INTRODUCTION: Sub Saharan Africa is the region hardest hit by HIV/AIDS , a
disastrous lentiviral retrovirus disease now the fourth largest cause of death worldwide,
claiming 3 million lives in 2001, including an estimated 2.3 million African
ref yyy.
Sub-
saharan Africa is however poverty ridden and cannot afford the savior regimen called
‘Highly potent or highly active antiretroviral therapy’ (HAART). In recognition of this
tragedy of developing nations, patency waivers, and direct supply of cheaper drugs
from the manufacturer has come to be today’s solution and the drugs are already
being delivered to the various countries . But how is HAART expected to perform in
these regions? . HAART is the cornerstone of current therapy of HIV/AIDS and
defines a beneficial combination of highly efficacious drugs that has been found to
allow clinical improvement and undetectable viral load in HIV patients. Such defining
points of HAART may not be true across viral types, clades or clinical situations and
therefore needs careful reviews.
Pre-HAART:
The history of HIV before 1995 was that of an illness that leads to
sure death: a kind of death sentence. This pessimism was broadcasted by its early
claims of the lives of stars and was not unrelated to the fact that in the early 1990s,
therapy was essentially limited to monotherapy (zidovudine [ZDV] and later didanosine
[ddI]) and further dismayed with the European-Australian Concorde study data
released in 1993 suggesting that the benefits of zidovudine monotherapy were limited
and transitory 1. Therapy therefore was mainly supportive while waiting a sure death.
THE HAART ERA: The demonstration in 1996 that that dual nucleoside analogue
regimens were effective in reducing viral load and delaying disease progression was
relieving and initiated the use of dual NRTI-based regimens
2,3.
Mainly as a result of
this, AIDS-related morbidity and mortality decreased4. The improved understanding of
the pathogenesis of HIV infection, availability of tests that could measure plasma HIV
RNA levels (" viral load ") and development of new and more powerful drugs such as
the protease inhibitors (PIs) set the stage for the Widespread optimism over the
advantages of combination therapy and has sustained the positive effect of treatment
on AIDS-related morbidity and mortality 4 .The philosophy behind the current treatment
rationale was sequel to the work of Ho et al 5 which put to rest the ‘dormant period’
hypothesis of HIV pathogenesis. Treatment protocols came to include “hit early” and
“hit hard” and involve the efficacy of the drug (‘ how big is the harmer’) versus available
plasma AUC, and peak/ through concentration (‘how hard are you hitting’). Treatment
designs aim at combining agents that target more than one stage within the HIV life
cycle (so called ‘divergent combination therapy’) thus making it more difficult for the
virus to develop mutations that circumvent all classes at the same time 6. There is
also the added advantage that the drugs give rise to greater-than-additive antiviral
effect. The highly effective triple (or more) combination regimen became known as
highly active antiretroviral therapy (HAART). This regimen has been recommended for
the world and has contributed to the survival and overall health of patients with HIV
infection
6,7,8.
That HAART is not yet eureka was pointed out by the development of
resistance and the presence of viral reservoirs that for now appear untouchable.
These drawbacks are addressed by strategies like treatment switching, sequencing,
and genotypic screening for drug choice while further search for alternative drugs
continue. One other difficulty of HAART is the unforgiving pharmacokinetic of the
components demanding a religious drug regimen by well-motivated patients; a
compliance problem made more difficult by the rather toxic nature of these
medications. The wide variations in the disease progression, the prospect of
(prolonged) life long need for medications in the climate of emerging resistance
against shrinking drug alternatives has raised concern and various arguments as
regards the right time to start antiretroviral medications 9 and whether HAART should
be withheld from non adherent patients10.
Given that the drugs are available, the essential components of successful
implementation of HAART include may include:
1. A combination of at least three efficacious drugs
2. Ability to evaluate CD4 cell count
3. Ability to evaluate viral load.
4. A helpful user profile
5. Competent provider
6. Non drug treatment: psychosocial
. These may be restated as: the viral factors and ‘a quadrangle interaction’.
Evaluated as such, how is HAART expected to perform in West Africa?
THE VIRAL FACTORS: HIV type 1 and / or Type 2 viruses cause AIDS. Type 1 is
further divided into three subtypes (M, N, O) and subtype 1 M is further subdivided into
clades A to J. Type 2 is more highly divergent and at present subtypes A to F is
recognized 8, while G has recently been introduced 11. However subtypes 2 A and 2 B
are the more clinically significant subtypes 12. The common type in Europe and North
America is Type 1 subtype M, clade B and mainly due to economic arguments most
researches and therapy are designed with this strain as the primary target 13. Type 1 M
clade A to J, Type 1 N and O. and type 2 all exist in Africa
with type 2
almost
exclusively found in this region, though subtype 2 A is said to be more common in the
West African region
14.
In West Africa, the infection pattern includes type 1 only
patients, type 2 only patients and combined infection either as dual infection (HIV 1
and 2) or recombinant strains. Except in Nigeria where Type 1A and A/G recombinants
appear to be more common15, HIV type 2 and dual infection (1 and 2) appears to be
very common in West Africa while an epidemics of the A/G recombinant virus is
expected to emerge 15. Studies have shown that AIDS caused by HIV 1 and HIV2 are
clinically different
16,17.
Human immunodeficiency virus (HIV) type 2 infections are
associated with a better clinical outcome, slower rates of CD4 T cell decline, and lower
viremia than is HIV-1 17. It has been shown that a productive infection of peripheral
blood lymphocytes by HIV-1 was severely inhibited by the simultaneous infection of
these cells with HIV-2 and that dual infection cause a lower virological set point for
HIV-1
18
though others disagree 19. Also HIV-2 has lower vertical transmission rates
(4%) as compared to HIV-1 (24%) 20. However the intriguing differences in the natural
course,
transmissibility,
and
epidemiological
characteristics
of
human
immunodeficiency virus type 1 (HIV-1) and HIV-2 are still insufficiently explained.
Differences in plasma viral load are an obvious possibility, but this has been difficult to
consistently investigate because of the lack of generally standardized tests for HIV-2
RNA. Yet an important research suggestion has been that HIV-2-infected patients with
a high viral load may need to be treated as vigorously as HIV-1 patients21,
22.
Considering that viraemia level, projected disease progression pattern, chance of
vertical transmission and drug efficacy are important criteria for initiation of HAART,
can the same acronym describe its use in West Africa?
THE QUADRANGLE INTERACTION: The Drugs, The Virus, The User And The
Provider: At present, there are 15 licensed antiretroviral drugs in 5 classes23 but
almost all being final hits in a wide compound screen using Type 1 clade B as the
bioassay candidate. The result is that compared to the efficacy against HIV type 1, the
nucleoside analogues and protease inhibitors have compromised efficacy with HIV 2
while the non-nucleoside reverse transcriptase inhibitors are not effective completely
as a class against type 2 viruses
24.
With these important classes widely combined in
HAART so compromised, one but wander if HAART means ‘HAART’ in West Africa
(especially as the term is supposed to alternate with ‘highly potent’). In fact while the
adage outside west Africa is “ not only how big is your harmer, but how hard are you
hitting”, In West Africa, the adage may be “ not only how hard you are hitting but how
big is your harmer”. The skewed viral sensitivity may give a selection advantage to the
type 2 viruses and sub optimal drug efficacy may increase the incidence of resistance
strains. To add to the dilemma evidence now exists that genotypic resistance to
nucleoside analogues may exist in antiretroviral-naïve patients25.
Like all drug use, but especially in antiretrovirals with its side effect profile and an
unforgiving pharmacokinetic, successful outcome depend among others, on user
profile and include stage of the disease, patients compliance, ability to meet patient’s
expectation in the short run and drug interactions with concurrent unreported
medication by the patient. Provider related factors like motivation, level of training and
availability of response monitors are also important. In most of Africa, the still poor
awareness of HIV and denials of its existence (even by Governments)
26
ensure that
patients present rather late. Even in the developed world, compliance is still a major
factor in treatment failures and particularly in Africa, with low literacy level and poverty,
compliance promises to be particularly poor, especially with a complicated combination
treatment regimen
27.
The recent finding that garlic reduces the AUC of the protease
inhibitor saquinavir 28 may represent the tip of the iceberg concerning drug interaction
and antiretroviral use in developing nations. The use of alternative medication has
increased in the developed economy but is home in developing nations. Many natural
products have been shown to have anti-HIV activity with many being reverse
transcriptase interactors
29
with unevaluated interactions with formulated antiretroviral
drugs. Also most diets in developing world are unprocessed and therefore contain a lot
of phytochemicals many of which are pharmacologically active 30. HAART is probably
compromised in such a setting.
Doctors doctoring deprived areas are also deprived. Specialist training in
HIV medicine is scanty and experience is poor on antiretroviral use. There is poor
insurance climate, inadequate office protection facilities and inadequate laboratory
back up for encouraging practices. In many tertiary hospitals CD4 cells quantification
facilities barely exist. Studies in these areas have to rely on either clinical parameters
and CD4 count as treatment assessors 31
In one clinical setting in Sokoto, Northern Nigeria (West Africa) out of 25
consecutive patients that presented in 12 months with clinical markers of advanced
AIDS ( WHO clinical stageref xxx 3 or 4 ) and positive serology. 20 (80%) had positive
serology for type 1 and type 2 viruses, 2 for type 2 virus and 3 for type 1 virus. 8 made
failed attempts to get fund for treatment and died within 4 months of diagnosis and 13
were lost to follow up. Of the remaining 4 (all type 1 and 2 serology positive), 3 could
afford the current drugs. Treatment decision and response evaluation was based only
on serology and clinical surrogates. Even CD4 required about 500 kilometers Journey
from treatment point, and with poor sample transportation facilities. Treatment failure
took much longer to detect and drug switching was done blindly. Two patients finally
spent a lot of money and died, the other who had a similar clinical stage of disease,
chose to stop the treatment for factors related to side effects, sourcing prescriptions
(about 9000 kilometers away from his residence in Northern Nigeria) and no clear
clinical benefit after 2 months of (discontinuous) use (Unpublished observations). He is
alive and is clinically status quo 2 years later. The remaining patient has been
managed with diet and as-required treatment for opportunistic infection and is doing
well clinically and psychologically.
Three (one male and two female) got married after knowing their HIV status. The
male infected his two wives. One female had an unaffected male child (husband’s
status unknown), the other female got pregnant and died in the third trimester
(husband’s status unknown). One highly literate discordant couple (wife negative) had
unprotected marital relationship in spite of counseling and the wife represented with
acute HIV syndrome and became positive later. The husband, who later died, claimed
that a traditional medical practitioner reassured him that he had been cured! Drug
therapies in West Africa obviously have able and sometimes disastrous competitors in
alternative/ complementary medicines. HIV/AIDS may be the scourge of the 20 th /21st
century but it also appears to be the quacks’ dream come true. Such scenarios are
not uncommon and suggest a difficult time for HAART use.
HAART has been the cornerstone of successful control of viraemia in HIV
infection. However its design and experience has been mainly with clade B type
infection. The wholesale extrapolation of the concept to non-B areas without evidencebased trials evaluated by reliable disease markers is questionable, especially in view
of known differences in ‘type and clade’ susceptibility to antiretrovirals in addition to
significant differences in use situations and user profiles. Correct use of HAART
demands the ability to evaluate response surrogates like viral load and DT4 as these
provide important information on when to start therapy, assessment of viral response,
emergence of resistance strains and decisions for drug switching and sequencing. In
the whole of northern Nigeria for example viral load assay is available only in 2 centers
and costs more than the monthly income of the average citizen (unpublished findings).
While the problems in the interpretation of results using commercial reagents is
daunting enough
32,
the available assay centers are many kilometers from many
urban areas and facilities for sample transportation are poor. The kinetics of viral load
decay after sample collection and the influence of pre assay sample handling on the
assay result
33makes
the assay result of long distance specimen unreliable. This
predicts that antiretrovirals, even if provided free may have to be used and monitored
mainly on clinical grounds. This is a rather suspicious setting and even dangerous
because undetected or late detection of resistance increases the chance of its
transmission and increases the resistance pool. Also, the continuing use of costly
(about $100000 over a patient’s lifetime)
34
and rather toxic antiretrovirals
35,36,37
in
such a scenario reverses the cost-benefit argument of therapy and transforms HAART
to haart “ highly active antiretroviral toxicants”
CONCLUSION:
The overall argument is that while reducing the price of
antiretrovirals may be of substantial benefit to poor nations, it may be equally
important to ensure facilities that enable proper drug use are in place and that the cost
benefit arguments are evidence based. It may also important to re-screen earlier
antiretroviral candidates rejected in B areas trials in Africa in the hope that the
experience with the ACE-inhibitors and hypertension may be repeated 38. Perhaps with
more targeted designs and trials, less costly but more efficient combinations of
antiretroviral medications may be obtained. It is important for the donor Nations to
ensure proper drug use in Africa, because while one argument is that the “first
generation HIV” might have originated in Africa, the “ second generation highly
resistant HIV” may definitely well return from the same region. Providing drugs without
the other components of drug use looks similar to providing the chauffer without the
car.
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