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(FCH/HIV, 22 April 2002)
Application for Inclusion of lopinavir/low dose ritonavir (LPV/r)
combination on
WHO Model List of Essential Medicines
Drugs are members 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 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.
Combination treatment with the protease inhibitors lopinavir and low dose ritonavir
(LPV/r) is proposed for listing on the WHO Model List of Essential Medicine. Low
dose ritonavir is included in this treatment, not for its intrinsic anti-retroviral activity,
but because it inhibits the metabolism of lopinavir. This is sometimes known as
pharmaco-kinetic ‘boosting’.
A search of several data-bases, including the Cochrane Library, Medline and
Embase, and some specialised data-bases, 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 HIVinfected subjects. The literature search also provided evidence that combinations of
3 anti-retroviral drugs are superior to dual or single drug therapy. The latter are no
longer regarded as satisfactory treatment, because of low efficacy rates and the
development of resistance.
Extensive library searches compiled by the Cochrane Review Group for HIV/AIDS
retrieved details of 5 randomised clinical trials involving LPV/r. The clinical evidence
for LPV/r appears more comprehensive than for another protease inhibitor
combination being considered for listing – indinavir/ritonavir (IDV/r). Three trials in
ARV-naïve subjects documented high rates of viral suppression when LPV/r was
combined with two NRTIs, usually a combination of d4T and 3TC. LPV/r, as a single
dose, is equi-effective to the drug given twice daily, and in combination with d4T and
3TC, LPV/r was found to be superior to a nelfinavir-containing combination. In two
trials, LPV/r was found to be a potent rescue therapy in subjects who had increased
viral loads despite treatment with multiple ARVs.
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Presently LPV/r is available as a fixed dose combination from 2 manufacturers. The
annual costs of treatment vary from $US 650 to $US 1916.
1. Summary statement of the proposal for inclusion, change or deletion.
Combination treatment with lopinavir and ritonavir 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. Lopinavir
and low dose ritonavir (LPV/r) is marketed as a fixed dose combination product.
Other examples of the protease inhibitor group may sometimes be preferred when
local factors such as availability and price are taken into account.
Antiretroviral therapy is recommended for HIV-infected children, adolescents, and
adults with symptomatic disease, and also for asymptomatic patients with CD4+ cell
counts at or below 200/mm3. Where CD4+ cell testing is unavailable, clinicians can
use the presence of a total lymphocyte count below 1200/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 submitted – please contact Dr Robin Gray (WHO/EDM) at
[email protected]
4. International Nonproprietary Name: Co-formulated lopinavir + ritonavir
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.
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
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2001, there were an estimated 250 000 new infections in this region, bringing to 1
million the number of people living with HIV. In Asia and the Pacific, an estimated 1
million people became infected in 2001; about 7.1 million people in this region are
now living with HIV/AIDS3. More than 1.8 million people in Latin America and the
Caribbean are living with HIV/AIDS, including the 190,000 adults and children who
became infected in 2001
In countries often already burdened by huge socio-economic challenges, HIV/AIDS
threatens human social welfare, developmental progress, and social stability on an
unprecedented scale. HIV/AIDS cripples the economic development of entire
countries, because it often strikes people during their most productive working years.
Of the 14,000 persons who became infected each day in 2001, about 12,000 were
aged 15 to 49 years3.
Left untreated, HIV infection results in a period of clinical latency that may last a
median of 3 to 10 years. Once symptomatic disease or AIDS develops, without
access to antiretroviral treatment, death results within an average of two years.
In high-income countries, an estimated 1.5 million people live with HIV, many of
them productively, thanks to antiretroviral therapy. In the USA, the introduction of
triple combination antiretroviral therapy in 1996 led to a decline of 42% in deaths
attributable to HIV/AIDS in 1996-973.
The feasibility efficacy and adherence with antiretroviral therapy has been
demonstrated in a number of national and smaller pilot programs in middle- and lowincome countries.
In Brazil, the policy of universal access to antiretroviral drugs has reduced the
number of AIDS-related deaths by nearly 50% and cut the incidence of opportunistic
infections by 60 - 80%4. Between 1997 and 2000, Brazil saved approximately US
$677 million in averted hospitalisations and treatment of HIV-related infections.

In Argentina a program similar to that of Brazil provides even greater coverage. A
special fund has been established to pay for 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
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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,
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
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of drugs to the Model List of Essential Drugs (with appropriate consideration of their
use in resource-limited settings).
7. Treatment details: Double protease inhibitor combinations
Recommended Dosage: Adults and adolescents over the age of 12 years: 400 mg
lopinavir with 100 mg ritonavir twice daily taken with food. LPV/r comes in fixed dose
combination capsules containing 133mg Lopinavir/33mg Ritonavir each. The
recommended standard dose is therefore 3 capsules PO BID. LPV/r also comes as
an oral solution containing 80mg LPV/20mg RTV/mL.
Doses in children: Children 6 months to 12 years: 12 mg/Kg lopinavir with 3 mg/Kg
ritonavir for children 7 to <15 Kg, and 10 mg/Kg lopinavir with 2.5 mg/Kg ritonavir for
those 15 to 40 Kg, twice daily taken with food, to a maximum dose of 400 mg
lopinavir with 100 mg ritonavir in children >40 Kg twice daily.
Concomitant Antiretroviral Therapy: Lopinavir/ritonavir 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 lopinavir/ritonavir (in combination with two nucleoside analogue
reverse transcriptase inhibitors) as a first-line or alternative regimen for the treatment
of HIV/AIDS.
Special Requirements: Adequate resources for monitoring and specialist oversight
are a pre-requisite for the introduction of this class of drugs.
8. Comparative effectiveness in clinical settings:
In compiling the evidence for this and related submissions for anti-retroviral drugs we
have created a common ‘stem’ in the form of information that is relevant to all of the
antiretroviral group. This is followed by information that is relevant to use of this
class of drug under the conditions described in this application, followed by
information which is specific to the individual agent under consideration.
Because of time constraints and the growing acceptance of the efficacy of highly
active anti-retroviral drug regimens in the last 5 years, we have relied in part on
secondary data sources – systematic reviews of randomised and non-randomised
studies conducted by the Cochrane Collaboration, or by independent groups who
have generally met standards that are considered appropriate to this type of work.
We have relied on individual trials where these provided data and insights not
available from systematic reviews.
Details of literature searches conducted
The principal data-bases that were searched were:
o The Cochrane Data-base of Systematic Reviews
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o
o
o
o
o
o
o
o
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
AIDSLINE
AIDSTRIALS
AIDSDRUG
Search terms included:
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: lopinavir, ritonavir
Study selection:
o
o
Randomised comparative parallel-group controlled clinical trials
Examined the performance of lopinavir/ritonavir when included in
combinations comprising 3 or more drugs, involving concomitant use of
NRTIs, NNRTIs or other PIs.
Categorisation of levels of evidence
The following rating scheme was used11:
 Level 1 – evidence from relevant high quality systematic reviews of unbiased
randomised comparative clinical trials
 Level 2 – evidence from at least one relevant unbiased randomised
comparative clinical trial.
 Level 3 – evidence from relevant controlled observational studies
Additional considerations for use in resource-poor settings





Co-morbidity
Simplicity (frequency of dosing, number of tablets)
Tolerability
Cost
Prior exposure to ARVs
General therapeutic issues: (common to the therapeutic category of antiretroviral drugs)
1. What is the validity of surrogate markers as predictors of morbidity and
mortality in patients with HIV/AIDS?
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2. What evidence is there that triple (or quadruple) ARV therapy is superior to
single or dual therapy?
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Class specific questions
3. Which combinations of drug classes have the best evidence in relation to
benefits and harms?
Agent-specific questions
4. What is the evidence for the efficacy and toxicity of anti-retroviral drug
combinations that include didanosine?
Results
1. What is the validity of surrogate markers as predictors of
morbidity and mortality in patients with HIV/AIDS? (Level 3
evidence)
Trials of anti-retroviral compounds have relied heavily on measuring the effects of
drugs on surrogate markers, usually CD4 cell counts and plasma HIV-1 RNA levels.
The validity of these markers depends on showing that they are correlated with
clinical outcomes, and that they should be able to capture the effects of treatment on
the major clinical outcomes12. Both of these markers may be viewed as being on the
‘causal pathway’ between viral infection and disease outcomes, but more directly in
the case of viral measures. The viral end-point has come to be 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 metaanalysis 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.
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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 5.6 (95% CI 3.1, 9.8). These results complement an earlier
systematic review, which synthesised data from 6 trials that compared the results of
zidovudine monotherapy with treatment combinations comprising ZDV with DDI or
DDC20. Although mainly of historical interest now, the review studies clinical
outcomes and showed that the addition of DDI to ZDV resulted in a reduced odds of
disease progression and death (OR 0.74, 95% CI 0.67, 0.82) and (0.72, 95% CI
0.64, 0.82) respectively. The addition of DDC gave similar results: disease
progression, 0.86 (95% CI 0.78, 0.94); and death, 0.87 (95% CI 0.77, 0.98). After 3
years the rates of mortality were ZDV 59%, ZDV+DDC 63% and ZDV+DDI 68%. The
reviewers concluded that the combination of ZDV and DDI was probably superior to
ZDV plus DDC.
The most recent review of the importance of multiple drugs in treatment of HIV/AIDS
was published in the BMJ21. These investigators pooled data from 54 randomised
clinical trials. The odds ratio for disease progression with 3 drugs compared with 2
drugs was 0.62 (95% CI 0.50, 0.78), but data were considered inadequate to
determine if there was a further advantage in adding a fourth drug.
3. Which combinations of drug classes have the best evidence in
relation to benefits and harms? (Level 2 evidence)
Unfortunately this is a question that is not yet addressed in published systematic
reviews. Enquiries directed to the AIDS/HIV review group in the Cochrane
Collaboration revealed that relevant reviews are underway but results are not yet
available. Some of the data from the limited number of trials comparing different
combinations of 3 or more anti-retroviral drugs will be reviewed in relation to the
individual drugs (see below section 8.4). 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-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
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requires long-term (albeit sometimes intermittent) drug therapy. An additional
consideration is a wish to ‘preserve’ more active anti-retroviral regimens for later in
the course of therapy. This has led to recommendations to conserve PI-containing
regimens, using those based on combinations of NRTIs and NNRTIs early in
therapy. These considerations are reflected in the advice contained in the draft WHO
Antiretroviral Guidelines for Resource Limited Settings10. The summary of regimens
recommended in this document is in 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 antiretroviral drug combinations that include combined therapy with
lopinavir/ritonavir? (Level 2 evidence)
The combined formulation of Lopinavir 400mg/Ritonavir 100mg (henceforth referred
to as LPV/r) is the most powerful protease inhibitor available, achieving trough
plasma levels more than 30-fold above the EC50 of the drug for wild-type HIV. This
is due both to the potency and bioavailability of LPV, and the inhibition of LPV
metabolism by low-dose Ritonavir, which does not itself exert much antiretroviral
activity at the 100mg dose (see submission for indinavir for more details of
pharmacokinetic interactions with low dose ritonavir).
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However LPV/r is associated with some disadvantages. It requires 3 pills twice a
day, with food. Its use is associated with increased transaminases, triglycerides, and
cholesterol in a substantial minority of patients (up to 22%). Because LPV/r inhibits
the CYP3A4 microsomal enzyme system, dose adjustments are often necessary in
medications given concurrently.
LPV/r has been studied in two main clinical settings: (1) as initial therapy for HIV
infection; and (2) as rescue therapy in multiple PI-experienced patients with viral
rebound.
Three randomized, blind, controlled trials (Murphy, 200122; King, 200123; Eron,
200224) have established the antiviral efficacy of LPV/r in treating ART-naïve patients
(see Attachment 1 for details of the trials). In a dose-ranging study of
LPV/r+d4T+3TC, Murphy found that as many as 86% of patients randomized to
LPV/r 400/100mg BID had HIV VL<50 copies/mL after 48 weeks of treatment,
without drug-related discontinuations for clinical or laboratory abnormalities, despite
the occurrence of elevated cholesterol, triglycerides, and transaminases. A recent
study by Eron demonstrated that once daily dosing of LPV/r (800/200mg) was
roughly as effective as standard BID dosing over 48 weeks. Finally, a comparison of
LPV/r with the protease inhibitor Nelfinavir, both given with d4T and 3TC, showed a
statistically significant increase in the proportion of patients with undetectable VL, at
both the 400c/mL and 50c/mL thresholds, among patients randomized to LPV/r.
Two randomized trials (Danner, 200125; Benson, 200226) and one open-label (Ruiz,
200227) trial have demonstrated the usefulness of LPV/r as the backbone of rescue
therapy in patients with extensive history of ARV therapy (see Attachment 1),
including multiple PI failures, with up to 67% of patients having a VL<400c/mL at 72
weeks (Benson). The study by Danner showed a dose response between the
number of LPV mutations present and a decline in efficacy: patients with 6-7 prestudy mutations still had a 71% probability of suppressing viral load to below
400c/mL, while those with 8-10 pre-study mutations had a 33% probability of doing
so.
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9. Comparative evidence on safety (See attachment 1 for results from
clinical trials of co-formulated lopinavir/ritonavir):
Adverse effects/reactions: Adults: diarrhea, nausea, asthenia, headache, abnormal
stools, vomiting, abdominal pain, rash, insomnia.
Laboratory abnormalities in adults (Grade 3 or 4) include neutropenia; elevated
cholesterol, triglycerides, AST, ALT, GGT, glucose, uric acid.
Adverse effects/reactions in children: Rash (2%) was the only drug-related clinical
adverse event of moderate or severe intensity reported in 2% of paediatric study
subjects.
Laboratory abnormalities in children (Grade 3 or 4) include thrombocytopaenia,
neutropaenia; elevations in AST, ALT, amylase, total bilirubin, total cholesterol;
hyponatraemia.
Warnings: Co-formulated lopinavir/ritonavir must not be used as a single agent to
treat HIV or added on as a sole agent to a failing regimen.
Pancreatitis: pancreatitis has been observed in patients receiving lopinavir/ritonavir,
including those who developed marked triglyceride elevations. In some cases,
fatalities have been observed. Although a causal relationship to lopinavir/ritonavir
has not been established, marked triglyceride elevation is a risk factor for the
development of pancreatitis. Patients with advanced HIV disease may be at
increased risk of elevated triglycerides and pancreatitis, and patients with a history of
pancreatitis may be at increased risk of recurrence during lopinavir/ritonavir therapy.
Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal
pain) or abnormalities in laboratory values (such as increased serum lipase or
amylase values) suggestive of pancreatitis should occur. Patients who exhibit these
signs or symptoms should be evaluated and lopinavir/ritonavir and/or other
antiretroviral therapy should be suspended as clinically appropriate.
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:
Hepatic impairment and toxicity: Lopinavir and ritonavir are principally
metabolized by the liver. Therefore, caution should be exercised when administering
this drug to patients with hepatic impairment. Patients with underlying hepatitis B or
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C or marked elevations in transaminases prior to treatment may be at risk of
developing further transaminase elevations.
Lipid elevations: Treatment with lopinavir/ritonavir has resulted in large increases in
the concentration of total cholesterol and total triglycerides. Cholesterol and
triglyceride testing should be performed prior to initiating treatment with
lopinavir/ritonavir at a periodic intervals during therapy.
Haemophilia: There have been reports of increased bleeding, including
spontaneous skin haematomas and haemarthrosis, in patients with haemophilia 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: Ritonavir is a potent inhibitor of the P450 isozyme CYP3A.
Coadministration of lopinavir/ritonavir and drugs primarily metabolized by CYP3A or
CYP2D6 may result in increased plasma concentrations of the other drug that could
increase or prolong both its therapeutic and adverse effects.
Lopinavir/ritonavir is itself metabolized by CYP3A. Coadministration of
lopinavir/ritonavir and drugs that induce CYP3A may decrease lopinavir plasma
concentrations and reduce its therapeutic effect. Coadministration of
lopinavir/ritonavir and drugs that inhibit CYP3A may increase lopinavir plasma
concentrations.
Drugs that must not be coadministered lopinavir/ritonavir: flecainide, propafenone,
astemizole, terfenadine, ergot derivatives, midazolam, triazolam, cisapride,
pimozide, lovastatin, simvastatin, rifampin, St. John's wort (Hypericum perforatum) or
St. John's wort-containing products.
Drugs which require a dose reduction when coadministered with lopinavir/ritonavir: A
dose of at least 75% of the usual 300 mg/day dose of rifabutin (i.e., maximum
rifabutin dose of 150 mg every other day or three times a week) is necessary if
lopinavir/ritonavir and rifabutin are co-administered. Further reductions in rifabutin
dose may be required. When co-administered with lopinavir/ritonavir, sildenafil dose
should be reduced to 25 mg every 48 hours with increased monitoring for adverse
events.
Drugs which may require a dose increase when coadministered with lopinavir/
ritonavir: methadone, atovaquone.
Drugs which require careful monitoring when coadministered with lopinavir/ritonavir:
lopinavir/ritonavir increases plasma concentrations of dihydropyridine calcium
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channel blockers (felodipine, nifedipine, nicardinpine) and HMG-CoA reductase
inhibitors (atorvastatin and cerivastatin).
Other potentially clinically significant drug interactions with lopinavir/ritonavir:
carbamazepine, phenobarbital, phenytoin, and dexamethasone may decrease
lopinavir plasma concentrations. Plasma concentrations of estrogen-based hormonal
contraceptives are decreased by lopinavir/ritonavir; alterative or additional
contraceptive measures should be used.
Coadministration of lopinavir/ritonavir with other antiretrovirals:
When administered with efavirenz or nevirapine, the lopinavir dose should be
increased from 400 mg to 533 mg and ritonavir increased from 100 mg to 133 mg,
twice daily with food.
When administered with didanosine, the didanosine dose should be taken either one
hour before or two hours after lopinavir/ritonavir.
c) Variation in safety due to health systems and patient factors:
Antiretroviral therapy cannot be successfully introduced in a healthcare system
vacuum. However, facilities and personnel infrastructure can be expanded in parallel
with the implementation of antiretroviral agent delivery programmes. Health care
provider and patient education, an essential health care package, and the ability to
do at least limited clinical and laboratory monitoring are all necessary to try to insure
programmatic success. [WHO Draft Antiretroviral Guidelines for Resource Limited
Settings, p. 2.]
It is well established that the introduction of any antimicrobial therapy for an
infectious disease is association with the induction and spread of drugs resistance as
an inevitable consequence. Although an obvious concern, this is not a reason to
delay introduction of large-scale antiretroviral therapy programmes. Rather,
education of providers and patients, attention to drug adherence, monitoring the
population for drug resistance, and institution of strategies to try to limit drug
resistance are the components of an appropriate response. It is possible that the risk
of the spread of resistant viral strains in the population may be balanced by the
potential for the reduction of HIV transmission by the introduction of antiretroviral
therapy. [WHO Draft Antiretroviral Guidelines for Resource Limited Settings, p. 15.]
10. Summary of available data on comparative cost and cost-effectiveness
within the pharmacological class or therapeutic group:
Lopinavir + Ritonavir (Trade name KaletraTM) is available from Abbott at
$US650/year; the price quoted by Hetero (India) is 1916 USD/year for the same
combination.
15
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 clinical trials of
lopinavir/ritonavir. Pages 15- 18
17
Author
Study Details
Lpv/r Regimen
Murphy et al.
200122
RCT
Group 1: RTV 100mg + LPV
200mg vs. 400mg q12h x 3 wks,
then d4T+3TC added.
Group 2: RTV 100mg vs. 200mg
+ LPV 400mg q12h + d4T + 3TC.
N=100 ART-naïve, HIV
VL>5000c/mL followed for 48
weeks.
No baseline differences in HIV
VL, CD4. Mean VL=4.9 log10;
Mean CD4= 398(group1);
310(group2).
King et al.
200123
M98-863 Study
RCT
Benefits
Comparator
Pts w/ VL<50c/mL @
Wk48:
No comparator
regimen
Grp1 LPV/r 200/100mg:
100%
LPV/r 400/100mg:
50%
(p=0.002)*
Grp2 LPV/r 400/100mg:
86%
LPV/r 400/200mg:
73%
Mean change in CD4 @
w48:
Grp1: +244/mm3
Grp2: +213/mm3
*6/8 pts in 400/100
group w/ VL>50c/mL at
wk48 had VL<50c/mL
at next visit.
Pts w/ virologic suppression at 48 weeks:
LPV 400mg/rtv 100mg BID vs.
NEL 750mg TID (double blinded)
+ d4T/3TC (open label).
<400c/mL:75%
(p=0.001)
<400c/mL: 63%
N=653 ART-naïve pts.
<50c/mL: 67%
(p<0.001)
<50c/mL: 52%
Tolerability/Adverse Effects
Lpv/r Regimen
Comparator
--No drug-related discontinuations
(clinical or laboratory-related).
--7 withdrawals (2 LTFU; 2noncompliance; 1 personal reasons; 1
lymphoma; 1 relocation).
--incidence of diarrhea, nausea,
vomiting similar among arms, except
significantly higher in group 2 arm
receiving 200mg Ritonavir.
--Most common grade III/IV lab
abnormalities:
-elev. triglycerides
-elev. total cholesterol
-elev. liver enzymes.
No genotypic/phenotypic resistance
among 37 LPV/r failures.
18
Author
Eron et al.
200224
Danner et al.
200125
M98-957 Study
Study Details
Randomized (no blinding info in
abstract) trial.
D4T+3TC BID, plus LPV/r
800/200mg OD vs. LPV/r
400/100mg BID x 48 weeks.
N=38 ART-naïve pts with median
baseline VL 4.7 log10 c/mL, CD4
264/mm3.
RCT
LPV/r 400/100mg BIDvs.
533/133mg BID plus open EFV +
NRTIs; converted to open-label
LPV/r 533/133mg BID after week
24.
N=57 multiple-PI-experienced,
NNRTI-naïve; VL on
ART>1000c/mL.
Median BL HIV VL 4.5 log10c/mL.
Benefits
Pts. with HIV VL<50c/mL at 48 weeks:
OD LPV/r: 74%
Median Ctrough/IC50: 40.
BID LPV/r: 79%
Median Ctrough/IC50: 84.
Adherence (MEMS-caps)
similar across groups
No comparator
regimen.
Tolerability/Adverse Effects
--Comparable frequency of nausea,
asthenia, diarrhea across groups.
--2 grade III cholesterol elevations.
--3 grade III triglyceride elevations.
Pts. with HIV VL <400c/mL at week 72:
Pooled arms: 67% (ITT,
missing = failure).
No comparator
regimen
Antiviral efficacy stratified by BL # LPV
mutations:
# mutations:
0-5
6-7
8-10
pts w/VL<400c/ml@72wks:
91%
71%
33%
13 pts withdrew by week 72
--4 for LPV/r-related events
--5 for virologic failure
Most common EA: diarrhea;
asthenia; lipid elevations.
19
Author
Benson et al.
200226
Study Details
Benefits
RCT
Pts. with suppressed HIV VL at 48 weeks:
(Blinded) LPV/r 400/100mg vs.
400/200mg substituted for prior
PI, followed by addition of openlabel NVP + new NRTI(s) on day
15.
<400c/mL:
LPV/r 400/100mg: 67%
LPV/r 400/200mg: 74%
N=70 pts, naïve to NNRTI and at
least one NRTI, with HIV VL
1000-100,000c/mL on stable PIcontaining ART x 12 weeks.
No significant baseline
demographic, immunologic,
virologic, or antiretroviral
differences between arms.
<50c/mL:
LPV/r 400/100mg: 56%
LPV/r 400/200mg: 68%
No significant difference
between dosages.
Mean CD4 change @ 48
weeks:
LPV/r
400/100mg:+140/mm3
LPV/r
400/200mg:+108/mm3
No significant difference
between dosages.
Withdrawals/Adverse Events
No comparator
regimen
No statistically significant difference
in incidence rates of adverse events
between 400/100mg and 400/200mg
groups.
--Most common adverse events:
diarrhea (19% and 24%); asthenia
(3% and 9%).
Significantly increased total
cholesterol (30 and 38mg/dL,
p<.001); triglycerides (135 and 124
mg/dL, p<.05) vs. baseline.
No withdrawals due to lab
abnormalities.
20
Ruiz et
al.200227
Open-label randomized
prospective trial.
Rescue therapy consisting of
LPV/r+SQV+3TC+ABC+ddI with
(group a) or without (group b) a
preceding 3-month treatment
interruption.
N=46 pts. with HIV VL>1000c/mL
on >2 three-drug ART regimens
and with resistance mutations to
all three classes of antiretroviral
drugs.
At Baseline:
Mean #prior drugs: 8
Mean years of prior ART: 5.7
Mean VL: 4.3 log10 c/mL
Mean CD4/mm3: (a)396; (b) 322
Pts with HIV VL<80c/mL at 24 weeks:
(a):47%
(b):36%
No significant difference.
Abstract does not state
reason for choosing 80c/mL
as threshold for
undetectability.
Baseline VL <20,000c/mL
associated with better
virologic suppression.
No comparator
regimen.
Adverse events and withdrawals not
reported in abstract.
21
Attachment 2
Overview of protease 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:
22
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
23
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 shelflife 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)
24
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