related,
can be severe;
* cannot be used with
rifampin;
*multiple potential
drug interactions;
*both capsule and
liquid formulations
contain alcohol;
*capsules must be
stored in
refridgerator;
*liquid has 30 day
shelf-life at room
temperature 20-25C;
*high level resistance
usually confers crossresistance with other
protease inhibitors
(only as low dose
‘boost’ therapy
with other PI
drugs)
22
References
1
Blatt SP et al. Total lymphocyte count as a predictor of absolute CD4+ count and CD4+ percentage in
HIV-infected persons. JAMA 1993 Feb 3;269(5):622-6.
2
French N, Mujugira A, Nakiyingi J, Mulder D, Janoff EN, Gilks CF. Immunological and clinical staging in
HIV-1-infected Ugandan adults are comparable and provide no evidence of rapid progression but poor
survival with advanced disease. J AIDS 1999;22:509-516.
Joint United Nations Programme on HIV/AIDS. ‘AIDS epidemic update -- December 2001.’ Available at:
http://www.unaids.org/epidemic_update/report_dec01/index.html
3
4
AIDS Drug Policy. Ministry of Health Brazil. Available at
http://www.aids.gov.br/assistencia/aids_drugs_policy.htm
5
Improving access to antiretroviral therapy in Latin America. Family Health International. Available at
http://www.fhi.org/en/aids/impact/iohiv/ioh11/ioh16.html
6
Djomad G, Roels T, Chorba T, Diomandé F, Nkengasong J, Monga B, Maurice C, Wiktor SZ. HIV/AIDS
Drug Access Initiative: Preliminary report covering the period August 1998-March 2000. Ministère de la
Santé, Programme National de Lutte contre le SIDA/MST/TUB, République de Côte d’Ivoire, May 2000.
Available at:
www.unaids.org/publications/documents/care/UNAIDS_DAI/cote_ivoire_drug_access_initiative.doc
7
Source: Laurent C, Diakhaté N, Ngom Gueye NF, Touré MF, Sow PS, Faye MA, Gueye M, Lanièce I,
Touré Kane TC, Liégeois F, Vergne L, Mboup S, Badiane S, Ndoye I, Delaporte E. The Senegalese
government HAART initiative: an 18- month follow- up study of feasibility, effectiveness, adherence,
toxicity and viral resistance. [Abstract and Poster 460-W] 9th Conference on Retroviruses and
Opportunistic Infections, Seattle, Washington, USA, February 24 - 28, 2002.
d’Adesky A-C, HIV meds come to rural Haiti, The AmFAR Treatment Insider, October-November 2001
2(5):5-8. Available at: http://199.105.91.6/treatment/HIV+/insidermenu.html
8
9
S. Pujari, E. Naik, A. Patel, and S. Bhagat. Safety, Tolerability, and Efficacy of Nevirapine-Based
HAART amongst Antiretroviral Naïve HIV-1-Infected Patients in India. Paper presented at the 9th
Retrovirus Conference, Washington State Convention and Trade Center, Seattle, February 24 th-28th
2002. Available at www.retroconference.org
World Health Organization. ‘Scaling up antiretroviral therapy in resource-limited settings: Guidelines for
a public health approach’. WHO 2002.
10
11
National Health and Medical Research Council of Australia. How to use the evidence: assessment and
application of scientific evidence. Available at: http://www.nhmrc.gov.au/publications/pdf/cp69.pdf
12
Gilbert, PB et al. Virologic and Regimen Termination Surrogate End Points in AIDS Clinical Trials.
JAMA 2001; 285: 777-784
13
Skowron, G. Base Line CD4 Cell Count, Not Viral Load, Correlates with Virologic Suppression Induced
by Potent Antiretroviral Therapy. Journal of Aquired Immune Deficiency Syndrome 2001; 28: 313-319
14
Hill, AM et al. Meta-Analysis of Antiretroviral Effects on HIV-1 RNA, CD4 Cell Count and Progression
to AIDS or Death. Antiviral Therapy 1998; 3: 139-145
15
Carpenter, CCJ et al. Antiretroviral Therapy in Adults: Updated Recommendations of the International
AIDS Society – USA Panel (Consensus Statement). JAMA: 2000; 283: 381-390
23
16
Gallant, JE. Strategies for Long-term Success in the Treatment of HIV Infection. JAMA 2000; 283:
1329-1334
17
World Health Organization. Safe and Effective Use of Antiretroviral Treatments in Adults with
particular reference to resource limited settings. WHO/HSI/2000.04
18
Rutherford, GW et al. Three- or Four- versus Two-Drug Antiretroviral Maintenance Regimens for HIV
Infection. Cochrane Database of Systematic Reviews. Issue 1, 2002
19
Darbyshire, J et al. (AZT) versus AZT plus didanosine (ddI) versus AZT plus zalcitabine (ddC) in HIV
infected adults. Cochrane Database of Systematic Reviews. Issue I, 2002
20
Eron, JJ et al. A Phase II Trail of Dual Protease Inhibitor Therapy: Amprenavir in Combination with
Indinavir, Nelfinavir or Saquinavir. J AIDS 2001; 26: 458 - 461
21
Saag, MS et al. Randomized, Double-blind Comparison of Two Nelfinavir doses plus nucleosides in
HIV-Infected Patients. AIDS 2001; 15: 1791 - 1978
22
Chavanet, P et al. Randomized Salvage Therapy with Saquinavir-Ritonavir versus SaquinavirNelfinavir for Highly Protease Inhibitor-Experienced HIV-Infected Patients. HIV Clinical Trials 2001; 2:
408- 412.
23
Gartland, M. AVANTI 3 : A Randomized, Double-blind Trial to Compare the Efficacy and Safety of
Lamivudine plus Zidovudine versus Lamivudine plus Zidovudine plus Nelfinavir in HIV-1-Infected
Antiretroviral-Naive Patients. Antiviral Therapy 2001; 6: 127 – 134
24
Albrecht, MA et al. Nelfinavir, Efavirenz, Or Both after the Failure of Nucleoside Treatment of HIV
Infection. N Engl J Med 2001; 345: 398 – 407.
25
Jensen-Fangel, S et al. The Effect of Nevirapine in Combination with Nelfinavir in Heavily Pretreated
HIV-1-Infected Patients: A Prospective, Open-Label, Controlled, Randomized Study. J AIDS 2001; 27:
124 – 129.
26
Smith, D et al. A Randomized Trail of Nelfinavir, Ritonavir, or Delavirdine in Combination with
Saquinavir-SGC and Stavudine in Treatment-Experienced HIV-1-Infected Patients. HIV Clinical Trials
2001; 2: 97 – 107.
27
Gulick, RM et al. Randomized Study of Saquinavir with Ritonavir or Nelfinavir together with
Delavirdine, Adefovir, or both in Human Immunodeficiency Virus-Infected Adults with Virologic Failure on
Indinavir: (ACTG Study 359). J Infec Dis 2000; 182: 1375 – 1384
28
Wiznia, A et al. Combination Nucleoside Analog Reverse Transcriptase Inhibitor(s) plus Nevirapine,
Nelfinavir, or Ritonavir in Stable Antiretroviral Therapy-Experienced HIV-Infected Children: Week 24
Results of a Randomized Controlled Trial (PACTG 377). AIDS Research and Human Retroviruses 2000;
16: 1113 – 1121.
29
Moyle, G et al. The SPICE Study : 48 Week Activity of Combinations of Saquinavir Soft Gelatin and
Nelfinavir with and without Nucleoside Analogues. J AIDS 2000; 23: 128 – 137.
30
Roca, B et al. A Randomized, Comparative Study of Lamivudine plus Stavudine, with Indinavir or
Nelfinavir, in Treatment-Experienced HIV-Infected Patients. AIDS 2000; 14: 157 – 161.
31
Reijers, MH et al. Maintenance Therapy after Quadruple Induction Therapy in HIV-1 Infected
Individuals : Amsterdam Duration of Antiretroviral Medication (ADAM) Study. Lancet 1998; 352; 185 –
190