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Past Issues
Volume 17, number 10
October 2003
Disease and Development
A world of bugs and drugs
Tuberculosis
Treatment strategies refined
Hepatitis B
Preventable, treatable, deadly
Comparative Virology
Lives of the viruses
Malaria
Resistance is futile
Hepatitis C
In the field, under the microscope
TB is about People
Winstone Zulu on living with TB
The Burden of Disease
HIV, TB, Malaria and Hepatitis
By Bob Huff
The "S" in AIDS stands for "syndrome," which refers to a pattern of illness
proceeding from the immune deficiency that develops in the years after a person
becomes infected with HIV: the human immunodeficiency virus. Many people
have pointed out the semantic illogic of "getting AIDS," that "you can't catch a
syndrome," but, despite liberties taken with the name, the illnesses associated
with HIV disease are real and deadly. In classical AIDS, the infections that began
to appear in otherwise healthy gay men in 1980 were rare in Western medicine.
Some, such as pneumocystis carinii pneumonia (PCP), a disease known to
strike immune suppressed transplant patients, gave a clue to the underlying
damage to immunity. A constellation of other runaway fungal and viral infections
— opportunists that flourished when defenses were low — quickly joined the list
of illnesses that defined the syndrome of acquired immunodeficiency.
The opportunistic infections of HIV disease were easy to recognize because they
stood out so starkly against the typical health status of the young, productive
middle-class persons who first came to the attention of doctors in California and
New York. Eventually, the set of symptoms that prefigured AIDS became well
known and the disease was understood to progress along a continuum from
primary infection to a terminal stage.
But if AIDS had first appeared among people with poor health and
many other problems (and there is evidence that it did) it would
not have been so easily discerned. While AIDS allows a number of
characteristic infections to cause disease, for most of the people
in the world with HIV, these occur on top of endemic infections
or health problems that can be deadly in themselves. For too many
people in the world, the burden of disease they face is amplified
by HIV.
HIV exists in a complex web of interactions with other infections
and pathologies. Some venereal diseases, such as herpes and chlamydia,
may enhance the likelihood of becoming infected through sexual contact.
Other problems, such as addiction and mental illness, also increase
the risk of acquiring HIV and other infections, and, for the infected,
make care and treatment much more difficult. Chronic poverty, lack
of education and inadequate infrastructure may also be considered
pathologies that exacerbate and sustain poor health.
Worldwide, each year, about 20 percent of all deaths are caused by infectious
disease, with the overwhelming majority of these occurring in resource-poor
regions. And about half of these deaths in the developing world are due to
tuberculosis, malaria, and HIV. These are diseases that strike poor people and
young people disproportionately and help perpetuate poverty by affecting people
in the prime of their productive lives. The losses in lack of development, lost
opportunities and lost lives due to preventable and curable infectious diseases
are incalculable.
HIV is a transmissible infection acquired through sexual contact,
during birth, or by contaminated blood, that depletes an individual’s
immune capacity to fight off deadly infections and some cancers.
Nearly 50 million people may be infected with HIV, and HIV disease
killed more than three million people last year, with this number
set to rise dramatically in the coming decade. An estimated five
million people will become newly infected this year, with rates
of new infections poised to explode in Asia and Eastern Europe.
Currently, about 70 percent of all people with HIV live in sub-Saharan
Africa, where the disease mostly affects women, children and young
people, most with few economic resources. Treatment is effective
but out of reach for most who need it due to cost.
Selected Preventable
Causes of Death |
| Cause of death |
Deaths in 2001 |
| HIV/AIDS |
2,886,000 |
| TB |
1,664,000 |
| Malaria |
1,124,000 |
| Diarrheal diseases |
2,001,000 |
| Perinatal conditions |
2,504,000 |
| Childhood diseases |
1,318,000 |
| Cirrhosis |
796,000 |
| Liver cancer |
616,000 |
| Lung cancer |
1,213,000 |
| Traffic accidents |
1,194,000 |
| Suicide |
849,000 |
| War |
230,000 |
The World Health Report 2002, WHO |
Tuberculosis is a contagious respiratory infection that follows poverty and urban
crowding, infecting 30 million each year and killing 5,000 people every day.
Worldwide, TB is the leading killer of people with HIV, and the course of both
HIV and TB is much more rapid and deadly in persons with both infections. In
Africa, half of all TB cases are associated with HIV, and although relatively rare
in the U.S. due to robust prevention and treatment efforts, 10 to 20 percent of TB
cases are associated with HIV.
Malaria is endemic in many resource-poor tropical and sub-tropical regions
where the Anopheles mosquito thrives, particularly in Africa. Worldwide, as many
as 500 million cases of clinical malaria occur each year and over 3000 people
die each day — many of them children in Africa. For people with HIV, especially
pregnant women, episodes of acute malaria are complicated and more serious.
Hepatitis B virus (HBV) is responsible for chronic liver infection in 350 million
people around the world and is a major contributor to 1.4 million annual deaths
from liver disease and cancer. Transmitted by sex, blood or at birth, chronic HBV
infection is a long, slow illness that can produce serious liver damage later in life.
In the developing world, particularly in Asia, most HBV infections occur in
children, with from 50 to 90 percent of those exposed developing chronic
infections. Individuals with chronic HBV infection from childhood have a 25
percent lifetime risk of dying from liver disease. In addition, persons with both
HIV and Hepatitis B may be more likely to develop serious liver disease than
those with HBV alone.
Infection with another liver virus, hepatitis C (HCV) is nearly
universal among injection drug users with HIV in the U.S. Worldwide,
an estimated 170 million people are chronically infected with HCV.
With a long, slow course of progression, many people infected with
HCV during the 1970s and 1980s are now experiencing serious liver
disease, including cirrhosis and cancer. For those with HIV, liver
damage may be more severe and treatment less successful. In the
developed world, where death rates from AIDS have plummeted due
to antiretroviral therapy, liver disease has emerged as one of the
leading causes of mortality in people with HIV.
The Top Ten Risk Factors
for Disease and Injury throughout the World |
| In Developing Countries |
In Developing Countries With Low Mortality |
In Developed Countries With High Mortality |
| 1. Tobacco |
1. Alcohol |
1. Underweight |
| 2. Blood Pressure |
2. Blood Pressure |
2. Unsafe Sex |
| 3. Alcohol |
3. Tobacco |
3. Unsafe Water, Sanitation, Hygiene |
| 4. Cholesterol |
4. Underweight |
4. Indoor Smoke from Solid Fuels |
| 5. Overweight |
5. Overweight |
5. Zinc Deficiency |
| 6. Low Fruit and Vegetable Intake |
6. Cholesterol |
6. Iron Deficiency |
| 7. Physical Inactivity |
7. Low Fruit and Vegetable Intake |
7. Vitamin A Deficiency |
| 8. Illicit Drugs |
8. Indoor Smoke from Solid Fuels |
8. Blood Pressure |
| 9. Unsafe Sex |
9. Iron Deficiency |
9. Tobacco |
| 10. Iron Deficiency |
10. Unsafe Water, Sanitation, Hygiene |
10. Cholesterol |
For the year 2000. The World
Health Report 2002, WHO.
Annex Table 14 |
It’s About Partnership
Collectively, these diseases may be responsible for over six million deaths per
year, with many more trailing in their wake as the burden on economies and
health care capacity becomes overwhelming. Increasingly, the fear that
destabilized societies and economies may impact the security of Western
nations has stimulated a great deal of rhetoric and an increasing amount of
money dedicated to addressing the burden of disease in the world. Hopefully,
several emerging global partnerships will be able to direct a coordinated and
effective response to these threats as the promised resources become available.
Indeed, there are opportunities to be mined in these overlapping epidemics.
Infrastructure in place to deliver TB treatment has been proposed as a platform
on which to build a network to provide antiretroviral therapy. The high rate of
antenatal clinic attendance in some parts of Africa gives an opportunity to detect
HIV and sexually transmitted diseases, forestalling transmission to infants and
preventing complications due to malaria.
The Global Fund for AIDS, Tuberculosis and Malaria (GFATM) was established
to respond to these intertwining threats and has taken the first tentative steps
towards underwriting expanded treatment programs on a country and regional
basis. Although commitments to spend $2 billion by 2005 have been made, so
far only $150 million has been disbursed. Despite the growing recognition that
these diseases are a linked catastrophe, political will by the donor nations has
lagged and the GFATM remains underfunded.
The Gates Foundation recently committed $168 million to fighting malaria and
has issued challenges to develop affordable tests to diagnose infectious
diseases and monitor therapy for HIV. The Grand Challenges in Global Health
initiative is a $200 million partnership with the National Institutes of Health to get
scientists to address open scientific questions in such fields as childhood
vaccines, insect control, nutrition, and new treatments for debilitating latent
infections that impede international development.
But the largest world body addressing the multiplicity of disease in the
developing world is the World Health Organization (WHO), which, together with
the UN’s UNAIDS and other partners has launched an ambitious plan to bring
HIV treatment to 3,000,000 people who need it over the next two years. While
the thrust of this program is to procure drugs and diagnostics and establish
guidelines for treating HIV with a restricted list of standard regimens, the
necessary expansion of training and capacity improvement in the health care
sector to allow ARV delivery is also expected to strengthen the ability to deliver a
broader range of health services.
Despite the existence of an effective vaccine for hepatitis B virus, few children in
the world’s poorest countries have been immunized. WHO is a leader in the
Global Alliance for Vaccines and Immunization (GAVI), another broad-based
partnership with the mission of vaccinating as many children as possible against
preventable disease, such as hepatitis B.
WHO is also a leading agency in the Stop TB Partnership, a global association
of all organizations and individuals working to control and eliminate TB in the
world. Stop TB has set a goal of reducing the global burden of the disease by
half by the year 2010. The means to accomplish this require a broad
commitment from governments and NGOs to "ensure that every person with TB
has access to a cure, that vulnerable populations are protected from infections,
and that the social and economic damage of TB is minimized."
Roll Back Malaria is another WHO-founded global partnership with a goal of
cutting the world’s malaria burden in half by 2010. With a shorter treatment
period, effective prevention technology and recent successes in fighting malaria
in affected countries, this effort may have the best chance among the large-scale
disease initiatives for hitting its marks Demonstrating success in rolling back
malaria on a global scale is seen to be crucial for demonstrating that similar large
partnerships for TB and HIV are feasible.
World Health Organization (WHO): www.who.int
UNAIDS: www.unaids.org
Global Fund for AIDS, TB & Malaria: www.theglobalfund.org
Global Alliance for Vaccines: www.vaccinealliance.org
Roll Back Malaria: mosquito.who.int
Stop TB Partnership: www.stoptb.org
TB Treatment Evolves
By Bob Huff
Over the past 50 years, and without any significant advances in the past 30
years, a number of fairly reliable medicines have been developed that effectively
treat tuberculosis — as long as they are consistently and correctly taken. But
simply knowing that there are drugs to treat TB is not enough, and much recent
treatment research has focused on understanding the infrastructure and
conditions that must be present to assure that courses of therapy are completed
without interruption.
The Infectious Disease Society of America (IDSA), in association with the
American Thoracic Society and the CDC has recently published updated
guidelines for treating TB. The guidelines not only stress a provider’s
responsibility to prescribe appropriate regimens but also to assure that they are
completed successfully. Directly observed therapy (DOT), which entails actually
watching the patient swallow the mediation, is strongly recommended.
Increasingly, this demands that providers embrace patient-centered case
management to assure treatment adherence; it is not acceptable to simply
prescribe drugs and send a patient home, or even to demand that patients show
up at a prescribed time and place to take their pills. "Treatment of patients with
tuberculosis is most successful within a comprehensive framework that
addresses both clinical and social issues of relevance to the patient." Enhanced
DOT may now include arranging for "social service support, treatment incentives
and enablers, housing assistance, referral for treatment of substance abuse, and
coordination of tuberculosis services with those of other providers." Studies have
reported 91 percent treatment completion when enhanced DOT is used
compared to 86 percent for DOT and 61 percent for unsupervised therapy.
Adherence is measured by counting doses taken, and a complete course is
accounted for down to the last pill. To do less has proven to yield suboptimal
results.
In clinical trials, a trade-off was seen between duration of treatment and
adherence. While a 9-month course of treatment was proven effective, gains
were undermined by poor adherence. It has always been a problem for TB
treatment that patients will stop taking their drugs after symptoms resolve, well
before the TB organism has been eradicated. Better adherence — and better
overall outcomes — have been demonstrated by using a 6-month course of
treatment that is strictly adhered to, hence the emphasis on DOT and dose
counting.
Treatment is generally planned in two stages, a first intensive stage that may last
two months, and, depending on the results of sputum culture test, a second
phase that may last from 4 to 7 months. For adults with previously untreated TB,
the initial two-month course of treatment will use a four-drug regimen of isoniazid
(INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) given daily for
at least the first two weeks. Modifications may be made depending on drug
susceptibility results. If TB therapy is given at the same time that certain anti-HIV
drugs are being taken, rifabutin may be substituted for rifampin to avoid potential
drug interactions.
For people without HIV who respond to the initial stage, the continuation phase
may be as simple as once-weekly DOT to complete the six months. But
regimens for people with HIV are more stringent, because their response to TB
therapy is often less certain, and daily therapy, or thrice weekly at a minimum, is
continued throughout the second phase.
Many of the TB drugs can cause hepatitis, which may pose special problems for
patients with preexisting viral hepatitis or for persons with HIV taking
antiretroviral drugs such as nevirapine that can cause hepatic toxicity. In general,
the guidelines recommend toughing it out, giving precedence to finishing the
course of therapy. In some cases, regimen modifications can be made, such as
removing one of the liver toxic TB drugs while extending the duration of therapy.
In all cases, frequent and careful monitoring should be performed to detect drug-
induced liver injury.
TB Treatment in Resource-poor Settings
The Guidelines discussed above are designed for the U.S. and appropriate for a
setting with a low incidence of TB, a public health commitment to TB elimination,
and the resources to accomplish this through comprehensive case management.
But, what is appropriate in regions where TB is epidemic and these resources
are not present? Given that most new TB cases in the U.S. occur in foreign-born
individuals, the world TB problem is a persistent factor in any plan to eliminate
TB domestically. The World Health Organization has developed guidelines for
countries without recourse to sophisticated drug susceptibility testing and exotic
backup drugs. While there are some difference in available drugs and
recommended regimens, the underlying goals are the same: to assure treatment
adherence and completion of the course of therapy. The strategy WHO offers to
accomplish this is based on the familiar DOT, but within a national case
management context called DOTS, for directly observed therapy, short course.
The principles of DOTS are: "1) government commitment to sustained
tuberculosis control activities, 2) case detection by sputum smear microscopy
among symptomatic patients self-reporting to health services, 3) a standardized
treatment regimen of 6 to 8 months for at least all confirmed sputum smear-
positive cases, with DOT for at least the initial 2 months, 4) a regular,
uninterrupted supply of all essential antituberculosis drugs, and 5) a
standardized recording and reporting system that enables assessment of
treatment results for each patient and of the tuberculosis control program
overall."
CDC. Recommendations and reports: Treatment of tuberculosis. MMWR,
June 20, 2003 / 52(RR11);1-77
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm
Targeting Persistence:
The Next Frontier in TB Drug Development
The Global Alliance for TB Drug Development
As if it weren’t bad enough that tuberculosis affects a third of the world's
population, 99.5% of those cases, or roughly 1.8 billion people, exhibit no
outward symptoms of infection. They have a latent form of the disease. It sounds
almost benign, but the reality is that the bacterium that causes the active disease
— Mycobacterium tuberculosis or M.Tb persists in their lungs, cleverly concealed
and notoriously hard to detect.
The persistence of M.Tb helps explain why TB has been so difficult to treat
effectively. Each year, 8 million people who carry "latent" disease will experience
reactivation of their disease to full-blown pulmonary tuberculosis. Only 27% of
the world's TB patients are fully and properly treated. Even if they are lucky
enough to finish treatment, some 5-20% of these patients will go on to
experience a reactivation of disease. Most people don't know that they are not
completely "cured" and that persistent bacteria can linger even after treatment
with current drugs. Due to the large number of latent cases, reactivation is one of
the most common ways the disease spreads from one person to another.
Since M.Tb was first identified, scientists have wrestled with its unusual ability to
persist in a non-replicating state. It creates a problem for traditional antibiotics
and raises some vexing questions: What is the bug doing in a persistent state?
What causes it to go "active"? How critical is the immune system response?
Perhaps most importantly, how can we begin to answer these questions?
These questions underscore the need for more basic research to address the
complex biology of persistent M.Tb during latent disease. At the same time, it's
been noted that persistent bacteria seem to play a role in both active and latent
disease. Most antibiotics only target bacteria inside the body that are actively
replicating. With tuberculosis, however, the bulk of infecting bacteria persist
without replicating and live inside the very cells designed to destroy the disease.
That makes it difficult to determine whether a patient is free from the disease.
Furthermore, if a particular patient suffers another bout of TB symptoms, one
can’t be sure if it's a reactivation of persistent bacteria or a wholly new infection.
A Drug Strategy for Latency
A drug that targets latent disease is critical to improved therapy, reducing the
spread of disease, and ultimately reversing the TB epidemic. However, latent
disease poses a number of challenges to scientists trying to develop new drugs.
One possible approach to targeting the persistent bacteria — without waiting for
the basic science to get up to speed — is to work on developing a new, faster-
acting treatment for the latent bacteria in patients with active tuberculosis.
Research to date suggests that persistent bacteria behave similarly in both
active and latent cases. The hope is that drugs developed to fight persistent
bacteria will ultimately prove effective in treating latent disease.
Another clue supporting the validity of this approach is that research suggests
that drugs that most effectively shorten TB therapy are most effective at
attacking persistent M.Tb. Faster-acting drugs will offer benefits far beyond
pointing the way to therapies aimed at latent disease. Drugs that need to be
taken for relatively short periods of time will also ensure that more patients
receive proper treatment, while reducing the associated healthcare expenses by
up to 65%. Equally important, the shorter treatment duration will make it easier
for people to see therapy through to the end. This will increase the likelihood of
full compliance, limiting the opportunity for the bacteria to evolve beyond
antibiotics' reach.
The Global Alliance for TB Drug Development is building a portfolio of promising
drug candidates and creating partnerships in order to deliver a new anti-
tuberculosis drug in a decade. A key part of the R&D strategy of the TB Alliance
is to promote a productive environment for new TB research and drug
development. For more about the Alliance: www.tballiance.org
Vaccinate to Prevent Hepatitis B
By Bob Huff
Susan Goldstein and colleagues from the Centers for Disease Control (CDC)
have projectedthat if everyone born in 2000 were considered as a single cohort,
and none were vaccinated for HBV, over their lifetimes they would experience
64.8 million HBV infections resulting in 9.7 million chronic infections. In this
imaginary cohort there would be 1.4 million deaths from chronic infection and
65,000 deaths due to acute hepatitis B. Perinatal infection would contribute 21
percent of these deaths, infections occurring between birth and age 5 would
account for 48 percent, and infections acquired after the age of 5 would lead to
31 percent of the deaths. They estimate that HBV infection would be responsible
for 1.3 percent of the deaths of all people born in 2000.
They then modeled the effect that vaccination would have on these estimates.
Infant vaccination with 90 percent 3-dose coverage starting within 24 hours of
birth could prevent 84 percent of these projected HBV-related deaths.
Preventable HBV in a U.S. Prison
Despite general agreement that healthcare in prison settings is terrible,
remarkably little research appears at the major infectious disease conferences to
document the results of treatment or the epidemiology of disease behind bars.
William Bower, of the CDC in Atlanta, presented a poster at the IDSA conference
in San Diego that tracked the molecular epidemiology of HBV transmission in a
Georgia state prison. Prisons are prime settings for transmitting HBV through
sexual activity, shared needles, shared tattooing equipment or in fights. The
CDC recommends hepatitis B vaccination for all inmates in correctional facilities
without evidence of immunity.
A baseline serologic survey was conducted in June of 2000 of 1,124 participating
prisoners. Of these, 11 were found with acute HBV infection, 11 had chronic
infection and 208 had a resolved infection for a total of 230 or 20.5 percent of the
sample. This left 894 inmates susceptible to infection. A year later, in June of
2001, a second survey of the susceptible inmates was conducted with 653 of the
894 remaining at the facility. Of these, 503 of 653 (77 percent) consented to
retesting. One year after the baseline survey, 18 new infections were detected,
with one of these a chronic infection. This results in an annual infection rate of
3,579 per 100,000 persons in this prison.
DNA sequence analysis identified 11 different strains within three HBV
genotypes. Eight of the chronically infected and one of the acutely infected
inmates had unique strains. But ten of the sequences represented the other two
strains, with one of those found in four inmates with chronic infection. The other
shared strain was found in six inmates, two with chronic and four with acute
infection. Three of these acute infections turned up in the June 2000 survey and
one in 2001. Two inmates with acute infection reported having sex with one of
the inmates with chronic infection.
This study is remarkable for a number of reasons. First, it documents the sexual
transmission of disease within a correctional facility, a phenomenon that is rarely
acknowledged by corrections officials who then deny the need for providing
condoms inside. It also confirms that, with an annual incidence of HBV infection
in this facility over 120 times that of the estimated national incidence, prisons are
incubators of infectious disease. It also shows the role that an individual can play
in sparking an epidemic. Finally it shows that a prison in Georgia, willing to
collaborate with the CDC in its research, routinely ignores its recommendation
that all inmates be vaccinated against hepatitis B.
HBV in EuroSIDA
The EuroSIDA cohort reported on the impact that chronic HBV infection has on
AIDS progression and response to antiretroviral therapy. Of 5,833 individuals in
EuroSIDA tested for HBV surface antigen, 530 (9%) were found positive. The
incidence of all-cause and liver-related death was greater in those with chronic
HBV than in others (12 vs. 2.6 and 0.5 vs. 0.2/100 patient years, respectively).
The authors conclude that HBV antigen status did not impact virological or
immunological response in 1752 patients receiving HAART. This confirms
previous reports that, although HBV may not make HIV worse, coinfection with
HBV increases the risk of dying from liver disease in people with HIV.
Goldstein S, et al. Hepatitis disease burden: global estimates and reduction from
vaccination. 41st IDSA, 2003, San Diego.. Abstract 583.
Bower W, et al. Molecular epidemiology of hepatitis B virus transmission in a
United States correctional facility. 41st IDSA, 2003, San Diego.Abstract 585.
Konopnicki D, et al. Hepatitis B (HBV) in the EuroSIDA Cohort: prevalence and
impact on mortality, AIDS progression and response to HAART. 9th European
AIDS Conference,Warsaw, Poland. Abstract F9/3.
Comparing Three Viruses
| |
HIV |
HBV |
HCV |
| EPI |
Slowly progressing disease, with ~10 years to life threatening
stage. High
mortality if untreated.
Transmitted by blood, sex, and from mother to child. Not easy
to transmit |
Slowly progressing disease with ~40 years to life threatening
stage. 5% to
25% mortality if untreated.
Transmitted by blood, sex, and from mother to child. Extremely
easy to
transmit |
Slowly progressing disease with ~20 years to life threatening
stage. Uncertain
mortality if untreated.
Transmitted by blood, sex, and from mother to child. Easy to
transmit |
| Therapy |
No vaccine available.
Viral eradication not possible. |
Effective vaccine is available.
Eradication is unlikely. |
No vaccine available.
Viral eradication is possible. |
| |
Lifetime therapy required. |
Lifetime therapy required to control chronic, replicating
disease. |
Duration of therapy ranges from 6 months to 1 year for ~50%
success rate.
|
| |
Viral suppression with therapy offers clinical benefits. Immune
recovery is
possible. |
Therapy may offer clinical benefits. Recovery from liver damage
is possible.
Conversion from chronic replicating to inactive state is possible.
|
Therapy may offer clinical benefits despite failure to eradicate.
Recovery from
liver damage is possible. |
| |
Disease progresses if therapy is halted. |
Life-threatening flares are possible if therapy is halted. |
Disease progression is possible if therapy is halted. |
Click here to enlarge.
|
| |
Retrovirus |
Hepadnavirus |
Flaviviridae virus |
| Virology |
Contains 2 strands of RNA. |
Usually contains 2 circular strands of DNA |
Contains 1 strand of RNA. |
| |
Infects immune cells using CD4 receptors by fusion with cell
membrane.
The genetic material (RNA) is uncoated in the cytoplasm. DNA
is transrcibed by
RT in the cytoplasm then delivered to the nucleus and integrated
into the nuclear
DNA. |
Infects liver cells using an uncertain receptor. Cell membrane
fusion is likely.
The genetic material (DNA) is delivered directly into the nucleus
where it resides
as circular DNA. Pre-genomic RNA is exported to the cytoplasm
and reverse
transcribed to genomic DNA |
Infects liver cells using uncertain receptors. Fusion occurs
within a vesicle
The genetic material (RNA) is uncoated in the cytoplasm and
never enters the
nucleus. Templates for the genomic RNA are produced in the cytoplasm
|
| |
New virus is produced when the cell divides.
RNA exported from the nucleus and viral proteins produced in
the cytoplasm are
packaged using cellular membrane. |
New virus is produced when the cell divides.
Viral proteins are produced in the ER and packaged with genomic
DNA in the
Golgi. |
New virus production is stimulated by infection.
Viral proteins are produced and packaged with genomic RNA in
the cytoplasm
using vesicle membranes. |
The Ecology of Drug Resistance
By Bob Huff
The perils of prophylaxing against one disease only to introduce drug-resistant
strains of another bug were the topic of a poster at the annual conference of the
Infectious Disease Society of America (IDSA) in San Diego.
Researchers from the Universities of Maryland and Malawi joined forces to find
out which opportunistic infections were striking people with HIV in Malawi and
what drugs would be useful for treating and preventing those infections. This was
done in preparation for a clinical trial of trimethoprim-sulfamethoxazole (TS,
Bactrim) to be used as prophylaxis against salmonella and streptococcus, two
pathogens that cause serious intestinal and respiratory disease in Africans with
HIV. Yet there is a concern that, in Malawi at least, these organisms may have
developed resistance to TS. A further concern is that widespread use of TS will
produce cross-resistance to one of the only affordable drugs left to treat malaria
in the region, sulfadoxine-pyrimethamine (SP). TS acts in a way similar to SP,
but it has far less activity against malaria.
The researchers enrolled 548 HIV-positive adults and children with a mean CD4
count of 247 cells/mm3. More than half of the participants were women. The
rates of hospitalization and death, not surprisingly, were increased in those with
lower CD4 counts.
The most common diagnoses in this group during 2537 person months of
observation were:
uncomplicated malaria (84 events);
non-specific diarrhea (69);
unspecified respiratory illness (60);
bacterial pneumonia (52);
fever of unknown origin (49);
oral candidiasis (48);
bacterial sepsis (38);
pulmonary TB (21); and
PCP (5).
One striking finding in this population is the low frequency of PCP, the signature
infection of the AIDS epidemic in the U.S. and the rationale for TS prophylaxis in
developed countries for persons with fewer than 200 T-cells.
Bacterial samples (62) were collected and analyzed by disc diffusion for
antibiotic susceptibility. Salmonella typhimurium represented 52% of the
pathogens, with 90% of those isolates having resistance to TS and 46% with
resistance to azithromycin. Streptococcus pneumoniae accounted for 17% of the
pathogens, with 91% of isolates resistant to TS, but all isolates retaining
susceptibility to azithromycin. All other gram negative rods (E. coli and Klebsiella)
were resistant to TS; 25% retained susceptibility to azithromycin.
Since most of the pathogens isolated were resistant to TS, the authors question
the efficacy of TS as prophylaxis in the region. Any potentially effective
prophylactic agent would have to prevent non-typhi Salmonella and
Streptococcus pneumoniae and have broad-spectrum activity against respiratory
and enteric pathogens. Such antibiotics, like azithromycin or ciprofloxacin, would
likely be unaffordable. While the introduction of TS prophylaxis may not be very
effective, the greater concern is the potential for harm if the prevalence of SP-
resistant malaria in the region were to increase as an unintened result.
Coming Crisis in Malaria Treatment
Treatment for severe malaria in Africa is approaching a crisis point. The global
burden of malaria is worsening due to drug resistance, with mortality increasing
as resistance spreads. Resistance to chloroquine, a cheap drug that had been
used for years, is now nearly universal. Its replacement, sulfadoxine-
pyrimethamine (SP) is also cheap and effective, but its days are numbered as
resistance spreads.
Resistance to SP originated in Asia, appeared in South America, and is rapidly
spreading through Africa. The development of SP resistance may owe its origins
to the earlier, widespread use of pyrimethamine by itself. SP resistance is now
so common in South Africa that the drug is no longer used there. Resistance has
gradually spread north to Mozambique, probably carried by mosquitoes.
Although resistance to SP has been reported in many other African countries,
including Kenya, Malawi and Tanzania, many outbreaks of malaria can still be
treated by SP. However, if drug resistance against SP continues spread, the
region will be left without an affordable weapon against this deadly infection.
When SP is no longer an option, the next alternative will cost 10 times as much,
rendering it virtually unobtainable in most malarious regions. With no likely
vaccine candidate on the horizon for at least 10 years, a new drug — and a new
approach — for treating severe malaria in Africa is needed. And while there is no
obvious successor to SP, in the future it seems certain that combination therapy
— the norm for treating TB and HIV — will have to be adopted for malaria if the
tide of drug resistance is to be stopped and malaria rolled back.
One of the most promising candidates for the next generation of malaria drugs is
arteminisin, a plant-derived compound that originated in China. References to
the plant as a malaria treatment have been found in documents dating back
1700 years, yet its activity was only rediscovered in 1972. Arteminisin is one of
the most potent and fast acting malaria treatments available, killing up to 99.99
percent of parasites. In killing a young form of the parasite, it acts earlier during
the 48 hour cycle of an episode of severe malaria than conventional drugs.
Thailand leads the world in drug-resistant malaria. After SP ceased to be
effective there, mefloquine was introduced in 1984, yet resistance to it developed
within 6 years. Faced with untreatable malaria, a combination of mefloquine with
artesunate was attempted, which proved successful, producing sustained levels
of efficacy greater than 95 percent. There was a reduction in the incidence of
malaria and parasites were less mefloquine-resistant than before combination
therapy was introduced. Transmissibility also seemed to be reduced. With this
success, randomized trials of artesunate plus existing drugs were conducted in
Africa. Although the existing drugs at that point were mostly worthless, the
combinations had better efficacy than either drug alone. This led to a program in
KwaZulu Natal in South Africa that employed mosquito control along with a fixed-
dose combination of artesunate plus mefloquine as therapy. The result was
virtual eradication of malaria in the region. This plan is now being replicated in
Mozambique.
Artemether, another arteminisin derivitive, is an oil-based compound that
requires intramuscular injection. A 1,900-person randomized trial of artemether
versus quinine to treat severe malaria reported fewer deaths with the new drug,
although marginal statistical significance has limited the impact of the study.
Although this form of the drug is unlikely to be well absorbed, which may have
limited its efficacy, it was shown to be safe, with the neurotoxicity seen in
animals not observed in humans. Artesunate, a water-based compound, is now
being manufactured, but current supply sources do not meet FDA approved
manufacturing standards, and it could years before an acceptable formulation
appears. One practical formulation of artesunate for the tropics may be a rectal
suppository that the WHO is now assessing.
Artesunate champion Nicholas John White argues that a crucial principle for the
success of new treatment campaigns will be to make the drugs available for free.
In markets where ineffective drugs are common and inexpensive, the only way to
introduce an effective drug is to out-compete the ones that don’t work. Free
drugs will forestall an influx of counterfeit artesunate as was seen in Cambodia
two years ago.
Much progress stands to be made in rolling back malaria and the tools, spraying,
bed nets and treatment, are available and affordable. Dr. White argues that it is
important to prove that progress can be made while the interest of funders is
high. Malaria offers a more tractable problem than treating HIV or TB in the short
run, yet the gains made in malaria would help the situation with those diseases
as well. With effective drug combinations, eradication could be achieved with an
investment of between $1 billion to $2 billion a year, and countries could see
results within 5 years.
Yet there is much education and convincing to be done. Most proposals
submitted to the Global Fund for malaria treatment rely on chloroquine
and SP. Dr. White responded, "Countries are asking for drugs that
don’t work. We have to provide an incentive for them to ask for
drugs that do work. It may be best to argue from an economic perspective;
that it makes economic sense to ask for effective treatments."
MSF Supports ACT
The Campaign for Access to Essential Medicines organized by Medicins sans
Frontieres (MSF) has issued a call to support artemisinin-based combination
therapy (ACT) for malaria treatment in African countries facing resistance to
classical antimalarials. In 2002, "after extensively documenting resistance to
current treatments in MSF projects and carefully considering data gathered by
ministries of health in endemic countries," MSF decided to switch to ACT in all its
programs.
MSF produced a report that criticised some international donors for supporting a
"leave it alone" policy that doesn’t press endemic countries to break away from
failing past practices and programs that depend on single-drug, resistance-prone
drugs. Financial and technical support is needed to help these countries
implement more effective strategies.
Next on the agenda is a movement to get WHO to push harder for
implementation of its own recommendation that malaria treatment programs get
their ACT together.
www.accessmed-msf.org |
HCV Snapshots: Macro to Micro
By Bob Huff
HCV Prevalence in Europe Tracked
The enormously productive EuroSIDA study has reported on the prevalence of
HCV in the cohort and on the effect that hepatitis C infection has on response to
HAART. At the 9th European AIDS Conference in Warsaw, Poland, Jurgen
Rockstroh, from Bonn, presented an evaluation of 4,957 members (50.6%) of the
large cohort who have had an HCV antibody test. About a third (1685) were HCV
positive. In general, coinfected persons were slightly more likely to be female
and to be Caucasian. Not surprisingly, 75% of those with HCV had used IV drugs
compared to less than 4 percent of those without HCV. Ominously, the median
age of coinfected persons (34.2 years) was about 3 years younger than people
with HIV alone, which suggests ongoing and recent infections. In the U.S. the
median age of HIV-positive people with HCV would likely be several years older.
An explanation might be the nearly 50 percent prevalence found in individuals
from Eastern Europe, on the borders of states of the former Soviet Union where
injection drug use, and HIV incidence is exploding. In central and northern
Europe the prevalence was less than 25 percent.
Fewer coinfected individuals were receiving HAART, and fewer had an AIDS
diagnosis, although median viral load and CD4 counts were not dramatically
different between the groups. About 11.5 percent of HCV-infected individuals
also had hepatitis B antigen, meaning that they were triply infected. The
prevalence of chronic HBV in the non-HCV group was 5.8 percent.
In a multivariate analysis, and after controlling for other factors, there was no
correlation between HCV status and progressing to an AIDS diagnosis or dying
of any cause. However, those with HCV had a significantly higher relative risk
(HR=3.8) for dying of a liver-related illness. The rate of liver-related death (n=53)
was 0.5 per 100 patient years in the HCV-positive group and 0.1/100 per 100
patient years in HCV-negative persons.
In this cohort, no impact of HCV on HIV progression for individuals on HIV
therapy was apparent. Within 12 months of starting HAART, the time to
virological failure (<400 copies/mL) was about the same for both groups
(p=0.77). Similarly, within 12 months of starting HAART, the time to achieve a 50
percent increase in CD4 counts was not significantly different between the
groups (p= 0.3).
While there are other issues to consider (see the effect of hepatic impairment on
Kaletra blood levels reported below), these findings may give some guidance to
clinicians deciding whether to treat HCV before HIV in coinfected persons. If the
liver disease is not serious, and if there are immunological gains to be made by
starting HAART, then there seems to be little reason to expect that response to
HIV therapy should be unsatisfactory.
Sexually Transmitted HCV in London
Also at the European meeting, Brian Gazzard of Chelsea and Westminister
Hospital in London, reported on an epidemic of acute HCV infection in HIV-
positive gay men presenting in their clinic over the past two years. Men with
elevated ALT or reported contact with other HCV-positive men are now routinely
screened for hepatitis C.
Of the 49 men who seroconverted, 24 were given treatment, and of the 15 who
have completed therapy, 10 have become HCV antigen negative, a relatively
good showing compared to treatment results in HIV-positive people with chronic
HCV. Also encouraging was that 12 individuals who were not treated have had
spontaneous clearance of HCV antigen. These tended to be people with higher
CD4 counts and higher ALT levels. In the future the clinic will recommend waiting
12 weeks after seroconversion before initiating treatment to allow time for
spontaneous clearance to occur. Five treatment failures were reported, including
one discontinuation due to toxicity.
Anecdotely, Gazzard commented, he thought nearly all the men had been
passive anal sex partners and that many had participated in fisting. About half
the men had a recent diagnosis of syphilis. Future reseach plans include genetic
fingerprinting of the HCV strains, which will allow drawing a map of the social
path this epidemic has followed.
Kaletra PK with Hepatic Impairment
At long last a few studies are starting to investigate the impact that having
hepatitis may have on blood levels of some of the most commonly used
antiretroviral drugs. Jose Arribas, from Hospital La Paz in Madrid, Spain,
presented a report in Warsaw about the effect of mild or moderate hepatic
impairment in people with HCV and HIV on the pharmacokinetics of Kaletra
(lopinavir/ritonavir). He took six patients with mild hepatic impairment (Child Pugh
score 56), six with moderate impairment (scores of 7-9) and matched them with
12 HIV-positive, but HCV-negative controls. Everyone received lopinavir/ritonavir
(400/100mg) twice-daily for 14 days, when they underwent intensive 24-hour
pharmacokinetic testing.
They found that lopinavir levels were increased to a similar degree in people with
both mild and moderate hepatic insufficiency. At 12 hours after a dose, the total
exposure (AUC) to lopinavir was about 30 percent higher in the HCV patients
than in the controls. However, ritonavir levels were increased to a greater extent
in those with moderate hepatic insufficiency than in those with mild impairment.
The authors recommend caution when administering Kaletra to persons with
either mild or moderate hepatic impairment. With the ever-increasing number of
drugs and combinations, the potential for unexpected pharmacokinetic
interactions increases, especially in persons with coinfections or taking
concomitant medications. Hopefully, more of these small but important studies
will continue to fill in the blanks about how to use these drugs in the variety of
patients who are out there.
Abnormalities in Liver Mitochondria
An interesting study presented at the European Conference by Leonardo Calza
and colleagues from Bologna, Italy looked carefully and closely at the differences
in liver cell mitochondria between people with HIV/HCV coinfection and people
with HCV alone. Past studies have described ultrastructural mitochondrial
abnormalities in HCV-positive persons both with and without HIV, although some
studies found a stronger association in those receiving antiretroviral therapy.
Calza obtained liver biopsies from 68 patients and prepared two samples, one
for examination by electron microscopy and the other for conventional histologic
examination. Persons in Group A (n=40) were coinfected with HIV/HCV. Those
in Group B (n=28) had HCV alone. The only significant differences between the
groups were increased triglycerides and higher HCV RNA in Group A. Most of
those in Group A were on HAART, with half receiving a PI-based regimen.
The histological examination reported more severe disease in Group A (33% vs
12%). Microvesicular liver steatosis was also more common in Group A (97% vs.
63%) as were moderate to severe ultrastructural abnormalities (55% vs. 30%).
Intramitochondrial inclusions or crystals were twice as common in Group A
(35.9% vs. 17.9%) but universal in persons with HCV genotype 1b (100%).
Differences were apparent between these groups, yet it can’t be said if these
were due to the impact of HIV on HCV disease or due to the mitochondrial
toxicity of the HIV drugs that most of the coinfected patients were taking.
References:
Rockstroh J, Mocroft A, Soriano V, et al. Influence of hepatitis C coinfection on
the HIV disease progression within the EUROSIDA cohort. Program and
abstracts of the 9th European AIDS Conference; October 25-29, 2003; Warsaw,
Poland. Abstract F12/4.
Nelson M, et al. Increasing incidence of acute hepatitis C in HIV-positive men
secondary to sexual transmission: epidemiology and treatment. Program and
abstracts of the 9th European AIDS Conference; October 25-29, 2003; Warsaw,
Poland. Abstract F12-3.
Arribas J, Pulido F, Peng JZ, et al. Evaluation of multiple-dose pharmacokinetics
of lopinavir/ritonavir (LPV/R) in HIV and HCV coinfected subjects with mild or
moderate hepatic insufficiency. Program and abstracts of the 9th European AIDS
Conference; October 25-29, 2003; Warsaw, Poland. Abstract F2-6.
Calza L, Verucchi G, Biagetti C, et al. Liver mitochondrial abnormalities
associated with HCV-monoinfection, HIV-HCV-coinfection, and antiretroviral
therapy in a cohort of 68 adult patients. Program and abstracts of the 9th
European AIDS Conference; October 25-29, 2003; Warsaw, Poland. Abstract
F16/3.
TB is About People
By Winstone Zulu
Remarks at the opening plenary of the 34th World Conference of the
International Union Against Tuberculosis and Lung Disease (IUATL), Paris,
2003.
I've been an HIV/AIDS activist for the past ten years. Although I knew that I was
going to die of AIDS, no one specified exactly what that really meant in terms of
the opportunistic infection that would take me. In my life as a person living with
HIV, the nearest that I came to actually dying was when I had tuberculosis. And if
I had died of tuberculosis, I would have been one of the AIDS statistics.
Everybody, because they know I am HIV-positive, would have said I died of
AIDS. Now technically, that would probably be true, because the underlying
cause would have been HIV. But the fact that I took the TB medicines and got
well shows that something is missing — that in our fight against AIDS, we are
not looking at the individual opportunistic infections that can be cured. I’m HIV
positive. I took the TB drugs when I had TB and I am here speaking to you today.
My brothers were HIV-positive too. They had tuberculosis but they didn’t take the
TB drugs because they were not available, and they are no longer here.
In my recent travels, I found that this gives a different perspective to people.
When you go to countries like France or the U.S.; when you talk about 50 million
people living with HIV in Africa, many people just want to look away because the
problem looks so insurmountable. They think, how can we deal with this? And
the fact is that AIDS is known as an incurable disease. So when you say, "50
million people living with HIV in Africa," people then make the equation: HIV is
equal to AIDS and AIDS is equal to death; there’s no cure. But if you say, hey
wait: the biggest killer of people living with HIV in Africa and many other
developing countries is tuberculosis — and if you give them drugs that cost ten
dollars, you can save someone’s life — and you can avoid having more
orphans… then people see it differently. In place after place that I recently visited
people said, well, this gives some hope.
We all know that antiretrovirals are ultimately what we need. They are
medications that are available now that have shown they can prolong life and
improve the quality of life. But for many of us the dream of getting antiretrovirals
is much more farfetched than the dream of getting drugs for ten dollars that can
cure you of your disease. Even to me, who has been an AIDS activist for a long
time, this is a new way of looking at things. And now when I see someone living
with HIV, I say, well, if you don’t have antiretrovirals now, you should go and get
checked for tuberculosis. If you have tuberculosis, it can be cured. Now, I know
there are difficulties in case finding, the diagnostics are very old, the drugs are
difficult to take — six months is too long to take drugs — and there needs to be
research and drug development around tuberculosis. But if you have TB, you
can take these drugs we have and be cured.
I'm very encouraged that the organizers of this conference have invited, not only
scientists, but also people living with tuberculosis and people living with HIV. I
think this conference needs to have a community component so that you can
actually see the people that you are talking about. It's not only about the germs
and the pills, but also about the people under the microscopes and behind
PowerPoint presentations. I'm also very glad that the WHO is now looking into
social and community mobilization around the issues of tuberculosis. I believe
that tuberculosis cannot be fought in the labs alone, and I think this is what has
been missing. TB is about people; it is about our relatives, our friends; it’s about
people who are actually living with this disease.
Winstone Zulu is founding member of the Zambian Network of People Living with
HIV.
© 2003 Gay Men's Health Crisis |
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