Document in microsoft internet explorer

CENTRE FOR SEXUAL & REPRODUCTIVE HEALTH
Professor Charles Gilks
Liverpool School of Tropical Medicine
Manager 1995-2000 HIV/AIDS Work/Knowledge Programme the Department for International Development Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 THE CENTRE FOR SEXUAL & REPRODUCTIVE HEALTH
is managed by JSI (UK) on behalf of the Department for International Development. For further information on JSI (UK) please contact: JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 This paper was produced by the Resource Centre for Sexual and Reproductive Health on behalf of DFID, and does not necessarily represent the views of policy of the Department for International Development.
JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 Table of Contents

Table of Contents .0
List of Acronyms and Abbreviations .4
1. Background/Context.5
2. Current prevalence of ART in resource-poor settings .5
3. The risks associated with ART .6
4. Relative priority of secondary/tertiary HIV prevention vis a vis other health
concerns .6
5. Interventions currently being pursued; roles of bilaterals and multilaterals .7
6. Likely impact of greater ART access on views about ART for wider
populations .8
7. The main issues raised by HIV/AIDS civil society groups and health advocates8
8. The lobbying and market strategies of the International Pharmaceutical
Industry.9
9. Key players in the field .9
10. Minimum systems requirements to make interventions feasible for wider
replication .11
11. Gaps in the field – current knowledge or intervention.11
Appendix 1: Antiretroviral drugs and notes on combination therapy .13
Appendix 2: A heirarchy of different care levels for resource-poor countries .15
Appendix 3: Core reading and source material .17
JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 List of Acronyms and
Abbreviations

ART
International Association of Physicians in AIDS Care Non-nucleoside reverse transcriptase inhibitors Nucleoside reverse transcriptase inhibitors JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 1. Background/Context

1.1 The HIV/AIDS epidemic has shattered the comfortable dichotomy between tropical and
temperate medicine. For the first time in generations, a major public health problem and treatable
disease is a top priority in both resource rich and resource poor countries. The huge disparities in
the responses generated - dictated by resource availability rather than need - is highlighted by
differences in care, especially ART.
1.2 Up till now, the main thrust of development/health assistance has been in HIV/STI control.
This is clearly identified as a public good and is highly cost-effective. After STI services are
strengthened and condoms are distributed what are the next targets? Critical in this is sustained
behaviour change but this requires a more mainstreamed approach that properly includes
provision of services for those infected.
1.3 The HIV epidemic is a great threat to development. How a problem is defined determines
what will be done about it. It is increasingly short-sighted just to see HIV as an STI within
reproductive health. A broader definition and approach is needed within the health sector; and
beyond health, which can help to inform and promote inter-sectoral policies on HIV/AIDS. This
definition will need to include HIV as a disease as well as a problem just to be prevented. Access
to ART is at present the dominant care issue.
1.4 Different classes of ARV drugs exist and there are several proprietary preparations in each
(see Appendix 1). These should be used in combination and may be toxic. ART is very complex
and specialist training is required to administer it. Monitoring usually relies on sophisticated
laboratory services, which are expensive and only available in a few (private-for-profit or
research) settings in large cities in resource-poor countries.
1.5 The five main manufacturers of antiretroviral (ARV) drugs recently announced
unprecedented cost slashing of proprietary drugs for resource-poor countries.To date no prices
have been announced but the discount is likely to be as much as 90% of current US or European
price; and far below (>50%) the current discounted prices negotiated by UNAIDS for the pilot
Drug Access Initiative. However, these proposed price cuts are based on several conditions,
including certain government commitments and health service capacity, which make it unlikely
that cheaper drugs will be available in the near future.
2. Current prevalence of art in resource-poor settings

2.1 There appears to be no national statistics from any low-income country that report on
importation of individual drugs used in ART. Such figures would probably be unreliable,
reporting licensed proprietary drugs imported through legitimate channels rather than generic
drugs - produced illegitimately in India and Thailand. Importation gives no handle on how drugs
are prescribed. Counterfeiting is allegedly occurring.
2.2 The Ugandan UNAIDS drug access initiative monitors how many clients are using
discounted ART on a relatively regular basis. The most recent report identified about 900
patients (approx 0.1% PWAs)
JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 2.3 Informal links between NGOs and PWA/patient support groups, and with relatives (e.g. in
UK), in the North ensure the (erratic) supply of issued/prescribed but unused or even time-
expired drugs.
2.4 It is believed (no data exist) that many desperate PWAs at some stage buy ARVs or
traditional/quack medicines in the search for a cure. Knowledge is extremely limited (see 10.2).
Invariably improperly used, the risks of ART are enhanced (Section 3); and significant
income/reserves will have been wasted.
2.5 In middle-income countries of Latin America, ART is widely accessible, financed by
insurance or the state. In Thailand, with generic ARV production, it is assumed that ART is
being widely promoted.
3. The risks associated with ART

3.1 Drugs are potentially toxic for the individual. Few data exist on incidence or relative
importance.
3.2 Improper use (by physician unfamiliar with ART; by patient who poorly adheres because of
toxicity or ability to pay) is a grave threat in the promotion then spread of HIV drug resistance.
HIV is particularly prone to develop resistance mutations to some agents – in particular
nevirapine. (cf MTCT).
3.3 All cost analyses conducted in LDCs assume fully sensitive HIV infection with predictable
response to ART. Widespread resistance will complicate ART and undoubtedly increase costs (cf
MDR TB)

4. Relative priority of secondary/tertiary HIV
prevention vis a vis other health concerns

4.1 It is important to note that provision of specialist HIV/AIDS services, which includes ART,
is the highest level of HIV care services when these are laid out in a hierarchical fashion
(Appendix 2). It makes little sense to concentrate on the higher levels without the basics.
Politically, ART is symbolising care.
4.2 ART effectively reduces plasma viral levels and this will translate into reduced transmission
of HIV sexually as well as vertically. It is unclear how much secondary prevention comes from
ART. Viral load reduction depends on what combination regimen is used; HAART/triple therapy
is most effective but dual therapy also reduces viral load (appendix 1). No modelling has been
done and no cost-effectiveness data or DALY figures have been generated for ART in resource-
poor settings to date. Of concern, there are data from the US that suggest safer sexual behaviour
is reduced in people taking ART.
4.3 Additional tertiary benefits include the effects of voluntary counselling and testing (VCT)
that needs to be implemented to identify clients for ART. It is well documented that with good
JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 counselling, knowing HIV status is a powerful incentive to behaviour change for both HIV-
infected and uninfected.
4.4 A recent population projection model for S. Africa (Wood et al Lancet 2000: 355;2095-
2100) noted that triple therapy for 25% of HIV-infected adults would prevent a 3.1 year decline
in life expectancy that was sustained; and avert more than 430,000 incident AIDS cases. Neither
secondary nor tertiary effects on transmission were modelled. The intervention would consume
12.5% of health-care expenditure.
4.5 Influential publications (Confronting AIDS; World Bank 1997) conclude that ART is not a
public good because of the overwhelming number of more cost-effective health priorities. Recent
price shifts and modelling exercises as in 4.4 are beginning to challenge these conclusions.
Moreover, the political environment in several countries seems to be moving, prioritising care
(thus ART) more prominently.
5. Interventions currently being pursued; roles of
bilaterals and multilaterals

5.1 UNAIDS co-ordinates a four-country (pilot) HIV/AIDS drug access initiative (DAI). This
focuses on drugs for opportunistic infections as well as ART, though most activity has been with
ART. The idea is preferential, not subsidised drug pricing negotiated with industry, delivered by
approved centres for whom guidelines and training is provided. Cost is the main barrier to uptake
(see 2.2) and will remain so even with massive price cuts unless/until ART is highly subsidised.
Equity is a secondary issue as there are few centres (all in the cities) with the capacity and
infrastructure to implement the initiative.
5.2 A consortium of researchers (Gilks, LSTM lead investigator) is poised to evaluate
Developments of ART (DART) appropriate for Uganda (pulse therapy or structured treatment
interruptions where regular drug-free periods are taken) and Hydroxyurea a potentially valuable
but toxic immuno-modulator. The study site is the MRC/DFID AIDS in Uganda Programme, in
partnership with TASO. MRC are likely to fund the study (banded alpha+) because of its
strategic importance but drug-company support is a pre-requisite for this. A secondary benefit if
funded will be the development of a Ugandan trial centre.
5.3 Similar (smaller) ART studies focussing on local issues are underway through the HIVNAT
collaboration in Bangkok (Netherlands, Lange; Australia, Cooper; Thailand, Phanupak) in
existence since 1998. A secondary benefit is the development of a Thai trials centre, independent
of industry.
5.4 Few other interventions in adult therapy are underway to our knowledge. Uncertainty of
public good, affordability and strategic relevance/priority are widespread. The field is however
fast moving (cf major drug discounting). Increasing attention in MTCT trials is focussed on the
need to offer therapy to the mother after delivery and perhaps also the child, as this is standard of
care in Industrialised countries.
JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000
6. Likely impact of greater ART access on views about
ART for wider populations

6.1 The prevailing view is that, except for MTCT, ART is not a public good (see 4.5). How the
political climate will change, and the consequences for government policy in individual countries
is difficult to predict. If ART is shown to be beneficial, and an intervention that richer members
of society are prepared to purchase for themselves from private-for-profit providers then
governments are unlikely to step in and suddenly want to subsidise this (except perhaps in
francophone Africa for the elite). If ART is shown to be widely abused (see 3.2) then
governments may be forced to introduce some sort of regulation to guard against HIV drug
resistance, although this could be difficult.
6.2 Private use will be highly price sensitive but will always exclude the poor. Donors may wish
to support ART for poor people because of equity, though it is likely to continue to be seen as a
low priority by most bilaterals. There may be some argument for supporting ART because of
secondary benefits on HIV transmission (see section 4) but if adverse impacts on sexual
behaviour are seen, this is unlikely.
7. The main issues raised by HIV/AIDS civil society
groups and health advocates

7.1 Equity of access to care is the main argument used by AIDS activists in the West. There is a
certain zeal to these advocates who have just “discovered” the huge gaps between developed and
developing countries (see 1.1). There is little in the way of structured argument including cost-
effectiveness, capacity to implement, financing or prioritisation in the approach of most activists.
HIV/AIDS is not just one of many priority issues, it is the only issue that counts. This can make
dialogue with them frustrating. Particularly challenging groups here include the French activists
in Act-up Paris.
7.2 There is far less of an outcry from low-income countries. Few activists are very vocal or
visible; most are pragmatic - there appears to be more acceptance of the power of money to
purchase advantage including health. With a more normalised approach activist groups may
become far more vocal.
7.3 These arguments are translated into viewing the pharmaceutical industry as a profit-driven
monster accountable only to shareholders with no morality or concern to act on the obvious
inequity. Whilst naïve, emotional pressure on companies can secure major results in drug pricing
(cf 1.5; and the announcement by Pfizer in early 2000 following Act-up pressure in the US that it
was to offer to donate fluconazole to South Africa to treat cryptococcal meningitis1. Fluconazole
is soon out of patent; and cheap Thai generics are available).
1 This offer has recently been rejected by the South African Government JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 7.4 The second issue is the obvious fact that HIV is very much a developing country epidemic
now with most of the burden falling on those countries and communities least able to cope.
Increasingly the impact on life expectancy and development is also being referred to. Working
with NGOs, CBOs, and care groups in a responsible way is led by IAPAC (see section 9).
8. The lobbying and market strategies of the
International Pharmaceutical Industry

8.1 Industry is very aware of the access to ART debate. Slashing drug prices for resource-poor
countries is a significant step, although prices probably remain above production costs. Cynics
argue this is partly motivated by an attempt to preserve brand name and image in the face of
cheap generic imports (cf Pfizer and fluconazole see 7.3). ART is highly price sensitive and use
will undoubtedly rise when massive discounting eventually hits the marketplace. The risks
discussed in section 3 will be very real. Private health care delivery is not supervised and the
health market is universally poor at regulating itself.
8.2 Bristol Myers Squibb announced in 1999 a substantial ($100m) initiative in southern Africa
“Secure the future” (managed by Jim Sapirstein). The political problems around ART and the
cause of AIDS in South Africa have generated several problems for the initiative and it has had
to date a relatively low profile.
8.3 In the past, Pharmaceutical companies have invested in small-scale trials of specific ARVs in
low-income countries, often to generate safety and tolerability data for FDA licencing. There
may also have been in the past the desire to show activity in Africa to concerned shareholders.

9. Key players in the field
UNAIDS and the Drug Access Initiative (DAI) Badara Samb; Policy, Strategy and Research (PSR), UNAIDS Jos Perriens, PSR, UNAIDS Dorothy Ochola, DAI coordinator, MoH Uganda Jose Zuniga, Director International Association of Physicians in AIDS Care (IAPAC) Marie de Cenival, Act-up Paris There are many small PWA groups in Africa but few are really key players yet Janet Darbyshire and Ab Babiker, MRC clinical trials unit Steven Forsythe, Charles Gilks, LSTM David Cooper, NCHECR, New South Wales Australia and former IAS chair Peter Mujenyi, Dorector JCRC, Kampala Jim Sapirstein; BMS and Secure the Future Dorothy Bray; Glaxo Wellcome Brian Elliot, Joseph Saba, Axios (independent consultants to industry) JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 10. Minimum systems requirements to make
interventions feasible for wider replication

10.1 Trained and knowledgeable health professionals are critical for the safe and effective use of
ART. Few centres exist in Africa where such training could be offered (JCRC, Kampala; several
in S. Africa). Ideally clinical guidelines should be developed based on local evidence and
efficacy results.
10.2 Education and information for patients as purchasers of ART is very important. At present
it is assumed that with desperate patients who have little or no knowledge of what to expect that
sub-standard
care and even fraudulant practice is widespread. Demand for “quack” medicine or traditional
cures is widespread and is equally impoverishing to households and should be a target for
information as well.
10.3 The laboratory services required for monitoring ART toxicity and tolerability, and for
evaluating clinical progress are well rehearsed in several publications (eg Guidance modules on
ART, nunber 5).
10.4 Improved capacity (extra staff and clinic space for privacy) for VCT. VCT is the entry
point to any care initiative. DFID-funded studies in Kenya (HAPAC, Arthur/Forsythe/Gilks)
show how rapid testing can be implemented at health centres. Any service delivering ART will
be new, be very labour intensive and will require extra trained staff and space for it to be set up
then run efficiently and effectively.
10.5 Regional clinical trial centres need to be supported and developed, which will have the
expertise and capacity to ask questions about new ARV drugs and ART combinations relevant
for local settings. This is accepted with HIV vaccine trial centres by many organisations.
11. Gaps in the field – current knowledge or
intervention

11.1 It is generally assumed that treatment regimes developed for the US/Europe and standard of
care will be used in resource-poor settings. There is however a need to evaluate regimens that
may be more suitable where resources are limited (eg older generation dual therapy, cheaper but
less effective; see 5.2).
11.2 Studies to examine/model the secondary and tertiary benefits/impacts of ART on HIV
transmission.
11.3 Innovative ways of working in effective partnership with the private-for profit sector need
to be explored and evaluated (training, guidelines, supervision, a system of accreditation)
11.4 IEC material and strategies for likely users or purchasers. Realistic expectations must be
generated: No cure, some benefit but at a significant cost, access through a trained physician and
JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 Appendix 1: Antiretroviral drugs
and notes on combination therapy

Generic Name
Proprietary or
Daily Dose
Cost in US$
Brand Name
70kg adult
for 3 Months
Brand/proprietary names may differ in different countries; generic names or initials do not.
Costs are for single drug in standard dose for three months. These are NOT the discounted prices.
Notes:
A. Three classes of drug are licensed and widely used. These are the nucleoside reverse
transcriptase inhibitors (NRTI), the first effective anti-AIDS drugs which inhibit DNA
being formed from viral RNA (reverse transcription). Non-nucleoside reverse
transcriptase inhibitors (NNRTI) inhibit the same enzyme but in a different fashion and
thus enhance NRTIs. Protease Inhibitors (PI) inhibit viral assembly. Hydroxyurea is
believed to be an effective modulator and it is very cheap; widely used in Africa. No
evidence exists on efficacy or toxicity (cf DART study in Uganda see section 5.2).
B. As with anti-tuberculosis therapy, prolonged single drug therapy should be avoided as it is
will inevitably with time generate drug-resistant mutants. This can happen very quickly over a
few weeks with some Pis and NNRTIs (including Nevirapine). Drug resistance is usually broad
and across the class of drug, though there is especially with the NRTIs considerable
heterogeneity.
C. Current standard of care involves three drugs from at least two different classes. The so-called
Highly Active Antiretroviral Therapy (HAART) has superseded dual NRTI therapy, which was
the standard of care in the West before the development of PI class of drug. Dual therapy may
have a role to play in improving quality of life and survival - at less cost thus with wider access.
Some consider that only the best standard of care should be used and it is unethical to prescribe
“sub-standard” care.
JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 D. Considerable expertise is needed to prescribe these drugs in combination properly. Some
combinations are ineffective, while some potentiate toxicity. Monotherapy must be avoided.
With no supervision, little or no training but widespread demand for drug there is much
illegitimate prescribing and use which exacerbates the emergence of drug resistance. Therapy for
drug resistant infection is (again like multi-drug resistant TB) very complex and can be very
expensive.
E. Monitoring is needed for side-effects and toxicity. Progress is judged clinically and also by
expensive markers of disease progression which include CD4 count (@$15) and viral load
measurment (@$60-80). Access to quality-controlled and reliable laboratory facilities is at
present very limited in most regions.
F. Adherence to therapy is increasingly recognised as a problem in the west, especially to the
more complex triple drug regimens.
JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 Appendix 2: A heirarchy of different
care levels for resource-poor countries

Care level
Services
Comments
The Essential Minimum
Support and counselling for the person minimum essential services. To be able to deliver any form of certain minimum level of specific Basic care delivery within the
existing health-care services
Africa is delivered by the existing Introducing specific HIV/AIDS
clinical services
for opportunistic infections that are not It will usually be appropriate to Providing disease-modifying
anti-retroviral therapy
At present this is very expensive treatment clinics to accommodate antiretroviral therapy JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 JSI(UK) Centre for Sexual & Reproductive Health Provision of Anti-retroviral therapy for people with HIV/AIDS in developing countries June 2000 Appendix 3: Core reading and
source material
The implications of antiretroviral treatments: informal consultation
1997. WHO/ASD/97.2
The consultation was called in response to recent developments in ART announced when the first impact of HAART was appreciated in the west. It discusses and summarizes the essential points made during the presentations. The case presentations are interesting and broad. Although held in 1997 almost all the issues are still highly relevant. Guidance modules on antiretroviral treatments. WHO/ASD/98.1 and
UNAIDS/98.7
This set of 9 modules provides expert guidance on many of the complex issues surrounding decisions to introduce ART in resource-poor settings. Included are modules on 2. Introducing ARTs into health systems; economic considerations 3. Planning and integration into health systems 8. Regulation, distribution and control of ARVs Background
Confronting AIDS. Public priorities in a global epidemic World bank/OUP 1997 Care and support for people with HIV/AIDS in resource-poor settings DFID Health and Population occasional paper; Liverpool School of Tropical Medicine 1998 JSI(UK) Centre for Sexual & Reproductive Health

Source: http://www.jsieurope.org/docs/art_provision.pdf